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Diagnosis and

Treatment of Patients
with Primary and
Metastatic Breast Cancer
Herausgegeben von der Kommission Mamma
(vertreten durch: Anton Scharl)
der Arbeitsgemeinschaft Gynäkologische Onkologie e. V.
in der Deutschen Gesellschaft für Gynäkologie
und Geburtshilfe e. V.
sowie in der Deutschen Krebsgesellschaft e. V.

Table of Contents
Levels of Evidence and Grades of Recommendation
Abbreviations
Members of the AGO Breast Commission
Conflict of Interest
How to Use these Slides
Editor & Copyright

W. Zuckschwerdt Verlag
GmbH München

2015

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Table of Contents
Levels of Evidence and Grades of Recommendation
Abbreviations
Members of the AGO Breast Committee
Conflict of Interest
How to Use these Slides
Editor & Copyright
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Diagnosis and Treatment
of Patients with Primary
and Metastatic Breast Cancer
Guidelines of the AGO Breast Committee

Options for Primary Prevention: Modifiable Lifestyle Factors
Breast Cancer Risk and Prevention
Early Detection and Diagnosis
Pathology
Prognostic and Predictive Factors
Lesions of Uncertain Malignant Potential (B3) – ADH, LIN, FEA, Papilloma, Radial Scar
Ductal Carcinoma in situ (DCIS)
Breast Cancer Surgery Oncological Aspects
Oncoplastic and Reconstructive Surgery
Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients
Adjuvant Cytotoxic and Targeted Therapy
Neoadjuvant (Primary) Systemic Therapy
Adjuvant Radiotherapy
Therapy Side Effects
Supportive Care
Breast Cancer: Specific Situations
Breast Cancer Follow-Up
Loco-regional Recurrence
Endocrine and “Targeted” Therapy in Metastatic Breast Cancer
Chemotherapy with or without Targeted Drugs in Metastatic Breast Cancer
Osteooncology and Bone Health
Specific Sites of Metastases
CNS Metastases in Breast Cancer
Complementary Therapy & Survivorship
Gynecological Issues in Breast Cancer Patients
W. Zuckschwerdt Verlag
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2015

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Oxford Levels of Evidence (LOE)
© AGO

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LOE

Therapy/Prevention, Aetiology/Harm

Prognosis

1a

Systematic review (with homogeneity) of
randomised controlled trials

Systematic review (with homogeneity) of inception cohort
studies; clinical decision rule validated in different
populations

1b

Individual randomised controlled trials (with narrow
Confidence Interval)

Individual inception cohort study with > 80% follow-up;
clinical decision rule validated in a single population

1c

All or none

All or none case-series

2a

Systematic review (with homogeneity) of cohort
studies

Systematic review (with homogeneity) of either retrospective
cohort studies or untreated control groups in randomised
controlled trials

2b

Individual cohort study (including low quality
randomised controlled trials; e.g., <80% follow-up)

Retrospective cohort study or follow-up of untreated control
patients in a randomised controlled trials; Derivation of
clinical decision rule or validated on split-sample only

2c

"Outcomes" Research; Ecological studies

"Outcomes" Research

3a

Systematic review (with homogeneity) of casecontrol studies

3b

Individual Case-Control Study

4

Case-series (and poor quality cohort and casecontrol studies)

Case-series (and poor quality prognostic cohort studies)

5

Expert opinion without explicit critical appraisal, or
based on physiology, bench research or "first
principles"

Expert opinion without explicit critical appraisal, or based on
physiology, bench research or "first principles"

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Oxford Grades of Recommendation (GR)
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A

consistent level 1 studies

B

consistent level 2 or 3 studies or extrapolations
from level 1 studies

C

level 4 studies or extrapolations from level 2 or
3 studies

D

level 5 evidence or troublingly inconsistent or
inconclusive studies of any level

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AGO Grades of Recommendation
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++

This investigation or therapeutic intervention is highly beneficial
for patients, can be recommended without restriction, and should
be performed.

+

This investigation or therapeutic intervention is of limited benefit
for patients and can be performed.

+/-

This investigation or therapeutic intervention has not shown
benefit for patients and may be performed only in individual cases.
According to current knowledge a general recommendation cannot
be given.

-

This investigation or therapeutic intervention can be of
disadvantage for patients and might not be performed.

--

This investigation or therapeutic intervention is of clear
disadvantage for patients and should be avoided or omitted in any
case.

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Abbreviations – I
© AGO

10+ LN

≥ 10 tumor infiltrated axillary lymph nodes

A
ABCSG-8
AC
ACR
AD
ADH
adj. A
AGO
AH
AI, AIs
ALH
Alip
ALND
AML
ANC
AP
ARNO
ASCO
ATAC
autolog LADO
AxDiss
BC, bc
Bc-spec

Doxorubicin
Austrian Breast- and Colorectal Cancer Study Group
Doxorubicin / cyclophosphamide
American College of Radiology
Doxorubicin / docetaxel
Atypical ductal hyperplasia
Adjuvant doxorubicin
Arbeitsgemeinschaft Gynäkologische Onkologie e.V.
Atypical hyperplasia
Aromatase inhibitor(s)
Atypical lobular hyperplasia
Liposomal doxorubicin
Axillary lymph node dissection
Acute myeloid leukemia
Absolute neutrophil count
Doxorubicin / paclitaxel
Arimidex® versus Nolvadex® (trial on adjuvant therapy)
American Society of Clinical Oncology
Arimidex®, Tamoxifen Alone or in Combination Trial
Autologous latissimus dorsi muscle flap
Axillary dissection
Breast cancer
Breast cancer specific

BCS
BCSF
BCT
BIG 1-98
bilat.
Bip TRAM
BMD
BMI
BR
BRCA
BS-BM

Breast conserving surgery
Breast cancer-free survival
Breast conserving therapy
Breast International Group
Bilateral
Bi-pedicled TRAM
Bone mineral density
Body mass index
Breast reconstruction
Breast cancer
Basic score for brain metastases (Viani GA et al. BMC Cancer. 2007;7:53)

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Abbreviations – II
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C
CA
CAF
Castr.
CB
CBC
CBE
Cc
CC
CEA
CEF
CEF 120 F
CF
CGF
CHF
CHT
Circ.
Cis / Capec
CisG
CISH
Cl
CMF
CMFP
CNS
CREC
CT
CTR
CTX
cum. Dose
CUP
CYP2D6

Cyclophosphamide
Cancer
Cyclophosphamide / doxorubicin / 5-fluorouracil
Castration
Clinical benefit
Contralateral breast cancer
Clinical breast examination
CCNU (chemotherapy)
Capsular contracture
Carcinoembryonic antigen
Cyclophosphamide / epirubicin / 5-fluorouracil
“Canadian FEC” (“Levine”): Cyclophosphamide/ epirubicin 120 / 5-fluorouracil
Cyclophosphamide / 5-fluorouracil
Cyclophosphamide / gemcitabine / 5-fluorouracil
Congestive heart failure
Chemotherapy
Circulating
Cisplatin / capecitabine
Cisplatin / gemcitabine
Chromogenic in situ hybridization
Confidence interval
Cyclophosphamide / methotrexate / 5-fluorouracil
CMF + prednisolon
Central nervous system
Cardiac Review Evaluation Committee
Computed (assisted) tomography
Control (group)
Chemotherapy
Cumulative dose
Cancer of unknown primary
Cytochrome peroxidase P 450 2D6

Abbreviations – III
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D
D&C
D / Carbo
DAC
DARB
DC
DCIS
dd
DepoCyt®
DFI
DFS
DI
DIEP-flap
Doc + Cap
DOX, Doxo

Docetaxel
Dilatation and curettage
Docetaxel / carboplatin
Docetaxel / doxorubicin / cyclophosphamide
Darbepoetin
Docetaxel / cyclophosphamide
Ductal carcinoma in situ
Dose-dense
Liposomal cytarabine, liposomal ara-C
Disease-free interval
Disease-free survival
Dose intensity
Deep inferior epigastric perforator flap
Docetaxel + capecitabine
Doxorubicin

E2, E2
EBCTCG
EC
ECD
ECOG
ELISA
ENT
EORTC
Epi
EPO
ER
ErbB2

Estradiol
Early Breast Cancer Trialists’ Collaborative Group
Epirubicin / cyclophosphamide
Extracellular-domain
Eastern Cooperative Oncology Group
Enzyme-linked immunosorbent assay
Ear-nose-throat (otorhinolaryngologic)
European Organization for Research and Treatment of Cancer
Epirubicin
Erythropoetin
Estrogen receptor
v-Erb-B2-erythroblastic leukemia viral oncogene homolog 2 = neuro-glioblastoma-derived oncogene
homolog (avian) = human epidermal growth factor receptor = c-erbB2 = HER-2/neu = HER-2
Erythropoesis-stimulating factor
Epirubicin / paclitaxel / cyclophosphamide (dose-dense chemotherapy)
European Working Group for Breast Screening Pathology

ESF
ETC
EWGBSP

Abbreviations – IV
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F
F/U, f.-up
FA 60 C
FACT-F
FASG
FDG-PET / CT
FEA
FEC
FEC100
FISH
FNA / FNB / FNP
FSH
f-TRAM

5-Fluorouracil
Follow-up
“US-FAC”: 5-Fluorouracil / doxorubicin 60 / cyclophosphamide
Functional Assessment of Cancer Therapy (fatigue scale)
French Adjuvant Study Group
(18)F2-fluoro-D-2-desoxyglucose – Positron emission tomography / in combination with computed tomography
Flat epithelial atypia
5-Fluorouracil / epirubicin / cyclophosphamide
“French FEC”, (“Bonneterre”): 5-fluorouracil / epirubicin 100 / cyclophosphamide
Fluorescence in situ hybridization
Fine needle aspiration biopsy
Follicle stimulating hormone
Free TRAM-Flap

G
GABG
GCP
G-CSF
GEICAM
GnRHa
GnRHa + AI
GOS
Gy

Gemcitabine
German Adjuvant Breast Cancer Group
Good clinical practice
Granulocyte-colony stimulating factors
Grupo Español de Investigation en Cancer de Mamma (Spanish Breast Cancer Research Group)
Gonadotropin releasing hormone analogue / agonist
Gonadotropin releasing hormone analogue + aromatase inhibitor
Goserelin (Zoladex®)
Gray

Hand-Foot-Sy.
Hb
HDCT
HER-2
high-dose / AST
HIP
HR
HRT

Hand-foot-syndrome
Haemoglobine
High dose chemotherapy
Human epidermal growth factor receptor
High-dose chemotherapy with autologous stem cell transplantation
Health insurance plan
(Steroid) hormone receptor
Hormone replacement therapy

Abbreviations – V
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I/S-GAP-GRACILIS-Flap
IBC
IBCSG
ICE
IES
IGAP-Flap
ICH
Inh.
INT 0101
IR
ITA

Inferior / superior gluteal artery perforator-flap and gracilis-flap
Inflammatory breast cancer
International Breast Cancer Study Group
Ibandronat Capecitabine Elderly
International Exemestane Study
Inferior gluteal artery perforator-flap
Immunohistochemistry
Inhibitor
Intergroup study 0101
Implant reconstruction
Italian Tamoxifen Anastrozole Trial

JCO

Journal of Clinical Oncology

Ki-67
KPS

Kiel-antigen 67 (proliferation marker)
Karnofsky performance score

LABC
LADO, LDF
LCIS
LDH
LHRH
LIN
LITT
LN
Lnn.
LoE / GR
Locoreg
LRR
LVEF

Locally advanced breast cancer
Latissimus dorsi muscle flap
Lobular carcinoma in situ
Lactat dehydrogenase
Luteinizing hormone releasing hormone
Lobular intraepithelial neoplasia
Laser-induced thermotherapy
Lobular neoplasia
Axillary lymph nodes
Level of evidence / grade of recommendation (Oxford Centre for Evidence-based medicine)
Loco-regional
Loco-regional recurrence
Left ventricular ejection fractions

Abbreviations – VI
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MBC
MDS
Med
Menop.
MG / MS
MIB
Mitox
Mo / mo
mod.
MPA/MA
MRI
MRM
MTX
MUGA
Mx

Metastatic breast cancer
Myelodysplastic syndrome
Median
Menopause
Mammography / breast sonography
Minimal invasive breast biopsy
Mitoxantrone
Months
Modified
Medroxyprogesterone acetate / megestrole acetate
Magnetic resonance imaging
Modified radical mastectomy
Methotrexate
Multiple-gated acquisition scan
Mastectomy, mammography

n.s., ns
N+
Nab-Paclitaxel
NAC
NBS
NCI-CTC2
NEAT / SCTBG
Neg.
NMR
NSABP
NSABP B14
NSABP B17
NSABP B20
NSABP B-33
NSABP P1-trial
NX
NYHA

Not significant
Node-positive
Nanoparticle-albumin-bound-paclitaxel
Nipple-areola-complex
National Breast Screening Study (Canada)
National Cancer Institute – Common Toxicitiy Criteria
National Epirubicin Adjuvant Trial / Scottish Cancer Trials Breast Group
Negative
MRI
National Surgery Adjuvant Breast and Bowel Project
NSABP Breast trial 14
NSABP Breast trial 17
NSABP Breast trial 20
NSABP Breast trial 33
NSABP Prevention trial 1
Vinorelbine / capecitabine
New York Heart Association

Abbreviations – VII
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OAS
OFS
ONJ
OP
OR
ORR
OS
OSNA
Oxford

Ovarian ablation or suppression
Ovarian function suppression
Osteonecrosis of the jaw
Operation
Odds-ratio
Overall response rate
Overall survival
One-step nucleic acid amplification
Oxford Centre for Evidence-based medicine levels of evidence and grades of recommendations

P+L
P weekly, Pw
p.o., PO
Pac + Cap
PAI-1
PAP
PBI
PEG-Liposomal Doxo
PET
PFS
PgR
PMMA
PMRT
Pos. Cells
prosp.-rand. Phase III
PS
PST
Pts.

Paclitaxel + lapatinib
Paclitaxel weekly
Per os
Paclitaxel + capecitabine
Plasminogen-activator inhibitor type I
PAP-Smear (Papanicolaou), cytologic test of the uterine cervix
Partial breast irradiation
Pegylated liposomal doxorubicin
Positron emission tomography
Progression free survival
Progesterone receptor
Polymethylmethacrylate
Postmastectomy radiotherapy
Positive cells
Prospective and randomized phase III
Performance score
Primary systemic therapy
Patients

Abbreviations – VIII
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R0
RAD
rand. Pat.
RCT
Rec pos
reg. CT + OP
Rel. Risk
Reop
resp.
RFA
RFS
RPA
RR
RT
RT-PCR

No microscopic tumor residual
Radiotherapy
Patients randomized
Radiochemotherapy
Receptor positive
Regional chemotherapy and operation
Relative risk
Re-operation
Respectively
Radiofrequency ablation
Recurrence-free survival
Recursive partitioning analysis
Relative risk
Radiotherapy
Reverse transcriptase – polymerase chain reaction

S3
SABCS
Scottish CTPG and ICRF Breast
Unit
SD
SERD
SERM
SF
SGAP-flap
signals/nucl.
SIRT
SN
SNBSNE, SLNE
Solitary Meta.
Sonogr.
SPF
SSM
supra-/infraclav
SWE

Highest level of evidence based guidelines according the Delphi-technique
San Antonio Breast Cancer Symosium
Scottish Cancer Trials Breast Group and Imperial Cancer Research Foundation
Standard deviation
Selective estrogen receptor down-regulator
Selective estrogen receptor modulator
Shortening fraction
Superior gluteal artery perforator-flap
Signals per nucleus
Selective internal radiation therapy
Sentinel lymph node
Sentinel lymph node negative (not tumor infiltrated)
Sentinel lymph node excision
Solitary metastasis
Sonography
S-phase fraction
Skin-sparing mastectomy
Supraclavicular, infraclavicular
Sweden

Abbreviations – IX
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T
TAM
TAM + C
TBP
TCH
TEAM
Ther.
TIA
TLI
Tox.
TRAM
TT DR
TTR
UK/ANZ
uPA
Upper GI
US

Taxane
Tamoxifen
Tamoxifen and chemotherapy
Treatment beyond progression
Docetaxel / carboplatin and trastuzumab
Tamoxifen exemestane multicenter trial
Therapy
Treatment-induced amenorrhea
Thymidine labelling index
Toxicity
Transverse rectus abdominis muscle
Time to distant recurrence
Time to recurrence
United Kingdom / Australia and New Zealand
Urokinase-type plasminogen activator
Upper gastro-intestinal
Ultrasound

VAB
VAT
VATS
Vc
VNPI
Vomit.

Vacuum-assisted breast biopsy
Video-assisted thoracoscopy
Video-assisted thoracical surgery
Vincristine
Van Nuys Prognostic Index
Vomiting

WBI
WHO
Wks

Whole breast irradiation
World Health Organization
Weeks

XRT

Radiotherapy

Yrs.

Years

ZEBRA

Zoladex® Early Breast Cancer Research Association

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO

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Members of the
AGO Breast Committee

Members of the
Breast Committee 1
© AGO

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Prof. Dr. Ute-Susann Albert,
Frankfurt
Dr. Ingo Bauerfeind, Landshut

Dr. Joachim Bischoff, Dessau

Prof. Dr. Jens Uwe Blohmer, Berlin

Dr. Klaus Brunnert, Osnabrück

Prof. Dr. Wilfried Budach,
Düsseldorf

Prof. Dr. Peter Dall, Lüneburg

Prof. Dr. Ingo J. Diel, Mannheim

Prof. Dr. Tanja Fehm, Düsseldorf

PD Dr. Nikos Fersis, Bayreuth

Prof. Dr. Michael Friedrich, Krefeld

PD Dr. Kay Friedrichs, Hamburg

Prof. Dr. Bernd Gerber, Rostock

Prof. Dr. Volker Hanf, Fürth

Prof. Dr. Nadia Harbeck, München

Prof. Dr. Jens Huober, Ulm

Prof. Dr. Christian Jackisch, Offenbach

Prof. Dr. Wolfgang Janni, Ulm

Prof. Dr. Thorsten Kühn, Esslingen

Prof. Dr. Hans H. Kreipe, Hannover
(DGP)

PD Dr. Sherko Kümmel, Essen

PD Dr. Cornelia Liedtke, Lübeck

Prof. Dr. Sibylle Loibl, Neu-Isenburg /
Frankfurt

Prof. Dr. Hans-Joachim Lück,
Hannover

Prof. Dr. Michael Lux, Erlangen

Members of the
Breast Committee 2
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Prof. Dr. Nicolai Maass, Aachen

Prof. Dr. Gunter von Minckwitz,
Neu-Isenburg / Düsseldorf

Prof. Dr. Andreas Schneeweiss,
Heidelberg (AIO)

Prof. Dr. Ingrid Schreer, Kiel (DGS)

Prof. Dr. Volker Möbus, Frankfurt

Prof. Dr. Florian Schütz, Heidelberg

Prof. Dr. Volkmar Müller, Hamburg

Prof. Dr. Christoph Mundhenke,
Kiel
Prof. Dr. Ulrike Nitz,
Mönchengladbach

Prof. Dr. H. Peter Sinn, Heidelberg
(Pathologie)

Prof. Dr. Erich F. Solomayer, Homburg

Prof. Dr. Rainer Souchon, Berlin

Prof. Dr. Elmar Stickeler, Freiburg

Prof. Dr. Achim Rody,
Lübeck

PD Dr. Marc Thill, Frankfurt

Prof. Dr. Christoph Thomssen, Halle

Prof. Dr. Anton Scharl, Amberg

Prof. Dr. Michael Untch, Berlin

Prof. Dr. Marcus Schmidt, Mainz

Prof. Dr. Frederik Wenz, Mannheim

Prof. Dr. Rita Schmutzler, Köln

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Dr. Mahdi Rezai, Düsseldorf

Previous Members of
the Breast Committee
© AGO

Prof. Dr. Werner Audretsch, Düsseldorf

Dr. Michael Böhme, Magdeburg

Dr. Georg Heinrich, Fürstenwalde

Prof. Dr. Walter Jonat, Kiel (DKH)

Dr. H. Junkermann, Bremen

Prof. Dr. Manfred Kaufmann, Frankfurt

Prof. Dr. M. Kiechle, München

Dr. Björn Lisboa, Hamburg

Prof. Dr. Uwe-Jochen Göhring, Bonn

Prof. Dr. Dr. Serban D. Costa, Magdeburg

Prof. Dr. Gerhard Schaller, München

Prof. Dr. H. Seegenschmiedt, Essen

Prof. Dr. W. Simon, Stuttgart

PD Dr. Carsten Oberhoff, Essen

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Potential Conflict of Interest (COI)
© AGO

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The members of the editing committee of these guidelines are specialists
in diagnosis, treatment, and research in breast cancer. Most of the
members therefore have cooperations with industry. Thus, potential
conflict of interest cannot be excluded.

In order to minimize potential bias within the statements we followed the
pre-defined rules:

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These guidelines are strictly based on available evidence from the scientific
literature.

The chapters of each edition were prepared by annually alternating teams of
authors.

Each statement and the correspondent AGO-recommendations were
thoroughly discussed within the entire group and accepted by majority
decisions.

Each member of the editing committee is required to submit a written
declaration of his/her conflicts of interests to an elected internal COI committee
on an annual basis.

Members who do not submit a COI declaration may not participate in the
guideline preparation.

Potential Conflicts of Interest (COI)
2014-2015
© AGO

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All members of the AGO Breast Committee have submitted their COI report for
the past year. Members of the AGO Breast Committee indicated that they have
received support (e.g. research funding, lecture or consulting honoraria etc.) from
the following entities:

American Diagnostica, Amgen, AstraZeneca, Boehringer Ingelheim,
Celgene,
Chugai,
Eisai,
Fresenius
Biotech,
Genomic
Health,
GlaxoSmithKline, Johnson&Johnson, Luisenkrankenhaus, MCI München,
medac, Medigene, Merck, MSD, Myriad Genetics, Nanostring,
NeoDynamics, Novartis, Onkozert, Pfizer, Pharmamar, Pierre Fabre, Roche,
Sanofi-Aventis, Sividon Diagnostics, Teva, Wilex, Zeiss.
The Committee did not consider any of the reported support to represent a
conflict of interest that would preclude participation in AGO Breast Committee
discussions or voting.

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How to Use these Slides
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The AGO Breast Committee encourages everyone to use these slides for his or her
own information, improvement of patient care, medical education, presentations,
and publications.

For presentations, the slides should only be used in their original
version and layout, e.g. by using a PDF-copy of each slide. The
AGO-signet ("logo") should not be modified or erased. Extracting
single phrases or parts of the slides may change the guideline content and is
therefore not allowed.

The following citation needs to be used: "AGO Breast Committee. Diagnosis and
Treatment of Patients with Primary and Metastatic Breast Cancer.
Recommendations 2015. www.ago-online.de"

Prior to any print media or electronic publication (except for oral presentations), the corresponding tables or figures have to be submitted to the
chairman of the AGO Breast Committee in order to obtain written permission
(currently at scharl.anton@klinikum-amberg.de).

Further commercial distribution of the whole set of slides is only possible via W.
Zuckschwerdt Verlag (for contact: post@zuckschwerdtverlag.de).

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Editor & Copyright
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Kommission „Mamma“ der
Arbeitsgemeinschaft für gynäkologische
Onkologie
(AGO)
www.ago-online.de
Address for correspondence:

Prof. Dr. med. Anton Scharl
Frauenklinik
Klinikum St. Marien
Mariahilfbergweg 5
D-92224 Amberg
Tel. 09621-38-1371
Fax 09621-38-1358

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scharl.anton@klinikum-amberg.de
Editorial Assistance:

Dr. Tanja Hauzenberger, Dr. Gabriele Salzl

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO

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Options for Primary Prevention:
Modifiable Lifestyle Factors

Prevention
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Version 2011: Gerber / Thomssen

Version 2012–14:
Dall / Diel / Maass / Mundhenke

Version 2015:
Gerber / Mundhenke

Non-modifiable
Risk Factors for Breast Cancer
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1




Older age
Genetic risk factors
Family cancer history
Personal history of breast lesions





www.ago-online.de

Non-proliferative lesions
Proliferative lesions w/o atypia
High risk lesions (ADH, LIN)
Breast cancer (DCIS, InvBC)

Breast density
Chest irradiation
Lifetime number of menstrual cycles

Early menarche, late menopause, mat. pregnancy factors (e.g.
preeclampsia (risk reduction), gestational diabetes (risk increase)

Reproductive risk factors

Lower number of births or no pregnancy
Higher age at first full term delivery

1      Less breast feeding BMI < 18.ago-online. sowie in der DKG e.V.de    Recent oral contraceptive use Hormone therapy in postmenopausal women Alcohol intake Smoking Light exposure at night (night shifts) Low physical activity Toxic agents in fetal and early childhood development (DES. Guidelines Breast Version 2015. in der DGGG e.Modifiable Risk Factors for Breast Cancer © AGO e. V.V. polyfluoroalkyls) .5 and > 25 and especially > 40 (obesity) Diabetes mellitus Type II Food content Steroid hormone therapy     www.

Prevention by Changing Pregnancy Related Factors © AGO e. in der DGGG e.5–2 years) 2b B 2b B 2b B 3a B .1     www.ago-online.de Any full term pregnancy Number of pregnancies First full term pregnancy before age of 30 years Breast feeding (protective if total breast feeding time exceeds 1.V. sowie in der DKG e.V. V. Oxford / AGO LoE / GR Guidelines Breast Version 2015.

V. V.de Maintaining normal weight 2a B ++ (BMI at 18. sowie in der DKG e.V.1   www.ago-online.5 – 25 kg/m²)  Premenopausal  Postmenopausal 3a B 2a B ++ ++ Prevention/Screening and treatment 2b B of diabetes mellitus type II ++ (reduction of breast cancer incidence and mortality) . Guidelines Breast Version 2015. in der DGGG e.Prevention by Changing Lifestyle Factors: Body Mass Index / Diet © AGO Oxford / AGO LoE / GR e.

de Fat reduced food (unsaturated > saturated fatty acids) Reduced consumption of red meat Supplementation of vitamins. Guidelines Breast Version 2015. V. in der DGGG e. sowie in der DKG e.V.ago-online.Prevention by Changing Lifestyle Factors: Diet © AGO Oxford / AGO LoE / GR e.1 Preference of a healthy diet 2b B + 2a B 2a B + + 2a 3a 2a 2a 1b +/+/-* +/+ Dietary components    www.V. minerals. tracer elements  Vitamin D substitution for prevention  Vegetables / fruits  Phytoestrogens / Soya  Fiber containing food * Recommended as a part of healthy nutrition B B B B A .

Oxford / AGO LoE / GR Guidelines Breast Version 2015. sowie in der DKG e.Prevention by Modifying Lifestyle Risk Factors: Alcohol © AGO e.V.ago-online.de Reduction of alcohol intake reduces risk of breast cancer 2b B Particularly for  ER+/PgR+ tumors 2b B  Invasive lobular tumors 2b B .V. in der DGGG e.1  www. V.

Oxford / AGO LoE / GR Guidelines Breast Version 2015.ago-online. in der DGGG e. never smokers) . sowie in der DKG e. V.V.V. when smoking > 10 years before the first childbirth (vs.de  Young women smoking have a 60% increased risk of bc.1  Never smoking reduces risk of breast cancer 2a B ++ (~ 15-24% reduction of lifetime risk) www.Prevention by Modifying Lifestyle Risk Factors: Smoking © AGO e.

ago-online.Prevention by Modifying Lifestyle Risk Factors: Physical Activity © AGO e.V.1  Physical exercise (Metabolic equivalents to 3–5 hrs moderate pace walking per week) www. V. Oxford / AGO LoE / GR Guidelines Breast Version 2015. in der DGGG e. sowie in der DKG e.de 2a(-) B ++ .V.

V.ago-online. sowie in der DKG e.Prevention by Modifying Lifestyle Risk Factors: Hormone Therapy in Postmenopausal Women © AGO e.1  Avoiding hormonal therapy in postmenopausal women  Avoiding estrogen / progestin combinations 1b A + Avoiding estrogens only 1b A +/- www.de  (no enhanced breast cancer risk with estrogen only therapy.V. LoE / GR Guidelines Breast Version 2015. Oxford / AGO in der DGGG e. V. maybe even risk reduction. but increased risk for endometrial cancer) .

0-1.5) II 2321 1.3 (1.9) Thrombosen Med.40 Newkg. 2.6) koronare Events 1. follow-up EPIC 1.4-3.8 (1.6) HERS I 2763 1.4-2.2) E-Mono EPC > E 1. wie WHI + Cholzystektomien open-label.de Metaanalyse 16 Studien Nelson HD: JAMA 2002 Chlebowski SABCS 2010 . Guidelines Breast Version 2015.1 WHI N MC-RR(95%CI) Weitere Aussagen ~ 27 000 1.8) Beral V: Lancet 2003 ~ 50% HRT 4.45 (1.1-1.2-1.1 J.2-1.1 J (0. Alter 67 J keine sekundäre Prävention Newkg.9) Schlaganfälle 2.153 747 person- Int J Cancer 2010 years o 1.1-1.Prevention Hormone (EGC) in der Post-MP © AGO e.4 (1.V.2 Hulley S: JAMA 2002 RCT.3) Lungenembolien 2. sowie in der DKG e. in der DGGG e. wie WHI + www.6-1.084 110 1.21-1.4 (1.1 (1.66 (1.5-2. V.1 (1. med. 4.ago-online.6) 1.95-1.3 WHI: JAMA 2002 (1.7J Million Women EPC > E Art der Anwendung egal Einnahmedauer > 5 Jahre Tibolon RR 1.V.7) 1.

ago-online.1 www. in der DGGG e.Prevention by Modifying Lifestyle Risk Factors: Oral Contraception (OC) © AGO Oxford LoE e.V. endometrial cancer is decreased 1a 1a(–) . Guidelines Breast Version 2015. V. risk of ovarian.de  Overall.V. sowie in der DKG e. OC does not significantly increase risk of cancer  Risk of breast cancer may be slightly increased.

gov/cancertopics/pdq/treatment/breast/healthprofessional ASCO (American Association of Clinical Oncology.Options for Primary Prevention: Modifiable Lifestyle Factors (2/13) Further information and references: Screened data bases: Pubmed 2005 .pdf (download 13.asco.nccn.2014. Cochrane data base (2014) Screened guidelines: NCI (National Cancer Institute . Practice Guidelines. CMA (Canadian Medical Association . 2014): http://www.org/professionals/physician_gls/PDF/breast. 2014): http://www.cancer. 2014) http://www. JAn. SABCS 2012 – 2014.ca/cgi/content/full/158/3/DC1 NCCN (National Comprehensive Cancer Network . 2015) . ASCO 2012 – 2014.org/ASCO/Quality+Care+%26+Guidelines/Practice+Guidelines/Clinical+Practice+Guidelines/Bre ast+Cancer.cmaj. 2014): http://www.

2015) Ritte et al. 2012 Nov. 3.01. including 118 964 women with breast cancer from 117 epidemiological studies.13:584.: Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. Modified from American Cancer Society 2014 (http://www. 2. and breast cancer risk: individual participant meta-analysis. . BMC Cancer 2013 Dec 9.13(11):1141-51. Collaborative Group on Hormonal Factors in Breast Cancer: Menarche. Lancet Oncol.cancer.Non Modifiable Risk Factors for Breast Cancer (3/13) No further information References: 1. menopause.org/cancer/breastcancer/detailedguide/breastcancer-risk-factors) downloaded 01.

J Natl Cancer Inst. .Modifiable Risk Factors for Breast Cancer Risk (4/13) No further information References: 1.2013) Gaudet MM et al: Active smoking and breast cancer risk: original cohort data and meta-analysis.105(8):515-25. Modified from American Cancer Society 2010 (http://www.12.cancer. last revised 31.org/cancer/breastcancer/detailedguide/breastcancer-risk-factors. 2. 2013 Apr 17.

Collaborative Group on Hormonal Factors in Breast Cancer.12(3):R35 Martin RM: Breast-feeding and cancer: the Boyd Orr cohort and a systematic review with meta-analysis. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries.Prevention by Changing Pregnancy Related Factors (5/13) No further information References: 1. Li CI: Reproductive factors and risk of estrogen receptor positive. Ma H: Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort. Cancer Epidemiol Biomarkers Prev. 2005. and HER2-neu overexpressing breast cancer among women 20-44 years of age.137:579-87. 3.17(7):1723-30. 5.360:187-95. Breast Cancer Res. Breast Cancer Res Treat. 2013. Lord SJ: Breast cancer risk and hormone receptor status in older women by parity. 4. J Natl Cancer Inst. triple-negative. 2. 2008 Jul. age of first birth. . 2010. including 50302 women with breast cancer and 96973 women without the disease.97:1446-57. and breastfeeding: a case-control study. Lancet 2002.

2013 Nov 26. Brinton LA: Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results. Cheraghi Z: Effect of body mass index on breast cancer during premenopausal and postmenopausal periods: a metaanalysis.Prevention by Changing Life Style Factors: Body Mass Index / Diet (6/13) No further information References: 1.25(10):1901-14. J Mol Endocrinol. Washington DC. . 2012. 4.7(12):e51446. World Cancer Research Fund and American Institute for Cancer Research: Food.51(3):T51-9. physical activity. 2014 Mar. 2009 Mar 18. PLoS One. J Natl Cancer Inst. doi: Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. J Natl Cancer Inst. nutrition. 6. Simpson ER: Obesity and breast cancer: role of inflammation and aromatase. 2014 Oct. and the prevention of cancer: a global perspective. 2. 2007.101(6):384-98 Chan DS: Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. 3.106(3):djt465. Ann Oncol. 5. AICR.

2013 Aug. Trichopoulou A: Conformity to traditional Mediterranean diet and breast cancer risk in the Greek EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Am J Clin Nutr. Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study. Anticancer Res. Zamora-Ros R: Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.348:g3437 . Zheng JS. J Natl Cancer Inst.92(3):620-5. Cho E. Breast Cancer Res Treat. Breast. BMJ. 2014 Dec. 2. Rossi RE: The Role of Dietary Factors in Prevention and Progression of Breast Cancer. Yang J. Chen WY. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. 3. Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. BMJ. 2014 Jun 10. 2013 Jun 27.346:f3706.Prevention by Changing Life Style Factors: Diet (7/13) No further information References: 1.101(6):384-98. 2013 May. Brennan SF: Dietary patterns and breast cancer risk: a systematic review and meta-analysis.34(12):6861-6875. 2009 Mar 18. Zhao YM. Eliassen AH. 2010 May. 2010 Sep. Li D. Am J Clin Nutr. 7. Farvid MS. Hu XJ..139(1):163-76. 5. Willett WC.91(5):1294-302. 4.. 6. Chlebowski RT: Nutrition and physical activity influence on breast cancer incidence and outcome.22 Suppl 2:S30-7. 8.

[Epub ahead of print] Li CI: Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: The Women’s Health Initiative Observational Study.Prevention by Modifying Life Style Risk Factors: Alcohol (8/13) No further information References: 1.5(3). 4. McDonald JA: Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence. Curr Breast Cancer Rep.102:1422–1431 Suzuki R: Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a metaanalysis of epidemiological studies.2014. Gerber B: Nutrition and lifestyle factors on the risk of developing breast cancer.79(2):265-76.579. 2003 May.122(8):1832-41. 2013 Sep. Br J Cancer. 2. 5. J Natl Cancer Inst 2010. 3. . Int J Cancer. doi: 10. 2008 Apr 15. Breast Cancer Res Treat. Bagnardi V: Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. 2014 Nov 25.1038/bjc.

2. J Natl Cancer Inst. 2013 Apr 17.105(8):515-25 Bjerkaas E: Smoking duration before first childbirth: an emerging risk factor for breast cancer? Results from 302.865 Norwegian women. 2013 Jul. Int J Cancer. Gaudet MM: Active smoking and breast cancer risk: original cohort data and meta-analysis.Prevention by Modifying Life Style Risk Factors: Smoking (9/13) No further information References: 1. . Dossus L: Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort. Cancer Causes Control.24(7):1347-56. 3. 2014 Apr 15.134(8):1871-88.

Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. Physical activity and breast cancer: review of the epidemiologic evidence and biologic mechanisms. Breast Cancer Res Treat. 5.Prevention by Modifying Life Style Risk Factors: Physical Activity (10/13) No further information References: 1. Gerber B: Nutrition and lifestyle factors on the risk of developing breast cancer. Wu Y. 6.137(3):869-82. Friedenreich CM.137(3):869-82. Breast. . 4. 3. Breast Cancer Res Treat. 2011. Wu Y: Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Physical activity and risk of breast cancer: a meta-analysis of prospective studies.188:125-39.22 Suppl 2:S30-7.101(6):384-98. Chlebowski RT: Nutrition and physical activity influence on breast cancer incidence and outcome. 2013 Feb. 2003 May. 2009 Mar 18. 2013 Feb. Recent Results Cancer Res. Breast Cancer Res Treat. J Natl Cancer Inst. Kang S. 2013 Aug. Zhang D.79(2):265-76 2.

: Breast cancer and hormone-replacement therapy in the Million Women Study. 4. 5. Tidsskr Nor Laegeforen (2012) 132: 1330–1334 6. 2012 Jul 11.Prevention by Modifying Life Style Risk Factors: Hormone Therapy in Postmenopausal Women (11/13) No further information References: 1. Lancet Oncol (2006) 7: 910–918. De P: Breast cancer incidence and hormone replacement therapy in Canada. Beral V. . Marjoribanks J: Long term hormone therapy for perimenopausal and postmenopausal women. JAMA. Cochrane Database Syst Rev. JAMA (2010) 304: 1684–1692 2. Chlebowski RT: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. 362: 419 – 27. 8. 102: 1489 – 95 7. Lancet 2003. Chlebowski RT: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. 3.310(13):1353-68. Manson JE: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.7:CD004143. Saether S: The risk of breast cancer linked to menopausal hormone therapy. 2013 Oct 2. Reeves GK: Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and metaanalysis. JAMA (2003) 289: 3243–3253. J Natl Cancer Inst 2010.

Prevention: Hormone (EGC) in der Post-MP (12/13) No further information No references .

Cibula D. . colorectal.16. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.6 pp. Human Reproduction Update. 3. No. cervical. J Clin Oncol. Cancer Epidemiol Biomarkers Prev. 631–650. 2. Moorman PG. 2013 Nov. and endometrial cancers: a systematic review.31(33):4188-98. Gierisch JM. 2010 Gierisch JM:Oral contraceptive use and risk of breast.Prevention by Modifying Life Style Risk Factors: Oral contraception (13/13) No further information References: 1.:Hormonal contraception and risk of cancer. Vol. 2013 Nov 20.22(11):1931-43. Havrilesky LJ.

in der DGGG e. Guidelines Breast Version 2015.V.V. sowie in der DKG e.1 Breast Cancer Risk and Prevention .Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. V.

de . V.1  Versions 2003–2014: Schmutzler with Albert / Blohmer / Fehm / Kiechle / Maass / Mundhenke / Rody / Thomssen  Version 2015: Schmutzler / Schmidt www.V.Breast Cancer Risk and Prevention © AGO e.V. Guidelines Breast Version 2015. sowie in der DKG e. in der DGGG e.ago-online.

V. sowie in der DKG e.1  Women at increased risk for breast cancer are not considered patients but healthy women or counselees  A comprehensive informed consent taking into consideration all potential side effects and risks is warranted prior to offering preventive measures www.de  Highest priority: „First. V.ago-online.Principles in Prevention © AGO e. in der DGGG e. Guidelines Breast Version 2015.V. do no harm!“ (Primum nil nocere) .

in der DGGG e. or at least one woman affected by breast and one by ovarian cancer or at least one woman affected by breast and ovarian cancer or at least two women affected by ovarian cancer or at least one woman affected by bilateral breast cancer. first < 51 yrs. V.000 families tested by 2013 . sowie in der DKG e.ago-online. Guidelines Breast Version 2015.V.1 www. one < 51 yrs. or at least one woman affected by breast cancer < 36 yrs.Who Should be Tested for BRCA1/2 Mutations? © AGO Oxford LoE: 2b e.V. or at least one man affected by breast cancer and one additional relative affected by breast or ovarian cancer* # * in one side of the family #Inclusion criteria of the German Consortium of Hereditary Breast and Ovarian Cancer (GCHBOC) based on a mutation detection rate ≥ 10% in ~17.de GR: B AGO: ++ Families with at least three women with breast cancer independent of age or at least two women with breast cancer.

in der DGGG e.ago-online.V.de C + . Guidelines Breast Version 2015.1 BRCA1/2 testing in patients with TNBC if an impact on treatment decisions is anticipated Oxford / AGO LoE / GR Regardless of age * 3b * Study participation recommended * The rate of BRCA 1/ 2 mutation is decreasing with increasing age www. V. sowie in der DKG e.V.BRCA1/2 Testing in Patients with TNBC (irrespective of family history) © AGO e.

ago-online. V. BC/OC: 42%) Kiel Berlin Hannover Münster Göttingen Dresden Düsseldorf Köln/Bonn www.875 in 2014. Leipzig) national DNA-biobank (center Cologne) *Institute for Medical Genetics. 15 centres national database (IMISE*. Statistics and Epidemiology.Recruitment of the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) © AGO e. +3. Guidelines Breast Version 2015.1 BRCA1/2 mutation frequency: 24% (OC only: 35%.000 new families in 2015 in der DGGG e. Leipzig Leipzig Würzburg Heidelberg Tübingen Regensburg Ulm München 6 .de    since 1996.V. 18. sowie in der DKG e.V. exp.

de/brustzentren-download .V.de *online tool provided by the Ärztekammer Westfalen-Lippe based on the inclusion criteria of the GC-HBOC www. in der DGGG e.aekwl. Guidelines Breast Version 2015.V. sowie in der DKG e.1 www.Suggested Use of a Screening Checklist * © AGO e. V.ago-online.

11q15. V. NBN.ago-online.V.State of the Art Unexplained Heritability: Oligogenic Traits and Genetic Heterogeneity © AGO e. CDH1. 2q35. high risk genes (OR >5. ATM. BRIP1.0) (BRCA1/2) disease risk Guidelines Breast Version 2015.5. 5p12. sowie in der DKG e. MAP3K1…) www.5) (FGFR2.) low risk variants / modifiers (OR/HR <1. TOX3. SLC4A7. PALB2 .0) (RAD51C.1 moderately penetrant risk genes (OR 1.5 . CHEK2. PTEN…. in der DGGG e.V.de minor allele frequency .

Guidelines Breast Version 2015. sowie in der DKG e. MSH6.1 Syndrome Gene alteration Lifetime Risk BC Li Fraumeni p53 ~ 50 %1 Cowden PTEN ~ 25 %2 Hereditary diffuse gastric cancer syndrome CDH1 ~40-50 % (lobular)3 Peutz-Jeghers Syndrome STK11/ LKB1 ~45-50 %4 Ovary: ~20 % Cervix: ~10 % Uterus: ~10 % www.Non BRCA-associated Hereditary Cancer Syndromes with Increased Risk for Breast Cancer © AGO e.V. in der DGGG e. PMS2 up to twofold increased risk compared to general population5 Endometrial: ~ 25-60 % Ovary: up to 25 % Recommendation: genetic counselling: GCP .ago-online. MSH2.V.de Lynch mismatch repair MLH1. V.

V. Guidelines Breast Version 2015.1 Nature Genetics April 18.5%) .Third Moderate to High Risk Gene Identified within the GC-HBOC © AGO e. 2010 www. 430 breast and ovarian cancer  6 deleterious mutations in BC/OC families only ( 1.ago-online. in der DGGG e.de  1.100 BRCA1/2 negative risk families: 670 breast only.V.V. sowie in der DKG e.

com/tests/breastnext in der DGGG e.V.edu/tests/genetics/BROCA Commercially Available.html ATM BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 EPCAM FANCA FANCC FANCD2 FANCE FANCF FANCG MEN1 MLH1 MRE11A MSH2 MSH3 MSH6 NBN PALB2 PMS1 PMS2 PTCH1 PTEN RAD50 RAD51C STK11 TP53 http://res.cegat.V. APC ATM ATR BAP1 BARD1 BMPR1A BRCA1 BRCA2 BRIP1 CDH1 CDK4 CDKN2A CHEK1 CHEK2 EPCAM FAM175A GALNT12 GEN1 GREM1 HOXB13 MLH1 MRE11A MSH2 MSH6 MUTYH NBN PALB2 PMS2 PRSS1 PTEN RAD50 RAD51 RAD51C RAD51D RET SMAD4 STK11 TP53 TP53BP1 VHL XRCC2 AMBRY Genetics BreastNext (16 genes) e.com/documents/products%5Cdatasheets%5Cdatasheet_trusight_cancer. V. http://web. sowie in der DKG e.1 http://www.und Ovarialkarziom (30 genes) Guidelines Breast Version 2015.labmed.centogene.com/centogene AIP ALK APC ATM BAP1 BLM BMPR1A BRCA1 BRCA2 BRIP1 BUB1B CDC73 CDH1 CDK4 CDKN1C CDKN2A CEBPA CEP57 CHEK2 CYLD DDB2 DICER1 DIS3L2 EGFR EPCAM ERCC2 ERCC3 ERCC4 ERCC5 EXT1 EXT2 EZH2 FANCA FANCB FANCC FANCD2 FANCE FANCF FANCG FANCI FANCL FANCM FH FLCN GATA2 GPC3 HNF1A CENTOGENE BC/OC panel (16 genes) TruSight™ Cancer (Illumina) http://www.de ATM BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 MRE11A MUTYH NBN PALB2 PTEN RAD50 RAD51C STK11 TP53 CEGAT CAN02: Brust. Non-validated Breast Cancer Gene Panels for Risk Prediction APC ATM BARD1 BMPR1A BRCA1 BRCA2 BRIP1 CDH1 CDK4 CDKN2A CHEK2 EPCAM MLH1 MSH2 MSH6 MUTYH NBN PALB2 PMS2 PTEN RAD51C RAD51D SMAD4 STK11 TP53 .ambrygen.ago-online.ATM BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 MRE11A MSH6 NBN PALB2 PTEN RAD51 RAD51C STK11 TP53 MYRIAD myRISK Panel (25 genes) HRAS KIT MAX MEN1 MET MLH1 MSH2 MSH6 MUTYH NBN NF1 NF2 NSD1 PALB2 PHOX2B PMS1 PMS2 PRF1 PRKAR1A PTCH1 PTEN RAD51C RAD51D RB1 RECQL4 RET RHBDF2 RUNX1 SBDS SDHAF2 SDHB SDHC SDHD SLX4 SMAD4 SMARCB1 STK11 SUFU TMEM127 TP53 TSC1 TSC2 VHL WRN WT1 XPA XPC https://www.pdf www.illumina.de/Tumorerkrankungen_171.washington. BROCA 40 gene panel © AGO (cross-cancer.

constant expansion and improvement 12 .V..de 10 BC/OC ´core genes´ (sufficient data for genetic counseling) 4 HNPCC genes (~1% of unselected OC cases show truncating mutations. 2014) 12 BC/OC ´research genes´ (validation in cooperation with the ENIGMA consortium) 8 candidate BC/OC genes (GC-HBOC.ago-online. unpublished) Strategy: Validation in large cohort.1 core gene core gene Lynch syndrome Lynch syndrome Lynch syndrome Lynch syndrome #1 #2 ENIGMA ENIGMA ENIGMA ENIGMA ENIGMA ENIGMA ENIGMA ENIGMA #3 #4 #5 #6 #7 #8 #9 #10 ENIGMA ENIGMA candidate candidate candidate candidate candidate candidate #11 #12 GC-HBOC GC-HBOC GC-HBOC GC-HBOC GC-HBOC GC-HBOC candidate candidate GC-HBOC GC-HBOC Gene selection: www. in der DGGG e. ATM BRCA1 BRCA2 CDH1 CHEK2 NBN PALB2 RAD51C core gene core gene core gene core gene core gene core gene core gene core gene RAD51D TP53 MLH1 MSH2 MSH6 PMS2 ENIGMA ENIGMA Guidelines Breast Version 2015.TruRisk™ BC/OC Gene Panel (34 genes) by the German Consortium GC-HBOC © AGO e. sowie in der DKG e.V. Song et al. V.

Guidelines Breast Version 2015. submitted  Genotype determines not only disease penetrance but phenotype and clinical disease course 13 . Nat. V. sowie in der DKG e. Genet 2010 www.V. in der DGGG e.V.ago-online.1 BRCA2 BRCA1 RAD51C* TNBC Normal 30 HER2 Luminal A Luminal B Molecular subtypes *Meindl et al.de Gevensleben et al.Clinical Implication: Genotype/Phenotype © AGO e.

1 www. sowie in der DKG e.V.Genetically Defined Subtypes are Distinct Tumor Entities © AGO e. Guidelines Breast Version 2015.ago-online. V. Prior to the offer of prophylactic measures the following questions should be adressed:  Disease penetrance?  Typical histopathological features?  Sensitivity to current screening modalities?  Better survival of early detected tumors?  Natural disease course?  Response to anti-tumor therapy? Genotype-phenotype-correlations must be employed .V.de  Distinct genetic subtypes of breast cancer may show distinct clinical features. in der DGGG e.

in vitro splicing assay.ago-online. V. sowie in der DKG e. >80%)  Additional analyses required.1 www.de  Most VUS are private (>60%) or extremely rare (≤3. e. segregation analysis.g.V. in der DGGG e.VUS: Problems and Questions © AGO e.V. co-occurence analysis. SIFT) are not adequate for clinical decision making  VUS classification and clinical decision making are not standardized yet . large case / control studies  in silico prediction tools (PolyPhen2. Guidelines Breast Version 2015. functional assay.

20 5x10-16 0.Low risk Variants from Genome Wide Association Studies (GWAS) Locus © AGO SNP Häufigkeit e. V.9 2x10-8 0.ago-online.95 10-8 0. in der DGGG e.09 2x10-15 0.94 2x10-7 0.07% ANKRD16 rs2380205 43% 0.08 5x10-11 0.12 3x10-34 0.11 4x10-23 0.6% TOX3 rs3803662 25% 1.09% COX11 rs6504950 27% 0.V.5% 11q15 rs614367 15% 1.1% 2q35 rs13387042 51% 1. Guidelines Breast Version 2015.11 3x10-20 0.01% .92 3x10-8 0.88 4x10-15 0.de TOTAL BCAC FRR (%) Odds Ratio P-trend FGFR2 rs2981582 38% 1.4% MAP3K1 rs889312 28% 1.10 7x10-10 0.V.1 www. sowie in der DKG e.2% 1p11.12 4x10-23 0.10 8x10-15 0.4% 5p12 rs10941679 26% 1.1% CDKN2A/B rs1011970 17% 1.21 8x10-52 1.08 7x10-8 0.3% 8q24 rs13281615 40% 1.2% ESR1 rs2046210 33% 1.5% SLC4A7 rs4973768 46% 1.2 rs11249433 39% 1.3% CASP8 rs1045485 13% 0.2% ZNF365 rs10995190 15% 0.2% ZMIZ1 rs704010 39% 0.01% RAD51L1 rs999737 24% 0.2% LSP1 rs3817198 30% 1.24 5x10-87 1.98 4x10-7 0.

11q13)  Couch et al.1 Retrospective Gaudet et al. 3p24. 12p11. Clin Cancer Res.V. ESR1. RAD51L1. V. CI = 1.1. 5p12.. CDKN2A/B.. 8q24.ago-online. LSP1. ZNF365. 5q11. in coop with GC-HBOC 2013: Combined genotype distribution of 14 variants in 8. in coop with the GC-HBOC 2013: Combined genotype distribution of 10 variants in 11. 6q25.5. 2008 . Guidelines Breast Version 2015.2 to 14.221 BRCA2 mutation carriers (FGFR2. TOX3.705 BRCA1 mutation carriers (1q32. 12p11. 2q35. 19p13.. LSP1. in der DGGG e.Low Risk Variants as Modifiers © AGO e. sowie in der DKG e. 10q25. 12q24.1. 2013: combined genotype distribution of 7 low-risk SNP in 909 BRCA2 carriers www. 95%. TERT)  5% of BRCA1 carriers at lowest risk (28–50%) compared to the 5% at highest risk (81–100%) Prospective Mavaddat et al. P = . TOX3.02)´ first ´proof of principle´ Associations are breast cancer subtype specific Garcia-Closas et al.3.V.de BRCA2 carriers at the highest tertile of the score distribution were at significantly higher risk than women at he lowest tertile (HR = 4.

Potential multiplicative effects that may be relevant for risk stratification and the provision of clinical prevention strategies remain to be elucidated. Low risk variants confer only small risk elevations and also seem to be associated with specific tumor subtypes. e.V.g. Guidelines Breast Version 2015. in der DGGG e.1 www. Therefore genetic testing of moderate and low risk genes and variants should only be performed within large prospective cohort studies like the German Consortium for Hereditary Breast and Ovarian Cancer GC-HBOC. sowie in der DKG e.ago-online.V. gene panels  Clinical genetic testing for low risk variants  Referral to centres of the GC-HBOC or cooperating centres Oxford / AGO LoE / GR 2b 3b 5 B D D -++ . Moderate risk genes such as RAD51C exhibit very low mutation detection rates and may be associated with specific tumor subtypes.Current Clinical Impact of Other Risk Genes © AGO e.or polygenic trait of moderate and low risk genes and alleles.de The remaining cancer susceptibility is most likely be transmitted by an oligo.  Clinical genetic testing for RAD51C. CHEK2 and/or other moderate risk genes. V.

1 www. Guidelines Breast Version 2015.ago-online. in der DGGG e.de  The risk collective is clearly defined by risk criteria  The positive predictive value of risk critiera with respect to the identification of the genetic risk factor is known  The cut-off values for genetic testing evolved through a transparent consensus process  The genetic test is valide and reliable  A spectrum bias is excluded or defined  A clinical prevention strategy exists that leads to early detection or prevention and mortality reduction of the genetically defined subset of the disease . V.V.V. sowie in der DKG e.Requirements for the Introduction of New Diagnostic or Predictive Genetic Testing © AGO e.

g.1 www. V.V. e. risk assessment requires professional training and expertise  Communicate absolute risks within a manageable timeframe  Communicate competing risks.ago-online. Guidelines Breast Version 2015.Non Directive Counseling for the Uptake of Preventive Measures © AGO e.g.de  According to the Genetic Diagnostic Law  According to the Medical Devices Act. sowie in der DKG e. risk of progressive disease in relation to the risk of a secondary primary in case women have already been affected by primary breast cancer  Allow for appropriate time for consideration . in der DGGG e.V. e.

ago-online.g. sowie in der DKG e. BRCA2 1a A ++  Heterozygous risk of >= 20% or remaining life time risk of >= 30% acc. Oxford / AGO LoE / GR in der DGGG e.1 www. Guidelines Breast Version 2015.V. Hodgkin disease) 2a B ++ . V.Definition of Women at Moderate to High Risk © AGO e.V. to a validated standard risk prediction model 2b B +  Childhood cancer survivors after chest irradiation in adolescence (e.de  Deleterious mutation in the BRCA1.

Guidelines Breast Version 2015.Surveillance Program for Women with Deleterious BRCA-mutations* © AGO e.de  For mortality reduction (10 year survival) 4 C *Referral to centres of the GC-HBOC or cooperating centres is recommended + .V.ago-online.V. V. Oxford / AGO LoE / GR in der DGGG e. sowie in der DKG e.1 Multimodal intensive surveillance program lifelong For the detection of early stage breast cancers 2a B  Clinical breast exam >=25 years semi-annually  Sonography >=25 years semi-annually  Mammography >=40 years biannual  Breast MRI (until ACR1) >=25 years annual ++ www.

de  Referral to centres of the GC-HBOC or cooperating centres for the evaluation of structured surveillance and follow-up .V. V. in der DGGG e. sowie in der DKG e.ago-online. Guidelines Breast Version 2015.V. Women at Moderate to High Risk or Survivors of Hodgkin Disease © AGO e. however.Modified Surveillance Program for BRCA-neg. lower than in women from BRCA1/2 positive families www.1 Rationale:  Increased risk of breast cancer after chest irradiation because of Hodgkin lymphoma in childhood (8-18 years)  Increased risk of breast or ovarian cancer in women from BRCA1/2 negative families at risk that is.

de 2a B +* .V. V. in der DGGG e. Oxford / AGO LoE / GR Guidelines Breast Version 2015. sowie in der DKG e.V.ago-online.1 • Unilatertal or bilateral mastectomy is not indicated in the absense of clearly defined genetic risk factors www.Surgical Prevention © AGO e.

Guidelines Breast Version 2015. PBM) reduces BrCa incidence and mortality RR-BSO is performed after completion of family planning RR-BM revealed a high incidence of premalignant lesions *Study participation recommended .Surgical Prevention for Healthy BRCA1/2 Mutation Carriers © AGO Oxford / AGO LoE / GR e.V. in der DGGG e.V. V. sowie in der DKG e.1 • Risk-reducing bilateral salpingo-oophorectomy (RR-BSO.de Risk-reducing bilateral mastectomy (RR-BM.ago-online. PBSO) around 40 years of age 2a B ++* 2a B +* reduces OvCa incidence and mortality reduces BrCa incidence and mortality reduces overall mortality • www.

Guidelines Breast Version 2015.V. V.Risk-reducing Interventions for BRCA1/2 Mutation Carriers Affected by Breast Cancer © AGO Oxford / AGO LoE / GR e. in der DGGG e.ago-online.de + Overall prognosis has to be considered *Study participation recommended .V. sowie in der DKG e.1 • Bilateral salpingo-oophorectomy (RR-BSO) 2b B +* reduces OvCa incidence and mortality reduces BrCa mortality reduces overall mortality (contradictory results for reduction of cl BrCa incidence) • Bilateral mastectomy + (RR-BM) 2b B +/-* • Tamoxifen (reduces cl BrCa incidence) 2b B +/-* • Indication for PBM should consider age at onset of first breast cancer and the affected gene 2a B ++* reduces cl BrCa incidence www.

sowie in der DKG e.1 www. JAMA 2010. V. in der DGGG e. Guidelines Breast Version 2015. Table 4.ago-online.Risk-reducing Salpingo-oophorectomy and All-cause Mortality © AGO e.V.de Domchek et al. .V.

Contralateral Cancer Risk in 6235 BRCA1/2 Positive and Negative Patients (retrospektive) © AGO e.V. sowie in der DKG e.V. Guidelines Breast Version 2015. V.de .1 www. in der DGGG e.ago-online.

ago-online.1 Breast conserving therapy: Adequate local tumor control (10 years observation) www.V. Limited prospective cohort studies with short follow-up time Oxford / AGO LoE / GR Guidelines Breast Version 2015. sowie in der DKG e.de 2a B + Systemic therapy according to sporadic breast cancer 3a B + BRCA1 mutation status is predictive for chemotherapy 3b B response + Carboplatin (vs. V. in der DGGG e.Therapy of BRCA1/2-associated Breast Cancer+ © AGO e. Docetaxel) in MBC 2ba B + PARP inhibitor in breast cancer 2b D +/-* + Overall prognosis has to be considered *Study participation recommended .V.

1 Counselling and testing Check list (inclusion criteria) BC www. in der DGGG e.V.de Prophylactic surgery Communication. Exchange. BC Indication for prophylactic surgery . Guidelines Breast Version 2015. sowie in der DKG e. V.Cooperation of Certified Breast Centres (BC) with Specialized Centres of the GC-HBOC © AGO e.V. Advice Spec.ago-online.

Medical Prevention for Women at Increased Risk © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015. V. *Risk situation as defined in NSABP P1-trial (1. in der DGGG e. thyroid and urinary tract cancers Chemopreventive regimes should only be offered after individual and comprehensive counseling. age and pre-existing risk factors for side effects. as well as skin. The net benefit strongly depends on risk status.66% in 5 years) . sowie in der DKG e.V. and LN 1a A • Raloxifen for postmenopausal women Reduction of invasive BrCa only 1b A +* • AI for postmenopausal women 1b A +* +# www.V. hematologic.ago-online.de #Significant risk reduction was seen for anastrozole for ovarian and endometrial cancer. DCIS. colorectal.1 • Tamoxifen for women > 35 years Reduction of invasive BrCA.

ago-online. Rationale: Women with breast cancer have an increased risk for a second primary Oxford / AGO LoE / GR Guidelines Breast Version 2015. in der DGGG e.and Contralateral Breast Cancer © AGO e.1 www. sowie in der DKG e.de  Tamoxifen* 1a A +  Aromatase inhibitors* 1a A +  Suppression of ovarian function* + Tamoxifen 1b B + *Only proven for ER/PgR-positive primary sporadic BrCa .V. V.V.Risk Reduction for Ipsi.

and SABCS-abstracts No references .Breast Cancer Risk and Prevention (2/32) Further information: Literature from PUBMED. ASCO.

Principles in Prevention (3/32) No further information No references .

2.Who Should be Tested for BRCA1/2 Mutations? (4/32) No further information References: 1. Meindl et al. J Cancer 2002: 97:472-480 German Consortium for Hereditary Breast and Ovarian Cancer. personal communication of up-dated numbers.: Comprehensive analysis of 989 patients with breast and ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Molecular genetic testing is recommended for the above listed families in which the mutation probability exceeds 10%. . Int.

Davila JI. Hart SN. Yannoukakos D. Rack B. Vratimos A. Ambrosone C. Durcan L. Toland AE. Olswold C. Yao S.2014. Cross SS. Shapiro CL. Guidugli L. Pelttari LM. Vachon CM.1414. Cox A. Slamon DJ. 2015 Feb 1. Ekici AB. J Clin Oncol. Fasching PA.1200/JCO. Couch FJ.33(4):304-11. . Wang X. Beckmann MW.BRCA1/2 Testing in Patients with TNBC (irrespective of family history) (5/32) Further information: TED poll: N=5 „ as predictive marker“ N=21 „impact“ N=3. Olson JE. Janni W. Tapper WJ. omit N=9 ++ N=21 + References: Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. Slettedahl S. Godwin AK. Pilarski R. Sharma P. Klemp J.57. Nevanlinna H. Epub 2014 Dec 1. Eccles DM. Garber J. doi: 10. Pankratz VS. Fostira F. Konstantopoulou I. Brauch H. Miron P. Slager SL. 1. Fountzilas G. Hallberg E.

Recruitment of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) up to 2013 (6/32) No further information No references .

Suggested Use of a Screening Checklist (7/32) No further information No references .

State of the Art: Unexplained Heritability: Oligogenic Traits and Genetic Heterogeneity (8/32) No further information No references .

30(35):4409-15 . 3. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort.Non BRCA-associated Hereditary Cancer Syndromes with Increased Risk for Breast Cancer (9/32) No further information References: 1.. 3209 Engel et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. 2012 Jan 15.50(7):486-9 Hearle et al.133(3):1125-30 Tan et al.. J Med Genet. 2012 Dec 10. Clin Cancer Res May 15. Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome. 2012 Jun.. 12.. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study.. 2006. 2. Clin Cancer Res. 2013 Jul. 4. J Clin Oncol. Lifetime cancer risks in individuals with germline PTEN mutations.18(2):400-7 Benusiglio et al. Masciari et al. Breast Cancer Res Treat. 5.

Wichmann HE. 2. Schindler D. Niederacher D. 2012 Jul 1. Engel C. Erven V.: Germline mutations in breast and overian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Kubisch C. Schmutzler RK. Fernández F.Third Moderate to High Risk Gene Identified within the GC-HBOC (10/32) No further information References: 1.1038/ng. Schmutzler R. Honisch E. Wiek C. Schaal H.: Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Epub 2012 Mar 26 . Wappenschmidt B. doi: 10. Epub 2010 Apr 18. Kiechle M. Neveling K. Ramser J.1093/hmg/dds115. Hum Mol Genet. Meindl A. de la Hoya M. Endt D. Deissler H. Hartmann L. Kast K. Lichtner P. Caldés T. Müller-Myhsok B. Benitez J. Eirich K. Meindl A. Osorio A.42(5):4104. Freund M. Nature Genetics May. Hellebrand H. doi: 10. Mathew CG. Schindler D. Hanenberg H.21(13):2889-98.569.

Commercially Available. Non-validated Breast Cancer Gene Panels for Risk Prediction (11/32) No further information No references .

TruRisk™ BC/OC Gene Panel (34 genes) by the German Consortium GC-HBOC (12/32) No further information No references .

Clinical Implication:Genotype/Phenotype (13/32) No further information No references .

John EM.1200/JCO. Richesson DA et al.Genetically Defined Subtypes are Distinct Tumor Entities (14/32) No further information References: 1. Figueroa J. Eccles D. Pooley K. 4. Cox A. Sherman M.30(35):4308-16. Beckmann MW. Van't Veer LJ. Epub 2006 Nov 28. Kataja V. Van't Veer LJ. Southey MC. Olson JE. Blomqvist C. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death. Garcia-Closas M. Grenaker Alnæs G. Marme F. Lindblom A. breast cancer-specific death. Pharoah P.2012. Giles GG. Kristensen VN.7336. Dunning AM. Schmidt MK. Mannermaa A. Epub 2012 Oct 29. van Hien R. Leunen K. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. Broeks A. Easton DF. Couch FJ. Miron A. Schmidt MK. Shah M. 2007 Jan 1. Barrowdale D. Broeks A. Hall P. Christiaens MR. Peterse JL. Lambrechts D. and increased risk of a second breast cancer. Nevanlinna H. 2.42. Muranen TA. (2008) 4:e1000054. 2012 Dec 10. Meyer A. 3. doi: 10. Severi G. de Kemp SR. van Leeuwen FE. Hooning M. Devilee P. J Clin Oncol. Baglietto L. Margolin S. Smit VT. Hopper JL. Fasching PA. Garcia-Closas M. Cornelisse CJ. Sohn C. Domchek SM. J Clin Oncol. Reed MW. . Weischer M. Bogdanova N. Nordestgaard BG. Morrison J. Seynaeve C. Glendon G. Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. Tollenaar RA. Bolla MK. Wang Q. Wang X. Nevanlinna H et al. Bojesen SE. Czene K. Couch FJ. (2011) 13:R110. Knight JA. Mulligan AC. Phillips KA. Collée JM. Burwinkel B. PLoS Genet. Ziogas A. Anton-Culver H.25(1):64-9. Hall P. Kriege M. Tollenaar RA. Flyger H. Cross SS. Nevanlinna H. Liu J. Andrulis IL. Kosma VM. Børresen-Dale AL. Ekici AB. Breast Cancer Res. Dörk T. Li J. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

VUS: Problems and Questions (15/32) No further information No references .

Fletcher O. Easton DF. Michailidou K. Engel C. 3. 2. Chen B. Thompson D. Lichtner P. Ghoussaini M. 447: 1087-93 Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. MüllerMyhsok B. Ballinger DG et al. Hemminki K. . Turnbull C. Nature. Burwinkel B. …Schmutzler RK …Meindl A. Dicks… Schmutzler RK … et al. Pooley KA. Schmidt MK. TNRC9 and LSP1 in German familial breast cancer patients. Dunning AM. (2012) 44:312-8 Low-risk variants FGFR2. Pharoah PD. Genome-wide association study identifies novel breast cancer susceptibility loci (2007).Low Risk Variants from Genome Wide Association Studies (GWAS) (16/32) No further information References: 1. Int J Cancer (2010) 126:2858-62.

Barrowdale D. Anton-Culver H. Figueroa J. 4. 2. Baglietto L. Knight JA. Garcia-Closas M. Van't Veer LJ. Broeks A. Kriege M. Li J. Bolla MK. van Hien R. Margolin S. Ziogas A. Couch FJ. Dörk T. Grenaker Alnæs G. van Leeuwen FE. Blomqvist C. Schmidt MK. Pharoah P. Leunen K. (2008) 4:e1000054. Eccles D. Nevanlinna H. Beckmann MW. Kataja V. Lindblom A. Couch FJ. Bogdanova N. Kristensen VN. Liu J. Hopper JL. Burwinkel B. CHEK2*1100delC heterozygosity in women . Pooley K. Sohn C. John EM. Giles GG. PLoS Genet. Dunning AM. Reed MW. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. Wang Q. Tollenaar RA. Breast Cancer Res. Børresen-Dale AL. Ekici AB. 3. Richesson DA et al. Olson JE. Kosma VM.Low Risk Variants as Modifier (17/32) No further information References: 1. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Garcia-Closas M. Schmidt MK. Mannermaa A.25(1):64-9. Sherman M. Epub 2006 Nov 28. Christiaens MR. Easton DF. Seynaeve C. Domchek SM. Muranen TA. de Kemp SR. Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. Glendon G. Smit VT. Southey MC. Andrulis IL. Lambrechts D. Miron A. Bojesen SE. Fasching PA. Morrison J. Hall P. Tollenaar RA. Cross SS. Van't Veer LJ. Collée JM. Hooning M. Cox A. Wang X. Peterse JL. Phillips KA. Shah M. Devilee P. Broeks A. Nevanlinna H et al. Cornelisse CJ. Marme F. Meyer A. J Clin Oncol. Nordestgaard BG. Weischer M. Flyger H. Mulligan AC. (2011) 13:R110. Hall P. Czene K. Nevanlinna H. 2007 Jan 1. Severi G.

J Clin Oncol. and increased risk of a second breast cancer. . 2012 Dec 10. breast cancer-specific death.with breast cancer associated with early death.2012.42.1200/JCO.30(35):4308-16. Epub 2012 Oct 29.7336. doi: 10.

Michailidou K. Ruark E. Burwinkel B. TNRC9 and LSP1 in German familial breast cancer patients. Ramsay E. Ballinger DG et al. : Lowrisk variants FGFR2. Pooley KA. Lichtner P. 2. Dunning AM. 3. Nat Genet (2012) 44:312-8 Hemminki K. …Schmutzler RK . Easton DF. Nature. Ghoussaini M..Current Clinical Impact of Other Risk Genes (18/32) No further information References: 1. . Pharoah PDP Antoniou A. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Turnbull C. (2007) 447: 1087-93. Hughes D. Loveday C. Genome-wide association study identifies novel breast cancer susceptibility loci . Pharoah PD. Frankum JR. NEJM (2008) 358: 2796-803. Thompson D. 5. Turnbull C. Int J Cancer (2010) 126:2858-62. Nat Genet. Schmidt MK. Fletcher O. risk prediction and targeted prevention of breast cancer. Dicks… Schmutzler RK… et al.43:879-82. Easton DF. Chen B.Meindl A. Ponder BAJ. Müller-Myhsok B.: Polygenes. Bowden G et al (2011) Germline mutations in RAD51D confer susceptibility to ovarian cancer. Engel C. 4.

Requirements for the Introduction of New Diagnostic or Predictive Genetic Testing (19/32) No further information References: Risikoadaptierte Früherkennung.pdf . 2011 http://www. et al.de/fileadmin/dateien/Downloads/N/Nationaler_Krebsplan/Zielepapier_zum_Querschnittsthema_Ris iko-adaptierte_Krebsfrueherkennung. Ein Papier der Unterarbeitsgruppe „Risikoadaptierte Früherkennung der AG1 „Weiterentwicklung der Krebsfrüherkennung“ des Nationalen Krebsplans.bmg.bund. Schmutzler.

Non Directive Counseling for the Uptake of Preventive Measures (20/32) No further information No references .

Bouchardy C.3238/arztebl. Oncologist. Ditsch N. Kast K. 2. Darrington DL.1634/theoncologist. 2012 May 28. Rhiem K. Epub 2011 May 13. doi: 10. Appropriate surveillance for late complications in patients in remission from Hodgkin lymphoma. 4. 2011 May.12:197. Ibrahim EM.2011-0451. 2012. Al-Foheidi M.1007/s11899-012-0128-z. Kazkaz GA. new treatments. Rapiti E.1186/1471-2407-12197. characteristics. Vlastos G. doi: 10.7(3):200-7. doi: 10. Elmasri OA. 3. doi: 10.17(6):783-91.2011. Veit-Rubin N. Epub 2012 May 15 . Curr Hematol Malig Rep. 2012 Sep. Meindl A. BMC Cancer. Vinh-Hung V.0323. Risk. Benhamou S. Dtsch Arztebl Int. Hereditary breast and ovarian cancer: new genes. Vose JM. Review. Risk of second breast cancer in female Hodgkin's lymphoma survivors: a meta-analysis. new concepts. Schmutzler RK. Usel M.108(19):323-30. and prognosis of breast cancer after Hodgkin's lymphoma. Abouelkhair KM.Definition of Women at Moderate to High Risk (21/32) No further information References: 1.

Duffy SW. Efficacy of MRI and mammography for breast cancer screening in women with a familial or genetic predisposition. new treatments. N Engl J Med 2004: 351: 427-437 Leach MO et al. Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. and ultrasound for surveillance of women at high risk for hereditary breast cancer.0323. 6.108(19):323-30. et al. 5. MRI breast screening in high-risk women: cancer detection and survival analysis. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Evans DG. doi: 10. Eeles RA. Thompson DJ. Rhiem K. Comparison of breast magnetic resonance imaging. Hurley E. mammography. 3. Kesavan N. doi: 10. Kast K. Meindl A. Radiology (2000) 215:267-279 Warner et al.2011. Kuhl C. Rhiem K. Kast K.145(3):663-72. Gilbert FJ. Evans DG. Radiology (2009) 252:35868. Ditsch N. Epub 2014 Apr 1. Howell A. Massat NJ.3238/arztebl. Ditsch N. doi: 10. 2011 May.2011. MARIBS Group. Warren RM. .3238/arztebl. Hereditary breast and ovarian cancer: new genes.0323. 2011 May. Gadde S. Breast Cancer Res Treat. 2.1007/s10549-014-2931-9. Dtsch Arztebl Int. Epub 2011 May 13. Eeles R. Lim Y.Surveillance Program for Women with deleterious BRCA-mutations (22/32) Further information and references: 1. 7. Dtsch Arztebl Int. Lancet 2005 The German Consortium for Hereditary Breast and Ovarian Cancer has established an intensive surveillance program that is offered to mutation carriers and women at high risk within the 12 centres of familial breast and ovarian cancer in Germany (Meindl A. Schmutzler RK Hereditary breast and ovarian cancer: new genes. Schmutzler RK. Epub 2011 May 13. Kwan-Lim G. 2014 Jun. 4. new concepts. new treatments. Maxwell AJ. Ingham S. J Cin Oncol 2001: 19: 3524-3531 Kriege et al. Leach MO.108(19):323-30. new concepts.

These guidelines are in close agreement with the NICE-guidelines on Great Britain (McIntosh A et al. Int J Cancer 2002. The surveillance program allows the detection of early stage breast carcinomas (MARIBS study group Lancet 2005. 2000 ). Kriege et al. Kaas R et al. no data exist so far on long term follow-up and mortality reduction. Schmutzler et al. However. Hamilton LJ Clin Radiol 2004 ) .: Clinical Guidelines and evidence review for the classification and care of women at risk of familial breast cancer. Am J. BRCA associated breast carcinomas frequently present with specific imaging criteria that may be misinterpreted as benign lesions by sonography and mammography (Rhiem K et al. NEJM 2004. Tilanus-Linthorst M et al. Roentgenology 2006. Kuhl. London: national Collaborating Centre for Primary Care/University of Sheffield. Warner et al. Eur Radiol 2004. 2004). JAMA 2004.

.2011. Schmutzler RK Hereditary breast and ovarian cancer: new genes. Hereditary breast and ovarian cancer: new genes. Dtsch Arztebl Int. Lancet 2005 The German Consortium for Hereditary Breast and Ovarian Cancer has established an intensive surveillance program that is offered to mutation carriers and women at high risk within the 12 centres of familial breast and ovarian cancer in Germany (Meindl A. Kuhl C. Meindl A. London: national Collaborating Centre for Primary Care/University of Sheffield. mammography. 2011 May.0323. Leach MO et al. new concepts. new treatments. These guidelines are in close agreement with the NICE-guidelines on Great Britain (McIntosh A et al. Rhiem K. new treatments. Kriege et al. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. and ultrasound for surveillance of women at high risk for hereitary breast cancer. 2. Rhiem K. Ditsch N. doi: 10.Modified Surveillance Program for BRCA-neg. J Cin Oncol 2001: 19: 3524-3531 4.3238/arztebl. et al. Epub 2011 May 13.108(19):323-30.0323. Ditsch N. Comparison of breast magnetic resonance imaging. 2011 May.: Clinical Guidelines and evidence review for the classification and care of women at risk of familial breast cancer. Women at Moderate to High Risk or Survivors of Hodgkin Disease (23/32) Further information and references: 1.3238/arztebl. N Engl J Med 2004: 351: 427-437 5. Kast K.108(19):323-30. Radiology 2000: 215:267-279 3. Kast K.2011. doi: 10. new concepts. Efficacy of MRI and mammography for breast cancer sreening in women with a familial or genetic predisposition. Warner et al. Schmutzler RK. Epub 2011 May 13. Dtsch Arztebl Int. 2004).

Roentgenology 2006. Schmutzler et al. Warner et al. Kaas R et al. NEJM 2004. However. Hamilton LJ Clin Radiol 2004 ) . Kriege et al. Am J. BRCA associated breast carcinomas frequently present with specific imaging criteria that may be misinterpreted as benign lesions by sonography and mammography (Rhiem K et al. 2000 ). JAMA 2004. Int J Cancer 2002. Kuhl. no data exist so far on long term follow-up and mortality reduction.The surveillance program allows the detection of early stage breast carcinomas (MARIBS study group Lancet 2005. Tilanus-Linthorst M et al. Eur Radiol 2004.

JAMA. 2014 Sep 3. Clarke CA. Lichtensztajn DY. Kurian AW. Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California. Gomez SL. 1998-2011. .312(9):902-14. Keegan TH. Nelson DO.Surgical Prevention (24/32) No further information References: 1.

2001 Rebbeck et al. 2010 Sitzmann et al. 9. Prophylactic bilateral mastectomy (PBM) reduces the risk of breast cancer in BRCA1/2 mutation carriers by >95% (Meijers-Heijboer et al. Cochrane Database Syst Rev. 7. NEJM 2002 Domcheck et al. 3. 2004 Hoogerbrugge et al. The residual risk for peritoneal cancer after PBSO accumulates to 3. Kauff et al NEJM 2002 Rebbeck et al. 8. only few women opt for this intervention.. The Lancet 2006). 2006 Meijers-Heijboer et al. Carbine NE. 6. 4. However. Rebbeck et al. JCO 2004) and may be performed in these women after the age of 25. 5. Moreover. Wallace J. 2. 2006 Domcheck et al. PBSO improves overall survival of mutation carriers (Domchek et al.Surgical Prevention for Healthy BRCA1/2 Mutation Carriers (25/32) Further information and references: 1. Rebbeck et al. NEJM 2002). Prophylactic mastectomy for the prevention of breast cancer (2010) Lostumbo L. JAMA Surg 2013 Prophylactic bilateral salpingo-oophorectomy (PBSO) reduces the risk for ovarian cancer in BRCA1/2 mutation carriers to >95% and the risk for breast cancer to 50% (Kauff et al NEJM 2002. 11:CD002748. 2005). Gynecol Oncol 2005).5% after 20 years of follow up (Casey et al. Short term HRT does not negate the protective effect of PBSO on subsequent breast cancer risk (Rebbeck et al. These studies support the current strategy of the German consortium to recommend PBSO in mutation carriers after completion of childbearing around the age of 40. NEJM 2001. .

Premalignant lesions of the breast develop especially over the age of 40 (Hoogerbrugge N et al. The German Consortium for Hereditary Breast and Ovarian Cancer has developed guidelines for prophylactic surgery. ovarian cancer specific and overall survival benefit for PBSO (Domchek et al.deutsche-krebshilfe. A recent cohort study proved a breast cancer specific. Lancet Oncology 2006). genetic testing within a familial breast cancer centre (addresses are deposited at www. Prophylactic surgery should be preceeded by interdisciplinary counselling and.For women at high risk defined as having a heterozygote risk of >20% or a life time risk of >30% and in whom genetic analysis is not possible or not informative the beneficial effect of preventive surgery is not clear and requires an individualized strategy.de) . if possible. Eur J Cancer 2006).

J Clin Oncol 26: 1093-1097.136(3):668-77. 3. Domchek SM. 2009 Rhiem K. 2. Evans DG.. Seynaeve C. 7. Graeser M. Keymeulen KB. Rebbeck TR. Friebel TM. Kets CM. 2004 Metcalfe KA. Engel C. HEBON. Neuhausen SL et al. Ausems MG. Int J Cancer. et al: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. Lynch HT. Ghadirian P. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. J Clin Oncol 22: 2328-2335. et al: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation Carriers.Risk-reducing Interventions for BRCA1/2 Mutation Carriers Affected by Breast Cancer (26/32) No further information References: 1. The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Engel C. Ghadirian P. J Clin Oncol 27:5887-92. 6. 5. 4. Levin AM. Lynch HT. Heemskerk-Gerritsen BA. 2012 Dec 7. Lubinski J. et al. Friebel TM. Graeser MK. 2008 . Singer CF.14(6):R156. Koppert LB. Rookus MA. Mooij TM. Association of risk reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. 8. JAMA (2010) 304:967-75. Rhiem K. Jansen L. et al: Predictors of contra-lateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: the Hereditary Breast Cancer Clinical Study Group. Collée JM. Pierce LJ. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. 2006 Metcalfe K. J Clin Oncol 24: 2437-2443. Vasen HF. Breast Cancer Res. Tollenaar RA. Hooning MJ. Isaacs C et al. Meijers-Heijboer HE. 2015 Feb 1. Aalfs CM. Lancet Oncol (2006) 7: 223–229 Domchek SM. et al: Contra-lateral breast cancer in BRCA1 and BRCA2 mutation carriers.

Isaacs C et al. Friebel TM. (2010) JAMA. Domchek SM.Risk-reducing Salpingo-oophorectomy and All-cause Mortality (27/32) No further information References: 1. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. 304:967-75. Evans DG. Singer CF. Lynch HT. .

Contralateral Cancer Risk in 6235 BRCA1/2 Positive and Negative Patients (retrospektive) (28/32) No further information No references .

Nature 2005 Rottenberg et al. 12. Gynecl Oncol 2005 Tassone et al. JCO 2004 Pierce L. 9. et al.Therapy of BRCA1/2-associated Breast Cancer+ (29/32) Further information: TED poll: Caboplatin (vs Docetaxel): 3 ++. Cancer res. JCO 2006 Metcalfe et al. 2. 3. PNAS 2008 Fong et al. Lancet 2010 Tutt et al. 10. 7. 11. NEJM 2009 Tutt et al. 2009. 2008 Ashworth et al. 14. BJC 2003 Quinn et al. Metcalfe et al. JCO 2008 Rottenberg et al. 17 + References: 1. 2003 Farmer et al. 15. 5. BCR 2004 . 6. 8. 27(15S) CRA501 Audeh et al. Nature 2005 Bryant et al. ASCO abst. Lancet 2010 Robson et al. 4. 13.

Cooperation of Certified Breast Centres (BC) with Specialized Centres of the GC-HBOC (30/32) No further information No references .

The Lancet. doi:10. Early Online Publication.1016/S0140-6736(13)62292-8 . NSABP-P1 (Tamoxifen): Fischer B et al JNCI 1998 2. Cuzick et al.Medical Prevention for Women at Increased Risk (31/32) No further information References: 1. JAMA 2006 3.. 12 December 2013. Star (Raloxifen): Vogel VG et al.

Risk Reduction for Ipsi.and Contralateral Breast Cancer (32/32) Further information: Large RCTs have proven a risk reduction of breast cancer by Tamoxifen. aromatase inhibitors and the combination of GnRHa plus Tamoxifen No references .

V.1 Early Detection and Diagnosis . Guidelines Breast Version 2015. sowie in der DKG e. in der DGGG e.V. V.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.

ago-online. V.1  Versions 2005–2014: Albert / Blohmer / Fersis / Junkermann / Maass / Scharl / Schreer www. Guidelines Breast Version 2015. in der DGGG e.Early Detection and Diagnosis © AGO e. sowie in der DKG e.V.de  Version 2015: Schreer / Albert .V.

sowie in der DKG e.1 www.Early Detection Mammography © AGO e. V.V.ago-online.de AGO GR Age Interval < 40 na - - -- 40–50 12–18 1b B + 50–70* 24 1a A ++ >70 24 4 C + * National Mammography-Screening-Program .V. Oxford LOE / in der DGGG e. Guidelines Breast Version 2015.

sowie in der DKG e.73–0.81 Canadian Task Force.86 (0.V.86) US Task Force.de Metaanalyses RR 95%CI Independent UK Panel.Breast Cancer Mortality Reduction © AGO e.79 (0. 2012 Review of all trials and age groups 0.68 (0.90) Duffy et al.54–0. V. 2011 Women aged 50–69 years 0.V. in der DGGG e.87) 0.89) Cochrane Review. 2011 Fixed-effect metaanalysis of 9 RCT-trials 0. 2009 Women 50–59 years Women 60–69 years Estimates weighted average 0.1 www.74–0. Guidelines Breast Version 2015.86) .ago-online.73–0.80 (0.68–0.81 (0.79 (0.77 (0. 2012 13-year metaanalysis 0.75–0.99) 0. but excluding women <50 years 0..69–0.87) As above.

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V.V. Oxford / AGO LOE / GR in der DGGG e. Guidelines Breast Version 2015.ago-online.Early Detection Sonography © AGO e.1  Screening-Breast Sonography  Automated 3D-Sonography 5 D 3b C --- 2b B ++ 1b C ++ As an adjunct:  Dense mammogram (ACR 3– 4)  www. sowie in der DKG e.V.de Elevated risk  Mammographic lesion 2b B ++  Second-look US (MRI-only detected lesions) 2b ++ C .

V.ago-online. Guidelines Breast Version 2015. Oxford / AGO LOE / GR in der DGGG e. sowie in der DKG e.Early Detection Clinical Examination © AGO e. V.V.de CBE in combination with imaging BCP ++ * May improve breast cancer awareness * May increase breast awareness .1 As stand alone procedure  Self-examination 1a A -*  Clinical breast examination (CBE) by health professionals 3b C -*  CBE because of mammo/sonographic lesion 5 D ++ www.

in der DGGG e. sowie in der DKG e.V.ago-online. mammography and sonography do not allow a definite diagnosis .de  MRI* 2b B +/-  Minimally invasive biopsy 1c A ++ * If clinical examination.1  Clinical examination 3b B ++  Mammography 1b A ++ 2b B + 2b B ++  Additional Tomosynthesis (vs spot compression)  Sonography  Elastography (shear-wave) 2b B +  Automated 3D-sonography 3b B +/- www. V.V. Guidelines Breast Version 2015.Assessment of Breast Symptoms or Lesions © AGO Oxford / AGO LOE / GR e.

mammography and sonography (e.ago-online. suspicion of multilocular disease.V.g. highrisk patients. Guidelines Breast Version 2015. sowie in der DKG e. in der DGGG e. plus MRI) do not allow assessment of lesion extension . higher rate of initial mastectomy.1  Clinical examination 5 D ++  Mammography 2b B ++  Sonography 2b B ++ 2b B + Axilla + FNP/CNB www. ** If clinical examination. MRI-guided vacuum biopsy mandatory in case of MRI-detected additional lesions.invasive cancer but sign.Pretherapeutic Assessment of Lesion Extension and Staging © AGO Oxford / LOE / GR e. V.V. Lobular invasive tumors.de AGO  MRI * 1b B +/-  Minimally invasive biopsy** 1b A ++ * Weak reduction in reexcision rate in lobular.

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0.008)]  Re-excision after initial breast conservation 10. 1.031).64 (P = 0. adjusted OR.45).056).56 (P = 0. 0.ago-online. V.2% [OR.MRI: Preoperative Staging in Lobular Invasive Breast Cancer © AGO e. 1. 1.034)] N Houssami et al. 257 . Ann Surg 2013.V. sowie in der DKG e. 2.9% versus 18.1 www.36 (P = 0. adjusted OR.12 (P = 0.56 (P = 0. in der DGGG e.9% [OR.12 (P = 0.1% versus 24.0% [OR. Guidelines Breast Version 2015.de  766 patients with invasive lobular cancer (ILC)  Initial mastectomy: 31.0% versus 40.09)]  Overall mastectomy 43. adjusted OR.V.

V.ago-online. in der DGGG e.de  Early detection of cancer cases additionally to conventional imaging  Improved patient prognosis? (Mortality reduction? Reduction of interval cancers?) .MRI Sceening (High-risk) Benefit © AGO e.V.V. sowie in der DKG e.1 www. Guidelines Breast Version 2015.

Guidelines Breast Version 2015.MRI Screening in Women with High Familiar Risk © AGO e.7 92 H/M 687 27 93 98.1 M 594 97 77.4 33 99. V.V.4 89. sowie in der DKG e.1 MRT Autor Kriege 2004 Warner 2004 Hagen 2004 Leach 2005 Riedl 2007 Kuhl 2010 www.de Rijnsburger 2010 Sardanelli 2011 Passaperuma 2012 Gareth 2014 Mammographie Hochrisiko / Mutation Anzahl Frauen Anzahl Karzinome Sensitivität (%) Spezifität (%) Sensitivität (%) Spezifität (%) M 1909 50 80 90 33 95 M 236 22 77 95 36 99 M 491 25 86 - 50 - H/M 649 35 94 77 40 93 H/M 327 28 50 98 85.7 41 - H/M 501 52 91 97 50 - M 496 57 90 97 19 97 H/M 649 139 93 63 60 - Prospective study results for MRI screening in women with high familiar risk (H) and muatation carriers (M) .V. in der DGGG e.ago-online.

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3 - www. in der DGGG e.ago-online.MRI and DCIS © AGO e. V. Study No.de „Negative breast MRI findings should not be considered a sure marker of benignancy. (%) Spec.1 88 79.“ . Cases Overall accuracy (%) Sens. (%) Gilles et al 1995 172 70 95 51 Westerhof et al 1998 63 56 45 72 Bazzocchi et al 2006 112 80 79 68 Kuhl et al 2007 Baur et al 2013 75 58 - Guidelines Breast Version 2015.V. sowie in der DKG e.V.

Nachsorge Screened: Metaanalyses/ Systematic reviews / RCT / Cohort studies .ASCO .Medline .2014 2009 .S3 Diagnostik.2014 2009 .2014 2009 .2014 Guidelines: . Therapie.GIN 2009 .Early Detection and diagnosis (2/15) Further information and references: Screened data bases: .Cochrane .S3 Brustkrebsfrüherkennung .2014 2009 .Pubmed .

“the best “European” estimate of of breast cancer reduction is 25-31% for women invited for screening. The authors conclude “the imbalance suggests that there is substantial overdiagnosis. a marginal reduction at advanced stage. the relative risk reduction in breast cancer mortality from inivitation to mammography screening is estimated to be 20%. They conclude: 1. . false negatives. Since 2006 mammography screening is offered to women age 50-69 in Germany within a population-based organised quality assured program in accordance with the European Guidelines for Quality Assurance in Mammography Screening. This includes clear and understandable information in absolute terms about false positives. Meta-analysis and reviews from randomised trials: Conclusion of the meta-analysis of the Independen UK Panel on Breast Cancer Screening: “Considering the internal bias in the trials. and that screening at best. only has a small effect on the rate of death from breast cancer”. The population-based data from the United States (SEER-Cancer Statistics 1976 . and 28-38% for women actually screened. Professionals and women need to be infomed about the benefits and harms of cancer screening tests before making medical decisions. overdiagnosis and overtreatment. which were done a long time ago. Detecting invasive breast cancer at an early stage (Stage I-IIA) offers the chance of survival with less treatment impairement and better quality of life.2008) showed an increase in number of early-stage breast cancer.” Data from observational studies and registries: The EUROCREEN Working Group has published their report about the impact of population-based screening with mammography on breast cancer in Europe. The chance for saving a woman’s life by population-based mammographic screening of appropriate quality is greater than that of over-diagnosis”.Early Detection – Mammography (3/15) Further information: The aim of early detection and screening of breast cancer is to reduce the risk of dying from the disease. The estimate of overdiagnosis range from 1-10%.

17:25-30 Duffy SW. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. Clin Oncol 2009. from a randomized trial and from the Breast Screening Programme in England. Breast Cancr Management 2012. Absolute numbers of lives saved and overdiagnosis in breast cancer screening. Alexander M.33:112-121 Duffy S. Lynch JW. Welch H. J Med Screen 2012.1002/ijc. 12. Hiller JE. Altland H. 5. N Engl J Med 2012. J Med Screen 2012. 17(1):25-30 Euroscreen Working Group. 11. 19(Suppl 1):5-13 .9:34 De Gelder R. Farshid G. Duffy SW. 10. A time for caution BMC Women’s Health 2009. Nyström L et al.135:339-354 Armstrong K. Roder DM A novel case-control design to estimate the extent of overdiagnosis of breast cancer due to organized population-based mammography screening. Duffy S. 4. from a randomised trial and from the Breast Screening Program in England: Benefits and harms of breast screening.29124 Beral V. Epidemiol Rev 2011. Olsen Ae. Berlin. DOI: 10. Duda V et al 2008 update of the guideline early detection of breast cancer in Germany. Ming-Fang Yen A. Ann intern Med 2007 Apr 3. The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer. 3. Long-term benefits of breast screening. CMAJ 2011. Recommendations on screening for breast cancer in average-risk women aged 40-74 years. 7. J Med Screen 2010. et al. 13. Albert U. 1:31-38 Duffy S. Moye E. J Med Screen 2011. et al. Moss S. The impact of mammography screening on breast cancer mortality in Europe: a review of observational srudies. Tabar L. Olsen AH et al Absolute numbers of lives saved and overdiagnosis in breast cancer screening. J Med Screen 2010.References: 1. Int J Cancer2014. Reynolds EE Screening mammography in women 40-49 years of age : a systematic review for the American College of Physicians. 18:210-212 Bleyer A. van Ravesteyn NT et al Interpreting overdiagnosis estimates in population-based mammography screening. 183:1991-2001 Ciatto S The overdiagnosis nightmare. 8. 19(Suppl 1):14-25 Canadian Task Force on Preventive Health Care. 367:1998-2005 Broeders M. et al. Tabar L. Heijnsdijk EA. Williams S.146(7):512-526 Beckmann KR. Hsiu-Hsi Chen T. Houssami NA. 2. Effect of three decades of screening mammography on breast-cancer incidence. 9. 6.

de Koning HJ. De Wolf C. Puthaar E (eds. Sedlacek S Advantages and disadvantages of mammography screening. Overdiagnosis in mammography screening for breast cancer in Europe: a literature review. Duffy S. Otto SJ. de Munck L. 19.BMJ 2010.260:658-663 The Swedish Organized Service Screening Evaluation Group (Duffy W. Bougatsos C. Office for Official Publications of the European Communities.) European Guidelines for Quality Assurance in Mammography Screening and Diagnosis. 340:1-6 Kalager M. Holland R. Tyne. 26. Pandharipande PV. 4th ed. The benefits and harms of breast cancer screening: an independent review. Zahl PH. 20. et al. Kopans D et al Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography. Langmark F et al Effect of screening mammography on breast cancer mortality in Norway N Engl J Med 2010.23:439-444 Perry N. Gotsche PC. Lee JM. Lehman CD. 19(Suppl 1):42-56 Tabar L. Chen THH. Broeders M.203:952-956 Lee CH.J Am Coll Radiol 2010. Am J Roentgenol 2014. Verbeek ALM. v. breast ultrasound. Reduction in Breast Cancer Mortality from the Organized Service Screening with Mammography: Cancer Epidemiol Biomarkers Prev 2006. 23. and other technologies for the detection of clinically occult breast cancer. Zelen M. 17. Lancet 2012.Karsa L. van Doorne-Nagtegaal. 18. Vitak B. 22. Imhof-Tas M. Screening for breast cancer: an update for the U. Naik A. Luxembourg 2006Puliti D. The Breast 2014. 25. Preventive Services Task Force. Chen THH et al Swedish Two-County Trial: Impact of mammography screening on breast cancer mortality during 3 decades. 151:727-737 Paap E. 21. J Med Screen 2012. Törrberg S. 6:119-207 Independent UK Panel on Breast Cancer Screening. Olsen O Is screening for breast cancer with mammography justifiable? Database Syst Rev 2011 Jan 19(1): CD001877. Radiology 2011.).S. Chan B.14. van der Steen A. Humphrey L. Gotsche PC Breast cancer mortality in organised mammography screening in Denmark: comparative study. Ann Intern Med 2009. 380(1778):1786 Joergensen KJ. Holland R. Miccinesi G et al. Dershaw DD. Breast Care 2011. Broeders MJM Breast cancer screening halves the risk of breast cancer death: A case referent study.K. HJ. Lee CI Imaging-based screening: Understanding the controversies. Tabar L. beast MRI. den Heeten GJ.15/1: 45-56 . Review Heywang-Köbrunner SH . 16. Botterweck AAM. 15.7(1):18-27 Nelson H.363(13): 1203-1209 Lam DL. Hacker A.

Mainprize JG Risk of radiation-induced breast cancer from mammographic screening. 258(1):98-105 . Yaffee MJ.27. Radiology 2011.

Long-term benefits of breast screening. Naik A.Breast Cancer Mortality Reduction (4/15) No further information References: 1. Tyne. Hsiu-Hsi Chen T. 151:727-737 . Review Independent UK Panel on Breast Cancer Screening. 1:31-38 Gotsche PC. Canadian Task Force on Preventive Health Care. Ming-Fang Yen A. Bougatsos C. Chan B. The benefits and harms of breast cancer screening: an independent review. Breast Cancr Management 2012. 4.S.K. 3. 2. 5. 183:1991-2001 Duffy S. Ann Intern Med 2009. Olsen O Is screening for breast cancer with mammography justifiable? Database Syst Rev 2011 Jan 19(1): CD001877. Humphrey L. Preventive Services Task Force. Lancet 2012. Screening for breast cancer: an update for the U. Recommendations on screening for breast cancer in average-risk women aged 40-74 years. 380(1778):1786 Nelson H. CMAJ 2011. et al.

The only one especially designed for this age group (“Age-Trial”) achieved a mortality reduction of 17% for those invited and 24% for those participating. These results were not yet statistically significant (95% CI. To estimate overdiagnosis within the “Age-Trial” Markov-modelling was performed and yielded the following results (Gunsoy N.4-3.11 (0. Reichmann M.6-1.2) for preclinical invasive breast cancer. de Koning HJ Population-based mammography screening below age 50: balancing radiation-induced vs prevented breast deaths.19) years. Rosenblath R Screening mammography for women in their 40s: A retrospective study of the potential impact of U.4) and 0. In our main analysis.05-0. Br J Cancer 2011. Arleo EK.Preventive Task Force’s 2009 Breast Cancer Screening Recommendations.“ References: 1. overdiagnosis was estimated as 0. AJR 2013.8 years (0. because the follow-up time is to short for this young age group. Draisma G. The data have been underlined by study results of several service screening studies. respectively. yielded a range of 0.66-1. Babagbemi K. Dashevsky BZ.3 (0. Results also suggest annual screening is most suitable for women aged 40-49 in the United Kingdom due to short cancer sojourn times. The proportion of screen-detected in-situ cancers that were non-progressive was 55% (25-77) for the first and 40% (22-60) for subsequent screens. 2. and 0. respectively. Heijnsdijk EA.201:1401-1406 De Gelder R.” The authors conclude: “The extent of overdiagnosis due to screening in women aged 40-49 was small.04)).9%. A sensitivity analysis. 0. 2012): “The sensitivity of mammography for invasive and in-situ breast cancers was 90% (95% CI.Mammography Screening Women 40–49 years (5/15) Further information: On the basis of randomized controlled trials there is evidence of a 26% mortality reduction. The screen-detectable mean sojourn time of preclinical non-progressive and progressive in-situ cancers was 1.7% of screen-detected cancers. Drotman M.S. covering a wide range of alternative scenarios. 72-99) and 82% (43-99).5% to 2.104: 1214-1220 .

10. Sem Breast Disease 2004. 6. Waller M. Kopans D. 7. http://breast-cancerresearch. Cuckle H. 5. 18-27 Malmgren JA. Warren Burhenne L Breast cancer screening with imaging: Recommendations from the Society of Breast Imaging and the ACR on the use of mammography. Garcia-Closas M. Breast Cancer Res 2012. 4. Feig S. 9. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years follow-up: a randomised controlled trial. Gunsoy N. Lancet Oncol 2010. D’Orsi C. 7. Berg W. Johns L. Moss S. Atwood MK. single-arm. 368: 2053 – 2060 Moss SM. Cancer 2011. Kaplan HG Impact of mammography detection on the course of breast cancer in women aged 40-49 years. Parikh J. The Lancet 2006. 17: 37-43 Lee CH. Abdsaleh S et al Effectiveness of population-based service screening with mammography for women ages 40 – 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Monsees B. Duffy SW. J Med Screen 2010. Trial Management Group.262(3):787 Moss SM et al. Bassett L. Dershaw D. breast MRI. Modelling the overdiagnosis of breast cancer due to mammography screening in women aged 40-49 in the United Kingdom. Effect of mammographic screening from age 40 years on breast cancer mortality a 10 years follow-up: a randomised controlled trial. Brenner J. Hendrick E. Monticciolo D. . Evans A. Radiology 2012. Bobrow L. J Am Coll Radiol 2010. 117:714-722 Johns LE. 14:1-1. Sickles E. Mendelson E. breast ultrasound and other technologies for the detection of clinically occult cancer. 8.3.com/content/14/6/R152 FH01 Collaborative Teams Mammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective.11:1127-1134 Feig SA: Screening strategy for breast cancer. FH01 study. Evans P. 6: 161-172 Hellquist BN. Moss SM Randomized controlled trial of mammographic screening from age 40 (“Age Trial”): patterns of screening attendance.

Cormack J B. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate. Biopsy rates were in the range 2. low ppv for biopsy. or about one third of the PPV of biopsies due to mammography. otherwise occult. 21: 325-336 Berg W A.9 mm. Niehoff A. Koekkoek-Doll P. Obrist P. mean tumor size for those identified was 9. 90% with negative lymph node status. 299 (18): 2151-216 . inability to detect most DCIS cases. et al. The arguments against ultrasound use as stand alone screening modality are reproducibility. Blume J D. Automated ultrasound (ABUS/AVUS) is a potentially feasible way to meet the increasing demands for screening ultrasound in women with dense breasts as it shows a comparable diagnostic performance to hand held ultrasound examination. References: 1. Buchberger W. with PPV of 8.Early Detection Sonography (6/15) Further information: Results from the systematic review (Nothacker et al): The systematic search identified no randomized controlled trials or systematic reviews.7% for those biopsied due to positive ultrasound. Combined Screening With Ultrasound and Mammography vs Mammography Alone in Women et Elevated Risk of Breast Cancer. JAMA 2008. high false-positive rate. breast cancers. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Semin Ultrasound CT MR 2000.4-13. operator dependency and lack of quality assurance.7%. 2.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR). six cohort studies of intermediate level of evidence (3b) were found.3%-4.. Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0. Dunser M.

44:539-44 Corsetti V. Eur J Cancer 2011 May. mammography and pathology results. 225: 165-175 . Sohn C. breast MRI. Bani C. Arch Gynecol Obstet 2014 Oct 14. Junkermann H. Angnelli O.566 patient evaluations. Epub 2013 Mar 27.CD009632. doi: 10. Hong MJ. 12.Newhouse J. Heil J. Sickles E.. breast ultrasound and other technologies for the detection of clinically occult cancer. Eur J Cancer 2008. bellarosa S. Bellarosa S. Eur J Radiol. Breast screening with ultrasound in women with mammography-negative dense breasts:evidence on incremental cancer detection and false positives.15(21):9101-5. Mendelson E.03. J. 40 (3): 431-41 Hellquist BN. 2013 Apr 30. Schweitzer-Martin M.E. Abdsaleh S et al Effectiveness of population-based service screening with mammography for women ages 40 – 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Chae EY. 117:714-722 Kolb T. Corsetti V. 2014.1002/14651858. Schott S. Ciatto S. Harcos A. Duffy SW. 8. 5. Cancer 2011. Golatta M. Schuetz F. Shin HJ. Ultrasound for breast cancer screening and staging. Rauch G. Kim HH. 4. Gordon PB. Junkermann H. Warren Burhenne L Breast cancer screening with imaging: Recommendations from the Society of Breast Imaging and the ACR on the use of mammography.82(8):e332-6.held ultrasound in the detection of breast cancer: an analysis of 5.ejrad. Role of ultrasonography in detecting mammographically occult breast carcinoma in women with dense breasts. Ghirardi M et al Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. 2013 Aug. Houssami N. 6. Cochrane Database Syst Rev. 10. 7.M.2013. 9.47(7):1021-1026 E. Asian Pac J Cancer Prev. 11.005. Ghirardi. J Am Coll Radiol 2010. Angelini O. Galligioni. doi: 10. Lichy J. Radiology 2002. 13. Ciatto S. Rauch G. Cha JH. D’Orsi C. Choi WJ. Kim H. Harcos A. physical examination and breast US and evaluation of factors that influence them: an analysis of 27. 18-27 Golatta M. Ferrari A. 111: 440-448 Corsetti V.825 patient evaluations.pub2. Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS). Comparison of automated breast volume scanning and hand. Bani C. Evaluation of an automated breast 3D-ultrasound system (ABUS) by comparing it with handheld ultrasound (HHUS) and mammography. Houssami N. Domschke C. Sohn C.4:CD009632.1016/j.Radiol Clin North Am 2002. Comparison of the performance of screening mammography. Radiol Med (Torino) 2006. Baggs C. Remida G. 7. Scharf A. Bergonzini R. Ghirardi M. and associated cost. Franz D. Sardo P. Ferrari A. Rom J. Heil J.3. Scharf A.

Albert U: Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense tissue: A systematic review. Warm H. Monsees B. Thomas A. Gyapong S. Soergel P. 2013 Nov 12. Chapman A.. Radiology 2002. Schwesinger G. Kolb T. Farrokh A. [Epub ahead of print] . Diagnostic performance and interobserver concordance in lesion detection with the automated breast volume scanner (ABVS).1186/1471-2342-13-36. Eben EB. Kaminski-Hartenthaler A. Klug U. pii: 0284185114528835. Feig S.577 diagnostic procedures. J. Hillemanns P. Berzaczy D. Schulz-Wendtland R. Jonat W. Duda V. Diagnostic performance and interobserver concordance in lesion detection with the automated breast volume scanner (ABVS). 225: 165-175 Lee CH. Kohlmann T. Brenner J. 26: 3943-3955 Schaefer KW. Breast Cancer Res 2008. Gullien R. physical examination and breast US and evaluation of factors that influence them: an analysis of 27.analysis of 102. Sandhaug M. Kopans D. Madjar H. 16. Wefelnberg C. Eur Radiol 2010. Evans P. Dershaw D. 18. Degenhardt F. Schimming A. Degenhardt F.13(1):36 Wojcinski S. Soergel P. BMC Med Imaging. Hillemanns P.Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study. Weinbrenner S. Farrokh A.825 patient evaluations. Hahn M. 20. 15. doi: 10.13:36. Paepke S. Bassett L. Degenhardt F.1186/bcr1831). Berg W. Helbich TH. Non-palpable breast lesions in asymptomatic women: diagnostic value of initial ultrasonography and comparison with mammography. 2013 Nov 12. Hendrick Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. Thaler K. 21. Gartlehner G.14.Newhouse J. Acta Radiol 2014 Mar 28. Frese H. Stoeblen F. Martin L. Warm M. BMC Cancer 2009.10:(DOI:101. Heller M. Waldmann A. Monticciolo D. Anticancer Res 2006. 19. Nothacker M. Wodny M. Heyer H. Boyd N: Potentials mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. 20:1085-1092 Wojcinski S. Lichy J. Schulz K. Grunwald S. Katalinic A. Gyapong S. Comparison of the performance of screening mammography. 9: 335-344 Ohlinger R. Skaane P. Kohler G. Van Noord MG. BMC Med Imaging. 17. Schreer I Influence of additional ultrasound on cancer detection in a cohort study for quality assurance in breast diagnosis.

Radiology 2002: 225: 165-175 Kosters J. No randomized studies have been performed. Predictors of sensitivity of clinical breast examination (CBE). 200: 712-718 Kolb T. Contributions of clinical breast examination to mammography screening in the early detection of breast cancer. et al.825 patient evaluations. Wasif N. A randomized trial in Canada showed no difference in breast cancer mortality between a group of women offered clinical breast examination or mammography combined with clinical breast examination. 4. 2. Recent data (Haakinson and coauthors 2010) underscore this strategy. The only difference was that women in the self-examination arm had nearly twice as many biopsies for benign lesions than women in the control arm. One Japanese case-control study suggests that examination by health professionals might reduce mortality from breast cancer. Comparison of the performance of screening mammography. Chiarelli A. 5. where screening-examination by health professionals is compared to no screening. Apsey H. Newhouse J. J Med Screen 2003.Early Detection Clinical Examination (7/15) Further information: In a large well performed randomized study no difference in breast cancer mortality emerged after 11 years of follow-up. Bancej C. Gotzsche P. The Cochrane Database of Systematic Reviews 1 2003. This is the reason why in the US mammography screening is recommended in close connection with clinical examination. Regular self-examination or clinical examination for early detection of breast cancer. Pockaj B A significant number of women present with palpable breast cancer even with a normal mammogram within 1 year. References: 1. Gray RJ.. White E. Lehman C. Stucky CCH. Therefore based on current evidence breast self-examination cannot be recommended anymore. Oestreicher N. 3. 10: 16-21 Haakinson DJ. 76: 73-81 . Dueck AC. Decker K. Am J Surg 2010. physical examination. Nevertheless in asymptomatic women participating in mammography screening programs there is the risk of interval cancer development. et al. Lichy J. Breast Cancer Res and Treat 2002. and breast US and evaluation of factors that influence them: an analysis of 27.

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von Heyden D et al The influence of preoperative MRI of the breasts on recurrence rate in patients with breast cancer. Eur Radiol 2004. Makarov V. morphological diagnosis based on biopsy material is warranted. References: 1. Automated ultrasound (ABUS/AVUS) is a potentially feasible way to meet the increasing demands for screening ultrasound in women with dense breasts as it shows a comparable diagnostic performance to hand held ultrasound examination. Cella C. 3. In case of suspicious microcalcifications extensively distributed in mammography several percutaneous biopsies should be performed before deciding upon mastectomy. Clin Ultrasound 2005. Strano S. Koretz M.274 (2): 63-73 Fischer U. Ross SD. 4. Baum F. Shcharynsky S. 14: 1725-1731 .Assessment of Breast Symptoms or Lesions (8/15) Further information: If clinical examination. Brancato B. Minimally invasive biopsy allows definitive diagnosis in most cases at reduced expenditure. Bianchi S. Houssami N. Digital breast tomosynthesis allows an increased breast cancer detection rate and its use is recommended for screening centers in population-based trials. Zachariae O. 2. Linz H. Arch Gynecol Obstet 2006. Ciatto S. Breast Cancer Res Treat 2007. MRI has a high sensitivity but a low specificity to allow definitive diagnosis. 33: 47-52 Fahrbach K. Ambrogetti D. Risso GG. mammography and ultrasound are not conclusive. A comparison of the accuracy of two minimally invasive breast biopsy methods: a systematic literature review and meta-analysis. J Accuracy of sonographically guided 14-gauge coreneedle biopsy: results of 715 consecutive breast biopsies with at least two-year follow-up of benign lesions. Shear wave elastography (SWE) is a promising adjunct to greyscale ultrasound in differentiating benign from malignant breast masses (improved specificity of breast US mass assessment without loss of sensitivity thus reducing the need for core biopsy by downstaging US-BIRADS III and IVa lesions). Catarzi S. Sledge I. 101(3): 291-7 Crystal P. Accuracy and underestimation of malignancy of breast core needle biopsy: the Florence experience of over 4000 consecutive biopsies. Bonardi R.

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Röfo 2013 Sep.262(2):435-49. Xie Y. Bandos AI.266(1):89 Elastography 1.Characterization of focal breast lesions by means of elastography. 2. Acoustic radiation force impulse imaging with Virtual Touch™ tissue quantification: mean shear wave velocity of malignant and benign breast masses. doi: 10. Rathfon GY. Schäfer FK. 7. Doré CJ. Evans AJ. Ying L. Henry JP. Lu AH. Thomas A. Gao J. Li G. Cosgrove DO. McLean D. Hillemanns P.ejrad. Junkermann H. doi: 10. Juhan V. Radiology 2012 Feb. Locatelli M. Gay J. Kelly AE. 4. Eben EB. Schweitzer-Martin M. CohenBacrie C. [Epub ahead of print] 6. Cavanaugh BC. Eur J Radiol 2013 Nov. Sumkin JH. Li DW. Song YJ.82(11):e676-9.19(4):1-136.6. Radiology 2014:271(3)655-663 Zuley ML. Heil J. Fang YX. Wojcinski S. Bandos AI. BE1 Investigators.8(10):e76322. Sohn C. Gur D Digital breast tomosynthesis versus supplemental diagnostic mammographic views for evaluation of non-calcified breast lesions Radiology 2013. Health Technol Assess. Hubbard S. What are the characteristics of breast cancers misclassified as benign by quantitative ultrasound shear wave elastography? Eur Radiol. Catullo VJ. Thomson K. 2015 Jan. Rauch G. Tardivon A. retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone. Skaane P. Performance of shear wave elastography for differentiation of benign and malignant solid breast masses. Jordan LB.029. Schott S. Sack I. Vinnicombe SJ. Purdie CA. Haakenaasen U. BaluMaestro C. Izadi M. 2013 Dec 11. Comparison with digital breast tomosynthesis with full-field digital mammographic images. Hofwind S. Deng ZJ. Svensson WE. Berg WA.2013. Int J Womens Health 2013 Sep 30. 3. Jebsen IN. 2013 Oct 18. Stavros AT. Tourasse C. Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ). Yin TS. Hooley RJ. 5. Gullien R Two-view breast tomosynthesis screening with synthetically reconstructed projection images. Sadigh G. Whelehan P. Fischer T.5:61 .1016/j. Ekseth U. Brandhorst K. Harcos A. Ganott MA.3310/hta19040. PLoS One. Tang KF. Ohlinger R.185(9):816-23.06. Degenhardt F. Mendelson EB. Krager M. Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses. Golatta M.

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reduction of reexcision rate nor long time outcome parameter. mastectomy rate and margin status J Am Coll Surg 2009. Morrow M J Association of routine pretreatment magnetic resonance imaging with time to surgery.e.e ipsilateral recurrence and overall survival have not been assessed in randomized studies. multifocality/ multicentricity demonstrated at conventional imaging and pathologically proven. A general recommendation for the use of lymph node elastography cannot be given as data on quality assurance is lacking.invasive tumors. but considering the present evidence no general recommendation can be given for preoperative MRI in patients before breast conservation. i. The effect of MRI on the success of breast conserving therapy neither concerning short-time outcome parameter . Mammography delineates the in situ component better if microcalcifications are present. MRI for preoperative staging may be helpful in individual cases ( high-risk women. Therefore the overall contribution of MRI to successful breast conserving therapy cannot be assessed yet. Egleston BL. In these cases magnification mammography is warranted. References: 1.Pretherapeutic Assessment of Lesion Extension and Staging (9/15) Further information: Sonography corresponds better than mammography with the pathological tumor size of the invasive component of breast tumours. MRI is the most sensitive method for both invasive and non. In case of large areas of highly suspicious microcalcifications on mammography several percutaneous biopsies to define tumour size should be performed before deciding upon mastectomy. Thus MRI findings should be verified by percutaneous biopsy before definite treatment. i. Ciocca RM. Bleicher RJ. invasive lobular cancer with inconclusive findings at conventional imaging). Preoperative ultrasound of the axilla and guided lymphnode biopsy prevent completion axillary lymphnode dissection in breast cancer. but lacks specificity. Elastography of lymph nodes might add prognostic information additional to that provided by conventional preoperative tumor assessment and staging.209(2): 180-187 .

JCO 2008. 3. Irwig L Accuracy and surgical impact of Magnetic Resonance Imaging in Breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. 6. Hoogeveen Y L. MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. R. Thompson A. Magn Reson Imaging Clin N Am 2010. Lord. van den Bosch MAAJ. 9. Turner R.) Houssami N. Tuttle TM. Ciatto S Magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer: systematic review and metaanalysis of incremental cancer detection and impact on surgical management. 59:290-302 Houssami N.21:51-59 Evans A. Macaskill P. The Breast Journal 2004. Macaskill P. Houssami N. JCO 2009. Ciatto S. RM. Hayes DF Review of preoperative magnetic resonance imaging (MRI) in breast cancer: Should MRI be performed on all women with newly diagnosed early stage breast cancer. Breast Cancer Res Treat 2008.32(5):392-401 Mann R M. Veldhuis WB. 11. Ann Surg Oncol 2014. Wobbes T et al The impact of preoperative MRI on the re-excision rate in invasive lobular carcinoma of the breast. Whelehan P. 107 (1): 1-14 Mann RM The effectiveness of MRI imaging in the assessment of invasive lobular carcinoma of the breast. Meneghetti L. 5. SJ. Blickman J G. Bozzini A. 2013 Dec 4. Mali WPTM. Purdie CA. [Epub ahead of print] Harms SE. 10. Boetes C. Warren. Warren. Sever AR. BMC Cancer 2008. 26(19):3248-3258 Houssami N. et al. van Dahlen T. 8: 275 Brennan ME. Sensitivity of imaging for multifocal-multicentric breast carcinoma.Does shear wave ultrasound independently predict axillary lymph node metastasis in women with invasive breast cancer? Breast Cancer Res Treat. Dixon M. 7. 119: 415-422 . Solin L J An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. Breast Cancer Res Treat 2010. Buckens CFM. Irwig L. 10 (Suppl. 12. J Clin Oncol 2014. 27(33):5640-5649 Diepstraten SC. Renne G. Macaskill P.CA Cancer J Clin 2009. Lord S. Verkooijen HM Value of preoperative ultrasound guided lymphnode biopsy for preventing completion axillary lymphnode dissection in breast cancer: a systematic review and meta-analysis. Dixon M. McCready DR. Rauchhaus P. Jordan LB. Report of the Working Croups an Breast MRI. Turnbull LW.2. 4. Vapiwala N. Thomson K. 8. Loo CE. Michie CO. 18: 259-276 Mann RM. Vinnicombe S.

Brown J. Eur J Cancer 2011.47(6):879-886 . 2.MRI: Preoperative Staging (10/15) No further information References: 1. 368: 2053 – 2060 Peters NHGM. Turnbull LW. Sculpher M. Harvey I.32(5):392-401 Sardanelli F Overview of the role of preoperative breast MRI in the absence of evidence on patient outcomes. Tuttle TM. The Lancet 2006. 32 (9): 901-910 Moss SM et al. 3. Eur J Cancer 2010. Hanby A. Biltjes J. Walker LG. Breast 2010. Tjalma W. Manca A. Macaskill P. Verslegers J. Vapiwala N. Porizel P. Magnetic resonance imaging in breast cancer. Turner R. J Clin Oncol 2014. 6. 14(1):1 -182 Van Goethem M. Schelfout K. Houssami N. Eur J Surg Oncol 2006. Multicenter randomised controlled trial examining the costeffectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE) Health Technol Assess 2010. Boetes C. McCready DR. 5. Effect of mammographic screening from age 40 years on breast cancer mortality a 10 years follow-up: a randomised controlled trial. Solin L J An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. 19: 3-6 Sardanelli F. 4. Olivier C. Drew P. Brown SR. Borisch B et al Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. van den Bosch MAAJ et al Preoperative MRI and surgical management in patients with nonpalpable breast cancer: The MONET-Randomised Controlled Trial. Napp V. van Esser S. WalkerS on behalf of the COMICE Trial. 46: 1296-1316 Turnbull LW.

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MRI Screening (High-risk) – Benefit (12/15) No further information No references .

Styr B. About 33% of malignancies were detected by MRI alone. Skaane P. about 11% by mammography alone and only 3% by ultrasound alone.Gadde S.16:367-274 . 32: 2224-22302 Gareth ED. Yit L . Ingham S. Overall sensitivity levels ranged from 77% 100%. Therefore MRI should be the first imaging method used for intensified screening in high-risk women. Obdeijn IM. Kriege M. J Clin Oncol 2014. Apold J. Prummel MV. Nisha K. Efficacy of MRI and mammography for breast-cancer cancer screening in women with a familial or genetic predisposition. Maxwell AJ. 3. Vabo A. Kvistad KA.MRI Screening in Women with High Familiar Risk (13/15) Further information: Six prospective multicentre studies and further systematic reviews showed that additional use of MRI increased the sensitivity significantly and that cancers could be detected at a better stage. Boetes C et al. Duffy s MRI breast screening in high-risk women: cancer detection and survival analysis. The Breast 2007. 145(3): 663-67 Hagen AI. 28: 5265-5273 Chiarelli AM. Effectiveness of Screening With Annual Magnetic Resonance Imaging and Mammography: Results of the Initial Screen From the Ontario High Risk Breast Screening Program. J. References: 1. HolmenMM. 2. Hurley E. Howell A. 5. Kaas R et al. 351: 427-437 Rijnsburger AJ. Eeles R. Leach MO. Breast Cancer Res Treat 2014. 4. Aase H. Brekelmans CT. MARIBS Group. BRCA1-associated breast cancers present differently from BRCA2associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study. Moller P Sensitivity of MRI versus conventional screening in the diagnosis of BRCA-associated breast cancer in a national prospective series. N Engl J Med 2004. Massat NJ. Maehle L. Muradali D et al. It is still unclear whether early detection by MRI will translate into improved disease-free and overall survival. Clin Oncol 2010.

Podo F. Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carries and effects of MRI Screening-MRISC. Helbich TH Magnetic resonance imaging of the breast improves detection of invasive cancer. Loo CE. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: A national cohort study. Wagner T. Schild HH Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial. Breast Cancer Res Treat 2010. Santoro F et al Multicenter surveillance of women at high genetic breast cancer risk using mammography. Final results.13(20)6144 Saadatmad S. König R. Int J Cancer 2014. Bergers E. 9. Schrading S. Invest Radiol 2011.Tombach B. Honning MJ et al. Weigel S. Rijnsburger AJ. Bieling H. preinvasive cancer and premalignant lesions during surveillance of women at high risk for breast cancer. Klijn JGM. 11. Clin Cancer Res 2007. Heijnsdijk EAM. Cancer Epidemiol Biomarkers Prev 2012. and Canadian studies combined. Flöry D. Gilbert FJ et al. 135: 2940-2949 Sardanelli F. Reiser M. 21: 1458-1468 Kuhl C. Wasser MNJ. 7. ultrasonography and contrast-enhanced magnetic resonance (The High Breast Cancer Risk Italian 1 study.28:1450-1457 Obdeijn IMA. 119: 399-407 Riedl CC. 8. Kok T. 10. Weber M. Ponhold L. J Clin Oncol 2010. MARIBS. Rieber-Brambs A. Vos JR. Kroiss R. Arand B. Warner E. Leutner C. Fuchsjäger M. Heindel W.57(2):75-89 . Boetes C Assessment of falsenegative cases of breast MR imaging in women with a familiar or genetic disposition.6. Nordhoff D.

MRI Screening (High Risk) Problems (14/15) No further information No references .

207: 675-681 . 370 (9586): 485-92 Schouten van der Felde AP. Oestermann JW. Zafrani B. Radiology 1995. 2. Boetes C. Lancet. Zuiani C. Fischer U. Contrast-enhanced breast MRI in patients with suspicious microcalcifications on mammography. 196: 415-9 Kuhl CK. 186 (6): 1723-32 Gilles R. Bieling HB. Guinebretiere JM et al. results of a multicenter trial. Wobbes. Bazzocchi M. Schrading S.MRI and DCIS (15/15) No further information References: 1. 2006. 4. Ductal carcinoma in situ: MR imaging-histologic correlation. 3. 5. Schlooz-Vries MS. 298: 262-269 Westerhof J P. MR Imaging of Mammographically Detected Clustered Microcalcifications: Is There Any Value? Radiology 1998. et al. T Magnetic resonance imaging of ductal carcinoma in situ: what is it‘s clinical application. et al.Am J Surg 2009. AJR Am J Roentenol. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Moritz J D. Panizza P. 2007.

e. V. in in der der DGGG DGGG e. e.V.ago-online. e. Guidelines Guidelines Breast Breast Version Version 2015.Diagnostik und Therapie primärer und metastasierter Mammakarzinome © © AGO AGO e.V. sowie sowie in in der der DKG DKG e.1 2015.1 Pathology www.V.de .V. V.

1 www.Pathology © AGO e.ago-online. sowie in der DKG e.V.  Versionen 2004–2014: Costa / Fehm / Friedrichs / Huober / Kreipe / Lück / Sinn / Thomssen  Version 2015: Sinn / Friedrichs Guidelines Breast Version 2015.ago-online.de www. in der DGGG e.de . V.V.

ago-online. in der DGGG e.V.  Guidelines Breast Version 2015.1   www.de www.ago-online. sowie in der DKG e.de Any statement in the histological report should reflect its clinical significance The terminology used is chosen according to current national guidelines and international classifications Quality control measures are required in all areas of diagnostic pathology .General Principles for Histopathologic Examination of Breast Cancer Specimens © AGO e.V. V.

Oxford / AGO LoE / GR in der DGGG e.de  www.ago-online.72 h Use of neutral buffered formalin 5 D ++ 5 D ++ 5 D ++ 5 D ++ 5 D ++ .72 h for core biopsies Optimal fixation time for resection specimens: 12 .V. sowie in der DKG e.V. V.Preanalytics: Fixation © AGO e. Guidelines Breast Version 2015.1    www.de  Minimize time to fixation (cold ischemia time) Minimal fixation time of 6 hours for optimal antigen preservation Optimal fixation time 6 .ago-online.

in der DGGG e.V.Use of Fine Needle Aspiration Cytology* © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015.de www.de Nipple secretion Tumor Cyst Lymph node * Ultrasound-guided core biopsy recommended 5 D + 5 D - 5 5 D D +/+/- . V. sowie in der DKG e.V.1     www.ago-online.ago-online.

ago-online. in der DGGG e.V. multifocality. adjacent structures) for sampling and documentation  Routine documentation of macroscopic findings by using diagrams or macro image.V.ago-online. intraductal component.g.de www.1  Consideration of preoperative imaging results (e. Guidelines Breast Version 2015.Workup: Macroscopy and Specimen Radiography © AGO e.de . V. with relation to topography  Specimen radiography for non-palpable lesions and microcalcifications www. sowie in der DKG e.

V. use of B-classification 1b B ++  Frozen section diagnosis on core biopsies 5 D --  Routine evaluation of ER/PgR and HER2 status 3b C ++  Turn-around time < 24 h (histology) 5 D + www.ago-online. 8G: 6–8 sections) 5 D ++  Correlation with imaging (density. Oxford / AGO LoE / GR in der DGGG e. calcifications). Guidelines Breast Version 2015.ago-online.1  Routine workup in step sections (14G: 3 sections / 11G.de www.Workup: Core Needle Biopsies (US-guided or stereotactic) © AGO e. V.V.de . sowie in der DKG e.

at least 1 tissue block every 1 cm 5 D ++  Inking of resection margins. photodocumentation or diagram 5 D + www. Sampling of resection margins in all dimensions 5 D ++  Documentation after slicing using specimen radiography.ago-online.de . V.1  Slicing perpendicular to the longitudinal axis 5 (or perpendicular to the nipple-peripheral axis in case of spherical specimens) D ++  Systematic sampling.ago-online.V. Guidelines Breast Version 2015.Workup: Breast-Conserving Specimens © AGO e. sowie in der DKG e. Oxford / AGO LoE / GR in der DGGG e.V.de www.

Workup: Mastectomy Specimens © AGO e.V.de  More extensive sampling in prophylactic mastectomies (BRCA-1/2 pos.Deep margin . skin above tumor.V.ago-online. patients) 5 D ++ . Guidelines Breast Version 2015. Oxford / AGO LoE / GR in der DGGG e. and retroareolar region 5 D ++ www.1  Margins always to be sampled . V.de  Routine sampling of uninvolved quadrants. at least 2 directions .Other margins. if close (< 1 cm) 5 D ++  Attention to soft tissue margins in skin sparing mastectomy 5 D ++ www.Skin close to tumor. sowie in der DKG e.ago-online.

g.V. to detect micromet.If no clinical consequence from frozen section 5 (e. or in addition to frozen section 3b C +/-  RT-PCR for epithelial genes . cT1 or cT2 and cN0 and BCT)  Imprint cytology instead of.de .) .1  Full workup using step sections of ≤ 500 µm on paraffin embedded tissue  Cytokeratin immunohistochemistry . in der DGGG e. sowie in der DKG e.de Oxford / LoE / GR AGO 5 D ++ 2b 5 B D ++ +/- D D + +/- Frozen section (invasive Ca. Guidelines Breast Version 2015. .As a routine procedure  www.V.When suspicious.ago-online.OSNA 4 3b D B - www.Workup: Sentinel Node Biopsy © AGO e.If clinical consequence 5 . V.ago-online.

de  www.1   Sentinel node biopsy for invasive cancer .If macroscopically > 1 cm 5 5 D D + - Lesions ≥ 1 cm. cT1 or cT2 and cN0 and BET) 5 5 D D + +/- Closest margin of resection . sowie in der DKG e. V.ago-online.V.If no clinical consequence from frozen section (e.ago-online.Indications for Immediate Pathological Analysis Including Frozen Sections © AGO e. without core biopsy 5 D + Non-palpable lesions or lesions < 1 cm Asservation of fresh tissue (tumor banking) 5 5 D D -+ www.de   . Guidelines Breast Version 2015.g.V.If clinical consequence . Oxford / AGO LoE /GR in der DGGG e.If macroscopically < 1 cm .

Reporting: Histologic Tumor Type © AGO e.de Oxford LoE / GR AGO 3b ++ C .de www..ago-online.V. www. V. sowie in der DKG e. mixed type  Pure types: > 90% special tumor type Examples: tubular or cribriform Ca. (4th ed. 2012)  Partial special differentiation: > 50% NST component and < 50% special tumor type (minor component)  Mixed differentiation: > 50% special tumor type and < 50% NST component Example: mucinous breast cancer.ago-online. Guidelines Breast Version 2015.1  Histologic tumor typing according to WHOClassification.V. in der DGGG e.

ago-online.de www.. in der DGGG e.Reporting: Grade of Malignancy © AGO Oxford LoE / GR e. Guidelines Breast Version 2015. 2012) 5 D ++  Reporting of tumor grading in numeric form (e. sowie in der DKG e. G3) 5 D ++ www.de AGO .g.ago-online. pure nuclear grading or additional criteria.1  Use of Nottingham grading system (Elston & Ellis 1991) for all types of invasive breast cancer 5 D ++  In case of very little tumor tissue. (4th ed. such as Ki-67 proliferation fraction. V.V.V. may be used 5 D ++  Grading of DCIS according to WHOClassification.

de AGO  Reporting of invasive tumor size taking into accout macroscopic and histologic findings and clinical imaging results 5 D ++  Additional reporting of total extent of invasive carcinoma in case of satellite nodules or multifocality 5 D ++  Reporting of size of noninvasive component (DCIS or LCIS) when DCIS or LCIS component is extensive (more than 2x invasive Ca) 5 D ++ .ago-online.Reporting: Tumor Size and Total Extent of Tumor © AGO Oxford LoE / GR e.de www. V.V. Guidelines Breast Version 2015.V. sowie in der DKG e.ago-online.1 www. in der DGGG e.

Use of MX is not recommended.3: Invasive tumor size (largest focus in case of multiplicity) pT4: Invasion of dermis alone does not qualify as pT4. pM: pM1 indicates any non-regional disease. V.de pT4d: Negative skin biopsy does not rule out pT4d (inflammatory carcinoma).1  Use of current UICC classifikation (7th ed.ago-online. in der DGGG e. sowie in der DKG e. except 2nd primary contralaterally.V.Reporting: pTNM © AGO Oxford LoE / GR e.) pT 1 . 5 D AGO ++ .V. Criteria for pT4a/b/c/d must me met.de www. Guidelines Breast Version 2015. www.ago-online.

1    www.Reporting: Margins of Resection and R-Classification © AGO Oxford LoE / GR e.V.V. in der DGGG e.ago-online. Guidelines Breast Version 2015.de AGO Evaluation of distance to all resection margins macroscopically and close margins histologically (< 1 cm) 5 D ++ Reporting of minimal distance to resection margin and topography thereof 5 D ++ R-Classification 5 D ++ R0: No residual tumor R1: Microscopic invasive or noninvasive Carcinoma involving resection margin RX: Presence of residual tumour cannot be assessed (e.ago-online. V. tumor in multiple specimens) . sowie in der DKG e.de www.g.

in der DGGG e.1 www. Guidelines Breast Version 2015.V.ago-online. sowie in der DKG e.V. V.de D AGO  L1: Lymphovascular invasion L0: No lymphovascular invasion 5  IHC for evaluation of lymphovascular invasion 3b C -  Differentiation of peritumoral and extensive lymphovascular invasion 3b C ++  Reporting of venous invasion (V0/V1) optional.ago-online. prognostic significance not established 5 + D ++ .Reporting: Lymphovascular invasion © AGO Oxford LoE / GR e.de www.

Denkert.ago-online.ago-online. V. F..1  Identification of tumors with predominant lymphocytic infiltrate (> 50%) in tumor stroma (according to Salgado et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.. S. Sirtaine. N. R. (2014). Pruneri. et al. G. sowie in der DKG e..V. C.de *Salgado. Guidelines Breast Version 2015. Annals of Oncology 5 D AGO +/- . Demaria...Reporting: Evaluation of Tumor-Infiltating Lymphocytes (TIL) © AGO Oxford LoE / GR e.*) Consider only lymphocytic infiltrate in tumor stroma and at the invasion front www.de Do not consider central fibrosis and necrotic areas Reort average of lymphocytic infiltrate as percentage www. in der DGGG e..V. Klauschen.

ago-online. in der DGGG e.de  .Reporting: Evaluation after Neoadjuvant Chemotherapy © AGO Oxford / AGO LoE / GR e. V.V.de www. Guidelines Breast Version 2015. otherwise ypTX 4 D ++  Reporting of tumor size as total extent of tumor bed area involved by infiltrates of residual vital invasive carcinoma 4 D ++  pCR when absence of invasive Ca.V.1  Identification of tumor bed. sowie in der DKG e.ago-online. and absence of angioinvasion or LN metastases. Presence of ypTis should be recorded 2b D +  Use of IHC to identify tumor residues Reporting of ypTN after therapy 4 5 D D +/++ www.

Guidelines Breast Version 2015. tumor nuclei (0 .12) D + D + Re-evaluation on excision specimen if uncertain or triple-negative on core biopsy D +   www. if ≥ 1%) 1a A ++ Staining intensity of pos. Remmele Score (0 .de Oxford / LoE / GR 5 . sowie in der DKG e. tumor nuclei (pos.ago-online.ago-online. V. in der DGGG e.1 AGO  Immunohistochemical detection on paraffin embedded (FFPE) tissue 1a A ++  Reporting percentage of pos.de  www.V.V.3) 4 4 Allred Score (0 .Special studies: ER-Testing by IHC © AGO e.8).

tumor nuclei (0 .ago-online.3) 4 D +  Allred Score (0 . V.de  Immunohistochemical detection on paraffin embedded (FFPE) tissue 1a A ++  Reporting percentage of pos.Special studies: PgR-Testing by IHC © AGO e. if ≥ 10%) 1a A ++  Staining intensity of pos.de www.V.ago-online. Oxford / LoE / GR AGO Guidelines Breast Version 2015. Remmele Score (0 . in der DGGG e.1 www.8).12) D + 4 . sowie in der DKG e. tumor nuclei (pos.V.

V. Oxford / LoE / GR in der DGGG e.V.1 www. Guidelines Breast Version 2015.de AGO  Evaluation of hormone receptors using validated gene expression test kits 3b A  Evaluation of hormone receptor by RNAsequencing 5 D -  Use of molecular receptor analysis for subtyping 3b A + +/- . sowie in der DKG e.ago-online.ago-online. V.de www.Additional special studies: Molecular analysis of ER/PgR status © AGO e.

SISH. negative if signal counts < 4 signals/nucleus Reporting of dual-color ISH: . in der DGGG e.HER2+ if strong complete circular membrane staining of > 10% invasive cells (3+ staining pattern) .de   www.de   .HER2+ if signal counts ≥6 in at least 20 cohesive cells. FISH) A ++  Reporting of single-color In-Situ-Hybridisation (ISH): 3a C ++ 3a C ++ Equivocal results (2+ IHC.<6 HER2 signals ISH): Retest using other method and/or tissue block 3a C ++ Validation of immunohistochemistry on core biopsies 5 Guidelines Breast Version 2015.if > 10% circular but moderate/weak membrane staining or ≤ 10% strong staining (2+ staining pattern): ISH required (CISH. V.V.Special studies: HER2 Testing © AGO Oxford / LoE / GR e. sowie in der DKG e.1  www. ≥4 .V.positive if signal ratio HER2:CEP17 ≥ 2.ago-online. AGO  Reporting of immunohistochemistry (IHC): 1a .ago-online.0 and/or HER2signals ≥6 D ++ .

the HER2 overexpressing sample should be re-evaluated by a different method. V. Therefore. Alternatively. Expected rate of HER2-overexpression: 15% HER2 positive .ago-online.V. Guidelines Breast Version 2015. methods of individual laboratories should be validated by comparison of core biopsies and resection specimens.de False positive immunohistochemical labeling may occur in core biopsies.V. sowie in der DKG e.1 www. all G1 and G2 cases with HER2 3+ in core biopsies may be analyzed by ISH or may be re-evaluated in the resection specimen. Mucinous (at least 90% pure) Cribriform (at least 90% pure).ago-online. Background staining should be evaluated by comparison with normal duct epithelium. False positivity is likely when HER+ was reported in G1 tumors of the following types: Infiltrating ductal or lobular carcinoma.HER2 Testing on Core Biopsies © AGO e. Adenoid cystic carcinoma (90% pure) In case of discrepancy between core biopsy and specimen. If still discrepancy – anti-HER2-treatment if amplified in one of both samples. ER and PgR positive. Tubular (at least 90% pure). in der DGGG e.de www.

1 www.Additional Special Studies: Molecular Analysis of HER2 Status © AGO e.ago-online.V.V. Oxford / LoE / GR in der DGGG e. V.de www.ago-online. sowie in der DKG e.de AGO  Therapy decisions should be based on IHC and ISH only 1a A ++  Evaluation of HER2 durch using validated gene expression test kits 3b B +/-  Evaluation of HER2-amplification by RNAsequencing 5  D Use of molecular HER2-testing for subtyping 3b B - +/- . Guidelines Breast Version 2015.

Guidelines Breast Version 2015.ago-online. V.1  Counting of tumor nuclei at the invasion front 5 D ++  Consideration of weakly stained tumor nuclei 5 D ++  Reporting of Ki-67 positive nuclei as percentage 5 D ++  Establishing of laboratory standards and cutoff values 5 D ++  Use of image analysis for objective Ki-67 evaluation 5 D + www.V.de AGO .de www.V. sowie in der DKG e.ago-online. in der DGGG e.Special studies: Evaluation of Ki-67 Score © AGO Oxford / LoE / GR e.

de  www.V. HER2+ for HER2-type. ratio <2)) None of the available markers (Ki-67.) can reliably discriminate between luminal A and luminal B type Although derived from RNA expression studies. HER2) into immunohistochemical counterparts neither with regard to markers nor to thresholds In terms of practical consequences re-labelling of clinically established and immunohistochemically defined subgroups might be useful (ER/PR+ for luminal. V.ago-online. sowie in der DKG e.de  Currently there is no generally accepted and proven translation of molecularly defined types (basal. luminal A/B-Typ. RNA measurements are not suited for the definition of intrinsic types for purposes of therapy .V. triple negative for basal type) The basal type shows an 80% overlap with the triple negative subgroup of ductal invasive breast cancer (ER <1% & PgR <1% & HER2 0/1+2+ (non-amplified.1   www.ago-online. in der DGGG e. grading. recurrence score etc.Intrinsic Breast Cancer Types (Molecular and Immunohistochemical Definitions) © AGO e.  Guidelines Breast Version 2015.

1 www.g. tumor type.V.ago-online.V.de  Use of automated staining platform  Participation in ring trials  Strict adherence and monitoring of requirements of preanalytics (fixation)  Use of on-slide controls  Plausibility controls (e.de www. V.Quality Assurance: Immunohistochemistry © AGO e.ago-online. in der DGGG e. grading) . Guidelines Breast Version 2015. sowie in der DKG e.

V. V. in der DGGG e.V.ago-online. sowie in der DKG e.Quality assurance: HER2-Status © AGO e.1 www.de www.20%  Use of standardiszed and validated HER2 test kits  Participation in ring trials .de  Continuous documentation of HER2 tests  Quality goal: Rate of HER2-positivity: 15% .ago-online. Guidelines Breast Version 2015.

de www. sowie in der DKG e. Guidelines Breast Version 2015.1 www.Quality Assurance: Reporting © AGO e.V.ago-online. V. in der DGGG e.ago-online.V.de  Responsibility of one or two pathologists with special expertise in breast pathology  Regular interdisciplinary conferences with radiologic-pathologic correlation  Participation in quality circles .

EUSOMA position paper: Diagnosis of breast disease . January 2005 . .Interdisziplinäre S3-Leitlinie für die Diagnostik. Anleitung Mammapathologie.I. Further information can be found in the following reports: Screened data bases: PubMed 1970 – 2014 Guidelines screened: .Royal College of Pathologists & NHS Breast Screening Programme. Pathology Reporting of Breast Disease. Aktualisierung 2012 . It is highly recommended to adhere to national quality assurance protocols concerning all aspects of working up and reporting of pathology specimens removed from women with breast cancer. Therapie und Nachsorge des Mammakarzinoms. It is not intended to replace detailed protocols for the evaluation of operative specimens or for special studies.Pathology (2/30) Further information: This chapter contains basic recommendations for routine procedures in pathology.European guidelines for quality assurance in breast cancer screening and diagnosis 4th Edition References: 1.NCCN Breast cancer V.2014Cochrane: Decision aids for risk communication update 2009 . Arbeitsgruppe Qualitätssicherung Pathologie in der konzertierten Aktion zur Brustkrebsfrüherkennung in Deutschland (2002).

Page DL. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008.133(10):1515-38. de Wolf C. http://www.senologie. Recommendations for the reporting of breast carcinoma. 2009 Oct. Smith BL. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Winer E.ch Perry N. O'Malley FP. Leitlinien zur Sicherung und Förderung der Qualitätskontrolle.nhs. http://www. 5. Reiner-Concin. Broders M. NHSBSP guidelines for pathology reporting in breast disease.cancerscreening.pdf Association of Directors of Anatomic and Surgical Pathology (1996). 7.uk/breastscreen/publications/nhsbsp58. Mod Pathol.2. Weaver DL. 3. Reinthaller. Mammakarzinom Pathologie.html Association of Directors of Anatomic and Surgical Pathology.org/download/pdf/s3_brustkrebsfrueherkennung_2008. 985-8 . Holland R. Puthaar E (eds) European guidelines for quality assurance in breast cancer screening and diagnosis. Törnberg S. Fitzgibbons PL. 6. Chen YY. Tan LK. 8. Office for Official Publications of the European Communities. Luxembourg. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. 2006 Royal College of Pathologists (UK) (2005). Arbeitsgemeinschaft für gynäkologische Onkologie (AGO) der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) A. von Karsa L. Members of the Cancer Committee. 37 (8) pp. Hum Pathol (2006) vol. 4. de Baca ME. Hefler (Hrsg. Lax. Bose S.) http://www. Connolly JL.at/inhalt/i-mammakarzinom/15pathologie/ Schweizerische Gesellschaft für Pathologie (2002). Kleer C.ago-manual. Interdisziplinäre Leitlinie Diagnose und Therapie des Mammakarzinoms der Frau.pdf Lester SC.org/download/pdf/s3_ll_mammaca_11_02_2008.9(1):77-81. College of American Pathologists. 1996 Jan. L.senologie. S. Hayes DF. Deutsche Krebsgesellschaft und beteiligte medizinisch-wissenschaftliche Fachgesellschaften (2008).sgpath. 9. http://www. http://www. Arch Pathol Lab Med. In: Manual der gynäkologischen Onkologie.

uk/breastscreen/publications/nhsbsp58. von Karsa L.cancerscreening. Törnberg S.ecco-org.html Association of Directors of Anatomic and Surgical Pathology. Office for Official Publications of the European Communities. Holland R. 37 (8) pp.nhs. 9th European Breast Cancer Conference (EBCC-9) March 19-21. 2. Hum Pathol (2006) vol. Puthaar E (eds) European guidelines for quality assurance in breast cancer screening and diagnosis.General principles for Histopathologic Examination of Breast Cancer Specimens (3/30)) No further information References 1. 985-8 .eu/Events/Past-conferences/EBCC9/Manifesto Perry N. Broders M. The EBCC council: Breast cancer pathology .a manifesto for optimal care. Luxembourg. 3. 2014 http://www. NHSBSP guidelines for pathology reporting in breast disease. Recommendations for quality assurance and improvement in surgical and autopsy pathology. 4. 2006 Royal College of Pathologists (UK) (2005). de Wolf C. http://www.

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Intrinsic Breast Cancer Types (27/30) No further information No references .

European guidelines for quality assurance in breast cancer screening and diagnosis.Am J Clin Pathol. 453:537-43.118:675-82 Wasielewski von R. Rüschoff J. Wiese B. 3.org/download/pdf/s3_ll_mammaca_11_02_2008. Annals of Oncology (2008) vol. Mengel M. 2. http://www.Virchows Arch. Fourth edition-summary document. Rüdiger T.senologie. Müller-Hermelink HK. 2008. 5. Kreipe H. Interdisziplinäre Leitlinie Diagnose und Therapie des Mammakarzinoms der Frau. Rüdiger T.pdf . Kreipe HH et al. (2002) Quality assurance in immunohistochemistry: results of an interlaboratory trial involving 172 pathologists. 19 (4) pp. 4. 2002. Perry et al. Am J Surg Pathol 26:873-882 Deutsche Krebsgesellschaft und beteiligte medizinisch-wissenschaftliche Fachgesellschaften (2008). 614-22 von Wasielewski R. Hasselmann S. Hofler H. Fisseler-Eckhoff A. Proficiency testing of immunohistochemical biomarker assays in breast cancer. Kreipe H. Tissue array technology for testing interlaboratory and interobserver reproducibility of immunohistochemical estrogen receptor analysis in a large multicenter trial.Quality assurance: Immunhistochemistry (28/30) No further information References: 1.

Quality assurance: HER2-Status (29/30) No further information No references .

Quality assurance: Immunhistochemistry (30/30) No further information No references .

sowie in der DKG e.1 Prognostic and Predictive Factors . V.V.V. in der DGGG e.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. Guidelines Breast Version 2015.

1 www.V. in der DGGG e.Prognostic and Predictive Factors © AGO e.V. sowie in der DKG e.ago-online.  2002–2014: Costa / Friedrichs / Gerber / Göhring / Harbeck / Liedtke / Loibl / Mundhenke / Nitz / Rody / Schaller / Schmidt / Schmutzler / Schneeweiss / Simon / Solomayer / Thomssen  2015: Fersis / Janni Guidelines Breast Version 2015. V.de .

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V. V. but design accommodates tumor marker utility Accommodation of predictive marker requires Prospective randomized controlled trial (PRCT) Prospective observational registry. processed and archived with no prospective SOPs www. and archived prospectively using generic SOPs. Paik. treatment and follow-up not dictated No prospective aspect to study Patients and patient data Prospectively enrolled. but treatment and follow-up standard of care No prospective stipulation of treatment or follow-up.Elements of Tumor Marker Studies that Constitute Levels of Evidence Determination © AGO e. J Natl Cancer Inst 101: 1446-1452. especially if a predictive utility is considered. treated. treated. Assayed after trial completion Specimens collected.de Statistical design and analysis Study powered to address tumor marker question Result unlikely to be play of chance Validation Although preferred. processed. in der DGGG e.V. patient data collected by retrospective chart review Specimen collection. Retrospective study design confounded by selection of specimens for study Study not prospectively powered at all. and archived prospectively using generic SOPs. Category Element Guidelines Breast Version 2015. and followed in PCT Prospectively enrolled. Retrospective study design confounded by selection of specimens for study Focused analysis plan for marker question developed before doing assays No focused analysis plan for marker question developed before doing assays Result very likely to be play of chance Result very likely to be play of chance Requires subsequent validation studies Requires subsequent validation Simon. processed. Hayes. and followed in clinical trial and. and assayed for specific marker in real time Specimens collected. processed. a PRCT addressing the treatment of interest Prospectively enrolled in registry. validation not required Study powered to address therapeutic question and underpowered to address tumor marker question Focused analysis plan for marker question developed before doing assays Result more likely to be play of chance that A but less likely than C Requires one or more validation studies Study not prospectively powered at all. processing. sowie in der DKG e.1 A Prospective B Prospective using archived samples C Prospective/ observational D Retrospective/ observational Clinical trial Prospective controlled trial (PCT) designed to address tumor marker Prospective trial not designed to address tumor marker. 2009 . Assayed after trial completion Specimens collected. and archival Specimens collected.ago-online.

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V. sowie in der DKG e.de . margin 12% (JCO 2012)  pN0 from MIRROR study: pN0 was upstaged in 22%.1 www. LVI Kappa 0.Reproducibility © AGO  ER/PR discordance central vs local ≈20% (ASCO/CAP JCO 2010)  HER2 inaccurate testing suspected in approximately 20% (ASCO /CAP JCO 2007)  Impact of routine pathologic review in N0 BC: 20% changes : grading 40%. N 15%.ago-online. Guidelines Breast Version 2015. 15% downstaged in central pathology review (Ann Oncol 2012)  Consistency: 107 cases examined by 23 pathologists in 4 rounds: Grading: Kappa 0. pN1mi: 11% upstaged. V.38 (ECWGBSP. 1999) (Virchows Arch 1999) e. LVI 26%. in der DGGG e.V.53.

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ER+ endocrine treated 8 gene signature PAM 50 (Endopredict®) $ (Prosigna®) $ Sividon NanoString 11-gene assay 50-gene assay FFPE FFPE q-RT-PCR no prognostic (pre-) postmenopausal N-/+.ago-online.Commercially Available Molecular Tests © AGO 70 gene signature (MammaPrint®) $ e. in der DGGG e. ER+ HER2endocrine treated yes Direct hybridization no yes Clinical Laboratory Improvement FDA clearance as “In Amendments Vitro Diagnostic (CLIA) + College of CE-Mark Multivariate Index American Assay (IVDMIA)" Pathologists (CAP)accredited ref lab Validated clinical data only available for this assay prognostic postmenopausal N-/+.ago-online.V. V.1 Provider Agendia Type of assay 70-gene assay Type of tissue Technique Central lab fresh frozen (technical validation FFPE for FFPE available) Microarrays for RNA qRT-PCR Yes yes Indication and population studied prognostic N-/+. sowie in der DKG e. ER+ HER2endocrine treated Yes CE-Mark FDA 510(k) Clearance .de $ 21 gene Recurrence score (Oncotype DX®) $ Genomic Health 21-gene recurrence score prognostic N-/+.de Registration www.V. <61 Jahre Clinical Validation yes www. Guidelines Breast Version 2015.

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Philadelphia 2000.cmaj. EBCC 2007 (n. Morrow M. J Clin Oncol. In: Diseases of the breast.) Guidelines screened: A. H. 2007 Nov 25 (33): 5287-5312 References: 1. Graeff. S.. Goldhirsch et al. Harris JR. Jänicke. Lippincott-Raven Publishers. W.).Prognostic and Predictive Factors (2/20) Further information: Data bases screened: Pubmed 2008 . Ann Oncol..NCCN 2008: http://www. 2nd edition: Seiten 489-514. 2008.d.pdf . Prognostische und therapierelevante .medscape. Clark GM et al. Sauer.. Osborne CK (Hrsg). Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 Ann Oncol(2013) 1-18 Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009: Goldhirsch A et al. ECCO (n. F.com/files/editorial/articles/548868/breast.ASCO 2007: Harris L et al. (1997) Prognostische und therapierelevante Faktoren beim Mammakarzinom – Ergebnisse einer Konsensuskonferenz. SABCS 2003 – 20014 . . ASCO 2003 – 20014. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. 2006: http://www.2015. : Personalizing the treatment of women with early breast cancer: highlights of the St..d.Canadian Medical Association (CMA. H. Wilmanns. Classen.20:1319-39. In: Excerpta Oncologica. Cochrane data base (n. Prognostic and predictive factors.ca/cgi/content/full/158/3/DC1) . Lippmann ME.d.). 2.

Graeff H. S.). Classen S. Novartis Pharma Verlag. <10% Power) . Wilmanns W (Hrsg. Jänicke F. 2 & 3 (retrospective RCT’s. Nürnberg.158. Reasons given for the particular evidence level: Statement 1 (LoE 6): ref. Ergebnisse einer Konsensuskonferenz. 135 . Sauer H.Faktoren beim Mammakrzinom.

Definition (3/20) No further information No references .

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100. J. Davies... K. M. References: 1.C.. A.. McGale. Because of this. S. .C. proper risk assessment is mandatory. the benefit is closely related to the absolute risk of this individual patient. Di Leo.. 432–444.000 women in 123 randomised trials. et al. Pan. Bergh.. Godwin..1016/S0140-6736(11)61625-5. 2012. doi:10. R. S.. Lancet 379... J. H. Peto.. C. D. C. M. Darby. Wang. Cutter.Low Absolute Risk Implies Low Absolute Benefit (4/20) Further information: Adjuvant chemotherapy reduces breast cancer mortality by one third... Especially in ER positive tumors one has to weigh the benefit against potentially chemotherapy-induced side effects like chronic heart failure and leucemia / MDS. P. Swain. However. Y. & Piccart. Clarke. R. Gray.. Albain. Taylor.

the Tumor Marker Utility Grading System was introduced assigning different levels of evidence to a certain marker. levels LoE can be graded up or down. REMARK describes the informations which should be given when publishing a biomarker study such as study design. These original Oxford LoE and Grades of Recommendation were modified in 2011. preplanned hypotheses. Recently a refined system for biomarker study design and evaluation that incorporates a revised level of evidence scale for tumor marker studies. harms). (3) To obtain the highest level of evidence.cebm. the authors of the modified Oxford LoE state. Finally. These modified Oxford LoE also apply to prognostic factors.net). treatment. prognosis. that “levels be interpreted with a healthy dose of common sense and good judgment” . (2) Depending on the quality of a biomarker study. The novel classification was also modified to represent the natural flow of a clinical encounter (diagnosis. Level 1 can be reached with “systematic review of inception cohort studies”.(1) To improve the quality of research on biomarkers a guideline named REMARK (Reporting Recommendations of Tumor Marker Prognostic Studies) was defined. Based on study quality and effect size. a marker had to be tested prospectively in a prospectively randomized clinical study. and statistical analysis methods. The Oxford Levels of Evidence (LoEOx2001) and Grades of Recommendations (GR) were originally released in 2001by the Centre of Evidence Based Medicine (www. levels 1a-c were merged to level 1.Quality Criteria (5/20) Further information: Ranking of evidence is of pivotal importance for clinical decision-making. assay methods. The authors simplified the Levels in several ways. For example. patient and specimen characteristics. (4) Although fully prospective randomized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are still considered the gold standard. In this case. benefits. so more efficient indirect "prospective–retrospective" designs using archived specimens might reach level I . was introduced. including those using archived specimens. such trials are costly.

0454. Simon RM. Jeremy Howick. Iain Chalmers. 23 (36): 9067–9072. This recommendation was recently elaborated on and finally resumed by the NCCN Task Force Report for evaluation of the clinical utility of tumor markers in oncology. Sauerbrei W. Ladanyi M. Available: doi:10. McShane LM. Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence (Background Document).6858.6) In this chapter on prognostic and predictive factors the original Oxford LoE and the revised classification of Levels of Evidence using elements of tumor marker studies as proposed by Simon. Gion M et al. Hayes DF (2012) Publication of tumor marker research results: the necessity for complete and transparent reporting. Taube SE. Available: doi:10. Hammond ME et al. Altman DG.42. J. 5. Paik S. Desch CE. Kemeny NE et al. Bast RC. J. Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. Aldape KD. 6. 2. Bob Phillips. Oncol. Cancer Inst. 101 (21): 1446–1452. Paul Glasziou. References: 1.01.1093/jnci/djp335. and Hazel Thornton. (2011) NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. 30 (34): 4223–4232. Clin. (2005) Reporting recommendations for tumor marker prognostic studies. Ivan Moschetti. 3. Paik and Hayes. McShane LM. J. Hayes DF. . Carl Heneghan. Trish Greenhalgh. Clin. J Natl Compr Canc Netw 9 Suppl 5: S1-32. Fritsche H. 88 (20): 1456–1466.1200/JCO. Marzo AM de. (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. Available: doi:10. Alessandro Liberati. Oncol. Natl.evidence if validated with consistent results. Cancer Inst. Natl.1200/JCO. Febbo PG. (5. quiz S33. 4. J.2012. 2009 are used as applicable.2004. Oxford Centre for Evidence-Based Medicine.

30(34): 4223 – 4232 . J. Natl. Hayes DF. Paik S. 2. 101(21): 1446 – 1452 McShane LM. Oncol. 2009. Cancer Inst.Elements of Tumor Marker Studies that Constitute Levels of Evidence Determination (6/20) No further information References: 1. Use of archived specimens in evaluation of prognostic and predictive biomarkers. Publication of tumor marker research results: the necessity for complete and transparent reporting. Hayes DF. J. Simon RM. 2012. Clin.

101(21): 1446 – 1452 McShane LM. Cancer Inst. Simon RM. Oncol. 2009. Publication of tumor marker research results: the necessity for complete and transparent reporting. Clin.Revised Determination of Levels of Evidence Using Elements of Tumor Marker Studies (7/20) No further information References: 1. 30(34): 4223 – 4232 . Paik S. Natl. J. Use of archived specimens in evaluation of prognostic and predictive biomarkers. 2. Hayes DF. J. Hayes DF. 2012.

Oncol. 2009. Hayes DF. J. Hayes DF.Requirements of a Marker-Based test to Reach Level IB Evidence (8/20) No further information References: 1. 30(34): 4223 – 4232 . Natl. Simon RM. Paik S. J. Cancer Inst. 2. 101(21): 1446 – 1452 McShane LM. Publication of tumor marker research results: the necessity for complete and transparent reporting. Clin. 2012. Use of archived specimens in evaluation of prognostic and predictive biomarkers.

doi: 10.. Coates. 1736–1747 Febbo PG. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011.1093/annonc/mdu042 PMCID: PMC4176449. Ann Oncol. Oct 2014. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. (2011) NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. M.pdf ASCO 2007: Harris L et al. Thürlimann. Aldape KD. 3.com/files/editorial/articles/548868/breast. Statement: Obesity 1.-J. A. quiz S33. Hammond ME et al. W. Wood. 4. Chan et al.ca/cgi/content/full/158/3/DC1) NCCN 2008: http://www. S. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Goldhirsch et al. H. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies Ann Oncol. 22.. A. 2006: http://www. B. : Personalizing the treatment of women with early breast cancer: highlights of the St. D. 2007 Nov 25 (33): 5287-5312 Goldhirsch. . 2011..20:1319-39. Marzo AM de.C. 5.Prognostic Factors I in Early Breast Cancer (9/20) No further information References: 1. 25(10): 1901–1914. 2. J Natl Compr Canc Netw 9 Suppl 5: S1-32. Ladanyi M.medscape. 2014. Ann. 6.S. J Clin Oncol. Oncol.D. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 Ann Oncol(2013) 1-18 Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009: Goldhirsch A et al. R. Canadian Medical Association (CMA.cmaj. 7. Gelber. 2008.. Published online Apr 27. & Senn.

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Fitzgibbons.. Schwartz. L. et al.. Sloane. M. & Rhodes. Dervan.P. Hayes.E.M. Hagerty.P. D. 118–145. K. D... Allred.F. Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and . L. ASCO-CAP guidelines estimate discordance between central and local pathology in about one fifth of cases for ER and PgR and HER2 status.C. R.. P.H. & Miller. P. E.. 2784–2795. 2. V. C.D.. Bianchi.Reproducibility (10/20) Further information: Conventional pathology and immunohistochemistry is for methodological reasons subject to high inter-observer varaibility/variable reproducibility. Francis. A. D.. W. Thus the clinician should be aware of potential problems and pitfalls when decision for adjuvant treatment is taken together with the patient.. Press. J. 3. McShane. N. Wolff. Lester.25.2775. doi:10.. M. W..J. R. 2010.M. 28. Connolly. S. Coleman.. Paik. M. G. Perez. Mangu.N. Goldstein. P. M. 2007. de.. D. Boecker.E.. Faverly. Clin. S.. N. M.G.. Cote.. Badve... American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Hicks.. Apostolikas.B.C. K. References: 1. Fitzgibbons... Bussolati.W..L. McShane. Love. Dowsett.E... I. M. G. 25.. doi:10. et al. R...2009.1200/JCO. K..L.A.2006. MIRROR trialists report upgrading of N0 status by central pathological review in an comparable amount.. C.S.H. J. et al.. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. M.L. J. Eusebi. Hagerty. S. Hammond. Clin. Oncol.F. Oncol.. A.. Dowsett. J. Allred. P. Amendoeira. A. Hanna. Pegram. Bellocq. S...1200/JCO. D... C.09.C.. Langer. Elston. D. Hammond.. 1999. Drijkoningen..L. Miguel.. & Gad. J.6529. A. Hayes.

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age and grading.33 for lobular luminal B. HER2 overexpression. Same is true for PG receptor levels.Predictive Factors – Endocrine Therapy (18/20) Further information: EBCTCG analysis provides ample evidence that hormone receptor status is predictive for endocrine response. In postmenopausal women ATAC trialist report a nonsignificantly better relative benefit of AI vs Tam in thin women vs overweight women (BMI > 35). 0.95 for ductal luminal A.64 for ductal luminal B. According to the ASCO /CAP guidelines the panel recommended endocrine therapy in patients whose breast tumors show at least 1% ER positive cells. whereas little effect can be attributed to tumor size.49 for lobular luminal a and 0.(Dowsett M) Cyp2D6 polymorphism detection is not recommended in daily routine as the metaanalysis done by Goertz is not conclusive. quantitative ER and PR expression as single markers do not identify patients with better outcome after AI.HER2 overexpressing tumors present primarily with more aggressive biology. The HR were 0. 0.49) and a three-fold risk of death for overweight patients (BMI > 25) receiving AI+ Gos in comparison to TAM. HER2-). who compared AI + Goserelin vs Tam in premenopuasal women report a nearly 50% increase in the risk of didease recurrence (HR 1. ABCSG12 trialists. . when compared to TAM. A retrospective analysis from a representative subgroup of more than 2500 patients from BIG 1-98 demonstrated a strong correlation of AI superiority with invasive lobular histology and luminal B like tumors (ER+/PR+/Ki 67 >14. nodal status.

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84 in the intermediate and 1. tumor diameter . intermediate risk and low risk patients. In N0 patients from B-20 the RR was 0. . The prospecitvely randomized chemo N0 trial demonstrated that high levels of upA/PAI-1 are associated to increased CMF chemotherapy benefit. FISH) is highly predictive for anti HER2 therapy. PAM50 has been only evaluated in a neoadjuvant setting as surrogate parameter for pCR and Endopredict data refer to patients treated with endocrine therapy only.18 in the low risk group resulting in a net 10 yrs dfs benefit of 12 % for the high risk group. Most data are derived from trials evaluating chemotherapy + endocrine therapy versus endocrine therapy alone in HR+ patients (Viale IBCSG VIII + IX. In SWOG 8814 evaluating N+ patients the HRs for 5 yr overall survival were 0.56 in the high risk group. For other genomic signatures there are no data.chemotherapy.6) in the low risk group. with an net chemotherapy benefit of 28 % 10 year distant free survival benefit in the high risk group. Albain SWOG 8814 and Paik NSABP B-20) . 58 (p= 0. 0. HR status and grading.Predictive Factors – HER2 Targeted Therapy / Adjuvant Chemotherapy (19/20) Further information: Her2 overexpression (ICH.01) compared to 0. 0. Uniformely the degree with chemotherapy interaction is non significant independently whether evaluated by central DAKO Hercept testing or her2 gene group as part of Oncotype DX. nodal status. Data for Mammaprint (Knauer et al) refer to 541 patients from pooled study series from patiens who received endocrine therapy +/. During SABCS 2012 Baselga presented biomarker analyses evaluating patients with higher benefit from addition of pertuzumab from the CLEOPATRA trial. Neither HER2 or HER3 (mRNA). The last EBCTCG metaanalysis involving over 100 000 chemotherapy patients from 123 randomized trials demonstrated proportional risk reduction little affected by age.21 (p < 0.31 for high risk.26. The evidence for HER2 overexpression is much less well evaluated.61 and 1. nor EGFR (mRNA) were predictive. In the high risk group the univariate HR was 0. In N0-1/HR+ patients the the same has been demonstrated by retrospective analyses from the prospective trials NSABP – B20 and SWOG 8814 for CAF /Tam vs Tam alone .

Identification of low proliferating tumors by central ki-67 evaluation was predictive for taxane outcome in EC-Doc. Endopredict and Oncotype DX did not predict taxane response in the GEICAM trial and in NSABP B28 respecively. Those for Topo normal versus Topo altered were 0. BCIRG 001 and PACS 001. In a subgroup of the patients analysed by Gennari Di Leo published a metaanalysis comparing the impact of Her2 status and TOP2A (FISH). PACS 01.89 and 0.71 respectively. The HR for her2 amplification and non amplification were 0. but these third generation trials do not have endocrine only arms. HER2 overexpression was highly predictive for anthracyline outcome . but not in the GEICAM trial. Response to taxanes has been evaluated in different third generation trials comparing anthracycline based chemotherapy vs taxane/anthracycline based regimens.EC-Doc) demonstrate that luminal A like tumors identified by IHC are likely to have small benefit. TOP2A coamplification.88 vs 0. Retrospective subgroup analyses of patients from large taxane trials (GEICAM.64 respectively. BCIRG 01.Baseline Ki-67 is as Viale et al demonstrated from retrospective analyses of two IBCSG trials no independent predictor of chemotherapy outcome. No references . is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. not HER2 amplification. when compared to CMF.

J.1186/bcr2907...T. Med.A. G. Reuben.V. Engl.. Miller.M. doi:10. A. M. Cristofanilli. R67.. Giuliano.. Hortobagyi... W. Valero. 2004.. de. Clin.F. Matera. Hess. 1420–1430. Ellis. L. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. M. 781–791. Stopeck. disease progression.. J. S.. Circulating tumor cells.. U.T. Alvarez. B. S.J.N.J. A number of trials showed that CTC can be used for treatment monitoring or direct treatment target.2005. M. M. Jackson. W. J... M. N. G. Terstappen. & Terstappen. de.C. K. Laurentiis. Ellis.M.V. 2011. G. 3.M.J.. CTC detection helps to identify patients with increased risk for relapse.. A.1056/NEJMoa040766.. Nevertheless the role of CTC in breast cancer is still currently limited and further development in techniques will be pivotal in enhancing the broad applicability of CTCs and advancing the field of personalized breast cancer therapy. Doyle. de.R.M.F. M. doi:10. Ueno. Reuben. Giordano.. Oncol. Fritsche. A...M. Placido. and survival in metastatic breast cancer. Hortobagyi.. 351. L. D. Budd. Matera.M.140. . Giorgi..H.. N.. Hayes. G. & Cristofanilli. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer.Prognostic factors – Metastatic breast cancer (20/20) Further information The prognostic value of circulating tumor cells (CTC) in primary and metastatic breast cancer is subject of several publications.C. H..M. Budd. D. Allard. doi:10.. J. M. 2. J. V. 2005.W. References: CTC 1. J. 13.08. G.W. 23.J.N. M.. R.C.. Breast Cancer Res. Allard. J..1200/JCO. Doyle. Miller..T. M. M. Stopeck. Cristofanilli. & Hayes. Mego.. Handy. Reuben. G.

Lebofsky R. SABCS 2013. 32 (31): 3483-9 . Stebbing J. Agelaki S. Generali D. Janni W. Solomayer E. Sandri M-T. Krell J. Pooled analysis of circulating tumor cells in metastatic breast cancer: Findings from 1944 individual patients data. Gisbert-Criado R. Nole F. Mavrudis D. Michiels S. Reis-Filho J.4. Peeters D. Raimondi C. Gazzaniga P. Bidard F-C. Politaki E. Johannes H. Garcia-Saenz JA. Manso L. Vidal-Martinez J. Ignatiadis M. Smerage JB et al : Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500 J Clin Oncol 2014 Nov 1. Dirix L. Antelo M-L. Caldas C. Zamarchi R. Meier-Stiegen F. Zorzino L. Almici C. Fehm T. Diaz-Rubio E. 5. Pantel K. Rutten A. Grisanti S. de Mattos-Arruda L. van Laere SJ. Dawson S-J. Pierga J-Y. Bottini A. Caranana V. Consoli F. Munzone E.

Guidelines Breast Version 2015. in der DGGG e.V. Papilloma. Radial Scar) . FEA.V.1 Lesions of Uncertain Malignant Potential (B3) (ADH. sowie in der DKG e.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.V. LIN.

Lesions of Uncertain Malignant Potential (B3) (including “Precursor Lesions”) © AGO e. sowie in der DKG e.de . in der DGGG e.ago-online. Guidelines Breast Version 2015.V.V.V.1  Versions 2005–2014: Albert / Audretsch / Brunnert / Fersis / Friedrich / Gerber / Kreipe / Nitz / Rody / Schreer / Sinn / Thomssen  Version 2015: Kreipe / Thomssen www.

V. S3-Leitlinien . Guidelines Breast Version 2015. in der DGGG e. sowie in der DKG e.V.V.Pathology Reporting for Minimal Invasive Biopsies © AGO e. E.ago-online. metastatic * National Coordinating Group for Breast Screening Pathology (NHSBSP). Working Group on Breast Screening Pathology.1 B – Classification* B1 = unsatisfactory / normal tissue only B2 = benign lesion B3 = lesion of uncertain malignant potential B4 = suspicion of malignancy B5 = malignant www.C.de B5a = non-invasive B5b = invasive B5c = in-situ/invasion not assessable B5d = non epithelial.

complex sclerosing lesion . if incompletely removed • Radial scar.1 www.V.B3-Lesions © AGO e.de  Lesions with risk of associated DCIS or invasive Ca: • Atypical ductal hyperplasia (ADH) • Lobular neoplasia (ALH. LCIS) • Flat epithelial atypia (FEA)  Inhomogenous lesions with sampling risk: • Phyllodes tumor. Guidelines Breast Version 2015. cellular fibroadenoma • Atypical papilloma. in der DGGG e.V.ago-online.V. sowie in der DKG e.

in der DGGG e. sowie in der DKG e.V.Major B3-Lesions and Prospektive Prediktive Value (PPV) for Malignancy in Resection © AGO e.V.1 B3-Lesions:        www.V.ago-online.de Atypical ductal hyperplasia (ADH) Lobular intraepithelial Neoplasia (LN/LIN) Flat epithelial atypia (FEA) Radial Scar Complex sclerosing lesion Papilloma without atypia Cellular fibroepithelial tumors / phyllodes tumors ~PPV 40-50% 0-20% 15% 3% 3% 0% ? . Guidelines Breast Version 2015.

de  yes: proceed according to histologic type 3a C ++  no: open biopsy 3a C ++ . in der DGGG e.1  Interdisciplinary conference: Concordant findings in pathology and imaging? www.V.V.V.ago-online. sowie in der DKG e. Oxford / AGO LoE / GR Guidelines Breast Version 2015.Management after Minimally Invasive Biopsy © AGO e.

. well demarcated cell borders and occupy less than two separate duct spaces. sowie in der DKG e.  Indicator/Precursor lesion: Ipsi.de  Synonyms: Atypical intraductal epithelial proliferation (AIDEP). The extension of all involved lumina within one ductulo-lobular unit is less than 2 mm.ago-online.V. in der DGGG e.3 is not sufficiently validated.V.  Classification in ductal intraepithelial neoplasia grade 1 .Atypical Ductal Hyperplasia (ADH) © AGO e. Guidelines Breast Version 2015.and contralateral breast cancer risk: RR 3 . atypical epithelial proliferation of ductal type  Definition: Atypical intraductal proliferations with cytologic and structural features of well differentiated DCIS.1 www.5 x after 3 . Atypical ductal proliferations larger than 2 mm or in at least two ductules are classified as DCIS (low-grade).V.5 years. such as rigid bridging or micropapillae.

ago-online.Strategy after Diagnosis of ADH © AGO e.1 ADH in core. with: a) A small lesion (≤ 2 TDLU* in vacuum biopsy) and b) Complete removal of imaging abnormality 5a www./ vacuum-assisted biopsy:  Open excisional biopsy 3a  Open excisional biopsy may be omitted.V.V. if incidental finding accompanying invasive or intraductal carcinoma * Terminal ductal-lobular unit 3a . Oxford / AGO LoE / GR Guidelines Breast Version 2015. in der DGGG e.V.de C ++ C + C ++ ADH at margins in resection specimen:  No further surgery. sowie in der DKG e.

25: 2671-2677 .21 RR = 4.V.Risk of Breast Cancer after Atypical Hyperplasie (ADH.67 www.33 RR = 5.de *AC Degnim et al.V. Guidelines Breast Version 2015.1  Number of Foci: 1 2 >3 RR = 2.76 RR = 5.26 RR = 7. Stratification of breast cancer risk* in der DGGG e.V. sowie in der DKG e. ALH) © AGO e.10 RR = 2.67 RR = 7.21  Type ductal lobular both RR = 3.83 RR = 3.10  Age < 45 45 – 55 > 55 RR = 6.97  Microcalcifications: present not present RR = 3. J Clin Oncol 2007.ago-online.

sowie in der DKG e.and contralateral enhanced breast cancer risk: 7 x at 10 years .3 classification is not sufficiently validated prognostically  Pleomorphic LIN and LIN with are classified as → B5a  Indicator/Precursor lesion: Ipsi.ago-online.V. Guidelines Breast Version 2015.1 www. LCIS/CLIS  LIN1 . in der DGGG e.V.V.de  Includes: Atypical lobular hyperplasia. lobular carcinoma in situ.Lobular Intraepithelial Neoplasia (LIN) © AGO e.

Variants of Lobular Neoplasia © AGO e.V.V.V. in der DGGG e.ago-online.1 Classical LIN LIN with comedo type necrosis www.de Florid LIN Pleomorphic LIN . sowie in der DKG e. Guidelines Breast Version 2015.

in der DGGG e. sowie in der DKG e.V. frequent involvement of ductules. Guidelines Breast Version 2015. Am J Surg Pathol 2011 35: 750–6 . extension to ductules and neighbouring TDLU  Type of LCIS with 21 cases of LCIS with microinvasion*: .ago-online.florid LCIS: n=4 .pleomorphic LCIS: n=1 * Ross DS.LIN with High Risk © AGO e.1 www.classical LCIS: n=11 . comedo-type necroses.de  Pleomorphic LCIS: high grade cellular atypia.V. microcalcifications  Florid LCIS: Involvement of numerous lobuli with distension and near confluence.V.

florid LIN. with pleomorphic LIN. florid LIN.de  LIN in core./ vacuum-assisted biopsy:  Open excisional biopsy.V. Guidelines Breast Version 2015. in der DGGG e. or LIN with comedo type necrosis or when not concordant with imaging findings  LIN at margins of resection specimen (BCT):  No further surgery Exceptions: a) Pleomorphic LIN.1 www. or LIN with necrosis b) Imaging abnormality is not removed  Complete resection 2b C ++ 3a C ++ 5 D ++ . sowie in der DKG e.V.Strategy after Diagnosis of LIN © AGO Oxford / AGO LoE / GR e.V.ago-online.

V.de  Synonyms: Columnar cell hyperplasia with atypia. correlation with imaging is mandatory.Flat Epithelial Atypia (FEA) © AGO e.ago-online. . ductal intraepithelial neoplasia grade 1A (DIN 1A)  Differential diagnosis:  ADH is discriminated by architectural features (micropapillary. columnar cell metaplasia with atypia.V.V. sowie in der DKG e. cribriform) → B3  Clinging carcinoma is discriminated by high grade nuclear atypia (G2/G3) and classified as → B5a  Marker lesion: FEA is frequently associated with calcifications and may be associated with intraductal carcinoma. Guidelines Breast Version 2015. in der DGGG e. Therefore.1 www.

V. Guidelines Breast Version 2015.de  FEA in core biopsy/vacuum-assisted biopsy:  Open excisional biopsy 3b  Open excisional biopsy may be omitted.1 www. sowie in der DKG e. unless calcifications have not been completely removed * Terminal ductal-lobular unit 3b C + C + C ++ .Strategy after Diagnosis of FEA © AGO e.V. Oxford / AGO LoE / GR in der DGGG e.V. with: a small lesion (≤ 2 TDLU* in vacuum biopsy) and complete removal of imaging abnormality 5  FEA at margins in resection specimen:  No further surgery.ago-online.

V. in der DGGG e.V.6% to 13% in case of atypical papilloma) . Guidelines Breast Version 2015. increased ipsilateral risk for cancer (4. in case of atypical papilloma up to 20% ). major duct papilloma.Papilloma © AGO e. may be multiple  To be discriminated from intraductal papillary carcinoma and encapsulated papillary carcinoma  Indicator lesion: May be associated with in-situ or invasive cancer (10%. sowie in der DKG e.ago-online. intraductal papilloma. large duct papilloma.V. atypical intraductal papilloma (B3)  To be discriminated from papilloma with DCIS and from peripheral papillomas arising in the TDLU.1 www.de  Includes: central papilloma. size ≤ 2 mm.

ago-online.1 www. when biopsy sufficiently representative (100 mm2) and no discordance to imaging 3a  Papilloma with atypia in core needle or vacuum biopsies:  open biopsy 3a Papilloma at resection margin:  no published data available C ++ C ++ .V.Strategy after Diagnosis of Central Papilloma © AGO e. sowie in der DKG e. in der DGGG e.de  Papilloma without atypia in core needle or vacuum biopsies: → no further therapy. Oxford / AGO LoE / GR Guidelines Breast Version 2015.V.V.

Guidelines Breast Version 2015. in der DGGG e.complex sclerosing lesion (> 1 cm)  Additional risk factor in patients with benign epithelial hyperplasia (proliferating breast disease)  Risk for upgrade in open biopsy after diagnosis of radial-sclerosing lesion in core biopsy: 8.ago-online.V. Breast.V.3% (79/948)* * Bianchi S et al. .de  Benign pseudoinfiltrative lesion with central fibroelastic core and radical configuration.  Includes: .Radially Sclerosing Lesion © AGO e. sowie in der DKG e. (2012) 21: 159–64.radial scar .V.1 www.

with a small lesion and complete removal of imaging abnormality  Radial scar / CSL at margins in resection specimen:  No further surgery 3b C + 5a C + 3b C ++ . Guidelines Breast Version 2015.de  Radial scar / CSL in core biopsy/ vacuum-assisted biopsy:  Open excisional biopsy  Open excisional biopsy may be omitted. Oxford / AGO LoE / GR in der DGGG e.Strategy after Diagnosis of Radial Scar. Complex Sclerosing Lesion (CSL) © AGO e.1 www.V. sowie in der DKG e.ago-online.V.V.

1 FEA. Guidelines Breast Version 2015.V.V.V. non-atypical Papilloma  Screening mammography LIN  Mammography (12 months) ADH  Mammography (12 months) 5 C ++ 3a C ++ 3a C ++ 3a C ++ www. sowie in der DKG e.ago-online. Oxford / AGO LoE / GR in der DGGG e.de  Women with LIN and ADH should be informed about their elevated risk of breast cancer .Follow-up Imaging for Women Age 50-69 Years with B3-Lesions © AGO e.

the net benefit strongly depends on risk status. sowie in der DKG e.V.Medical Prevention for Women at Increased Risk (including Women with LIN and ADH) © AGO Oxford / AGO LoE / GR e.V.66% in 5 years) .1    www.ago-online. age and preexisting risk factors for side effects. Guidelines Breast Version 2015.de Tamoxifen for women >35 years – Risk reduction of invasive BrCa and DCIS 1a A + Raloxifen for postmenopausal women Risk reduction of invasive BrCa only 1b A +/-* Aromatase inhibitors (Exemestan. *Risk situation as defined in NSABP P1-trial (1. in der DGGG e. Anastrozole) for postmenopausal women 1b A +/- Medical prevention should only be offered after individual and comprehensive counseling.V.

83 > 3 relatives 1.93 11.28-0.27 3.V.52 0.69 2.28 0.48 1.48 0.24 2.91 3.66%): •LIN.49 0. in der DGGG e.51-0.46-0.97 2. grade Fraktures Endometriumcancer 11.grade 6.67 0.64 0.58 0.68 5.02 0.34 0.27-1.77 11.78 0. Guidelines Breast Version 2015.1 Placebo Rate / 1000 WE Tamoxifen Rate / 1000 WE RR 95% CI All women ± LCIS + LIN w/o ADH + ADH 5-year risk <2% 5 year risk > 5% Relative 1.87 10. update 2005 © AGO e.18 5.ago-online.70 0. ADH • Family history of breast cancer Should not be offered to women: • With moderate risk > 50year of age Lebensjahr •With enhanced risk for thrombembolism .10-0.V.de Should only be offered to women with enhanced breast cancer risk (Gail 1.70 5.50-0.63 0.46-0.25 0.42 4.24 0.16-1.54 0.41 6.15 3.92 1.98 6.87-6.V.55 3.43 0.34-0.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen) NSABP-P1 Study.88 0.59 3.43-1.72 0.29 5.01 0. sowie in der DKG e.54 0.03 5 www.47 3.57 0.

27-2. .72 1.87-0.70-0.84 0. Visvanathan K et al. sowie in der DKG e.58-0.99 1.21-2.27:3235-3258.74 1.94 1.82 15 12 14 9 68 81 73 115 0.10 25 64 39 16 0.93 1.77 0.ago-online.58-0.1 www. NNT/NNH** = number needed to treat or number needed to harm: shown are statistically signifikant associations for a follow-up-period of 96 month. in der DGGG e.V.73 0.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen.84 58 17 5 AR*:Absolute risik per 1000 women.de Incidence RR 95% CI AR je 1000* NNT / NNH** Breast cancer Invasive carcinoma Thrombembolism Deep vein thrombosis leg Headache Gynekological-/ vasomotoric symptoms Chest pain 0.91 0. JCO 2009.36 1. Side Effects) © AGO Risks and Benefits with long-term Tamoxifen use compared with placebo: results from the IBIS-I Trial 96 months median follow-up (Cuzick J et al J Natl Cancer Inst 2007:272-282) e.V.V. Guidelines Breast Version 2015.08 0.06-1.

de Tamoxifen : Rate / 1000 WE 4.02 1. STAR trial 2006 e.81-1.98 0.1 All women ± LIN + LIN ± ADH + ADH www.81 RR 95% CI 1.76-1.58-1.63 0.66%) or postmeopausal Should not be offered to women: • With moderate risk > 50year of age • With enhanced risk for thrombembolism .28 0.89 9. in der DGGG e.82-1.03 0.61 4.72-1.ago-online.74 Should only be offered to women with enhanced breast cancer risk : (Gail 1.99 1.28 0.83 4.V.12 0.30 3.06 5.41 3. sowie in der DKG e.V. Guidelines Breast Version 2015.21 Raloxifen Rate / 1000 WE 4.33 0.03 5.76 9.Medical Prevention after Diagnosis of B3 Lesion (Raloxifen) © AGO NSABP-P2 Study.V.

31 (0.3: www.364(25):2381-91 . N Engl J Med.V.11–0.7%)  Yes (7y-BC-risk 12. Placebo: 190 (9.1%).Prevention for Lesions with Uncertain Biological Behaviour (Aromatase Inhibitors) © AGO e. LCIS (HR AI vs Plac):  IBIS.1 Inclusion criteria: Results for prior ALH.V. 2011 Jun 23. sowie in der DKG e.ago-online. Lancet 2014.3%)  Yes: HR=0. or LCIS: Exemestane: 185 (8.78)  MAP. ALH.31–0.20–1. 383: 1041–48 Goss PE et al. in der DGGG e.26 (0.64) Cuzick J et al.de  Prior ADH.12–0.52 (0. ALH. or LCIS Anastrozole:154 (8.V. ADH.0%).1%): HR 0.61 (0.9%): HR 0.84)  No (7y-BC-risk 4.82)  No HR=0.2:  Prior ADH. Placebo: 188 (8. Guidelines Breast Version 2015.

Lesions of Uncertain Malignant Potential (B3) (2/25) Further information and references: Pubmed 2010-2015 (plus earlier publications if relevant): Pubmed Search Strategies: Lobular neoplasia (135 Results): (Breast Diseases/CL[mh] OR Breast Diseases/DI[mh] OR Breast Diseases/EP[mh] OR Breast Diseases/GE[mh] OR Breast Diseases/MO[mh] OR Breast Diseases/PA[mh] OR Breast Diseases/RA[mh] OR Breast Diseases/RT[mh] OR Breast Diseases/SU[mh] OR Breast Diseases/TH[mh] OR Breast Diseases/US[mh]) AND ("2005/01/01"[dp] : "2014/01/01"[dp]) AND ("lobular neoplasia"[ti] OR "lobular intraepithelial neoplasia"[ti] OR "atypical lobular hyperplasia"[ti] OR "lobular carcinoma in situ"[ti] OR "LIN"[ti] OR "ALH"[ti] OR "LCIS"[ti]) AND ("english"[la] OR "german"[la]) Atypical ductal hyperplasia (65 Results): (Breast Diseases/CL[mh] OR Breast Diseases/DI[mh] OR Breast Diseases/EP[mh] OR Breast Diseases/GE[mh] OR Breast Diseases/MO[mh] OR Breast Diseases/PA[mh] OR Breast Diseases/RA[mh] OR Breast Diseases/RT[mh] OR Breast Diseases/SU[mh] OR Breast Diseases/TH[mh] OR Breast Diseases/US[mh]) AND ("2005/01/01"[dp] : "2014/01/01"[dp]) AND ("atypical ductal hyperplasia"[ti] OR "atypical hyperplasia"[ti] OR "ADH"[ti]) AND ("english"[la] OR "german"[la]) Flat epithelial atypia (79 Results): (Breast Diseases/CL[mh] OR Breast Diseases/DI[mh] OR Breast Diseases/EP[mh] OR Breast Diseases/GE[mh] OR Breast Diseases/MO[mh] OR Breast Diseases/PA[mh] OR Breast Diseases/RA[mh] OR Breast Diseases/RT[mh] OR Breast Diseases/SU[mh] OR Breast Diseases/TH[mh] OR Breast Diseases/US[mh]) AND ("2005/01/01"[dp] : "2014/01/01"[dp]) AND ("flat epithelial atypia"[ti] OR "columnar cell"[ti] OR "FEA"[ti]) AND ("english"[la] OR "german"[la]) .

2013 NZ: HTA risk assesment 2007 CMJA: no update NICE: no update SIGN: no update Cochrane: Decision aids for risk communication update 2009 DARE: no relevant references.Papilloma (227 Results): (Breast Diseases/CL[mh] OR Breast Diseases/DI[mh] OR Breast Diseases/EP[mh] OR Breast Diseases/GE[mh] OR Breast Diseases/MO[mh] OR Breast Diseases/PA[mh] OR Breast Diseases/RA[mh] OR Breast Diseases/RT[mh] OR Breast Diseases/SU[mh] OR Breast Diseases/TH[mh] OR Breast Diseases/US[mh]) AND ("2005/01/01"[dp] : "2014/01/01"[dp]) AND ("papilloma"[ti] OR "papillary"[ti]) AND ("english"[la] OR "german"[la]) NOT virus[Title] Radial scar (17 Results): (Breast Diseases/CL[mh] OR Breast Diseases/DI[mh] OR Breast Diseases/EP[mh] OR Breast Diseases/GE[mh] OR Breast Diseases/MO[mh] OR Breast Diseases/PA[mh] OR Breast Diseases/RA[mh] OR Breast Diseases/RT[mh] OR Breast Diseases/SU[mh] OR Breast Diseases/TH[mh] OR Breast Diseases/US[mh]) AND ("2005/01/01"[dp] : "2014/01/01"[dp]) AND ("radial scar"[ti] OR "complex sclerosing lesion"[ti] OR "radial sclerosing lesion"[ti]) AND ("english"[la] OR "german"[la]) Screened Guidelines: Interdisziplinäre S3-Leitlinie für die Diagnostik.2014 NCCN Breast Cancer Risk Reduction I 2013 NCCN Breast Cancer Screening and Diagnosis 2. 2010 ASCO 2012: done National Institute of health (NIH): done San Antonio Breast Cancer Conference (SABCC 2013): done .I. Aktualisierung 2012 NCCN Breast cancer V. Therapie und Nachsorge des Mammakarzinoms.

Interdisziplinäre S3-Leitlinie für die Diagnostik. (Hrsg).(4):1-35. Langversion 3. und Deutschen Krebshilfe e. 1 ed.V. 2008 update of the guideline early detection of breast cancer in Germany. Stacey D et al. Christchurch: New Zealand Health Technology Assessment (NZHTA). 135:339-354 Albert US. Breast cancer risk reduction V. 2013. Pathologe. raloxifen and aromatase inhibition for breast cancer risk reduction. Altland H. NCCN. Hurley P et al. National Comprehensive Cancer Network.). Duda V et al. Bennett C. Breast cancer screening and diagnosis V. 2013. 2014 ed.I. 2007.2. Muenchen: Zuckschwerdt Verlag. Chlebowski R.0. American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. Ali W.Aktualisierung 2008.2013. National Comprehensive Cancer Network. Mammakarzinom: aktuelle Empfehlungen fur Pathologen auf Basis der S3-Leitlinie.34(4):293-302 Visvanathan K. Schlake W. The Cochrane Library 2009.I. 27:3235-3258 Weir R. 2014.V. Risk factors for breast cancer in women:a systematic review of the literature.2013. National Comprehensive Cancer Network. . USA: NCCN. Leitlinienprogramm Onkologie der AWMF. Kreipe H. 2008. Day P. O'Connor A. Breast cancer V. JCO 2009. Aktualisierung 2012 AWMF-Register-Nummer: 032 – 045OL Lebeau A. Kreienberg R. J Cancer Res Clin Oncol 2009. NCCN. (Hrsg. USA: NCCN. NCCN. 2013 ed. Dietel M. Deutschen Krebsgesellschaft e. Decision aids for people facing health treatment or screening decisions (Review). Therapie und Nachsorge des Mammakarzinoms.2014. 2013 ed.National and international guidelines Albert US. USA: NCCN. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 1. 2013.

and E.7:100. Holzhausen HJ. de Wolf C. References: 1. Koch von F. Broeders M. World Health Organization. Kluttig A. BMC Cancer. Guidelines Working Group of the National Coordinating Committee for Breast Pathology. In: European guidelines for quality assurance in breast cancer screening and diagnosis. Heinig A. Sheffield: NHS Screening Programmes and The Royal College of Pathologists. Tan PH. Trocchi P. editors. Reliability and validity of needle biopsy evaluation of breast-abnormalities using the B-categorization--design and objectives of the Diagnosis Optimisation Study (DIOS). World Health Organization: WHO Classification of Tumours of the Breast. Holland R. Hauptmann S. Boecker W. Luxembourg: Office for Official Publications of the European Communities. Perry N. Pathology reporting of breast disease. SchmidtPokrzywniak A. Buchmann J. 2012. 2007 Jun 14. editors. . 2. Loening T. Törnberg S. Decker T. Working Group on breast screening pathology encompasses the heterogeneous B3 category. Lakhani SR. Stang A. 2006: 221-256 NHSBSP. Lantzsch T. Ellis IO. Wells C: Quality assurance guidelines for pathology: Cytological and histological non-operative procedures. Schnitt SJ. Taege C.Pathology Reporting for Minimal Invasive Biopsies (3/25) Further information: The histologic B-classification of breast core biopsies as based on recommendations of the National Coordinating Group for Breast Screening Pathology (NHSBSP). C. 4. 2005. 3. Thomssen C.

et al. ALH. Sgroi DC. flat epithelial atypia (FEA). atypical papillary proliferations. References: 1. careful attention must be paid to the pathologic-radiologic correlation for the guidance of the clinical management. Breast. but also as precursor lesions. such as phyllodes tumor.15(10):459–69. and LN are characterized by a homogeneity of cell type and marker expression. Hayes BD. editors. Dinarès C. J Pathol.3% discordance for B5 lesions [5]. 3. The recognition of atypical epithelial proliferation is based on the distinction of hyperplastic from neoplastic lesions. Bombonati A. cellular fibroadenoma. B3 lesions are associated with a high rate of 6-16% discordance among first and second pathology compared to 0. With all types of precursor lesions. Diagnostic Histopathology.B3-Lesions (4/25) Further information: Lesions of uncertain malignant potential include atypical ductal hyperplasia (ADH). and radial scars. As a general rule. and are part of the low-grade pathway of breast cancers [1-4]. Andreu FJ. 2009 Oct 1. Sáez A. 2007 Jan 31. Pathology of B3 lesions ofthe breast. Ladanyi M. and lesions with sampling risk because of inhomogeneity. Breast core biopsy reporting categories. while ADH.16(1):94–101. 2. lobular neoplasia (LN). Sentís M. 2010 Nov 16. The molecular pathology of breast cancer progression. that is on the identification of a clonal process. FEA. . The lesions with atypical proliferations (ADH.223(2):308–18. The accurate pathological identification and classification of lesions with atypical proliferations is important to assess the individual risk of the patient. Quinn CM. LCIS.5-1. Hogendoorn PC. Fernández S. Rey M. An internal validation in a series of 3054 consecutive lesions. usual type epithelial hyperplasia is morphologically and phenotypically heterogeneous. FEA) are regarded both as an indicator of increased risk. Elsevier Ltd. and to decide if the lesion should be excised.

2007 Apr 22. Houssami N. Pathologe. Stang A. Ergebnisse der Referenzpathologie im MammographieScreening. Trocchi P. Ciatto S. Bilous M. Vezzosi V. . Kreipe H-H. 2008 Oct 9.29(S2):178–80. Buchmann J. Schmidt D. Boecker W. Loening T.7:100. Lebeau A. 6. Taege C. Reliability and validity of needle biopsy evaluation of breast-abnormalities using the B-categorization--design and objectives of the Diagnosis Optimisation Study (DIOS). Thomssen C. Heinig A.4. 5. BMC Cancer.96(8):1253–7. Br J Cancer. Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). Decker T. Kluttig A. Lantzsch T. Höfler H. Bianchi S. Pickartz H. SchmidtPokrzywniak A. 2007 Jun 14. Hauptmann S. Holzhausen HJ.

Besides these diagnoses papillomas. In older studies approximately one-third of CNB results classified as B3 were malignant on excision. with central pathology).3% disconcordance for B5 lesions (Kreipe HH et al 2008). Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation.51. which only rarely shows upgrade to higher lesions in resection when carful correlation between imaging and histology of CNB has been performed.269(2):340-7. Nicholson B. and lobular intraepithelial neoplasia (LN/LIN) are grouped together as lesions of uncertain biological behaviour. Whereas cases may be selectively managed without surgery. 2013 Nov. flat epithelial atypia (FEA). radial scar and phyllodes-tumour belong to the B3 group. . the majority warrant excision biopsy (Rakha 2010.Major B3-Lesions and Prospektive Prediktive Value (PPV) for Malignancy in Resection (5/25) Further information: In this category atypical intraductal hyperplasia (ADH). But B3 lesions are associated with a high rate of 6-16% disconcordance among first and second pathology compared to 0. References: 1. Houssami 2010). No clinical and radiologic findings and/or comprehensive evaluation of multiple histologic parameters on CNB specimen are distinctive enough to predict final classification of equivocal cellular fibroepithelial lesions. In recent years publications demonstrated a decline in PPV except for ADH. Atkins KA. Cohen MA. Also papilloma without atypia usually shows no upgrade in resection. but the likelihood of malignancy varied substantially between specific lesion groups. Rao S. Radiology. This is partiularly obvious for LIN. With regard to FEA different frequencies of upgrade to higher lesions are published. B3 lesions are diagnosed with less than 10% in mammography screening (6000 core biopsies.

Roder DM. Calhoun BC. Cattani MG. 11. 2013 Sep. Webster F. Doualliez V. Chaveron C. Loreto CD. 3.137(7):927-35. Antonacci CM. Hayes MM. J Clin Pathol 2009. Schnitt SJ.200(3):682-8. Bendinelli B. 6. Histopathology. Rocourt N. Flippo T. Dante S.2. [Epub ahead of print] Ceugnart L. Chiu YL. Degnim AC. Robin YM. Annals of Surgical Oncology 2007. Palli D. Carrillo G. Chauvet MP. Pouliquen G. Bianchi S. 2014 Nov-Dec. Hayes B et al: Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience. Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated? AJR Am J Roentgenol. 12. D'Alfonso TM. Wilson CM. Dialani V. Buckley ES. Harrison DA. 8. 2015 Jan 1. Gordon PB. Morphological parameters of lobular in situ neoplasia in stereotactic 11-gauge vacuum-assisted needle core biopsy do not predict the presence of malignancy on subsequent surgical excision. Atypical hyperplasia of the breast--risk assessment and management options. White RL. Livasy CA.2014. Jarraya H. Venkataraman S. N Engl J Med. Does isolated flat epithelial atypia on vacuum-assisted breast core biopsy require surgical excision? Breast J. van Niekerk D.do we have the answer yet? Eur J Surg Oncol. Laurino L. Br J Cancer 2007. 14(2):704-711 Hartmann LC. Taieb S. 2013 Mar.94(9):861-9. Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. doi: 10. 10. Dupont WD. Shin SJ.372(1):78-89. Mehta TS. Ghosh K. Wang K. Stefano DD. Santen RJ. Frieling G. 2013 Jul.159. Bersiga A.40(2):168-75. Sobel A. Hassell PR.63(1):83-95. 2014 Nov 21. Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies.1038/modpathol. Piubello Q. Pure flat epithelial atypia: is there a place for routine surgery? Diagn Interv Imaging. Becker AK. 62:1136-1140. Hiller JE. Renne G. 9. Pathologic upgrade rates on subsequent excision when lobular carcinoma in situ is the primary diagnosis in the needle core biopsy with special attention to the radiographic target.20(6):606-14. 4. Quero C. Farshid G. Mod Pathol. 2014 Feb. Castellano I. Bachelle F. 7. A systematic review of surgical biopsy for LCIS found at core needle biopsy . Gromet M. Giardina C. 5. 96:1253-1257 . 2013 Jul. Houssami N et al: Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). VANCB Study Group. Arch Pathol Lab Med. Sarantou T.

Mayo Clin Proc.23(5):651-5. Lee MC. Jorns J. Joh JE. [Epub ahead of print] Resetkova E et al: Clinical and radiologic data and core needle biopsy findings should dictate management of cellular fibroepithelial tumors of the breast. Tsugawa K. [Epub ahead of print] Menes TS. 17.23(3):487-503. 2014 Jan. Prowler VL. Diagnosis and management of benign. Pang JC.23(4):352-6. 2010 Nov. Sandhu NP. Jaffer S. Hayami R. Garewal S. Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast. Miglioretti DL. Dilaveri CA. Dempsey P. Breast Cancer. Surg Oncol Clin N Am. doi: 10. Surgical excision of pure flat epithelial atypia identified on core needle breast biopsy. Acs G. Positive predictive value for malignancy of pure flat epithelial atypia diagnosis by percutaneous needle biopsy of the breast: management of FEA in ultrasonography. Tozaki M. Cancer Med. Ghosh K. Reis-Filho JS.06. Oana Y. Koizumi H. 14. 2014 Jun. Glazebrook KN. Middleton LP. and indeterminate breast lesions detected on core needle biopsy. Yabuki Y.016.3(3):492-9 Neal L.13. 2014 Oct.138(10):1344-9. 18. 2014 Jul. Int J Cancer. Bevers TB. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium.89(4):536-47 Parkin CK. Breast. 24. J Clin Pathol. Visscher DW. 29(Suppl):178-180 Maeda I. Kreipe H et al: Ergebnisse der Referenzpathologie im Mammographie-Screening. Kojima Y. 20. 22. Arch Pathol Lab Med. Sneige N. Lobular neoplasia. Hieken TJ. Outcomes of patients with lobular in situ neoplasia of the breast: the role of vacuum-assisted biopsy. 25.16(6):573-80 . 2014 Apr. 19. Laronga C. Der Pathologe 2008. Kerlikowske K.2014. Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting. 2010 Dec 2. Mac Bride MB. 2014 Aug.1016/j. 2010 Nov-Dec. King TA. 2014 Apr 24. Dong W. Coyne R. Rakha EA et al: Characterisation and outcome of breast needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening.breast. Nishikawa T.207(1):24-31. 21. Wahner-Roedler DL. Breast J. Waugh P. Lobular neoplasia: morphology and management. 16. Khakpour N. Takagi M. Kiluk JV.63(11):987-93. 2014 Oct. atypical. Maxwell AJ. Am J Surg. Shimo A. 15. Rosenberg R. Kanemaki Y. 23. Shen Y. Kawamoto H. Okanami Y. Sabel MS. Breast. Tsuchiya K. Balch S.

Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision? Ann Surg Oncol.26. Rageth CJ. Huynh KT. Ann Surg Oncol. 27.20(4):394-401. Wyss P. Chung A. Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia. 28. 2010 Sep 28. Rössle M. Sim MS. .20(13):4137-44 Weir R et al: Risk factors for breast cancer in women:a systematic review of the literature. 29. 2013 Dec. Shamonki J. Papillary lesions of the breast: outcomes of 156 patients managed without excisional biopsy. Breast J. 2014 Jul-Aug. Christchurch: New Zealand Health Technology Assessment (NZHTA). Giuliano A. Varga Z. Kinnaird M. 2007.

95). Holland A. 0.84 (95% CI.8-5233. Algorithm for quality assurance of minimal invasive guided biopsies. .4). 0. Dershew D. Risso G: Accuracy and underestimation of malignancy of breast core needle biopsy: the florence experience of over 4000 consecutive biopsies. Breast 2006.997-0. Houssami N. Morris E. Brem RF. VAB is a highly sensitive and specific biopsy method for evaluating mammographically detected breast in women. Ambrogetti D.Management after Minimally Invasive Biopsy (6/25) Further information: What kind of treatment has to follow when a B3 diagnosis has been rendered should be individually determined in an interdisciplinary discussion of the imaging findings and the patholgy results.177-0. AJR 1999. Experience of 47 cases diagnosed at vaccumassisted biopsy. diagnostic accuracy of VAB were evaluated. 93. Sanow L. The summary estimates for VAB in diagnosis of breast carcinoma were as follows: sensitivity. Bertelle L. 0. Bianchi S. Wynn R: Underestimation of atypical ductal hyperplasia at MRI-guided 9-Gauge vacuum-assisted breast biopsy. Gatewood OM: Atypical ductal hyperplasia: histologic underestimation of carcinoma in tissue harvested from impalpable breast lesions using 11-gauge stereotactically guided directional vacuum-assisted biopsy. Breast Cancer res Treat 2007. 0. 0. negative likelihood ratio.55-211. 172:1405-1407 Ciatto S.987).245) and 11.128).7 (95% CI. Brancato B.03-0.999 (95% CI.05 (95% CI. specificity. 1891. Marjan D. 41. 4. 0. 0. Catarzi S. underestimate rate of ADH and DCIS were 20. positive likelihood ratio (PLR). 3.972-0. Murray M. References: 1. diagnostic odds ratio. After a review and quality assessment of 21 studies. 188:684-690. AJR 2007.981 (95% confidence interval [CI]. Sanna P: Atypical ductal hyperplasia of the breast: the controversional management of a borderline lesion.999). respectively. Behrndt VS. 101:291-307 Bedei L.2% (95% CI. Liberman L. 2.9% (95% CI. Falcini F. 15:196-202. 683.098-0.09). Bonari R. 0.

Atypical ductal hyperplasia at margin of breast biopsy Is Re-excision indicated? Ann Surg Oncol 2007. Rao S. 2015 Jan 1. Radiology. atypical. Cancer Med. Cohen MA. Breast Cancer Res and Treat 2008.89(4):536-47 Hartmann LC.269(2):340-7. Nonni A. 15(3):843-847 Neal L. Jaffer S. Atkins KA. Visscher DW. Dong W. Sergentanis T. Shen Y. Ghosh K. Arora S. Sandhu NP. 10. 2014 Apr. Bevers TB. Menes T. 7. Dupont WD. Atypical hyperplasia of the breast--risk assessment and management options.3(3):492-9 . Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation. Dempsey P. 2014 Jun.5. Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting.372(1):78-89. Foliadis C. Hieken TJ. Coyne R. Zagouri F. Ghosh K. Bleiweiss I. Sneige N. Zagrafos G. Degnim AC. Bramis J: Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: ablind study. 2013 Nov. Nicholson B. 109:397-402. Koulocheri D. 6. Mac Bride MB. N Engl J Med. Glazebrook KN. Panopoulou E. Middleton LP. Mayo Clin Proc. Wahner-Roedler DL. Santen RJ. Diagnosis and management of benign. Moung C. 9. and indeterminate breast lesions detected on core needle biopsy. Nagi C. Dilaveri CA. Folou M. Paranas N. 8.

35 (95%CI 6. Stratification of breast cancer risk in women with atypia: A Mayo Cohort Study.00-4.J Clin Pathol. doi: 10. According to the data of the Breast Cancer Surveillance Consortium (USA) rates of ADH decreased from 5. 2006. Less than 45 years at diagnosis of ADH RR 6.78 (95%CI 3.1007/s00292-008-1101-4. 2009 Feb.Atypical Ductal Hyperplasia (ADH) (7/25) Further information: ADH and breast cancer are asoziated with postmenopausal hormone treatment. Atypical ductal hyperplasia and atypical epithelial proliferation of ductal type]. Hungermann D. 4. Pathologe.59:138-45. JCO 2007.18:2822-2828 Degnim A:. Menes T: Rates of atypical ductal hyperplasia have declined with less use of postmenopausal hormone treatment: Findings from the Breast Cancer Surveillance Consortium. Böcker W. 2.4). Weigel S.30(1):42-8.13-16.24-12.4). three lesions RR10.88 (95%CI 3. 3. Cancer Epidemiol Biomarkers Prev 2009. .5/10000 mammograms 1999 to 2.94). 25(19):2671-2677 Ellis IO: Impact of a national external quality assessment scheme for breast pathology in the UK. Decker T. Roterberg K.4/10000 mammograms in 2005 Statement: indicator-/ precursor-lesion: Women have an enhanced breast cancer risk after ADH: one lesion RR 3. References: 1.

14(2):704-711 Hartmann LC. 2. Radiological calcification with supicious or malignant characteristics and histological B3 with evidence of epithelial atypia has the highest positive predictive value (50%) (Rhaka et al. 3. Nicholson B. Degnim AC.0006). presence of significant cytologic atypia suspicious for intermediate or high-grade carcinoma (P < . An open excisional is recommended with exception of very small lesions (≤ 2 TDLU) and minimal atypia and complete removed imaging abnormality. Therefore. Radiology. and with complete removal of the targeted calcifications. 2015 Jan 1.372(1):78-89. Cohen MA. Allison KH 2010). >2) involved (P = . Santen RJ. Atkins KA.0001). Atypical hyperplasia of the breast--risk assessment and management options. ADH in core. . N Engl J Med. Rao S. 2013 Nov.Strategy after Diagnosis of ADH (8/25) Further information: Significant histologic predictors of upgrade from ADH to carcinoma included number of terminal duct-lobular units (TDLU. and necrosis (P = . Even in the case of complete removal of microcalcifications there is a risk of 5 % of underestimation of malignancy (Penco 2010).0306). 2010). regardless of extent of involvement. Dupont WD. is associated with a minimal risk (<3%) of carcinoma and may undergo mammographic follow-up only (Nguyen CV 2010./ vacuum-assisted biopsy (LoE 3a) ADH at margins in resection specimen (LoE 3a) References: 1. Annals of Surgical Oncology 2007. ADH without these features. Ghosh K. Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation.269(2):340-7. ADH lesions with significant cytologic atypia and/or necrosis are most likely to be associated with carcinoma and should be excised.

Kerlikowske K. Br J Cancer 2007. Wahner-Roedler DL. Glazebrook KN. 2010 Sep 28. Balch S.4. 6. and indeterminate breast lesions detected on core needle biopsy. Ghosh K. Mayo Clin Proc. 8. Miglioretti DL.89(4):536-47 Rakha EA et al: Characterisation and outcome of breast needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening. atypical. 7. Ann Surg Oncol.207(1):24-31. 96:1253-1257 Menes TS. Hayes B et al: Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience. [Epub ahead of print] Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia. Int J Cancer. Mac Bride MB. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium. Am J Surg. Dilaveri CA. 2014 Apr. Visscher DW. 2010 Dec 2. 9. Sandhu NP. 2014 Jan. 5. Houssami N et al: Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). Jaffer S. Hieken TJ. 62:1136-1140. J Clin Pathol 2009. . Diagnosis and management of benign. Neal L. Rosenberg R.

Degnim A. Visscher W. JCO 2007. Stratification of breast cancer risk in women with atypia: A Mayo Cohort Study.Risk of Breast Cancer after Atypical Hyperplasie (ADH. ALH) (9/25) No further information References: 1. Berman H et al. 25(19):2671-2677 .

atypical lobular hyperplasia. After diagnosis of LIN on core neeedle. The distinction of pLCIS from classical LN relies on nuclear characteristics with pLCIS having larger. lobular carcinoma in situ. more pleomorphic nuclei with obvious nucleoli. and may show apocrine differentiation. or on vacuum-assisted biopy. necrosis and microcalcifications. References: 1. Lobular Intraepithelial Neoplasia (LIN. For a long time. LN was considered to be just as a risk indicator and not a precursor lesion for the subsequent development of carcinoma. Arch Pathol Lab Med 2009. 2) In cases of pleomorphic LCIS attention must be paid to the margin status like in low-grade DCIS. because of pathological and molecular studies.Lobular Intraepithelial Neoplasia (LIN) (10/25) Further information: Lobular neoplasia (LN) or lobular intraepithelial neoplasia (LIN) are the preferred terms for early neoplasia with lobular phenotype and include atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). to make sure that florid or pleomorphic LN has be completely excised. 133(7):1116-1120 . it is now believed that lobular neoplasia indeed is a non-obligatory precursor of invasive carcinoma. florid LCIS and pleomorphic LCIS were shown to be behave more aggressively compared to classical lobular neoplasia. Contreras A: Lobular Neoplasia of the breast: An update. More recently. and at the same time a risk lesion for ipsi. Specifically. 3) The metric extent of LN should be determined approximately by the pathologist since extensive LN may be associated with a higher risk and to help correlate the findings with the radiologic findings.and contralateral disease. The management of lobular neoplasia in excisional biopsies by the pathologist requires attention to the following points: 1) He should be aware of the risk of occult microinvasion and pay attention to the careful workup of the specimen. LIN is categorized as B3 as long the criteria for pleomorphic LIN and LIN with necrosis are not fulfilled which qualify for B5a. the average upgrade rate is about 15%. Several different morphologic variants of lobular neoplasia have been described to more precisely evaluate the individual risk. LCIS/CLIS) provides an incidental finding and is not suited to explain any radiographic abnormality.

4. Epidemiology. Chuba PJ: Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance. 39:208-216. 42:2205-2211 Arpino G:: Lobular neoplasia on core-needle biopsy: clinical significance. and End Results Data. Pinder S: Lobular in situ neoplasia and columnar cell lesions:diagnosis in breast core biopsies and implications for management.2. 23:5534-5541 . Lakhani I: The management of lobular carcinoma in situ (LCIS). 101:242-250 Statement: Indicator-/ precusor lesion 1. Cancer 2004. 3. Journal of Clinical Oncology 2005. Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur J Cancer 2006. Pathology 2007.

References: 1. Carter G.440(2):134-138. The distinction of pLCIS from classical LN relies on nuclear characteristics with pLCIS having larger. based on the extent of lobular cancerization (2). Hum Pathol. Pleomorphic lobular carcinoma in situ (PLCIS) on breast core needle biopsies: clinical significance and immunoprofile. Brufsky A. pleomorphic lobular carcinoma in situ (pLCIS) was shown to be behave more aggressively compared to classical lobular neoplasia (1).Variants of Lobular Neoplasia (11/25) Further information: Several different morphologic variants of lobular neoplasia have been described to more precisely evaluate the individual risk. Also. molecular profiling studies have shown that pLCIS is similar to classical LN. supporting its role as a special form of lobular neoplasia. Roy R. necrosis and microcalcifications. Lal A. Bratthauer GL. 2002. In this respect pLCIS mimics ductal carcinoma in situ (DCIS). Shin SJ. Lobular intraepithelial neoplasia: previously unexplored aspects assessed in 775 cases and their clinical implications. 2008. 2. . Haynik DM. Virchows Arch. Hwang ES. a classification of lobular neoplasia into three different grades of severity has been proposed. As another approach for risk assessment. The most severe grade (LIN 3) is called florid lobular carcinoma in situ nowadays (3). Schnitt SJ. 2013. Tavassoli FA. but characteristically it is associated with classical LN and not with DCIS. more pleomorphic nuclei with obvious nucleoli. Chen YY. Suzuki J. Florid lobular carcinoma in situ: molecular profiling and comparison to classic lobular carcinoma in situ and pleomorphic lobular carcinoma in situ.44(10):1998-2009. and may show apocrine differentiation. Chivukula M. De Vries S. 3.32(11):1721-1726. Am J Surg Pathol. Specifically. Waldman FM. Dabbs DJ.

pleomorphic lobular carcinoma in situ (pLCIS) was shown to be behave more aggressively compared to classical lobular neoplasia [1]. Bratthauer GL. In this respect pLCIS mimics ductal carcinoma in situ (DCIS). Ross DS. The most severe grade (LIN 3) is called florid lobular carcinoma in situ nowadays [3]. 4. As another approach for risk assessment. Haynik DM. 2011 May. Waldman FM. Hoda SA. Hum Pathol.440(2):134-138. Specifically. 2008. Brufsky A. supporting its role as a special form of lobular neoplasia. necrosis and microcalcifications. Chen YY. Pleomorphic lobular carcinoma in situ (PLCIS) on breast core needle biopsies: clinical significance and immunoprofile. Chivukula M. molecular profiling studies have shown that pLCIS is similar to classical LN. Lobular intraepithelial neoplasia: previously unexplored aspects assessed in 775 cases and their clinical implications. Florid lobular carcinoma in situ: molecular profiling and comparison to classic lobular carcinoma in situ and pleomorphic lobular carcinoma in situ.32(11):1721-1726. Also. The American journal of surgical pathology. Am J Surg Pathol. Lal A. The distinction of pLCIS from classical LN relies on nuclear characteristics with pLCIS having larger. . but characteristically it is associated with classical LN and not with DCIS. De Vries S.44(10):1998-2009. Microinvasive (T1mic) lobular carcinoma of the breast: clinicopathologic profile of 16 cases. 2013. a classification of lobular neoplasia into three different grades of severity has been proposed. References: 1. Tavassoli FA. Carter G. Schnitt SJ. more pleomorphic nuclei with obvious nucleoli.35(5):750–6. Virchows Arch. 2002. and may show apocrine differentiation. based on the extent of lobular cancerization [2]. It may be associated with microinvasion [4]. Suzuki J. Hwang ES. 2. Shin SJ. Dabbs DJ. 3.LIN with High Risk (12/25) Further information: Several different morphologic variants of lobular neoplasia have been described to more precisely evaluate the individual risk. Roy R.

.269(2):340-7. the nature of these lesions as non-obligate precursors. References: LIN in core. namely atypical lobular hyperplasia./ vacuum-assisted biopsy (LoE 2b) 1.Strategy after Diagnosis of LIN (13/25) Further information: In contrast to atypical ductal hyperplasia. Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation. Not surprisingly these small studies have led to widely discrepant results and conflicting interpretations of published data. but results were inconclusive with lesions of lesser extent. especially if multiple lobules are involved. An excisional biopsy was recommended in fully developed LCIS because of an upgrade rate of greater than of 25% [1] or 16% [2]. because of the reported upgrade rates in fully developed LCIS. it is less clear if a follow-up excisional biopsy is beneficial to the outcome of a patient with the finding of lobular neoplasia in the core biopsy. This argument has to be taken seriously. an open biopsy in classical LCIS should be considered as an option also [2]. and risk of missing a radiologically occult invasive cancer. Cohen MA. However. This is mainly due to the relative infrequency of lobular neoplasia as the most severe finding in core biopsies and the even lower number of excisional biopsies in this situation. 2013 Nov. and at least all cases with LCIS and a mass lesion should be followed up by a surgical biopsy. Rao S. it is unlikely that an excisional biopsy could yield anything more significant [3]. The argument against a routine follow-up biopsy is that LN as the most significant pathology usually is an incidental finding in an otherwise benign core biopsy and if there is no other clinical or radiological detectable lesion. Radiology. Atkins KA. Nicholson B. and therefore there is some disagreement if excision should be recommended as a rule or not.

3(3):492-9 Neal L. Outcomes of patients with lobular in situ neoplasia of the breast: the role of vacuum-assisted biopsy. Hieken TJ. 2014 Jun. Quero C. 2013 Jul. Shen Y. and indeterminate breast lesions detected on core needle biopsy. Stefano DD. 2013 Jul. Histopathology. 2014 Jul. 7. Sandhu NP. Surg Oncol Clin N Am. 11. Jorns J.do we have the answer yet? Eur J Surg Oncol. Webster F. Farshid G. Bersiga A.63(1):83-95. 12. Pathologic upgrade rates on subsequent excision when lobular carcinoma in situ is the primary diagnosis in the needle core biopsy with special attention to the radiographic target. Antonacci CM. 2014 Oct. Cattani MG.138(10):1344-9. Waugh P. 2014 Apr. Cancer Med. Mayo Clin Proc. Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting.89(4):536-47 Parkin CK. Wahner-Roedler DL. J Clin Pathol. 2014 Oct.016. 3. Bendinelli B. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium. Giardina C. A systematic review of surgical biopsy for LCIS found at core needle biopsy . Wang K. Middleton LP. Bianchi S. Jaffer S.137(7):927-35. Sabel MS. D'Alfonso TM. Dempsey P.breast. Mac Bride MB. Dong W.06. Miglioretti DL.1016/j. Breast. Morphological parameters of lobular in situ neoplasia in stereotactic 11-gauge vacuum-assisted needle core biopsy do not predict the presence of malignancy on subsequent surgical excision. Visscher DW.23(5):651-5. [Epub ahead of print] . Arch Pathol Lab Med.2. Buckley ES. Am J Surg. Lobular neoplasia.40(2):168-75. Diagnosis and management of benign. Balch S. Coyne R.2014. 6. Chiu YL. Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast. Carrillo G. 8. Roder DM. Menes TS. Rakha EA et al: Characterisation and outcome of breast needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening. Dilaveri CA. Kerlikowske K. 5. Shin SJ. Lobular neoplasia: morphology and management. atypical. Arch Pathol Lab Med. 10. 9.207(1):24-31. Glazebrook KN.63(11):987-93. Dante S. Laurino L. 2014 Jan. Renne G. Piubello Q. Sneige N. VANCB Study Group. doi: 10. 4. Palli D. Reis-Filho JS. Maxwell AJ. Bevers TB. Garewal S. 2014 Feb. 2010 Dec 2. 2010 Nov. Rosenberg R. Int J Cancer. Castellano I. Hiller JE.23(3):487-503. Pang JC. Ghosh K. Loreto CD. King TA.

LIN accompanying intraductal or invasive carcinoma in patients with BCT (LoE 2a) 1. Ann Surg Oncol 2008. 2010 Sep 28. Ann Surg Oncol.13. 15:2263-2271 . Ciocca R: Presence of lobular carcinoma in situ does not increase recurrence in patients treated with breastconserving therapy. Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia.

Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast.005) was observed. A 2. Flat ductal intraepithelial neoplasia of the breast: A review of diagnostic criteria. 30:36-41. FEA might be associated with noninvasive cancer but not with invasive cancer. a more worrisome lesion (Boulos FI). Statement: Marker Lesion (LoE 3b) . molecular-genetic findings. Pathologe 2009. DCIS and tubulär carcinoma. References: 1. It is characterized by mildly to severely atypical cells simply replacing the single layer of native epithelial cells in a flat fashion without appreciable proliferation. In about one-third to one-quarter of cases of FEA seen at core biopsy. a more advanced lesion is found at excision: ADH. Marker Lesion FEA is highly associated with microcalcification (77%). Böcker W: Flache epitheliale Atypie. and clinical relevance . J Clin Pathol. 2010 Nov.It is time to appreciate the Azzopardi concept! Arch Pathol Lab Med 2009.to 3-fold increase in the occurrence of ADH in the presence of FEA versus in their absence (P < .63(11):987-93. 3. A finding of FEA on benign breast biopsy may indicate the presence of ADH. Moinfar F. differential diagnoses.Flat Epithelial Atypia (FEA) (14/25) Further information: FEA represents one of the earliest morphologically recognizable neoplastic alterations of the breast. 2. The mammographic features are amorphous and pleomorphic microcalcification. 133(6):879-892.

2. 20:1149-1155 Boulos F: Histologic Associations and long-term cancer risk in columnar cell lesions of the breast. 113:2415-2421 . Kunju L: Significance of flat epithelial atypia on mammotome core needle biopsy:should it be excised? Hum Pathol 2006. Epub ahead of print. 27(suppl_1):S79-S89 Collins L: Clinical and pathological features of ductal carcinoma in situ associated with the presence of flat epithelial atypia: an analysis of 543 patients. 38:35-41 Noske A: Flat eoithelial atypia is a common subtyp of B3 breast lesions and associated with noninvasive cancer but not with invasive cancer in final excision histology. 4.1. Pandey S: Columnar Cell Lesions of the Breast: Mammographic Findings with Histopathologic Correlation. Modern Pathology 2007. Cancer 2008. Radiographics 2007. Hum Pathol 2009. 5. 3.

doi: 10. White RL. Sobel A. Sarantou T. Dialani V. Calhoun BC. . Hassell PR.94(9):861-9. Robin YM. Flippo T. Jarraya H. Bachelle F.Strategy after Diagnosis of FEA (15/25) Further information: If a FEA is detected in core biopsy further no further (open) biopsy is indicated if the underlaying lesion / calcification is completely removed (Lee TJ. 62:1136-1140. Statement: FEA in core (LoE 3a) Statement: FEA at margins in resection specimens (LoE 3b) References: 1. Mehta TS. [Epub ahead of print] Ceugnart L. J Clin Pathol 2009. 4. Venkataraman S. In cases of FEA combined with an ADH further surgery depends on the ADH lesion (Ingegnoli A.2014. Annals of Surgical Oncology 2007. 2013 Mar. Frieling G. Chauvet MP. Does isolated flat epithelial atypia on vacuum-assisted breast core biopsy require surgical excision? Breast J. 6. Becker AK. Pure flat epithelial atypia: is there a place for routine surgery? Diagn Interv Imaging. Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies.1038/modpathol. 2013 Sep. Wilson CM. Livasy CA. Gordon PB. Gromet M. Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated? AJR Am J Roentgenol.159. van Niekerk D. 3. 2. Rocourt N. 5. Chaveron C. Hayes MM. Taieb S.200(3):682-8. Schnitt SJ. Pouliquen G. Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. 2010). 14(2):704-711 Hayes B et al: Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience. 2010). 2014 Nov-Dec. Mod Pathol. Harrison DA.20(6):606-14. Doualliez V. 2014 Nov 21.

11. Tozaki M. Acs G. 10. 8. and indeterminate breast lesions detected on core needle biopsy. Joh JE. Br J Cancer 2007. Positive predictive value for malignancy of pure flat epithelial atypia diagnosis by percutaneous needle biopsy of the breast: management of FEA in ultrasonography.7. Hayami R. [Epub ahead of print] Neal L. Breast. Int J Cancer. Laronga C. Lee MC. 2014 Aug. Visscher DW. Mayo Clin Proc. Okanami Y. Ghosh K. Breast Cancer.89(4):536-47 Prowler VL. Sandhu NP. Shimo A. Kanemaki Y. Kawamoto H. Hieken TJ. 2010 Dec 2. atypical. Glazebrook KN. Tsuchiya K. Rakha EA et al: Characterisation and outcome of breast needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening. Mac Bride MB. Koizumi H. [Epub ahead of print] . 2014 Apr. 2014 Apr 24. Tsugawa K. Khakpour N. Diagnosis and management of benign. Kojima Y. Surgical excision of pure flat epithelial atypia identified on core needle breast biopsy. 9. Oana Y. 96:1253-1257 Maeda I.23(4):352-6. Dilaveri CA. Nishikawa T. Wahner-Roedler DL. Yabuki Y. Kiluk JV. Takagi M. Houssami N et al: Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3).

Schnitt SJ. Tan PH. References: 1. World Health Organization. This definition replaces alternative terminologies that were focused on the proportion of atypical cells (30% or 90%) within a papilloma. An intermediate or high grade DCIS within a papilloma can be diagnosed regardless of the extent of atypia. 2010 May 1. Both central and peripheral papillomas are characterized by fibrovascular cores with epithelial and myoepithelial cell layers. Intraductal papillomas and ductal adenomas may show regressive changes. Lakhani SR.Papilloma (16/25) Further information: Benign intraductal papillomas occur either as a central papilloma originating from the ducts in the subareolar region. and are usually of low grade. 2012. such as sclerosis or infarction. The term papillomatosis is not used in the WHO classification of the breast. Central intraductal papillomas with a predominant or exclusive glandular differentiation are called ductal adenoma [1]. the distinction of ADH and DCIS within a papilloma rests with quantitative criteria [1]. or peripherally. Bilous M. As with atypical intraductal proliferative lesions. These changes may cause diagnostic difficulties in core needle biopsy [2]. Breast core needle biopsy: issues and controversies. also also epithelial or myoepithelial hyperplasia or squamous or apocrine metaplasia. Ellis IO. while larger atypical epithelial proliferations within a papilloma fulfill the criteria of an intraductal papilloma with low grade [3]. Mod Pathol. Who Classification of Tumours of the Breast. because was historically used both for usual type ductal hyperplasia and for papillomas. 2. An intraductal papilloma with ADH is diagnosed when the atypical epithelial proliferation is < 3 mm. and both locations can be either solitary or multiple. World Health Organization.23 Suppl 2:S36–45. editors. Atypical epithelial proliferations (ADH and DCIS) may occur in papillomas. .

78(2):258–66. Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma. . Dupont WD. Salhany KE. Jensen RA.3. 1996 Jul 14. Cancer. Page DL.

this recommendation has been questioned by newer studies. Broeders M. editors. Wahner-Roedler DL. Management of benign intraductal solitary papilloma diagnosed on core needle biopsy. Jones KN.Strategy after Diagnosis of Central Papilloma (17/25) Further information: A policy of open excisional biopsy after the diagnosis of a central papilloma has been recommended by the European guidelines for quality assurance in breast cancer screening. 2013 Jun. References: 1. Dilaveri CA. The risk of up-grade is to be considered very low in central papilloma without atypia and not sufficient to justify routine surgical resection. However.89(4):536-47 Rakha EA et al: Characterisation and outcome of breast needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening. Glazebrook KN. Holland R. 6.20(13):4137-44 Swapp RE. 5.20(6):1900–5. 2. [Epub ahead of print] Shamonki J. atypical. Huynh KT. Karsa von L. and indeterminate breast lesions detected on core needle biopsy. Visscher DW. Mac Bride MB. Reynolds C. Brandts HM. Schnitt S. 2013 Dec. 2010 Dec 2. et al. 2008 Neal L. Papillary lesions of the breast: selected diagnostic and management issues. 4. Histopathology. Mayo Clin Proc. Glazebrook KN. Int J Cancer. Sim MS. de Wolf C. 3. Giuliano A. Visscher DW. Ann Surg Oncol. Hieken TJ. Collins L. Törnberg S. European guidelines for quality assurance in breast cancer screening and diagnosis. Chung A. Diagnosis and management of benign. Perry N. Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision? Ann Surg Oncol. 2014 Apr. 2008. . Ghosh K.52(1):20–9. Kinnaird M. Sandhu NP.

2012 Aug 10. Ann Surg Oncol. . 2014 Jul-Aug. Cheng W. Wen X.20(1):94–101. Rössle M. Breast J. Nonmalignant Breast Papillary Lesions at Core-Needle Biopsy: A Meta-analysis of Underestimation and Influencing Factors. 8.20(4):394-401. Papillary lesions of the breast: outcomes of 156 patients managed without excisional biopsy. Rageth CJ. Wyss P.7. Varga Z.

Radially Sclerosing Lesion (18/25) No further information No references .

Complex Sclerosing Lesion (CSL) (19/25) No further information No references .Strategy after Diagnosis of Radial Scar.

2010 Sep 28. Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia.2010. JCO 2007. Muenchen: Zuckschwerdt Verlag. National Comprehensive Cancer Network: Breast cancer screening and diagnosis V. 5. Epidemiology. 2007. AJR 2007. follow-up and medical intervention) providing comprehensive disclosure of risks and benefits in absolute terms. NCCN. 2. Atypia patients who drank alcohol and had a first-degree relative with breast cancer have an increased risk of breast cancer compared to those without atypia [1]. 2010 . Ann Surg Oncol. 7.Follow-up Imaging for Women Age 50-69 Years with B3-Lesions (20/25) Further information: Women with ADH and LIN need to be informed about their elevated risk for breast cancer. NCCN. 1 ed. Youk J: Sonographically guided 14-gauge core needle biopsy of breast mass: A review of 2. 4. Risk communication should provide women with information of risk reduction strategies (e.g. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 1.420 cases with longterm follow-up. USA. Christchurch: New Zealand Health Technology Assessment (NZHTA). References: 1. ed 2010.1. 2008. 190:202-207 Albert U. 25(19):2671-2677. (Hrsg). 3. 6.Aktualisierung 2008. Chuba PJ: Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance. [Epub ahead of print] Weir R: Risk factors for breast cancer in women:a systematic review of the literature. Journal of Clinical Oncology 2005. 23(24):5534-5541 Degnim A: Stratification of breast cancer risk in women with atypia: A Mayo Cohort Study. helping women to make an informed decision to her personal needs and values. and End Results Data.

8. The Cochrane Library 2009.(4):1-35 . O'Connor A: Decision aids for people facing health treatment or screening decisions (Review).

follow-up or medical intervention) providing comprehensive disclosure of risks and benefits in absolut terms (numbers needed to treat and numbers needed to harm). 2. helping women to make an informed decision to her personal needs and values.96 months follow-up of the randomized IBIS-I trial. Dinh P. 99:272-282 O'Connor A: Decision aids for people facing health treatment or screening decisions (Review). References: 1. JCO 2009. J Natl Cancer Inst 2007.P1: (LoE 1a A AGO +) . Azambuja E.(4):1-354 Bozovic-Spasojevic I1. Cancer Treat Rev. 2012 Aug. 4. 3.38(5):329-39. McCaskill-Stevens W. Studies on medical prevention for women at increased risk that included women with LIN and ADH are in bold.Medical Prevention for Women at Increased Risk (including Women with LIN and ADH) (21/25) Further information: Risk communication should provide women with information of risk reduction strategies (e. raloxifen and aromatase inhibition for breast cancer risk reduction. The Cochrane Library 2009. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer .g. Visvanathan K:. Cardoso F. Chemoprevention for breast cancer. Tamoxifen für Frauen > 35 Jahre –Reduktion von DCIS und invasivem Karzinom NSABP. American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen.

Cheung AM. Richardson H. 99:272-282. Spadafora S. Ruiz A. Ellard SL. Tu D. . N Engl J Med.3 Study Investigators. Pujol P. NCIC CTG MAP. Fabian CJ. Anastrozol) für postmenopausale Frauen (LoE 1b A AGO +/-) MAP.32(14):1427-36. Tu D. Maunsell E. Chlebowski RT. Thayer DW. Wactawski-Wende J. Hiltz A. Pruthi S. Quality of life in MAP. Alés-Martínez JE.96 months follow-up of the randomized IBIS-I trial. Cheung AM. Robbins J. Sarto GE. Rowland KM. Martin LW. 2. 2011 Jun 23. J Natl Cancer Inst 2005. Fabian CJ. Goss PE. Royal Marsden Italian Trial Aromataseinhibitor (Exemestan. Pater JL. Gelmon KA. Pujol P. Wactawski-Wende J. Farmer P. Dubé P.3 (Mammary Prevention 3): a randomized. 97:1652-1662 IBIS. Brundage M. Richardson H.3 1.364(25):2381-91. Alés-Martínez JE. Sarto GE. Ingle JN. Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . Johnston D.1. Lickley L. Ingle JN. J Clin Oncol.1 1. Gelmon KA. Fischer B: Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. Maunsell E. Johnson KC. J Natl Cancer Inst 2007. Goss PE. Hendrix S. Chlebowski RT. 2014 May 10. McTiernan A. placebo-controlled trial evaluating exemestane for prevention of breast cancer. Cooke AL. Winquist E. Exemestane for breast-cancer prevention in postmenopausal women. Garber JE.

383: 1041–48 . Palva T. Roche N.IBIS. Mansel RE. randomised placebo-controlled trial Lancet 2014. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international.2 1. Cawthorn S. Howell A. Forbes JF. Cuzick J. Saunders C. Dowsett M. double-blind. von Minckwitz G. on behalf of the IBIS-II investigators. Knox J. Bonanni B. Sestak I.

J Natl Cancer Inst 2007. 295(23):2727-2741. 3. 4. Visvanathan K: American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. raloxifen and aromatase inhibition for breast cancer risk reduction. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . JCO 2009.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen) (22/25) No further information References: 1.96 months follow-up of the randomized INIS-I trial. 99:272-282 Vogel V: Effects of tamoxifen versus raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P2 trial. Fischer B: Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. 97:1652-1662 . J Natl Cancer Inst 2005. 2. JAMA 2006.

J Natl Cancer Inst 2007. Side Effects) (23/25) Further information: Risk communication should provide women with information of risk reduction strategies (e.g. helping women to make an informed decision to her personal needs and values. raloxifen and aromatase inhibition for breast cancer risk reduction. References: 1. JCO 2009. Visvanathan K:. follow-up and medical intervention) providing comprehensive disclosure of risks and benefits in absolut terms (numbers needed to treat and numbers needed to harm). The Cochrane Library 2009. 3. American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . 99:272-282 O'Connor A: Decision aids for people facing health treatment or screening decisions (Review).Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen. 2.96 months follow-up of the randomized INIS-I trial.(4):1-354 .

97:1652-1662 . 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . J Natl Cancer Inst 2007. 2. Visvanathan K: American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. 3. Fischer B: Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. JAMA 2006. 295(23):2727-2741. 4. 99:272-282 Vogel V: Effects of tamoxifen versus raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P2 trial. JCO 2009.96 months follow-up of the randomized INIS-I trial. raloxifen and aromatase inhibition for breast cancer risk reduction. J Natl Cancer Inst 2005.Medical Prevention after Diagnosis of B3 Lesion (Raloxifen) (24/25) No further information References: 1.

Robbins J. Tu D. 2012 Aug. Farmer P. Maunsell E. NCIC CTG MAP. N Engl J Med. Chlebowski RT.364(25):2381-91. McTiernan A. Johnson KC.38(5):329-39. Gelmon KA. Richardson H. Alés-Martínez JE. Cardoso F.Prevention for Lesions with Uncertain Biological Behaviour (Aromatase Inhibitors) (25/25) No further information References: Exemestane for breast-cancer prevention in postmenopausal women. Winquist E. Wactawski-Wende J. Cheung AM. Ingle JN. 1. Fabian CJ. McCaskill-Stevens W. Goss PE. Chemoprevention for breast cancer. 2. Bozovic-Spasojevic I1. Garber JE. 1. Martin LW. Dinh P. Azambuja E.3 Study Investigators. Pujol P. 2011 Jun 23. Cancer Treat Rev. . Sarto GE.

Guidelines Breast Version 2015.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.1 Ductal Carcinoma in Situ (DCIS) .V. in der DGGG e.V.V. sowie in der DKG e.

V.1 www.Ductal Carcinoma in Situ DCIS © AGO e.V.V.ago-online.de . sowie in der DKG e. in der DGGG e.  Version 2002: Gerber  Versions 2003–2014: Audretsch / Brunnert / Costa / Fersis / Friedrich / Hanf / Junkermann / Lux / Maass / Möbus / Nitz / Oberhoff / Scharl / Solomayer / Souchon / Thill / Thomssen  Version 2015: Blohmer / Nitz Guidelines Breast Version 2015.

V. in der DGGG e. Guidelines Breast Version 2015.1   Mammography   ++ Magnification view of microcalcification 4 C ++  Increase of detection rate of G1/G2 DCIS by fullfield digital mammography (versus screen-film) 2b B + Stereotactic core needle / vacuum biopsy (VAB) 2b B ++  Specimen radiography 2b B ++  Marker (Clip) left at biopsy site for location if lesion is completely removed 5 D ++ 3a C +/- 5 D ++ 5 D - 5 D ++ Assessment of extension   A  www.V.de  1b MRI Clinical examination FNA / ductal lavage Interdisciplinary board presentation .Pretherapeutic Assessment of Suspicious Lesions (BIRADS IV) © AGO Oxford / AGO LoE / GR e.ago-online.V. sowie in der DKG e.

Oxford / AGO LoE / GR in der DGGG e. sowie in der DKG e.de  Immediate re-excision for close margins (specimen radiography)‫‏‬ 1c B ++  Intraoperative frozen section 5 D --  Interdisciplinary board presentation 2b C ++ Open biopsy in suspicious lesions (mammographical microcalcifications.V.ago-online. MRI etc.Surgical Treatment for Histologically Proven DCIS I © AGO e. suspicious US.) without preoperative needle biopsy should be avoided . Guidelines Breast Version 2015.V.V.1  Excisional biopsy (wire guided) 2b B ++  Bracketing wire localization in large lesions 5 D + 2b B ++ 3a C +/- Specimen radiography  Intraoperative ultrasound (visible lesion)  www.

ago-online. Guidelines Breast Version 2015.V. sowie in der DKG e.Surgical Treatment for Histologically Proven DCIS II © AGO Oxford / AGO LoE / GR e. in der DGGG e.V. multicentricity and local recurrence.1  Histologically clear margins (R0) 2b C ++  Multifocal DCIS: BCT if feasible (incl.de  In case of DCIS in the male breast  BCT:‫‏≥‏‬5‫‏‬cm‫‏‬or‫‏≥‏‬2.5‫‏‬cm‫‏‬+‫‏‬high‫‏‬nuclear‫‏‬grade/‫‏‏‏‏‏‏‏‏‏‏‏‏‏‏‬ comedonecrosis  ALND * Patients who present with a palpable mass have a significantly higher potential for occult invasion (26%). .V. no clear margins after re-excision  SNE*  Mastectomy www. RT) 2b B +  Re-excision required for close margin < 2 mm in paraffin section) 2b C + 2a B ++ 3b B + 3b B + 5 D + 3b B +/- 2b B --  Mastectomy*  Large lesions confirmed by multiple biopsies.

Ki-67+ HER2/neu (positive vs.DCIS – Prognostic Factors for the Incidence of Local./ Locoregional Recurrence © AGO Oxford / AGO LoE / GR e. p16+.V.ago-online.) Van Nuys Prognostic Index Palpable DCIS Palpable + COX-2+. in der DGGG e.de                   Resection margins Residual tumor-associated microcalcification Age Size Grading Comedo necrosis Architecture Method of diagnosis Focality (mod. triple negative) 1a 2b 1a 1a 1a 1a 2b 1a 1a 2b 2b 2b 2b 1a 1a 2b A C A A A A C A A C C C C B B C ++ ++ ++ ++ ++ ++ + ++ ++ +/+/+/+/+/+/+/- 3b 2b C C ++ - .V. sowie in der DKG e. HER2+.V. Guidelines Breast Version 2015. HER2+. Ki-67+ Palpable + ER-.1 www. B. negative) ER/PgR (positive vs. negative) DCIS-Score DCIS with microinvasion – treatment in analogy to invasive breast cancer Intrinsic subtypes (luminal A.

in der DGGG e.V. Omitting radiotherapy implies elevated risk for local recurrence without effect for overall survival even in the subset of “good risk” patients.de Side effects and disadvantages of radiotherapy must be balanced against risk reduction. There remains a lack of level-1 evidence supporting the omission of adjuvant radiotherapy in selected low-risk cases: < 2.ago-online. mammographically detected * Analysis in ongoing trials .V.1 Radiotherapy after:  Breast conserving surgery (BCS) 1a A ++  Mastectomy 2b B -- Partial breast radiotherapy (PBI) 3a D -- Hypofractionated radiotherapy regimens 2b D -/+* Radiotherapy boost on the tumor bed 2b D --  Women younger than 45-50 years 2b C +/- Modality: www. Guidelines Breast Version 2015 .V. low and intermediate nuclear grade. sowie in der DKG e.DCIS Radiotherapy © AGO Oxford / AGO LoE / GR e.5 cm.

V. 2013 Nov 21. Parker S.Cochrane Analysis Radiation after Surgery (all/with Radiation after Breast Conserving Surgery) © AGO e. Wilcken N. in der DGGG e.pub7. doi: 10.ago-online.11:CD000563. Cochrane Database Syst Rev.CD000563.V. www.1002/14651858.1 Goodwin A.V. Guidelines Breast Version 2015 .de . sowie in der DKG e. Post-operative radiotherapy for ductal carcinoma in situ of the breast. Ghersi D.

in der DGGG e.1  Tamoxifen (only ER+)  www.ago-online.de AI if postmenopausal and contraindication against tamoxifen 1a A + D D +/- D --  Other endocrine options 5 5  Trastuzumab (only HER2+) 5  For Prevention of opposite breast see Prevention chapter . Guidelines Breast Version 2015 .V. sowie in der DKG e.V.DCIS Postoperative Systemic Treatment © AGO Oxford / AGO LoE / GR e.V.

ago-online.CD007847. Breast.1 Staley H.breast.06. Cochrane Database Syst Rev. Staley H. McCallum I. .V.10:CD007847. in der DGGG e. doi: 10.V.pub2.1002/14651858.de ductal carcinoma in situ: Cochrane systematic review and meta-analysis. Bruce J. sowie in der DKG e. 2014 Oct.2014. Bruce J. Postoperative Tamoxifen for www. Guidelines Breast Version 2015 . Postoperative tamoxifen for ductal carcinoma in situ.Cochrane Analysis Tamoxifen after DCIS (all/with Radiation) © AGO e. McCallum I.1016/j. Epub 2014 Jul 9. doi: 10. 2012 Oct 17.V.015.23(5):546-51.

V.1 After radiation  Simple mastectomy + SN B  Second tumorectomy 3a 5 5 C D D + + +/- 3 C ++ is followed by recurrences in up to 30 % of patients (NSABP B17) www. About 50% of recurrences are invasive. Guidelines Breast Version 2015 . sowie in der DKG e.de No radiation after first tumorectomy  Treatment like primary disease Prognosis for invasive recurrences seems to be better than for primary invasive breast cancer.Local Recurrence of DCIS after Tumorectomy w/o Irradiation © AGO e. Oxford / AGO LOE / GR in der DGGG e. .ago-online.V.V.

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A nomogram for predicting underestimation of invasiveness in ductal carcinoma in situ diagnosed by preoperative needle biopsy. Paszat L.24:3809-11 MacAusland SG. Schulz S. 5. Chong FK. doi: 10. Ductal carcinoma in situ in core needlebiopsies and its association with extensive in situ component in the surgical specimen. Park BW. 2012 Jun 20. 3.22(5):869-73. et al. 2. Park BW. Bartelink H. Rauch G. J Clin Oncol 2007. de Abreu LC. [Epub ahead of print] .22(4):537-42. Kim SI.25:5548–5549 Rakovitch E. Golatta M. Silverstein MJ.25:5591–5596 (mod. Rutgers EJ. Cho J. Park S.23273. Pignol JP. 2. Fonseca FL. Cancer 2007. Prediction of underestimated invasiveness in patients with ductal carcinoma in situ of the breast on percutaneous biopsy as rationale for recommending concurrent sentinel lymph node biopsy. Page DL. Spayne J. Park S. Silverstein MJ. Wazer DE. Sinn P.  1. Junkermann H. Fokalität Meijnen P. Park HS.110:2648-53 Macdonald HR. Galper SL. J Clin Oncol 2006. Gass JS. Schuetz F. 3. Margin width as the sole determinant of local recurrence after breast conservation in patients with ductal carcinoma in situ of the breast. Hanna W. 2013 Aug. Epub 2012 Sep 24. Bartelink H. 4. Multifocal ductal carcinoma in situ of the breast: A contraindication for breast-conserving treatment? J Clin Oncol 2007. J Surg Oncol.2. 2013 Mar. Narod S.  1. Nofech-Mozes S. Hepel JT. Ann Surg Oncol 2007 Nov 7. Kim EK.1002/jso. Park HS. Breast. An attempt to independently verify the utility of the Van Nuys Prognostic Index for ductal carcinoma in situ. Kim HY. Lee LA. Ruthazer R. Valenti VE. Int Arch Med. Chartier C. Rossetti C. Risk predictors of underestimation and the need for sentinel node biopsy in patients diagnosed with ductal carcinoma in situ by preoperative needle biopsy. 4.) Van Nuys Prognose Index Lagios MD. Breast. Kim SI. Heil J. Barbalaco Neto G.5(1):19. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. Park JM.107(4):388-92. Significance of multifocality in ductal carcinoma in situ: outcomes of women treated with breast-conserving therapy. Sohn C. Am J Surg 2006 192:420-2 Meijnen P. Oldenburg HS. Peterse JL. 2013 Oct. Clinical outcome after selective treatment of patients diagnosed with ductal carcinoma in situ of the breast.

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Palpabel + COX-2+p16+Ki-67+
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HER2-Überexpression
ER/PgR (positiv vs. negativ)
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Noh JM, Lee J, Choi DH, Cho EY, Huh SJ, Park W, Nam SJ, Lee JE, Kil WH. HER-2 overexpression is not
associated with increased ipsilateral breast tumor recurrence in DCIS treated with breast-conserving surgery
followed by radiotherapy. Breast. 2013 Oct;22(5):894-7.

DCIS Radiotherapy (7/11)

Further information:
Alle Abstimmungen mit 100% Zustimmung.

References:
Radiotherapie nach:

Brusterhaltender Operation (BEO) (gesamte Brust, WBI)
1.

2.

3.

4.
5.
6.

Bijker N, Meijnen P, Peterse JL, Bogaerts J, Van Hoorebeeck I, Julien JP, Gennaro M, Rouanet P, Avril A, Fentiman
IS, Bartelink H, Rutgers EJ. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ:
ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a
study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol
2006;24:3381-7
Emdin SO, Granstrand B, Ringberg A, et al. Swedish Breast Cancer Group. SweDCIS. Radiotherapy after sector
resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered
mammography screening. Acta Oncol 2006;45:536-43
Viani GA, Stefano EJ, Afonso SL, De Fendi LI, Soares FV, Leon PG, Guimarães FS. Breast-conserving surgery with
or without radiotherapy in women with ductal carcinoma in situ: a meta-analysis of randomized trials. Radiat Oncol
2007:2:2
Wong JS, SC Lester, Smith BL. Reply Wong to Lagios Wong Letter. J Clin Oncol 2006;24:3811-2
Poortmans P. Evidence based radiation oncology: breast cancer. Radiother Oncol 2007;84:84-101
Sautter-Bihl ML, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sedlmayer F, Souchon R, Wenz F, Sauer R.
DEGRO Practical guidelines for radiotherapy of breast cancer I: Breast-conserving therapy. Strahlenther Onkol
2007;183:661-666

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Solin LJ. Is excision alone adequate treatment for low-risk ductal carcinoma-in-situ of the breast? J Clin Oncol
2006;24:1017-1019
Hum Pathol. 2000 Feb;31(2):131-9.
The Consensus Conference on the treatment of in situ ductal carcinoma of the breast, April 22-25, 1999.
Schwartz GF, Solin LJ, Olivotto IA, Ernster VL, Pressman PI.
J Clin Oncol. 2009 Oct 20;27(30):4939-47. Epub 2009 Aug 31.
Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the
EORTC boost versus no boost trial.
Jones HA, Antonini N, Hart AA, Peterse JL, Horiot JC, Collin F, Poortmans PM, Oei SB, Collette L, Struikmans H,
Van den Bogaert WF, Fourquet A, Jager JJ, Schinagl DA, Wárlám-Rodenhuis CC, Bartelink H.
Bijker N, G van Tienhoven (2010): “Local and Systemic Outcomes in DCIS Based on Tumor and Patient
Characteristics: The Radiation Oncologist’s Perspective” J Natl Cancer Inst Monogr (41) 178 – 180
Solin LJ (2010): “The Impact of Adding Radiation Treatment After Breast Conservation Surgery for Ductal
Carcinoma In Situ of the Breast” J Natl Cancer Inst Monogr (41) 187 – 192
Kane RL, BA Virnig et al. (2010) : “The Impact Surgery, Radiation, and Systemic Treatment on Outcomes in
Patients With Ductal Carcinoma In Situ” J Natl Cancer Inst Monogr (41) 130 – 133
Hughes LL, Wong M, Page DL et al. Local excision alone without irradiation for ductal carcinoma in situ of the
breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009; 27(32): 5319-24
Jeruss JS, Kuerer HM, Beitsch P et al. Update on DCIS outcomes from the American Society of Breast Surgeons
Accelerated Partial Breast Irradiation Registry trial. Ann Surg Oncol. 2011; 18(1): 65-71
Wapnir IL, Dignam JJ, Fisher B, et al. Long-Term Outcomes of invasive ipsilateral breast tumor recurrences after
lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 2011; 103: 478-488
EBCTCG Correa C et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.
J Natl Cancer Inst Monogr. 2010 (41); 162 – 77
Motwani SB, Goyal S, Moran MS et al: Ductal carciinoma In Situ Treated With Breast-Conserving Surgery and
Radiotherapy: A Comparison With ECOG Study 5194. Cancer 2011; 117: 1156-62.
EBCTCG Correa C et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.
J Natl Cancer Inst Monogr. 2010 (41); 162 – 77
Motwani SB, Goyal S, Moran MS et al: Ductal carciinoma In Situ Treated With Breast-Conserving Surgery and
Radiotherapy: A Comparison With ECOG Study 5194. Cancer 2011; 117: 1156-62.

24.

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Childs SK, Chen YH, Duggan MM, Golshan M, Pochebit S, Punglia RS, Wong JS, Bellon JR. Impact of margin
status on local recurrence after mastectomy for ductal carcinoma in situ. Int J Radiat Oncol Biol Phys 2012 Sep 10.
doi:pii: S0360-3016(12)03334-2. 10.1016/j.ijrobp.2012.07.2377. [Epub ahead of print]
Cobleigh MA, Anderson SJ, Julian TB, Siziopikou KP, Arthur DW, Rabinovitch R, Zheng P, Mamounas EP,
Wolmark N. NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation
therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx). SABCS 2012; OT1-2-01
Halasz LM, Sreedhara M, Chen YH, Bellon JR, Punglia RS, Wong JS, Harris JR, Brock JE. Improved outcomes of
breast-conserving therapy for patients with ductal carcinoma in situ. Int J Radiat Oncol Biol Phys 2012;82:e581-6.
Shaitelman SF, Wilkinson JB, Kestin LL, Ye H, Goldstein NS, Martinez AA, Vicini FA. Long-term outcome in
patients with ductal carcinoma in situ treated with breast-conserving therapy: implications for optimal follow-up
strategies. Int J Radiat Oncol Biol Phys 2012;83:e305-12.
Vidali C, Caffo O, Aristei C, Bertoni F, Bonetta A, Guenzi M, Iotti C, Leonardi MC, Mussari S, Neri S, Pietta N.
Conservative treatment of breast ductal carcinoma in situ: results of an Italian multi-institutional retrospective study.
Radiat Oncol. 2012 Oct 25;7(1):177. [Epub ahead of print]
Donker M, Litière S, Werutsky G, Julien JP, Fentiman IS, Agresti R, Rouanet P, de Lara CT, Bartelink H, Duez N,
Rutgers EJ, Bijker N.Breast-conserving treatment with or without radiotherapy in ductal carcinoma In Situ: 15-year
recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol.
2013 Nov 10;31(32):4054-9.
Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast.
Cochrane Database Syst Rev. 2013 Nov 21;11:CD000563. doi: 10.1002/14651858.CD000563.pub7.
Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, Mamounas EP, Julian TB, Geyer CE Jr,
Costantino JP, Land SR, Wolmark N. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen
receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol 2012;30:1268-73
Alvarado R, Lari SA, Roses RE, Smith BD, Yang W, Mittendorf EA, Arun BK, Lucci A, Babiera GV, Wagner JL,
Caudle AS, Meric-Bernstam F, Hwang RF, Bedrosian I, Hunt KK, Kuerer HM. Biology, treatment, and outcome in
very young and older women with DCIS. Ann Surg Oncol 2012;19:3777-84.
Amichetti M, Vidali C. Radiotherapy after conservative surgery in ductal carcinoma in situ of the breast: a review.
Int J Surg Oncol 2012;2012:635404. doi: 10.1155/2012/635404. Epub 2012 May 13.
Australian New Zealand Clinical Trials Registry website. The Trans Tasman Radiation Oncology Group (TROG)
07.01: A randomised phase III study of radiodoses and fractionation schedules in non-low risk Ductal Carcinoma In

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Situ (DCIS) of the breast to improve time to recurrence. http://www.anzctr.org.au/trial_view.a.... Accessed June 27,
2012.
Lambert K, Patani N, Mokbel K. Ductal carcinoma in situ: recent advances and future prospects. Int J Surg Oncol.
2012;2012:347385. doi: 10.1155/2012/347385. Epub 2012 May 17.
Lee RJ, Vallow LA, McLaughlin SA, Tzou KS, Hines SL, Peterson JL. Ductal carcinoma in situ of the breast.
Int J Surg Oncol. 2012;2012:123549. doi: 10.1155/2012/123549. Epub 2012 Jul 18.
Leitlinienprogramm Onkologie der AWMF, Deutschen Krebsgesellschaft e.V. und Deutschen Krebshilfe e.V.
Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms. 3. Auflage:
Aktualisierung 2012. Zuckschwerdt Verlag, 2012 ISBN: 978-3-86371-073-6; siehe auch:
http://www.awmf.org/leitlinien/detail/ll/032-045OL.html
McCormick B. RTOG 9804: A prospective randomized trial for “good risk” ductal carcinoma in situ (DCIS),
comparing radiation (RT) to observation (OBS). J Clin Oncol 2012;30 (suppl; abstr 1004).
McCormick B, Moughan J, Hudis C, Kuerer H et al. Low-risk breast ductal carcinoma in situ (DCIS): results from
the Radiation Therapy Oncology Group 9804 Phase 3 Trial. Int J Radiat Oncol Biol Phys 2012;84(5) Suppl., S5
abstract 11
Morrow M. Refining the use of endocrine therapy for ductal carcinoma in situ. J Clin Oncol 2012;30:1249-51.
Morrow M, Katz SJ. Margins in ductal carcinoma in situ: is bigger really better? J Natl Cancer Inst 2012;104:494-5
Wärnberg F, Garmo H, Emdin S, Hedberg V, Adwall L, Sandelin K, Ringberg A, Karlsson P, Arnesson LG,
ring Radiotherapy With Observation. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.57.9029
Mastektomie
Chadha M, Portenoy J, Boolbol SK, Gillego A, Harrison LB. Is there a role for postmastectomy radiation therapy in
ductal carcinoma in situ? Int J Surg Oncol 2012;2012:423520. doi: 10.1155/2012/423520. Epub 2012 Jun 13.

Sonderformen der Radiotherapie:
 Teilbrustbestrahlung

2.

3.
4.

5.

6.
7.

8.

9.

10.

11.

Monticciolo DL, Biggs K, Gist AK, et al Breast Conserving Therapy with accelerated partial breast versus external
beam whole breast irradiation: comparison of imaging sequela and complications in a matched population. The
Breast Journal 2011; 17(2) 187-190
Aburabia M, Roses RE, Kuerer HM, et al. Axillary failure in patients treated with MammoSite accelerated partial
breast irradiation. Ann Surg Oncol 2011; 18:3415-3421
Goyal S, Vicini F, beitsch PD et al. Ductal carciinoma In Situ Treated With Breast-Conserving Surgery and
Accelerated Partial Breast Irradiation: A Comparison of Mammosite Registry Trial With Intergroup Study 5194.
Cancer 2011; 117: 1149-55.
Stull TS, Goodwin MC, Gracely EJ, et al. A Single Institution Review of Accelerated Partial Breast Irradiation in
Patients considered “Cautionary” by the American Society for Radiation Oncology. Ann Surg Oncol 2011; (epub
ahead)
Punglia RS, Burstein HJ, Weeks JC et al. Radiation Therapy for Ductal Carcinoma In Situ. Cancer 2011; (epub
ahead)
Khan AJ, Arthur D, Vicini F, et al. Six-Year Analysis of Treatment-Related Toxicities in Patients Treated with
Accelerated Partial Breast Irradiation on the American Society of Breast Surgeons MammoSite Breast
Brachytherapy Registry Trial. Ann Surg Oncol 2011; (epub ahead)
National Cancer Institute website. NSABP B-39: Phase III randomized study of adjuvant whole-breast versus partialbreast irradiation in women with ductal carcinoma in situ or stage I or II breast cancer.
http://www.cancer.gov/clinicaltrials/search/view?cdrid=409590&version=HealthProfessional. Accessed June 26,
2012.
Riou O, Lemanski C, Guillaumon V, Lauche O, Fenoglietto P, Dubois JB, Azria D. Role of the radiotherapy boost
on local control in ductal carcinoma in situ. Int J Surg Oncol. 2012;2012:748196. doi: 10.1155/2012/748196. Epub
2012 Apr 8.
Wong JS, Chen YH, Gadd MA, Gelman R, Lester SC, Schnitt SJ, Sgroi DC, Silver BJ, Smith BL, Troyan SL, Harris
JR. Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal
carcinoma in situ (DCIS). Breast Cancer Res Treat. 2014 Jan;143(2):343-50.
John Paul Einck, Steven E. Finkelstein, Ben Han, Robert Hong, Lydia T. Komarnicky, Robert R. Kuske, Sudha B.
Mahalingam, Constantine Mantz, Serban Morcovescu, Stephen S. Nigh, Kerri L. Perry, Jondavid Pollock, Jay E.
Reiff, Daniel Scanderbeg, Jon F. Strasser, Catheryn M. Yashar, SAVI Collaborative Research Group; Department of
Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA; 21st Century

12.

13.

1.


1.
2.

3.
4.

Oncology of Arizona, Translational Research Center, Scottsdale, AZ; South Florida Radiation Oncology, LLC,
Boynton Beach, FL; Virginia Hospital Center, Arlington, VA; Drexel University College of Medicine, Philadelphia,
PA; Arizona Breast Cancer Specialists, Scottsdale, AZ; The Christ Hospital Cancer Center, Cincinatti, OH; 21st
Century Oncology, Translational Research Consortium (TRC), Fort Myers, FL; Texas Oncology, Denton, TX;
Northwest Community Hospital Cancer Services, Arlington Heights, IL; Kerri Perry, MD, Denton, TX; Schiffler
Cancer Center, Wheeling, WV; Helen F. Graham Cancer Center - Christiana Care Health System, Newark, DE.
Accelerated partial-breast irradiation using strut-based brachytherapy in ductal carcinoma in situ patients: A report
on 321 patients with median 25-month follow-up. J Clin Oncol 31, 2013 (suppl 26; abstr 92)
S. S. Park, I. S. Grills, P. Y. Chen, M. Ghilezan, L. L. Kestin, M. Wallace, A. Martinez, F. A. Vicini. Outcomes for
accelerated partial-breast irradiation (APBI) in pure ductal carcinoma in situ (DCIS) patients. J Clin Oncol 31, 2013
(suppl 26; abstr 100)
B. E. Amendola, C. P. Amendola, N. C. Perez. DCIS of the breast treated with balloon brachytherapy: 7-year followup. J Clin Oncol 31, 2013 (suppl 26; abstr 142)
Hypofraktionierte Radiotherapie
Hathout L, Hijal T, Théberge V, Fortin B, Vulpe H, Hogue JC, Lambert C, Bahig H, Provencher L, Vavassis P,
Yassa M. Hypofractionated radiation therapy for breast ductal carcinoma in situ. Int J Radiat Oncol Biol Phys. 2013
Dec 1;87(5):1058-63.
Boost-RT des Tumorbettes
Wong P, Lambert C, Agnihotram RV, et al. Ductal Carcinoma In Situ – The Influence of the Radiotherapy Boost on
Local Control. Int J Radiation Oncology Biol Phys 2011; (epub ahead)
Rakovitch E, Narod SA, Nofech-Moses S, Hanna W, Thiruchelvam D, Saskin R, Taylor C, Tuck A, Youngson B,
Miller N, Done SJ, Sengupta S, Elavathil L, Jani PA, Bonin M, Metcalfe S, Paszat L. Impact of boost radiation in the
treatment of ductal carcinoma in situ: a population-based analysis. Int J Radiat Oncol Biol Phys. 2013 Jul
1;86(3):491-7.
Guenzi M, Giannelli F, Bosetti D, Blandino G, Milanese ML, Pupillo F, Corvò R, Fozza A.
Two different hypofractionated breast radiotherapy schedules for 113 patients with ductal carcinoma in situ:

preliminary results. Anticancer Res. 2013 Aug;33(8):3503-7.
Bei Patientinnen unter 45-50 Jahren

Cochrane Analysis – Radiation after Surgery (8/11)

No further information

No references

DCIS Postoperative Systemic Treatment (9/11)

Further information:
Alle Abstimmungen mit 100% Zustimmung

References:

1.

2.
3.
4.
5.
6.
7.
8.

Tamoxifen (nur ER+, nur BET)
Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, Smith R, Begovic M, Dimitrov NV,
Margolese RG, Kardinal CG, Kavanah MT, Fehrenbacher L, Oishi RH. Tamoxifen in treatment of intraductal breast
cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999 Jun
12;353(9169):1993-2000.
Allred DC Breast Cancer Research and Treatment Vol 76 Suppl 1 Dec 2002: abstract 30
Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal Carcinoma In Situ of the Breast: A Systematic Review of
Incidence, Treatment, and Outcomes. J Natl Cancer Inst. 2010 Jan 13. [Epub ahead of print]
Cuzick J, I Sestak et al. (2010): “Effect of Tamoxifen and radiotherapy in women with locally excised ductal
carcinoma in situ: long-term results form the UK / ANZ DCIS trial” Lancet Oncol (12) 21- 29
Eng-Wong J, JP Costantino et al. (2010): “The Impact of Systemic Therapy Following Ductal Carcinoma In Situ” J
Natl Cancer Inst Monogr (41) 200 – 203
Wapnir IL, Dignam JJ, Fisher B, et al. Long-Term Outcomes of invasive ipsilateral breast tumor recurrences after
lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 2011; 103: 478-488
Badruddoja M. Ductal carcinoma in situ of the breast: a surgical perspective. Int J Surg Oncol. 2012;2012:761364.
doi: 10.1155/2012/761364. Epub 2012 Sep 4.
Staley H, McCallum I, Bruce J. Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev.
2012 Oct 17;10:CD007847. doi: 10.1002/14651858.CD007847.pub2.

9.
10.
11.

1.

2.

Lee DY, Lewis JL, Wexelman BA, Freedman BC, Ross RE, Tartter PI. The consequence of undertreatment of
patients treated with breast conserving therapy for ductal carcinoma in-situ. Am J Surg. 2013 Nov;206(5):790-7.
Sprague BL, McLaughlin V, Hampton JM, Newcomb PA, Trentham-Dietz A. Disease-free survival by treatment
after a DCIS diagnosis in a population-based cohort study. Breast Cancer Res Treat. 2013 Aug;141(1):145-54.
Staley H, McCallum I, Bruce J. Postoperative Tamoxifen for ductal carcinoma in situ: Cochrane systematic review
and meta-analysis. Breast. 2014 Oct;23(5):546-51. doi: 10.1016/j.breast.2014.06.015. Epub 2014 Jul 9
AI (wenn postmenopausal und
Kontraindikationen gegen Tamoxifen)
Andere endokrine Optionen
Trastuzumab (nur HER2+)
Cobleigh MA, Anderson SJ, Julian TB, Siziopikou KP, Arthur DW, Rabinovitch R, Zheng P, Mamounas EP,
Wolmark N. NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation
therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx). SABCS 2012; OT1-2-01
Siziopikou KP, Anderson SJ, Cobleigh MA, Julian TB, Arthur DW, Zheng P, Mamounas EP, Pajon ER, Behrens RJ,
Eakle JF, Leasure NC, Atkins JN, Polikoff JA, Seay TE, McCaskill-Stevens WJ, Rabinovitch R, Costantino JP,
Wolmark N. Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.
Breast Cancer Res Treat. 2013 Nov;142(2):415-21.

Cochrane Analysis – Tamoxifen after DCIS (10/11)

No further information

No references

Local Recurrence of DCIS after Tumorectomy w/o Irradiation (11/11)

Further information and references:
Abstimmung:
Lokalrezidiv des DCIS nach Tumorektomie nach Radiatio:
Einfache Mastektomie
++
4/19;
+
15719
Einfache Mastektomie + SNB:
++
3/22
+
14/22
+/3/22
2/22
-0/22
Lokalrezidiv des DCIS nach Tumorektomie mit Radiotherapie
Therapieindikation wie bei primärer Erkrankung:
++
10/21
+
7/21
+/1/21
1/21
-2/21
Nach Radiatio

Einfache Mastektomie

+ SN B
1.

2.

Silverstein MJ, MD Lagios et al (1998): “Outcome After Invasive Local Recurrence in Patients With Ductal
Carcinoma In Situ of the Breast” J Clin Oncol 16:1367-1373
Sekundäre Tumorektomie
führt zu Rezidiven in bis zu 30 % der Fälle
(NSABP B17)
Fisher ER, Dignam J, Tan-Chiu E et al. (1999): “Pathologic findings from the National Surgical Adjuvant Breast
Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma” Cancer 86: 429 – 438

Keine Radiotherapie
Therapieindikation wie bei primär Erkrankung

Diagnosis and Treatment of Patients with
Primary and Metastatic Breast Cancer
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Breast Cancer Surgery
Oncological Aspects

Breast Cancer Surgery
Oncological Aspects
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

www.ago-online.de

 Versions 2002–2014:
Bauerfeind / Blohmer / Böhme / Costa /
Fersis / Gerber / Hanf / Janni /
Junkermann / Kaufmann / Kühn /Kümmel
/ Nitz / Rezai / Simon / Solomayer /
Thomssen / Untch
 Version 2015:

Thill / Rezai

Breast Cancer Surgery
Oncological Aspects
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

AGO: ++
Surgery is only one sub-step out of multiple steps
in breast cancer treatment. Thus, both a
diagnostic and an oncological expertise are
indispensable and a definite requirement.

www.ago-online.de

Pretherapeutic Assessment
© AGO

Oxford / AGO
•LoE / GR

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Palpation

5

D

++

Mammography

2b

B

++

Ultrasound (breast & axilla)

2b

B

++

Minimalinvasive biopsy**

1c

A

+

MRI*

1c

B

+/-

www.ago-online.de

* No significant reduction of re-excision rate.
The possibility of MRI guided biopsy is the precondition of breast MRI (e.g. dense breast tissue and
invasive lobular cancer , suspicion of multifocal or multicentric disease )
** If clnical examitation, mammography, ultrasound and in some cases MRI
are not able to determine the extension of lesion

Perioperative Staging
© AGO

Oxford / AGO
LoE / GR

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

History and physical examination

5

D

++

Only recommended in high metastatic potential and / or with
symptoms:


www.ago-online.de




Chest X-ray
Liver ultrasound
CT-scan
Bone-scan
FDG-PET or FDG-PET / CT
Whole body MRI

5
5
5
5
4
4

D
D
D
D
C
C

+
+
+
+
-

Evidence of Surgical Procedure
© AGO

Oxford / AGO
LoE / GR

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Survival rates after lumpectomy + XRT are
equivalent to those after (modified) radical
mastectomy

1a

A

Survival rates after modified radical mastectomy
are equivalent to those after radical mastectomy 1b A

Local recurrence rates after skin sparing
mastectomy are equivalent to those after
mastectomy

www.ago-online.de

2b B

Conservation of the NAC (nipple areola complex)
is an adequate surgical procedure in tumors of the
periphery of the gland and after tumor-free
section of retroareolar tissue
4b C

Breast Conservation:
Surgical Technical Aspects
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.

Non-palpable lesion

Oxford / AGO
LoE / GR

Wire guided localisation

2b

B

++

Radionuclide guided localisation

2b

B

+/-

Specimen radiography or ultrasound

2b

B

++

2a

A

++

Immediate intraoperative re-excision for
close margins (specimen radiography
and/or intra-operative pathology)

1c

B

++

Re-excision required for involved margins
(paraffin section)

3b

C

+

Therapeutic stereotactic excision alone

4

D

--

Ultrasound guided surgery to prevent
1a

A

+/-

Guidelines Breast
Version 2015.1

Tumor-free margins required
(also in unfavorable biology „no cells on ink“ are enough)

www.ago-online.de

re-excision

Breast Conservation Surgery (BCS)
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.

Oxford / AGO
LoE / GR

Guidelines Breast
Version 2015.1

www.ago-online.de

Multicentricity

2b

B

+/-

Positive microscopic margins
after repeated excision

2b

B

--

Inflammatory breast cancer

2b

B

--

Surgery after neoadjuvant chemotherapy go to chapter „neoadjuvant
chemotherapy“

Axillary Lymph Node Dissection I
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

www.ago-online.de

Oxford / AGO
LoE / GR

Axillary lymph node dissection (>=10 LN)
 To improve survival
 For staging
 For local control
Axillary lymph node dissection:
 DCIS
 If SLNB is possible
 SN + ( cT1/2 cN*0; < 3 SN +, BCS + tangential
radiation field, no subsequent axillary radiation,
adequate systemic therapy)
 SN + (mic)
 SN (i+)
 SN + mastectomy (no radiotherapy of the chestwall)
 SN+ mastectomy (radiotherapy of the chestwall)

Only if T1, T2 and 1-2 pos. SLN

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Radiation according to AMAROS-trial

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Surgical Treatment of Axillary Lymph Nodes pre and
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© AGO

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*radiocolloid and blue dye,
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* *T1/T2, BCS, 1-2 SLN pos., breast radiation

ago-online. V.V.5 cm + high grade (see DCIS) if mastectomy is required 3b 3b B C +/+ Male breast cancer In the elderly Add. 2b 3b B B + + suspicious) in order to enable SNE 2a B + www. Guidelines Breast Version 2015. FNA/CNB of LN (clinical/sonogr.1  Clinically (cN0) / sonographically neg. 4a-c 3b B +  Multifocal / multicentric lesions 2b B +  DCIS  5 cm or 2. sowie in der DKG e.V.Sentinel Lymph Node Excision (SNE): Indications I © AGO e. Oxford / AGO LoE / GR in der DGGG e.de    . axilla 1b A ++  T 1-2 2b A ++  T 3.

V.Sentinel Lymph Node Excision (SNE): Indications II © AGO e.V.de  During pregnancy and / or breast feeding (no blue dye)  After previous tumor excision  Previous major breast surgery (e.g. sowie in der DKG e. reduction mammoplasty.ago-online. Guidelines Breast Version 2015. Oxford / AGO LoE / GR in der DGGG e.V. mastectomy)  Ipsilateral breast recurrence after prior BCS and prior SNE  SN in the mammarian internal chain  After axillary surgery  Prophylactic bilateral / contralateral mastectomy  Inflammatory breast cancer * Lymph node scintigraphy is necessary 3 C 2b B 3b C + + +/- 4 2b 3b 3b 3b +/-* +/-* -+/- D B B B C .1 www.

V.V.Sentinel Lymph Node Excision (SNE): Marking © AGO e.de  99mTc  Kolloid 1a A ++ Blue dye 1a B +/-  Methylen blue 4 D -  Indocyanin green (ICG)* 2b B +/-  SPIO* 2b B +/- SPIO: Superparamagnetic Iron Oxide * Study participation recommended .1 www. in der DGGG e. Oxford / AGO LoE / GR Guidelines Breast Version 2015. sowie in der DKG e.ago-online. V.

Procedure after Neoadjuvant Therapy © AGO e.V.1  Marking of tumor in a timely manner 5 D ++  Surgery 2b C ++  Microscopically clear margins 5 ++  Tumor resection in the new D www. in der DGGG e. sowie in der DKG e. Oxford / AGO LoE / GR Guidelines Breast Version 2015. V.ago-online.V.de margins 3b C + Surgery after neoadjuvant chemotherapy go to chapter „Neoadjuvant chemotherapy“ .

 Tamoxifen concurrent with radiotherapy  AI concurrent with radiotherapy A ++ A ++ 2b B ++ 5 3b 3b D C C ++ + + .a.) after surgery 1b  Start of adjuvant chemotherapy after surgery a.de  Start adjuvant systemic therapy and RT as soon as possible (a.s.p.s.ago-online.a.V.s.a. sowie in der DKG e.V. V.p.. in der DGGG e.1 www.p. and prior to RT 1b Without cytotoxic therapy:  Start irradiation 6-8 weeks after surgery  Start endocrine therapy after surgery and a. Guidelines Breast Version 2015.Adjuvant Therapy after Primary Surgery © AGO Oxford / AGO LoE / GR e.

2015.http://onlinelibrary. Gelber RD. Winer EP. Piccart-Gebhart M.com/cochranelibrary/search 1 .. EBCC 2014 Screened consensus conference: .Goldhirsch A.Breast Cancer Surgery Oncologic Aspects (2 and 3/15) Further information and references: Thill M. Thürlimann B.1093/annonc/mdt303. SABCS 2014. doi: 10.wiley. 2013 Sep. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Epub 2013 Aug 4.24(9):2206-23. Coates AS. ESMO 2014. Rezai M. Cochrane library: . ASCO 2014. Panel members.. Ann Oncol. Update Januar 2015 Screened data bases: Pubmed 1998 . Senn HJ.

AJR Am J Roentgenol. Tardivon A. Corsetti V et al. de Wolf C.Pretherapeutic assessment (4/15) No further information References: Statement: Palpation 1. Eur J Cancer.19(4):614-22. 5. et al: European guidelines for quality assurance in breast cancer screening and diagnosis. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. and Magnetic Resonance Imaging. Holland R.2011 Jan. 2011 Mar 16.196(1):225-6. Valente SA et al. et al: Guidelines from the European Society of Breast Imaging for diagnostic interventional breast procedures.: Accuracy of Predicting Axillary Lymph Node Positivity by Physical Examination.47(7):1021-6 Krekel NM et al: Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. Mammography. 4. 2007 Feb. Eur Radiol. Ann Oncol.17(2):581-8.11:8 2 . Perry N. 2011 May. 2. Statement: Mammography / Ultrasound 1. Microcalcifications associated with ductal carcinoma in situ: mammographic-pathologic correlation (1994) Semin Diagn Pathol 11:181-92 Wallis M. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial). Hendriks JH. Ultrasonography. Fourth edition--summary document. 2008 Apr. Broeders M. Helbich T. BMC Surg. GCP Statement: General 1. 3.

Ann Surg. Morrow M.43(13):1905-17 Wallis M. 2012 Feb. Prospective comparison of stereotactic core biopsy and surgical excision as diagnostic procedures for breast cancer patients (2003) Ann Surg 235:537-541 Cheng MS. Sprague BL.255(1):38-43. Collins LC. Liu P. Lei W. 2007 Feb. Andersen JJ. Bevers T. Krishnamurthy S. Eur Radiol. Dogan BE. Broeders M. et al.254(2):243-51 Solon JG. 2007 Sep. J Am Coll Surg. 4. 3. 3 . Craft P. Yang WT.6. 6. Kuerer H. Tardivon A. Eur J Cancer. Core needle biopsy rate for new cancer diagnosis in an interdisciplinary breast center: evaluation of quality of care 20072008. Power C. AJR Am J Roentgenol. 10. Hill DA. Onega T. 2014 Jun. 9.Ann Oncol. 5. 2012 Jan. 2012 Jan. Statement minimalinvasive biopsy 1. Al-Azawi D. Bennett C. Houssami N. Venta L.17(2):581-8. De Maiffe BM. 2. Gundrum JD. Miglioretti DL.145(3):765-73. et al: A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. Ann Surg. Impact of core biopsy on the management of screen-detected ductal carcinoma in situ of the breast (2003) ANZ J Surg 73:404-406 Lord SJ. Hill AD: Ultrasound-Guided Core Biopsy: An Effective Method of Detecting Axillary Nodal Metastases.198(2):W132-40. Rauch GM.214(1):12-7. Marcou KA. Fourth edition--summary document. 2012 Feb. Stinson T. 7. Fox J. Helbich T. et al: European guidelines for quality assurance in breast cancer screening and diagnosis. Landercasper J.AJR Am J Roentgenol. Smith TB. Linebarger JH. 8. et al: Guidelines from the European Society of Breast Imaging for diagnostic interventional breast procedures. Ellis RL.198(2):292-9. Yang WT.: Outcome Analysis of 9-Gauge MRI-Guided Vacuum-Assisted Core Needle Breast Biopsies. Breast Cancer Res Treat. Perry N.: Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Duke D. Accuracy of screening mammography in women with a history of lobular carcinoma in situ or atypical hyperplasia of the breast.: Multidisciplinary considerations in the management of high-risk breast lesions. de Wolf C. Hudak JM. Ciatto S.. Houssami N. Hart SA. 2011 Aug. Abraham LA.19(4):614-22. 2008 Apr.

Brennan ME. Michael M. Am Surg. Lord S.370(9586):485-92 Houssami N. J Clin Oncol. Hayes DF Review of preoperative magnetic resonance imaging (MRI) in breast cancer: Should MRI be performed on all women with newly diagnosed early stage breast cancer. Lennard F. The Lancet. Garzoli E. Karlan SR. Conant EF. Kwan-Lim G. Khazen M. Macaskill P. Gayther SA. Sonography and MRI for Detection and Characterization of Invasive Lobular Carcinoma of the Breast. Kuhl CK. 7. Easton DF. Ciatto S Magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer: systematic review and metaanalysis of incremental cancer detection and impact on surgical management. 4. Bieling HB. 2009 Oct 21.252(2):35868. 2009 Oct. J Clin Oncol. Warren RM. JCO 2009. R. Leach MO. Evans DG.11(6):R80. Reed S. Eeles RA. . Weinstein SP. Rosen M. Radiology. Reiner CS Mammography. Phillips EH. BMC Cancer 2008. Thomas KM. Meneghetti L. Localio AR.Statement MRI 1. The UK study of MRI screening for breast cancer in women at high risk (MARIBS). Ciatto S. 2009 Nov 11. 2007 Aug 11. 2008 Jul 1. Kwan-Lim G. Breast Cancer Res. Increased use of MRI for breast cancer surveillance and staging is not associated with increased rate of mastectomy. Irwig L. Bryant E. Macaskill P: Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer: the UK MARIBS study.27(36):6124-8. et al. Schrading S.26(19):3248-58. 10. 6. 8: 275 Gilbert FJ. Eeles RA. et al: MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. 27(33):5640-5649 Houssami N. 2009 Aug. 2. 8. Bozzini A. 9. Multimodality screening of high-risk women: a prospective cohort study. United Kingdom Magnetic Resonance Imaging in Breast Screening (MARIBS) Study Group Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. Breast Dis. Warsi I.CA Cancer J Clin 2009. Schnall MD. Ramus SJ. 2009 Dec 20.30:21-30. Sensitivity of imaging for multifocal-multicentric breast carcinoma. 59:290-302 Thompson DJ. 5. Evans DG. Boggis CR. Warren RM. Leach MO. Houssami N. [Epub ahead of print] Dang CM.75(10):937-40. Zaghiyan K. Renne G. Thompson DJ. Dixon M. Warren. 3. 4 .

Vapiwala N. Macaskill P. Wheeler SB. J Clin Oncol. Preoperative breast MRI and surgical outcomes in elderly women with invasive ductal and lobular carcinoma: a population-based study. 12. 2011 Oct.11. Turnbull LW. Multicentre randomised controlled trial examining the costeffectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE). Meyer AM. 2014 Jan. Biddle AK. Ko EY. Hanby A.77(10):1368-71. Cho EY. Lau B. Choe JH. Olivier C. Walker L. Does pre-operative breast magnetic resonance imaging in addition to mammography and breast ultrasonography change the operative management of breast carcinoma? Breast Cancer Res Treat. Choi JH. Reeder-Hayes KE. Kim WW. Kim JS. Tuttle TM. 2011 Jul. 2010 Jan. Turner R. Lee JE. 2014. 17.128(1):1-5. Houssami N. Muss HB. on behalf of the COMICE Trial Group. McCready DR.119(1):163-7. Solin . Carpenter WR. Manca A. Lee SK. Romero LM: Does preoperative magnetic resonance imaging beneficially alter surgical management of invasive lobular carcinoma? Am Surg. 15. Lim HI. Brown S. Sculpher M. An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence in individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. Breast Cancer Res Treat. Drew P. Walker S. Kim JH. 14. Shin JH. Yang JH. Kim SW.14(1):1-182. 13. Brown J. Epub 2011 Apr 16. Johnson L. Turnbull L. Napp V.32(5):392-401 Fortune-Greeley AK. Nam SJ. Han BK. 2010 Jan. Harvey I. Douek M Multiple foci of invasive breast cancer: can breast MRI influence surgical management? Breast Cancer Res Treat. Health Technol Assess.143(1):203-12 5 . Kim S. Kang SS. Pinder S.

3. Blaufox MD. 2013 Jun. Cardarelli R. 6 . 6. Surg Oncol. Seitz E. 4.33(2):97-101. Isasi CR. GCP Statement: high metastatic potential / symptoms 1. A meta-analysis.22(2):86-91 Hong S. Surg Oncol. Muller H et al: Perioperative screening for metastatic disease is not indicated in patients with primary breast cancer and no clinical signs of tumor spread.269(1):9-12. A meta-analysis. Rutgers. Shie P. Steiner RA et al: Frequency and distribution pattern of distant metastases in breast cancer patients at the time of primary presentation Arch Gynecol Obstet. Wang S. 18FDG PET-CT for diagnosis of distant metastases in breast cancer patients.Pre-operative staging (5/15) No further information References: Statement: history and physical examination 1. A meta-analysis of FDGPET for the evaluation of breast cancer recurrence and metastases. Breast Cancer Res Treat 82:29-37. 2003 Nov. 5. Moadel RM. 7. Yun M. Ye S.90(2):105–12.22(2):139-43. Brandon D et al: Meta-analysis: comparison of F-18 Fluorodeoxyglucose-positron emission tomography and bone scintigraphy in the detection of bone metastases in patients with breast cancer. 2008 Feb. Fehr MK. 2003 Schneider C. EJ et al: Quality control in the locoregional treatment of breast cancer (2001) EJC 37: 447-453 Gerber B. Zheng Z. Breast Cancer Res Treat 2005. Wang S. Clin Nucl Med. 2013 Jun. Ding Q. Comparison of 18 FDG PET-CT and bone scintigraphy for detection of bone metastases in breast cancer patients. 2. Rong J. Li J.

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Evidence of surgical procedure (6/15) No further information References: Statement: lumpectomy – mastectomy 1. Kroll SS. Johansen H. Duda RB et al. Bostwick J. Jensen MB. 3. Skin-sparing mastectomy.47(4):633-8 Statement: skin sparing mastectomy 1. 2. Acta Oncol. Jeong JH. Tadjalli HE et al. Anderson S. Risk of recurrence after treatment of early breast cancer with skinsparing mastectomy Ann Surg Oncol 1997. Margolese RG. Fisher B. A fifty-year follow-up to the Copenhagen Breast Cancer randomised study. Slavin SA. Styblo TM et al. 2008. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol. Mouridsen HAT: Extended radical mastectomy versus simple mastectomy followed by radiotherapy in primary breast cancer. Nielsen M. 8 . 2008.Acta Oncol. 3. and lumpectomy plus irradiation for the treatment of invasive breast cancer (2002) N Engl J Med 347:1233-1241 Veronesi U et al. 4. Wolmark N. 4:193-197. Carlson GW.: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.347(16):1227-32 Blichert-Toft M. Deutsch M. 225:570-575. Skin-sparing mastectomy and immediate reconstruction: oncologic risks and aesthetic results in patients with early-stage breast cancer. NEJM 2002 Oct 17. Twenty-year followup of a randomized trial comparing total mastectomy. Ann Surg 1997.47(4):672-81. Plast Reconstr Surg 1998. Oncologic and reconstructive considerations. Bryant J. Schnitt SJ. 2. Kaae S. lumpectomy. Long-term results of breast conserving surgery vs. Düring M. 102:49-62. Schusterman MA. Fisher ER.

96:47-51. 5. Paepke D. Dooley WC. 17:97-105. 7. Patani N. Pusic AL et al. Jacobs VR. Plast Reconstr Surg 2006. 4. Petit JY. 10. Howard MA. Orecchia R et al. 9. Simmons RM. 6:676-681. Eur J Surg Oncol 2006. Simmons RM. Ann Surg Oncol 1999. Schlossberg L. Local and distant recurrence rates in skin-sparing mastectomies compared with non-skin-sparing mastectomies. Devalia H. Perbeck L. 3. Breast cancer local recurrence after mastectomy and TRAM flap reconstruction: incidence and treatment options. Foster et al. Schmalfeldt B. Survival in breast cancer after nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants: A prospective trial with 13 years median follow-up in 216 patients. Caruso F.250(2):288-92 Gerber et al. Fifteen-year series of skin-sparing mastectomy for stage 0 to 2 breast cancer. Nipple-sparing mastectomy in association with intra operative radiotherapy (ELIOT): A new type of mastectomy for breast cancer treatment. Nipple sparing subcutaneous mastectomy: sixty-six months follow-up. Polo K. Pinotti JA. Breast cancer local recurrence after mastectomy and TRAM flap reconstruction: incidence and treatment options. Anderson A et al. 6:331-335. Fleckner S. Kiechle M. Howard MA. Pusic AL et al. Polo K. 32:937-940. Ann Surg 2009 Mar. Eur J Surg Oncol 2008. Cancer 2000. 9 . Veronesi U. Gayle L et al. Breast Cancer Res Treat 2006. Sacchini V. Am J Surg 2005. 2009. Barros AC et al.9(5):462-6 Greenway RM. 6. Niemeyer M. Fish SK et al. Castiglione G et al. Fish SK. Skin-sparing mastectomy and immediate breast reconstruction: a prospective cohort study for the treatment of advanced stages of breast carcinoma. Schmid R. 117:1381-1386. Oncological safety and patient satisfaction with skin-sparing mastectomy and immediate breast reconstruction. Ann Surg Oncol 2002 Jun. 8. 5. Rivadeneira D. 203:704-714. 34:143-148. 117:1381-1386 Benediktsson KP.4. Surg Oncol 2007. Plast Reconstr Surg 2006. 2.249(3):461-8 Statement: Nipple sparing mastectomy 1. Skin-sparing mastectomy with immediate breast reconstruction: a critical analysis of local recurrence. 11. Paepke S. Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications Ann Surg.: Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. 190:918-922. Ferrara M. Nipple-sparing mastectomy for breast cancer and risk reduction: oncologic or technical problem? J Am Coll Surg 2006.

6. Gadgil PV. Hardee M. 2013 Oct. 7. Ann Surg Oncol. Ochoa D. Suzanne Klimberg V. Gerber et al. Henry-Tillman R. Nipple skin-sparing mastectomy is feasible for advanced disease. Das C.: Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. 10 . Ann Surg 2009 Epub ahead of print Burdge EC.20(10):3294-302. Yuen J. Korourian S.

Nonpalpable breast lesions. van Hemelrijck M. 1. 1992 Apr. 2. World J Surg. Ultraschall Med. Breast Cancer Res Treat. Zurrida S. 2013 Jul. Breast Cancer Res Treat. Ahmed M. Hobbelink M.140(2):241-52 Statement: specimen radiography 11 .: The use of stereotactic excisional biopsy in the management of invasive breast cancer. Krause B. surgical technical aspects (7/15) No further information References: Statement: Wire guided . General considerations and a review of the literature in the light of the authors' own experience with 344 cases located preoperatively. Statement: Radioguided . 2007 Jun. 4. Radiol Med. Grunwald S. 2008 Jan. 2013 Aug.Breast conservation. Ohlinger R.28(3):283-90. 1. Paepke S. Ahmed M. 2. Ultrasound and mammography guided wire marking of non-palpable breast lesions: analysis of 741 cases. Thomas A.140(3):435-46. 3. Schimming A. Douek M. Eur J Surg Oncol. Jäger B. Douek M..34(1):1-5. Schwesinger G.29(11):1490-4 Köhler J. Cosmacini P..83(4):383-9 Hanna et al. van der Ploeg IM. Intra-operative ultrasound versus wire-guided localization in the surgical management of nonpalpable breast cancers: systematic review and meta-analysis.. Köhler G. van den Bosch MA: 'Radioguided occult lesion localisation' (ROLL) for nonpalpable breast lesions: a review of the relevant literature. Systematic review of radioguided versus wire-guided localization in the treatment of non-palpable breast cancers. 2005 Nov. Veronesi P..

Mason G.112(3):366-76. 2014 Oct. Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. Cendán JC et al. Ann Surg Oncol. Solin LJ.21(3):717-30 Buchholz TA. 5. Kunos C. 2006 Dec. 2002 Nov.. Houssami N.14(4):1458-71.32(14):1502-6. Radiol Med (Torino). 3.. Balleyguier C. 1. Metaanalysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breastconserving therapy.46(18):3219-32. 2014 Mar. Newman LA. Di Virgilio MR. Ann Surg Oncol. Tan KY et al. Sahin et al: Role for Intraoperative Margin Assessment in Patients Undergoing Breast-Conserving Ann Surg Oncol. Lyman GH. Menna S. Dixon JM. El-Eid S. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. 2006 Sep. Downs-Kelly E. Breast specimen ultrasound and mammography in the prediction of tumour-free margins. Brennan ME. 2. Hunt. Somerfield MR. Accuracy of Intraoperative Frozen-Section Analysis of Breast Cancer Lumpectomy-Bed Margins.76(12):1064-7. 2006 Jan-Feb. 2014 May 10. Houssami N. J Am Coll Surg 2005. Rouzier R. 7. Cabioglu N. J Clin Oncol. Macaskill P. Eur J Cancer.1. 12 . Hammond ME. 2007 Apr. 2. 4. Singletary: Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Breast J.201:194–198. Clin Radiol. Macaskill P. Morrow M. Specimen radiography as predictor of resection margin status in non-palpable breast lesions. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. 2010 Dec.61(9):789-96. Am J Surg. 4. Ciccarelli G.12(1):28-36 Statement: tumor free margins . Marinovich ML. Irwig L. Harness JK. 3. 2007 Apr. Marinovich ML. Griggs JJ. ANZ J Surg. Radiography of the surgical specimen in early stage breast lesions: diagnostic reliability in the analysis of the resection margins.184(5):383-93. Mazouni C.. Giuliano AE. Overmoyer B Breast conservation surgery achieving>or=2 mm tumor-free margins results in decreased local-regional recurrence rate.21(10):3192-7. Latson L. 6. Pockaj BA.

1. 2007 Dec 1. Leong T. J Clin Oncol. 1. Orell E. Winer EP. Ho A. J Surg Oncol.32(20):2142-50.30(2):146-51. Statement: stereotactic excision alone . Kurniawan ED. Cancer. Chung A. Wazer DE. Burstein HJ. 2.Triple negative breast cancer is associated with an increased risk of residual invasive carcinoma after lumpectomy. 3. Eaton A. 2002 Aug.96(7):569-74 McIntosh A. re-excision .224(2):548-54 13 . Breast-conserving therapy for triple-negative breast cancer.. 2014 Jul 10. Price LL.. Lomme MM. Edge SB. Mamet R.. Morrow M. Theriault RL. Hughes ME. Mirocha J. Weeks JC. Cramer C. Cawson JN. Ehdaivand S. 2012 Aug 15.. 2014 Mar. Pilewski M. 3. Van de Vrande SL. Boetes C: Residual disease after re-excision for tumor-positive surgical margins in both ductal carcinoma in situ and invasive carcinoma of the breast: The effect of time. Am J Clin Oncol. Eisenberg D: Recurrence rates and analysis of close or positive margins in patients treated without re-excision before radiation for breast cancer. Ann Surg Oncol. JAMA Surg. Birdwell RL. 2006 Jul. Freedman G. Ikeda DM: Atypical ductal hyperplasia: can some lesions be defined as probably benign after stereotactic 11-gauge vacuum-assisted biopsy. Giuliano AE. Outcomes by tumor subtype and treatment pattern in women with small. Patil S. Moore SE: Margins and outcome of screen-detected breast cancer with extensive in situ component. Ann Surg Oncol. Stempel M.76(7):591-5 Schouten van der Velden AP... Liou DZ.15(9):2542-9. Wong MH. Statement: . Kitchen PR. Gonzalez-Angulo AM. 2007 Apr.21(4):1209-14. node-negative breast cancer: a multi-institutional study.149(3):252-8 Vaz-Luis I. 4. Sioshansi S. Moy B. Ottesen RA. eliminating the recommendation for surgical excision? Radiology. 2. Rugo HS. Windle I: Predictors of surgical margin status in breast-conserving surgery within a breast screening program. ANZ J Surg. 2008 Sep.Statement: tumor free margins in intrinsic subtypes 1. Chen Y. 4.118(16):3893-8 Gangi A. Effect of margin width on local recurrence in triple-negative breast cancer patients treated with breast conserving therapy. Jackman RJ. 2014 Apr. Lin NU.

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Wischnewsky M. Intra M. Wolters R. Goldhirsch A. Janni W.1111/ans. Huston T.142(3):579-90. reexcision. Breast Cancer Res Treat. ANZ J Surg. Wallner PE. Amer J Surg. Botteri E. Da Lima L. and local recurrence of breast cancer. Gentilini O. Musmeci S. 2003 Aug 20.12942. Veronesi P. Amer J Surg 2005.935 patients. 2. 2014 Dec 5. Caliskan M. Conservative surgery in patients with multifocal/multicentric breast cancer. 81-85 Cellini C. 1. Galimberti V. 2013 Dec.95(16):1182-3.. 189. Luini A. Comparing the outcome between multicentric and multifocal breast cancer: what is the impact on survival. Mazzarol G. 2009 Feb. and is there a role for guideline-adherent adjuvant therapy? A retrospective multicenter cohort study of 8. Martins D. doi: 10. Breast Cancer Res Treat. Inflammatory breast issue. Ebner F. Viale G. Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue. Schwentner L. Veronesi U. Abrams JS. BRENDA Study Group. Garcia-Etienne CA. 2. 2. Sitoh NY. et al. Tan MP. Sosnovskikh I. Wöckel A. [Epub ahead of print] Statement: positive microscopic . Kreienberg R. Sim AS. 3. 2000. Novopashenny I.: Lumpectomy margins.113(3):577-83. Multiple re-excisions versus mastectomy in patients with persistent residual disease following breast conservation surgery..Breast Conservation Surgery (8/15) No further information References: Statement: Multicentricity 1. Coleman CN. 662-666 Statement: Inflammatory Carcinoma 1. Rotmensz N. 179. Tartter P. J Natl Cancer Inst. 15 .

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Julian TB. Avigdor S. McCready DR. Bogaerts J. Perkins CL. Mammolito DM. 3. Klinkenbijl JH.8(10):881-8. de Lara CT. American Society of Clinical Oncology Clinical 29 . 2007 Oct. J Clin Oncol. Mansel RE. Vaini-Elies V. Sentinel node identification rate and nodal involvement in the EORTC 10981-22023 AMAROS trial. Burstein HJ. Dravet F. Robidoux A. Lancet Oncol. Cataliotti L. Lorimier G. van de Velde CJ. Miller BJ. Pesek S. Houvenaeghel G. Giuliano AE. 2010 Jul. Harlow SP. Ashikaga T.17(7):1854-61. Ashikaga T. Rutgers EJ. Fondrinier E. Hurkmans C. Ferron G. The false-negative rate of sentinel node biopsy in patients with breast cancer: a meta-analysis. Brémond A. Krag LE. Ann Surg Oncol. Fogg L. Velten M. Avril A. Frazier TG. Mignotte H. Newman LA. Wool N. Brown AM. Prospective multicentric randomized study comparing periareolar and peritumoral injection of radiotracer and blue dye for the detection of sentinel lymph node in breast sparing procedures: FRANSENODE trial. Weaver DL.Sentinel Lymph node excision: Marking (13/15) No further information References: Statement radiotracer/blue dye: 1. Temin S. Jalovec LM. Routiot T. Surgery.144(4):606-9. Ali A. 5. Hayman J. 6. Bosserman LD. Benson AB 3rd. Straver ME. Anderson SJ. Wilt M.The use of radioisotope combined with isosulfan Blue dye is not superior to radioisotope alone for the identification of sentinel lymph nodes in patients with breast cancer. Duez N. discussion 609-10. van der Mijle H. Weaver DL.36(9): 2239-2251 Lyman GH. Snoj M. Podoloff DA. Classe JM. Mamounas EP. 2007 Aug 20. Wolmark N. Meijnen P. Cody H 3rd. van Tienhoven G. Rodier JF. 4. World J Surg 2012. Costantino JP. Scarth HM. Krag DN. Martel P.25(24):3664Bines S. Kopkash K. 2008 Oct. Noyes RD. Krag D. Turner RR. National Surgical Adjuvant Breast and Bowel ProjeTechnical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. 2. Edge SB. Westenberg HA.

Teo C.101(4):383-9. Forghani MN. Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer. J Ultrasound Med. Wiese D. Korant A. Shin JH. Birbas K.32(13):1365-83 Ang CH.16(8):2224-30. Loh SW. 2014 Mar.38(8):651-6. Br J Surg. Abdollahi A. A prospective trial comparing 1% lymphazurin vs 1% methylene blue in sentinel lymph node mapping of gastrointestinal tumors.102(3):169-81. Clin Oncol. 2009 Aug. Wishart GC. 2014 Oct. Han BK. Ann Surg Oncol. Yang JH. 2015 Feb. 8. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. Eur J Surg Oncol. Chan MY. 5. Mostafa A. Carpenter R.104(1):37-40. Fattahi AS. Wells CA. Lee JE. Tan MY. 4. 3. 30 . 2011 Jul 1. Prospective comparison of peritumoral and subareolar injection of blue dye alone. Gattuso J. Gayar A. 2012 Aug. Methylene blue dye-related changes in the breast after sentinel lymph node localization. Syrigos K. Soni M. Ko EY. J Surg Oncol. Akberali S. Kang SS. Tavassoli A. Douek M. Sadeghi R. Iddings D. Horgan K. discussion 389. Varghese P. Seah DW. Br J Surg. Blue dye is sufficient for sentinel lymph node biopsy in breast cancer. Bonatsos G. Statement: ICG: 1.19(10):918-22. Chakravarty B. Abdel-Rahman AT. Can methylene blue dye be used as an alternative to patent blue dye to find the sentinel lymph node in breast cancer surgery? J Res Med Sci. 2011. Kaklamanos IG. Cho EY. Practice. Canizales A. Purushotham AD. Bonatsos VG. Statement: methylene blue 1.7. Nam SJ. 2007 Mar.33(2):147-52. Benson JR. 2. Fritz P. Ahmed M. for identification of sentinel lymph nodes in patients with early stage breast cancer. Methylene blue dye versus combined dye-radioactive tracer technique for sentinel lymph node localisation in early breast cancer. Chen JC. Saha S. Tan EY.30(12):1711-21. Klaase JM. Rohbakhshfar O. A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer. Jones L. 2014 May 1. Eur J Surg Oncol. Sirop S.

Gao W.21(4):1254-9. Tong M. Purushotham AD.23(2):175-9.J Breast Cancer. Statement: Comparisons 1. 2015 Jan. Douek M. Park IH. Fogacci T. Ten Haken B. Wyld L. Frisoni G. Lee S Comparison of sentinel lymph node biopsy guided by the multimodal method of indocyanine green fluorescence. Kang SH. Zechmeister K. Pinder S. 31 . Guo W. Ahmed M. Use of Fluorescence Imaging in Combination with Patent Blue Dye versus Patent Blue Dye Alone in Sentinel Lymph Node Biopsy in Breast Cancer. Gianni L.17(3):250-5. Breast. Radioisotope. Eur J Surg Oncol.41(1):46-51 Thill M. Nicoletti S. and blue dye versus the radioisotope method in breast cancer: a randomized controlled trial. Tamburini E. Rubio IT. 2014 Apr.21(4):1237-45. Anninga B. Cortadellas T. Statement: SPIO: 1. The superparamagnetic iron oxide is equivalent to the Tc99 radiotracer method for identifying the sentinel lymph node in breast cancer. Cordoba O. Douek M. Lancet Oncol. Purushotham A. Brown D. Berclaz G. The CentralEuropean SentiMag study: sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. Grootendorst M. 3. Klaase J. Espinosa-Bravo M.15(8):e351-62. Shin KH. Kim SK. Hauser N. Lee ES. Kurylcio A. Eur J Surg Oncol. Joo J. Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG Multicentre Trial. Monypenny I. Kwon Y.2. Ann Surg Oncol. van Haasteren V. 2. Diaz-Botero S. Flenghi L. Hall-Craggs MA. 2014 Apr. Statement: General 1. Agbaje O. Novel techniques for sentinel lymph node biopsy in breast cancer: a systematic review. Kim SW. 3. Grosse B.41(1):64-70. Ricci M. Polkowski W. 2014 Apr. 2014 Sep. Jeong HJ. Panzini I. Rodriguez R. Ko KL. Esgueva A. 2014 Jul. Ann Surg Oncol. Fabbri E. 2015 Jan.The use of indocyanine green to detect sentinel nodes in breast cancer: A prospective study. Pankhurst Q. Ro J. Kang HS. Garmo H. Kothari A. SentiMAG Trialists Group. Accardi FG. Tassinari D. Drew P. Welter R. radioisotope. Lee KS. Samorani D. Jung SY.

Kinoshita T. Epub 2013 Feb 21.Comparison of the indocyanine green fluorescence and blue dye methods in detection of sentinel lymph nodes in early-stage breast cancer. Toi M. Ikeda T. Sugie T. Ann Surg Oncol. 2013 Jul. Tagaya N. Yoshimura K. Shimizu A.20(7):2213-8. Suwa H.2. Yamagami K. Niimi M. Sawada T. 32 . doi: 10.1245/s10434-013-2890-0.

why and why not clipping after breast biopsy? Breast Cancer Res Treat. Darai E. Uzan S.Surgical conservation planning after neoadjuvant chemotherapy for stage II and operable stage III breast carcinoma. Makris A.2011(43):147-51. Kaufmann M. Trop I. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. Ross MI. Kümmel S. Italy (2010). Sapino A. 2. Berruti A. 2012 Apr. Am J Surg. Singletary SE. Surgical treatment of primary breast cancer in the neoadjuvant setting. Fox SB. Conte P. Desmedt C. Cremona. Tortora G. Kennedy D. 2. Hunt KK.A plea for the biopsy marker: how. Dowsett M.132(3):881-93. Loibl S. Lalonde L. Untch M. Sotiriou C. Puztai L. 2014 Jul.97(3):188-94. Kuerer HM. Bottini A. Dogliotti L. J Natl Cancer Inst Monogr. Dontu G.Procedure after neoadjuvant treatment (14/15) No further information References Statement: clip marking 1. Ferrozzi F. Di Cosimo S. J Natl Cancer Inst. de Azambuja E. Statement: operation and : tumor resection in new margins 1. Mauri D. Holtschmidt J. Fenaroli P. Generali D. Tagliabue E. Pusztai L.101(8):912-24 33 . Thomassin-Naggara I. Petronini P. 2001 Dec. International expert consensus on primary systemic therapy in the management of early breast cancer: highlights of the Fourth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer. Bruzzi P. Damia G. Valero V. Harris AL. Hortobagyi GN. Mansel RE. Curigliano G. Pavlidis N. Br J Surg. Danova M. Ioannidis JP. Olivetti L. 2005 Feb 2. Gianni L. Thorne H. Tondini C. Bertolini F. Aglietta M. Daidone M. Buzdar AU. Van't Veer L.182(6):601-8. 3. Tampellini M. Buchholz TA. David J. Miller WR. Ames FC. 2011.

Marinovich ML. Accuracy of Intraoperative Frozen-Section Analysis of Breast Cancer Lumpectomy-Bed Margins. Morrow M. Menna S. Lederer B.. 2014 Mar. 2014 Oct.112(3):366-76. 5. Radiography of the surgical specimen in early stage breast lesions: diagnostic reliability in the analysis of the resection margins. Ann Surg Oncol. Houssami N. Ciccarelli G. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Blohmer JU. 4. Macaskill P. [Epub ahead of print] Statement: tumor free margins . Macaskill P. 7. Cendán JC et al.201:194–198. Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. Radiol Med (Torino). Irwig L. Somerfield MR. Lyman GH.4. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Cabioglu N. 2007 Apr. J Clin Oncol. 2007 Apr. Harness JK. Ann Surg Oncol. 6. 2014 May 10. Hammond ME. Di Virgilio MR. Hunt. Marinovich ML. Kühn T. Sahin et al: Role for Intraoperative Margin Assessment in Patients Undergoing Breast-Conserving Ann Surg Oncol. 34 .21(10):3192-7. Heil J. Dixon JM.21(3):717-30 Buchholz TA. El-Eid S..32(14):1502-6. Ann Surg Oncol. Impact of Multifocal or Multicentric Disease on Surgery and Locoregional. Solin LJ. Brennan ME. Denkert C. Newman LA. Ataseven B. Metaanalysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breastconserving therapy.14(4):1458-71. von Minckwitz G. 1. Downs-Kelly E. Pockaj BA. Kümmel S. 2010 Dec. Distant and Overall Survival of 6. 3. Eur J Cancer. 2014 Oct 9.134 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.. Loibl S. Gerber B. 2. Rezai M. Griggs JJ. Houssami N.46(18):3219-32. Mason G. Giuliano AE. J Am Coll Surg 2005.

2010. Chua BH. Azria D. Cole BF. Combining systemic therapies with radiation in breast cancer. Adamowicz K. Belkacémi Y. Marczewska M. Int J Radiat Oncol Biol Phys. Statement: Tamoxifen concurrent with chemotherapy 1. Tsoutsou PG.36(6):443-50. Christensen VJ. Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy. Karlsson P. International Breast Cancer Study Group. 3.a retrospective analysis. 35 . Timing of adjuvant systemic therapy and radiotherapy after breast-conserving surgery and mastectomy. Leonardi MC. 2009 Aug. Murray E. Goldhirsch A. Cancer Treat Rev. Hwang WT. Balduzzi A. 2009. Fox K.35(5):409-16 Harris EE. Castiglione-Gertsch M. Colleoni M. Koukourakis MI. 4. Gruber G.Ajuvant therapy after primary surgery (15/15) No further information References: Statement: Timing of radiation and chemotherapy 1. Roncadin M. Colleoni M. Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. 2005 Jan 1. 2008 Apr 23. Jassem J. Price KN. Solin LJ. Iorfida M. Dellapasqua S. J Clin Oncol. Sequencing chemotherapy and radiotherapy in locoregional advanced breast cancer patients after mastectomy .71(2):102-16.8:114. Orecchia R. Stanzel S. BMC Cancer. Goldhirsch A. 2. 2. Cardillo A. Eble MJ. Optimal timing for adjuvant radiation therapy in breast cancer: a comprehensive review and perspectives. Pinkawa M. Gagel B. 2011. Crit Rev Oncol Hematol. Cancer Treat Rev. Asadpour B.80(2):398-402.23(1):11-6. Piroth MD.

Motomura K. World J Radiol.Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. Bollet MA. Tamaki Y. 3. Coelho M. Treatment sequence of aromatase inhibitors and radiotherapy and long-term outcomes of breast cancer patients. Nakayama T. Osborne CK. Lemanski C.11(3):258-65 Chargari C. Ozsahin M. Belkacemi Y.34(8):4311-4. Nishiyama K.4(7):318-23. Statement AI concurrent with radiotherapy 1. J Clin Oncol.3. Albain KS. Hutchins LF. Shiba M. Gourgou S. Koyama H. Romieu G. Ishitobi M. Livingston RB. Cottu P. Kirova YM. Crompton NE. Toledano I. Castro-Pena P. Anticancer Res. Lancet Oncol 2010. Gralow JR. 2012. Pierce LJ. Rosenstein B. Lew DL. Gutowski M. Moscardo CL. 2014. Fenoglietto P. Concurrent use of aromatase inhibitors and hypofractionated radiation therapy.23(1):24-9. Laki F. Campana F. De Cremoux P. Azria D. Savignoni A. 2. 36 . Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. Green SR. Zaman K. Fourquet A. 2005 Jan 1.

V. sowie in der DKG e. Guidelines Breast Version 2015.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. V.1 Oncoplastic and Reconstructive Surgery . in der DGGG e.V.

1 www. V.V. sowie in der DKG e. in der DGGG e.ago-online.V.  Versions 2002–2014: Audretsch / Blohmer / Brunnert / Dall / Fersis / Hanf / Kümmel / Lux / Nitz / Rezai / Rody / Scharl / Thomssen  Version 2015: Bauerfeind / Brunnert Guidelines Breast Version 2015.de .Oncoplastic and Reconstructive Surgery © AGO e.

V. Guidelines Breast Version 2015.Definition of Oncoplastic Surgery © AGO e.de Use of plastic surgical techniques at the time of tumor excision to enable safe resection margins and to preserve aesthetic breast contour. .ago-online. in der DGGG e. increases the number of BCTs and leads to high patient satisfaction. sowie in der DKG e.1 www.V. V. Oncoplastic surgery reduces the number of reexcisions.

sowie in der DKG e. V.Oncoplastic Breast Conserving Surgery © AGO Oxford / AGO LoE / GR e.V.ago-online.V.1     www. in der DGGG e. Guidelines Breast Version 2015.de Reduction mammaplasty Mastopexy techniques Oncoplastic flap techniques Partial mastectomy with tissue transfer 2a 3a 2a B B B + + + 3b B + .

V. V.1 TRAM-Flap or Consider implant + additional acellular matrix and / or fat grafting LADO + implant if both not suitable if not suitable Microsurgery/free flaps www. in der DGGG e.de .V. Implant alone not suitable – hostile environment Guidelines Breast Version 2015.Algorithm of Breast Reconstruction © AGO 1st choice: Implant-Reconstruction e.ago-online. sowie in der DKG e.

Guidelines Breast Version 2015. age .1 www. V. in der DGGG e.V. sowie in der DKG e. RT.V.de  Use of silicone filled breast implants 2a B +  Autologous tissue reconstruction 2a B +  Pedicled tissue reconstruction 2a B +  Free tissue reconstruction 2a B +  Autologous tissue combined with implants 3a C + Attention: BMI >30.Postmastectomy Reconstruction © AGO Oxford / AGO LoE / GR e. smoking status. Diabetes.ago-online.

Timing of Reconstruction © AGO Oxford / AGO LoE / GR e.de  B ++ 3b B ++ B +/- No interference with adjuvant procedures (CHT. sowie in der DKG e. RT) Disadvantage: loss of skin envelope Immediate BR  3b Mandatory: SSM / NSM Avoidance of a postmastectomy syndrome „Delayed-immediate“ BR 3b .V.ago-online.1  Delayed BR     www. V.V. Guidelines Breast Version 2015. in der DGGG e.

in der DGGG e.ago-online. sowie in der DKG e.Timing of Postmastectomy Implant Reconstruction © AGO Oxford / AGO LoE / GR e. V.V. antibiotic therapy (at least 48 h) 3b C +  www.1  Implant reconstruction (IR) 2a B +  IR without radiotherapy (RT) 2a B ++  IR following MX and RT 2b B +/-  IR prior to RT / following PBRT (higher complication rate) 2a B + IR following Mx for local relapse after BCT 2a B +/- Periop.de  . Guidelines Breast Version 2015.V.

V.V.g. Guidelines Breast Version 2015. sowie in der DKG e.ago-online. in der DGGG e.1    Autologous tissue (e.V. LDF*) Acellular dermal matrix (ADM) Synthetic mesh 3b 2b 2b C +# B +# B +# * LDF = Latissimus dorsi flap www.de # Participation in register studies recommended .Soft Tissue Replacement Techniques © AGO Oxford / AGO LoE / GR e.

Guidelines Breast Version 2015. V. sowie in der DKG e.V.ago-online. Oxford / AGO LoE / GR in der DGGG e.Lipotransfer © AGO e.V.1   Lipotransfer after MX and breast reconstruction 2a B + Lipotransfer after breast-conserving therapy 4 D +/- Autologous adipose derived stem cells (ASCs)-enriched fat grafts 5 D - www.de  .

1 Reconstruction (BR) with autologous tissue TRAM. sowie in der DKG e. latissimus-dorsi-flap (both can be performed as a muscle-sparing technique) 3b C +  Delayed TRAM in risk patients 3a B +  Ipsilateral pedicled TRAM 3b A +  Radiotherapy:  www. V.ago-online.V. Guidelines Breast Version 2015.V.de  BR following RT 2a B +  BR prior to RT (more fibrosis. in der DGGG e.Postmastectomy Pedicled Reconstruction © AGO Oxford / AGO LoE / GR e. more wound healing problems. more liponecrosis) 2a B +/- .

Free Tissue Transfer © AGO Oxford / AGO LoE / GR e. Disadvantages:       Time. Guidelines Breast Version 2015. The DIEP has a lower rate of abdominal hernias.and personnel-consuming microsurgical procedure Intensified postoperative monitoring Higher rate of re-operations Higher total failure rate Pre-reconstruction RT increases rate of vascular complications No higher patient satisfaction than with pedicled TRAM in multivariate analysis . in der DGGG e.ago-online.1 Free tissue transfer      Free TRAM-flap DIEP-flap SIEA-flap SGAP. DIEP are potentially muscle-sparing procedures.V.de Free TRAM./ IGAP-flap Free gracilis flap (TMG) 3a 3a 3a 4 B B 4 +/+ C +/- C +/- C +/- Advantage:  www. V.V. sowie in der DKG e.

V. Free Tissue Transfer © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015. impaired muscle function) has to be taken into consideration in all flap techniques  A ++ .g. sowie in der DKG e.de Muscle-sparing techniques and accuracy of abdominal wall closure will lead to low rates of late donor site complications whatever method used 3a  Autologous abdominal-based reconstructions have the highest satisfaction in all patient groups without any difference  Perforator flaps appear to have a higher risk for fat necrosis than free or pedicle TRAM  Donor site morbidity (e. V.ago-online.Pedicled vs.1 www.V. in der DGGG e.

Flap-Implant Combination © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015.1 Flap-implant combination LDF* + implant  IR following RT  IR prior to RT Advantages:  www.V.V.ago-online. sowie in der DKG e.de   TRAM: staged procedure preferable Improved implant coverage Suitable for radiated tissue Disadvantage:  Muscle contraction (LDF) * LDF = Latissimus dorsi flap 2b 3b 5 C C D + + - . V. in der DGGG e.

in der DGGG e.1  Skin sparing mastectomy (SSM/NSM)    Safe (same recurrence rate as MX) Higher QoL for patients NAC can be preserved under special conditions  www. inframammary fold  Lowest incidence of complications 2b B + .V.de  Feasible after mastopexy / reduction mammoplasty 2b 2b B B ++ ++ 2b 4 B C ++ ++ Skin incisions  different options possible:    Periareolar („purse-string“) (higher risk of necrosis) Reduction pattern: „inverted-T“ or vertical Inferior lateral approach. sowie in der DKG e.V. Guidelines Breast Version 2015. V.Skin/Nipple Sparing Mastectomy (SSM/NSM) and Reconstruction © AGO Oxford / AGO LoE / GR e.ago-online.

ago-online. V. sowie in der DKG e. lifetime risk >=30% or heterozygote risk >=20%) but index case negative for BRCA1/2 mutations 3a C +/-*  High risk and no BRCA counselling in specialized centre* 5 D --  Non-directive counselling prior to RRBM 2b B ++*  RRBM should be considered with other prophylactic surgical options incl. in der DGGG e.V.Bilateral Risk Reducing Mastectomy in Healthy Women (RRBM) © AGO Oxford / AGO LoE / GR e.e.V. risk prediction and follow-up in • * Study participation recommended specialised centres recommended . salpingoophorectomy (BSO) 2a A ++* 1b A ++  Further need for education of physicians regarding possibilities and advantages of RRBM *Counselling.1 www. Guidelines Breast Version 2015.de  RRBM reduces breast cancer incidence 1b A ++  RRBM in deleterious BRCA1/2 mutation 2a B +*  RRBM in high risk (i.

bc-spec mortality reduction likely  Simple mastectomy 2b B +  RRBM by SSM 2b C +  RRBM by NSM (NAC sparing) 2b C + Contralateral prophylactic MX 4 C +/- www.ago-online.V.1 Risk Reducing Mastectomy reduces breast cancer incidence. in der DGGG e.V. Guidelines Breast Version 2015. V. sowie in der DKG e.de  * Study participation recommended .Types of Risk Reducing Mastectomy © AGO Oxford / AGO LoE / GR e.

de *Brunnert. Prax. in der DGGG e.V.. K. Guidelines Breast Version 2015. Gyn.ago-online. Band 31. V.V. sowie in der DKG e. 2007 .Algorithm of Breast Reconstruction © AGO e.1 www.

in der DGGG e.V. sowie in der DKG e.ago-online.1 www. V.Algorithm of Autologous Breast Reconstruction (1) © AGO e. Guidelines Breast Version 2015.V.de .

V. sowie in der DKG e. in der DGGG e.1 www.V.Algorithm of Autologous Breast Reconstruction (2) © AGO e.de (MS-2) Double MS-2 pTRAM or Free TRAM Bip TRAM (MS-2) fTRAM (MS-2) DIEP .ago-online. Guidelines Breast Version 2015. V.

I = implant. V. CF = Capsula fibrosis.V.1 www./ Implantat .ago-online. sowie in der DKG e.V. MPS = micropolyurethran surface + Exp. Guidelines Breast Version 2015. in der DGGG e.de Premastectomy Sentinel Node Biopsy SSM/NSM Expander/Implant Reduction pattern SSM+E/ I +Lado E/I E = expander .Algorithm of Implant Breast Reconstruction © AGO e.

SOPs für die Überarbeitung der AGO-Leitlinien zum Mammakarzinom 2006 2 Verwendete Guidelines zu Diagnostik und Therapie des Mammakarzinoms: National Institute of Health (NIH): http://www. Oxford Centre for Evidence-Based Medicine. Canadian Medical Association (CMA): http://www.ca/cgi/content/full/158/3/DC1 NCCN 2007: http://www.cmaj. and Hazel Thornton. Trish Greenhalgh.org/portal/site/ASCO/menuitem. Cochrane Breast Cancer Specialised Register) Einteilung in EBM-Grade nach Jeremy Howick. Alessandro Liberati. Iain Chalmers.pdf .net/index. Carl Heneghan. http://www.gov/cancertopics/pdq/treatment/breast/HealthProfessional/) American Association of Clinical Oncology (ASCO) and Technology Assessments: http://www.cebm.asco.Oncoplastic and Reconstructive Surgery (2/21) Further information and references: Literature research Pubmed 2003 – 01/2015 Cochrane data base (z. "The 2011 Oxford CEBM Evidence Levels of Evidence (Introductory Document)".B.medscape. Paul Glasziou. Bob Phillips. Ivan Moschetti. (Practice Guidelines).aspx?o=5653 und Thomssen et al.cancer.com/files/editorial/articles/548868/breast.

uptodate. MD. MD http://www.com/contents/oncoplastic-techniques-in-breastconservingsurgery?source=machineLearning&search=oncoplastic+surgery&selectedTitle=1%7E1&sectionRank=1&anchor=H14027 079#H14027079 .Definition of oncoplastic surgery (3/21) Further information: AGO Voting for giving a new definition 45/0 References: Definition modified after: Oncoplastic techniques in breast conserving surgery Benjamin Anderson. Kristine Calhoun.

Partial breast reconstruction using various oncoplastic techniques for centrally located breast cancer. Sitoh NY. Chung HY. Lee JW. Arch Plast Surg. Iera M. Hart AM. doi: 10. A meta-analysis comparing breast conservation therapy alone to the oncoplastic technique. Freitas AM. Kim HY. . Park HC. Capp E. Zucca-Matthes G. 2014 Sep. Long-Term Comparison of Aesthetical Outcomes After Oncoplastic Surgery and Lumpectomy in Breast Cancer Patients. Dugal CS. 7. doi: 10. Edelweiss MI. Spautz C. Losken A. Fakhr I. Kuroda F.41(5):520-8. 5. de Lima RS. 2014 Dec. 2014 Feb.1097/SAP. Aesthet Surg J. Ann Surg Oncol. Ann Plast Surg. [Epub ahead of print] Tan MP. de Oliveira VM. Styblo TM. Yang JD. 2.12942. Kim MC. Carlson GW. Sim AS. Styblo TM. Anselmi K. Urban C. Rietjens M. 4.Oncoplastic breast conserving surgery (4/21) Further information: AGO Voting for this new slide and content 45/0 References: 1. J Egypt Natl Canc Inst. [Epub ahead of print] Moustafa A. Arana GH. 6. Park HY. Pinell-White X.34(8):1185-91. ANZ J Surg. Cho BC.72(2):145-9. 2014 Dec 5.26(4):203-9.0b013e3182605598.1111/ans. 3. Carlson GW. Losken A1. 2014 Nov. Outcome of different oncoplastic surgical (OPs) techniques for centrally located breast cancer (CLBC). The oncoplastic reduction approach to breast conservation therapy: benefits for margin control. Santos G. Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue. 2014 Dec 18.

Algorithm of Breast Reconstruction (5/21) Further information: No voting this year No references .

Ann Surg Oncol. Plast Reconstr Surg 2014 Dec.134(6):871e-9e . 5. Liu LB. Aesthetic Plast Surg. Mun GH. DIEP. Ann Plast Surg. 2014 Apr. Werker PM. Deep Inferior Epigastric Perforator.063 cases from the 2005-2010 NSQIP datasets. Effects of Obesity on Postoperative Complications After Breast Reconstruction Using Free Muscle-Sparing Transverse Rectus Abdominis Myocutaneous.135(1):43-50. Falesiedi F. 6. Wu LC. Longo B. Serletti JM. and Superficial Inferior Epigastric Artery Flap: A Systematic Review and Meta-analysis. Latissimus dorsi flap for total autologous immediate breast reconstruction without implants. Fiscalini AS. Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. J Plast Surg Hand Surg.Postmastectomy Reconstruction (6/21) Further information: Voting for this new slide and content 45/0 References: 1. Lee KT. Fosnot J. Eltahir Y. Serletti JM. Au A. Peled AW. Foster RD. 4. Pagnoni M. Zeijlmans van Emmichoven IA. Basta MN. 2015 Jan. Tuggle CT 3rd. Ann Plast Surg. Hwang ES. 7. 2014 Oct. Alvarado M. Esserman LJ. Sbitany H. Fischer JP1. Sorotos M. Werners LL.38(4):681-91. 2014 Aug. Garwood E. Plast Reconstr Surg. de Bock GH. 2014 Santanelli di Pompeo F. Which Breast Is the Best? Successful Autologous or Alloplastic Breast Reconstruction: Patient-Reported Quality-of-Life Outcomes. and SIEA flaps forbreast reconstruction. Dreise MM. Ewing C. A Systematic Meta-analysis of Prosthetic-Based Breast Reconstruction in Irradiated Fields With or Without Autologous Muscle Flap Coverage. Meta-analysis of the safety and factors contributing to complications of MS-TRAM. Laporta R.21(10):3223-30 Fischer JP. 2014 Dec 19 Wang F. Song FM. Complications and morbidity following breast reconstruction--a review of 16. Shubinets V. Wang QY.48(2) Wang XL1. 2. 3. Nelson JA.

124(3):752-64. Buchel EW. Pockaj BA. Samson TD. Immediate Reconstruction of the Radiated Breast: Recent Trends Contrary to Traditional Standards. Plast Reconstr Surg. Ann Surg Oncol.DIEP and pedicled TRAM flaps: a comparison of outcomes. Kozlow JH. ASPS clinical practice guideline summary on breast reconstruction with expanders and implants. Plast Reconstr Surg. Ahuja A. Gray D. 2015 Jan 7 Garvey PB. 2014 Oct. Alderman A. 11. Gray RJ.8. Selber JC. . 2006 May Man LX. Postmastectomy Expander Implant Breast Reconstruction Guideline Work Group.134(4):648e-55e Agarwal S. Farberg A. Casey WJ 3rd. Abdominal wall following free TRAM or DIEP flap reconstruction: a meta-analysis and critical review. Momoh AO. Kidwell KM. 10. 2009 Sep. Plast Reconstr Surg. Hernández JL. 9. Gutowski K. Chung KC. Serletti JM.

Complications after microvascular breast reconstruction: experience with 1195 flaps. Ann Surg Oncol. Fedorowicz Z.126:1. Hofer SO. 7. Malata CM. D'Souza N. Da Lio AL.118:1100 .22(1):64-9.55:250-4. Darmanin G. Petit JY. Darmanin G. Earl H. De Boer RH. doi: 10. Cochrane Database Syst Rev. Immediate versus delayed reconstruction following surgery for breast cancer. Ann Plast Surg 2005. 2011 Jul 6. 2013 Feb. Martinelli G. 4. Bruce Mann G.(7):CD008674. Youssef O.Timing of Reconstruction (7/21) Further information: No voting this year References: 1. Epub 2012 Nov 22. 2.2012. Cook FE. 3. Influence of neoadjuvant chemotherapy on outcomes of immediate breast reconstruction. 2011 Jul 6.126:12. Arcilla E. D'Souza N. Irradiated autologous breast reconstructions: effects of patient factors and treatment variables.(7):CD008674. 8.008. Immediate breast reconstruction and highdose chemotherapy. Watson JP. Shaw WW. 5. Ismail A. De Lorenzi F. Fedorowicz Z. Koltz PF. Rietjens M. A Comparison of Surgical Complications Between Immediate Breast Reconstruction and Mastectomy: The Impact on Delivery of Chemotherapy-An Analysis of 391 Procedures. Zhong T.1016/j. Forouhi P.19(2): Chang RJ. Immediate versus delayed reconstruction following surgery for breast cancer. Azzawi K. 6. Mehrara BJ. Jacks LM. 2012 Feb. Kirkpatrick K. et al. Plast Reconstr Surg 2006.breast. McCready DR. Baxter N. Albino FP. Cochrane Database Syst Rev. Does immediate breast reconstruction compromise the delivery of adjuvant chemotherapy? Breast. Plast Reconstr Surg 2010. Rey P. Santoro TD.10. Langstein HN. Plast Reconstr Surg 2010. Ling MN.

2013 May. Schaverien MV.ejso. Eur J Surg Oncol.015.02.1016/j. doi: 10. .39(5):430-6.9.2013. Munnoch DA. Effect of neoadjuvant chemotherapy on outcomes of immediate free autologous breast reconstruction. Epub 2013 Mar 5.

2. Ahmed R. Smidt M. Falcinelli L.134(4 Aristei C. 2014 Oct. A systematic review of complications of implant-based breast reconstruction with prereconstruction and postreconstruction radiotherapy. 2014 Jan. Van Zee K. Petitto RP. 2012 Dec. Strahlenther Onkol. Perrucci E.50(16):2752-62 Kelley BP. Expander/implant breast reconstruction before radiotherapy: outcomes in a single-institute cohort. Farneti A.Timing of Postmastectomy Implant Reconstruction (8/21) Further information: AGO voting for implant reconstruction before radiation: 23 voting for + 2 voting for +/- References: 1. and satisfaction over 13 years. The impact of postmastectomy radiotherapy on twostage implant breast reconstruction: an analysis of long-term surgical outcomes. Tuinder S. Kidwell KM. McCormick B. Hu Q. Eur J Cancer. Chung KC. Ann Surg Oncol. Aliu O. Heuts E. A systematic review of morbidity associated with autologous breast reconstruction before and after exposure to radiotherapy: are current practices ideal? Ann Surg Oncol. Kelley BP. Chung KC. Ahmed R. Kozlow JH. 5. Reconstruction: before or after postmastectomy radiotherapy?' A systematic review of the literature. Berbers J. aesthetic results. Albornoz CR. 3. Momoh AO. Palumbo I. Boersma LJ. . Kidwell KM. Bini V. Bessems M.21(1):118-24 Cordeiro PG. 4. Gori S. Houben R. Plast Reconstr Surg. 2014 Nov. van Baardwijk A.21(5): Momoh AO. Keymeulen K. Kozlow JH.188(12):1074-9. 2014 May.

Part II.121(2):381-8. Brooks S. Plast Reconstr Surg. aesthetic outcomes.204(1):7-12 Cordeiro PG.1524-4741.122(1):19-28. Epub 2011 Jun 25. Wishart GC. Behranwala KA. Tran T.x.129(1):1e-7e. Am Surg. Risk factors for complications of radiation therapy on tissue expander breast reconstructions. 14.The impact of radiation on surgical outcomes of immediate breast reconstruction. Plast Reconstr Surg. doi: 10. 8.113(6):1617-28. Ward A. Serletti JM. Horan G. Lyons J. 2011 Oct. 7. Tran T. Plast Reconstr Surg. A'hern R. . Breast J. Hill M. A prospective analysis of early complications. Malata CM. J Plast Reconstr Aesthet Surg. Dietz J. Lee M. 16. 2004. Couturaud B. J Plast Reconstr Aesthet Surg. 12. 13. 2012 Jan.1111/j. Radiother Oncol. Djohan R. Fitoussi AD. Ross GM.18(1):28-34. Miles D. 2012 Jan. and patients satisfaction. Extended trimethoprim/sulfamethoxazole prophylaxis for implant reconstruction in the previously irradiated chest wall. Plast Reconstr Surg 2006 Sep 15. Tendulkar R. Wilson CB. Smartt JM Jr. 2008 Jul. Sonnad SS. 11. Jandali S. Does patient satisfaction with breast reconstruction change over time? Two-year results of the Michigan Breast Reconstruction Outcomes Study. Delayed-immediate breast reconstruction. infected implant-based breast reconstruction and strategies for salvage.2011. Gui GP.59(10):1043-51.64(10):1270-7. Dua RS. Epub 2011 Nov 20. Irwin MS.77(10):1349-52. Management of exposed.01182. J Am Coll Surg 2007 Jan. Plast Reconstr Surg. 9. 2008 Feb. 2011 Oct. True incidence of all complications following immediate and delayed breast reconstruction. McCarthy CM. 15. 10. Bennett SP. Links Mirzabeigi MN. 118(4): 825-839. 2006. Lum SS. Alderman AK et al.6. Salmon RJ. [ Whitfield GA. Berry MG. Isik FF. Nutter B. The influence of radiotherapy on capsule formation and aesthetic outcome after immediate breast reconstruction using biodimensional anatomical expander implants. A single surgeon‘s 12-year experience with tissue expander/implant reconstruction: part I. An analysis of long-term complications. 2008 Oct 31. Incidence of severe capsular contracture following implant-based immediate breast reconstruction with or without postoperative chest wall radiotherapy using 40 Gray in 15 fractions. Kronowitz SJ et al.

Management of exposed. Bennett SP. Couturaud B. J Plast Reconstr Aesthet Surg.64(10):1270-7.17. . Salmon RJ. infected implant-based breast reconstruction and strategies for salvage. 2011 Oct. Fitoussi AD. Berry MG. Epub 2011 Jun 25.

Nigriny JF. 2012 Nov. The cost effectiveness of acellular dermal matrix in expander-implant immediate breast reconstruction. Bui DT. Chatterjee A. doi: 10. Kniebusch N.0b013e318262df58. Breast Reconstruction and Revision Surgery for Implant-associated Breast Deformities Using Porcine Acellular Dermal Matrix: A Multicenter Study of 156 Cases. A Comparison of Dermal Autograft and Acellular Dermal Matrix in Tissue Expander Breast Reconstruction: Long-term Aesthetic Outcomes and Capsular Contracture. 3. . Henseler H. 5.Soft tissue replacement techniques (9/21) Further information: Voting for new headline 45/0 References: 1. Rinker BD. Scamoni S. Plast Surg Int. Jeffers L. Rosenkranz KM. Vidal DC. 2014 Oct. Khan SU. Selber J. Chung MT. Plast Reconstr Surg.14 Lynch MP.130(5 Suppl 2):118S-24S.1097/PRS. 2014 Krishnan NM.2014 Phillips BT.134(4 Suppl 1):83-4 Basu CB. Clemens MW. Ann Surg Oncol. Heyl V. Klapdor R. 2014 Oct 10 Craig ES. Kronowitz S. 2. Plast Reconstr Surg. A systematic review of infection rates and associated antibiotic duration in acellular dermal matrix breast reconstruction. J Plast Reconstr Aesthet Surg. 2014 Nov 11. Minuti A. Acellular dermal matrices and radiotherapy in breast reconstruction: a systematic review and meta-analysis of the literature. Valdatta L. Dagum AB.67(4):468-76 Hille-Betz U. 7. Garvey P. 2014. Bishawi M. Wren J. Ann Plast Surg. 4. 6. The role of acellular dermal matrices in capsular contracture: a review of the evidence. Cattaneo AG. Cherubino M. Krause-Bergmann B. Pellegatta I. Powell SG. Wojcinski S. 2014 Apr. Eplasty. Outcomes of acellular dermal matrix for immediate tissue expander reconstruction with radiotherapy. Koshy J. Ohlinger R. Paepke S.

Immediate breast reconstruction using porcine acellular dermal matrix (Strattice™): long-term outcomes and complications. Covarelli P. et al. 2011. Gurunluoglu A. Arcuri G. 15.2012. 2013 Jan.1097/SAP. The scarless latissimus dorsi flap for full muscle coverage in device-based immediate breast reconstruction: an autologous alternative to acellular dermal matrix. Vardanian AJ. McCarthy CM. Ann Plast Surg 2011 Hanna KR. doi: 10. Cost minimisation analysis of using acellular dermal matrix (Strattice™) for breast reconstruction compared with standard techniques.10. Williams SA. 2012 Nov. Johnson RK. Epub 2012 Sep 13. Plast Reconstr Surg. Tebockhorst S.12. Pusic AL. In Vivo. doi: 10. doi: 10. Eur J Surg Oncol. Society of Plastic Surgeons 2010.015. Plast Reconstr Surg.27(3):383-6.70(1):10-5. 2013 Mar.2012. Barr L. Dunavant C.1016/j. Stubert J. Reimer T. DeGeorge BR Jr. 128(1):71-9 Gurunluoglu R. Castellani E. Salzberg CA. Elliott LF et al.bjps. randomized controlled trial. Epub 2012 Dec 21. 128:403e–410e. A short-term follow-up of implant based breast reconstruction using a titanium-coated polypropylene mesh (TiLoop(®) Bra). 14. Mericli AF. Drake DB. 10. 2011 Jul. 2013 May-Jun. Charny MC.1097/PRS. Epub 2012 Nov 13.ejso. Gandhi A. Roostaeian J.38(12):1225-30.0b013e31825f05b4. Dieterich H. Plast Reconstr Surg.8.ejso. Current trends in breast reconstruction: survey of American. Optimizing therapeutic timing in patients undergoing mastectomy through use of the Tiloop® synthetic mesh: single-step surgery. 11. 2013 Mar. Gerber B.66(3):323-8. Mehrara BJ. Clayton JL. Halvorson EG. Lee CN. Noya G. Caracappa D.1016/j. J Plast Reconstr Aesthet Surg. Pataia E. The use of acellular dermal matrices in two-stage expander/implant reconstruction: a multicenter. 12. 2012 Dec. Barberini F. Rulli A. blinded. 16. doi: 10. 13. . Comparison of implant-based immediate breast reconstruction with and without acellular dermal matrix. Disa JJ.39(3):242-7.026. Dieterich M.130(5 Suppl 2):57S-66S. Nocera N.2012. Sanguinetti A.002. Wright CK. Riedel E. Lin KY.08. 9.0b013e31822f6765.1016/j. doi: 10. Comparison study of two types of expander-based breast reconstruction: acellular dermal matrix-assisted versus total submuscular placement. Eur J Surg Oncol. Ann Plast Surg.

Rigotti G. Ann Oncol. CADTH Rapid Response Reports. 2.34:475–80. Evaluation of fat grafting safety in patients with intra epithelial neoplasia: A matched cohort study.133(3):550-7. Clough KB. 3. Autologous Fat Grafting for Reconstructive Surgery: A Review of the Clinical and Cost-Effectiveness [Internet]. Botteri E.24:1479–1484.Lipotransfer (10/21) Further information: Ago voting for changing the wording from “lipofilling” to “Lipotransfer”: 45/0 Voting for new wording statement 1: 45/0 Reference: 1. Ann Plast Surg 2010. Determining the oncological risk of autologous lipoaspirate grafting for post-mastectomy breast reconstruction. Petit JY. 2013. Theory and principles. Plast Reconstr Surg 2011. 2014 May. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. Biggs TM. Stringhini P.128:341–6. et al. Plast Reconstr Surg. Marchi A. 5. Cardoso E. et al. et al. Lohsiriwat V. 4.Megavolume autologous fat transfer: part I. Rigotti G. Milan-Paris-Lyon experience of 646 lipofilling procedures. Rietjens M. The oncologic outcome and immediate surgical complications of lipofilling in breast cancer patients: a multicenter study. Khouri RK Jr. 2014 Mar. Petit JY. . Khouri RK1.

Rodrigues JR. Practice and techniques. Biggs TM Megavolume autologous fat transfer: part II.133(6):1369-77 Brenelli F1. Barbalho D. Rossetto F. 7. Rietjens M. Martella S. De Lorenzi F. Plast Reconstr Surg.6. Rigotti G.Oncological safety of autologous fat grafting after breast conservative treatment: a prospective evaluation. Khouri RK Jr.. Pinto-Neto A.20(2):159-65 . 2014 Jun.Breast J. Khouri RK1. Cardoso E. 2014 MarApr.

Kidwell KM. Huang SH. Garvey PB1. Cooney. Momoh AOA systematic review of morbidity associated with autologous breast reconstruction before and after exposure to radiotherapy: are current practices ideal? Ann Surg Oncol. Chang KP. Ou-Y Immediate transverse rectus abdominis musculocutaneous flap reconstruction is associated with improved cancer-specific survival in locally advanced breast cancer. José M. Kronowitz SJ. Hou MF. Lin SD. Plast Reconstr Surg. 2. Lee SS. 2000 Qadi. MD. Kelley BP1. BS. Zhang H. Abreu.21(5):1732-8.Muscle-sparing TRAM flap does not protect breast reconstruction from postmastectomy radiation damage compared with the DIEP flap. MPH. MD. Ahmed R. Lilian C. PhD. 3. Lai CS. Rosson. MScs. 2014 Feb. 2014 Sep. Clemens MW.Postmastectomy (pedicled) Reconstruction (11/21) Further information: Voting for whole content with one consent References: 1. Hoy AE. Butler CE. MD. Ann Plast Surg. Mohamud A. Azih. BS. Lin YN. Nicholas B.Volume 133 . Abt. Sashank MD. Baltodano.133(2):223-33 .Issue 4S . Kozlow JH. Smith B. MPH. Pablo A.514 Women Undergoing Breast Surgery from the ACS-NSQIP Database Plastic & Reconstructive Surgery: April 2014 . Francis M. Senologie Lugano. MD: Are Flaps Really Better Than Implants for Breast Reconstruction in Obese Females? An Analysis of 89. Flores. Chung KC. BS. Der TRAM-Lappen – vom Ausnahmeeingriff zur Standardoperation in der Onkoplastik beim Mammakarzinom.73 Suppl 1:S31-6. Carisa M. Chen FM.p 982–983 Hsieh TY1. Sarhane. Gedge D. 5. 4. Karim A. 2014 May. Brunnert K. Reddy.

50(16):2752-62. Smidt M3. . Tuinder S4. Keymeulen K3. Heuts E3. van Baardwijk A2. 2014 Nov. Boersma LJ5.6. Houben R2. Eur J Cancer.'Reconstruction: before or after postmastectomy radiotherapy?' A systematic review of the literature. Bessems M3. Berbers J1.

67(2):143-56 Schaverien MV1. Robb GL. 2014 Sep. Ann Plast Surg. Figus A3.128(6):581e-9e. Mun G. 5. Deep Inferior Epigastric Perforator. Mcculley SJ. Chang EI1. Comprehensive Evaluation of Risk Factors and Management of Impending Flap Loss in 2138 Breast Free Flaps. Wade RG2. Butler CE. Salavati S. Zhang H. Nosrati N. Soto-Miranda MA. 2.The increased risk of adverse outcomes in bilateral deep inferior epigastric artery perforator flap breast reconstruction compared to unilateral reconstruction: a systematic review and meta-analysis. [Epub ahead of print] Wormald JC1. Crosby MA. 3. Effects of Obesity on Postoperative Complications After Breast Reconstruction Using Free MuscleSparing Transverse Rectus Abdominis Myocutaneous.Free Tissue Transfer (12/21) Further information: Voting: For Free TRAM-flap 11 +. 4. 12 +/DIEP-flap + with one consent References: 1. Garvey PB. 2014 Feb. and Superficial Inferior Epigastric Artery Flap: A Systematic Review and Meta-analysis. Effect of obesity on outcomes of free autologous breast reconstruction: a metaanalysis. Reece GP. Microsurgery. Chang DW. Plast Reconstr Surg. [Epub ahead of print] . Perfusion-related complications are similar for DIEP and muscle-sparing free TRAM flaps harvested on medial or lateral deep inferior epigastric Artery branch perforators for breast reconstruction. Chang EI. 2011 Dec. 2014 Jul 4. J Plast Reconstr Aesthet Surg.34(6):484-97 Lee K1. 2014 Dec 19. Ann Plast Surg. Feng L.

38(4):681-91 . and SIEA flaps for breast reconstruction.6. 2014 Aug. Meta-analysis of the safety and factors contributing to complications of MS-TRAM. Aesthetic Plast Surg. DIEP. Wang XL1. Song FM. Liu LB. Wang QY.

Plast Reconstr Surg Glob Open. Colakoglu S. 2011 Jun 8. 2. Westvik TS. Tobias AM. Yueh JH. Ann Plast Surg. Momoh AO. Free Tissue Transfer (13/21) Further information: No voting this year Reference: 1.Pedicled vs. Lee BT. Curtis MS.2(5) . de Blacam C. Analysis of Complications and Patient Satisfaction in Pedicled Transverse Rectus Abdominis Myocutaneous and Deep Inferior Epigastric Perforator Flap Breast Reconstruction.A comparative analysis of 2 national breast reconstruction surveys: concerns regarding autologous and microsurgical breast reconstruction. 2014 Jun 6. [Epub ahead of print] Gurunluoglu R1. Bronsert M1.

2014 Dec 19. Kääriäinen M1. J Plast Reconstr Aesthet Surg. No need to cut the nerve in LD reconstruction to avoid jumping of the breast: a prospective randomized study. Shubinets V. Kuokkanen H5. Giordano S2. Fosnot J A Systematic Meta-analysis of Prosthetic-Based Breast Reconstruction in Irradiated Fields With or Without Autologous Muscle Flap Coverage. 2. Helminen M4. Kauhanen S3. 2014 Aug.67(8):1106-10 Fischer JP1.Flap-Implant Combination (14/21) Further information: No voting this year References: 1. Basta MN. [Epub ahead of print] . Ann Plast Surg. Serletti JM.

[Epub ahead of print] Blechman KM. Kuchenmeister I. predictors. 2014. Choi M. Wink JD1. Matros E2. Cordeiro PG1. J Plast Surg Hand Surg. Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. Botteri E. Mehrara BJ Bilateral implant breast reconstruction: outcomes. Orecchia R. McCarthy C. Pusic AL1. Martella S. Agrawal A. De Lorenzi F. Epub 2012 Dec 17. Reimer T.ejso. Shapiro RL. Nipple-sparing mastectomy: risk of nippleareolar recurrences in a series of 579 cases. Kundt G. Manconi A. 5. The lateral inframammary fold incision for nipple-sparing mastectomy: outcomes from over 50 immediate implant-based breast reconstructions. 2014 Dec. Garusi C. doi: 10. 2013 Jan-Feb. Disa JJ1. Direct-to-implant breast reconstruction: an analysis of 1612 cases from the ACS-NSQIP surgical outcomes database. Rey P. Ivaldi GB.Skin/Nipple Sparing Mastectomy (SSM/NSM) and Reconstruction (15/21) Further information: No voting this year References: 1. Mehrara BJ1. Muller H. Disa JJ.39(4):320-8. Levovitz C.48(6):375-81. Luini A. Gerber B.12. 4. Axelrod DM. Breast J.2012.12043.72(6):625-30 Albornoz CR1. and matched cohort analysis in 730 2-stage breast reconstructions over 10 years. Sibbering DM. 3.015. Rietjens M. Epub 2013 Jan 17. Ann Plast Surg. 2013 Apr. Veronesi P. Nelson JA. 7. Makovitzky J. Skin sparing mastectomy and immediate breast reconstruction: a review. Breast Cancer Res Treat. Rotmensz N. Ann Surg. Fischer JP. Eur J Surg Oncol. Krause A. Bosco R.19(1):31-40. Serletti JM.238(1):120-7.219(4):788-95. Veronesi U. 2014 Oct. Courtney CA. Galimberti V. 2. . Diminishing relative contraindications for immediate breast reconstruction: a multicenter study. 6. Karp NS. 2008 Mar 22. J Am Coll Surg. Petit JY. doi: 10. Friese K. Antony AK1.1111/tbj. Wu LC.1016/j. 2003 Jul. McCarthy CM1. Guth AA.

2014 Oct. . Garwood E.8. Wang F1. Foster RD. Hwang ES. Esserman LJ. 2014.21(10):3223-30. Fiscalini AS. Alexandre Mendonça Munhoz. Sbitany H. Ewing C. Ann Surg Oncol. 5(3): 478–494. Peled AW. and Rolf Gemperli Immediate nipple-areolasparing mastectomy reconstruction: An update on oncological and reconstruction techniques World J Clin Oncol. Eduardo Montag.Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. José Roberto Filassi. Alvarado M. 9. Aug 10.

Links Den Heijer M.1016/j. 2. doi: 10. Eur J Cancer. Bouhnik AD.49(13):2798-805. Nippert I. Brekelmans CT.ejca. Menke-Pluymers MB.04.Bilateral Risk Reducing Mastectomy in healthy women (RRBM) (16/21) Further information: No voting this year Please see chapter breast Cancer Risk and Prevention References: 1. Seynaeve C. 2013 Sep. Epub 2007 May 31. 2007 Dec. Tilanus-Linthorst MM. Heemskerk-Gerritsen BA. Tibben A. van Asperen CJ. Julian-Reynier C. International variation in physicians' attitudes towards prophylactic mastectomy . Harris H. Bartels CC. van Geel AN. Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic. Schmidtke J.14(12):3335-44. Meijers-Heijboer HE. Klijn JG. Epub 2013 May 18. Ann Surg Oncol.comparison between France. Tan M. .2013. the Netherlands and the United Kingdom.025. Germany. Evans DG.

Anne Radecki .Types of Risk Reducing Mastectomy (17/21) Further information: No voting this year Please see chapter breast Cancer Risk and Prevention References: 1. Polat AK. [Epub ahead of print] Jessica Gahm. Balci FL. One-staged silicone implant breast reconstruction following bilateral nipple-sparing prophylactic mastectomy in patients at high-risk for breast cancer. Aykan A. Ibrahim A. Thomas C. 1513e1520 . 2013 Apr. 2. 4. Soran A. Sahin I. Decision Making and Factors Influencing Long-term Satisfaction With Prophylactic Mastectomy in Women With Breast Cancer. Aesthetic Plast Surg. doi: 10. Jennifer McGrath . Ahrendt G. 1521e1527 Jonas A. Am J Clin Oncol.37(2):303-11. Isik S. Wu. Reconstructive & Aesthetic Surgery (2013) 66. 2013 May 2. Fischer . Delayed autologous breast reconstruction: Factors which influence patient decision making. Serletti . Breast sensibility after bilateral riskreducing mastectomy and immediate breast reconstruction: A prospective study. Nelson. Bonaventura M. Yıldız R. 3. Reconstructive & Aesthetic Surgery (2013) 66. Johnson R. Ozturk E. Epub 2013 Jan 16. Kanbour M. Journal of Plastic. Yvonne Brandberg. Christina Pasick . Marie Wickman. John P. Journal of Plastic. McGuire K. Per Hansson. Alhan D. Liza C. M. Joseph M.1007/s00266-012-0044-6.

Algorithm of Breast Reconstruction (18/21) and Algorithm of Autologous Breast Reconstruction (1) (19/21) and Algorithm of Autologous Breast Reconstruction (2) (20/21) and Algorithm of Implant Breast Reconstruction (4) (21/21) Further information: No voting this year No references .

sowie in der DKG e.V. Guidelines Breast Version 2015. in der DGGG e. V.and Postmenopausal Patients .V.1 Adjuvant Endocrine Therapy in Pre.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.

ago-online.  Guidelines Breast Version 2015.V. sowie in der DKG e.de  Version 2015: Scharl / Stickeler .Adjuvant Endocrine Therapy © AGO e. in der DGGG e.1 Versions 2002–2014: Bauerfeind / Dall / Diel / Fersis / Friedrichs / Gerber / Göring / Harbeck / Huober / Jackisch / Lisboa / Lück / Maass / Möbus / Müller / Oberhoff / Schaller / Scharl / Schneeweiss / Schütz / Solomeyer / Stickeler / Thomssen / Untch / von Minckwitz www.V. V.

V. sowie in der DKG e. cells: endocrine non-responsive 1 pos.Assessment of Steroid Hormone Receptor Status © AGO e. Guidelines Breast Version 2015. in der DGGG e. cells: endocrine responsive Status unknown: endocrine responsive .V.1 Oxford LoE: 1 GR: A AGO: ++ Endocrine responsiveness: Immunohistochemistry (ER and / or PgR) www.ago-online.V.de 0% pos.

E2 ++ . V.ago-online.V. Oxford / AGO LoE / GR Guidelines Breast Version 2015.Adjuvant Endocrine Therapy Assessment of Menopausal Status © AGO e.de  Menstruation history +  FSH.1 Assessment of menopausal status www. in der DGGG e. sowie in der DKG e.V.

Oxford / AGO LoE / GR Guidelines Breast Version 2015. in der DGGG e.ago-online.Adjuvant Endocrine Therapy © AGO e.V. sowie in der DKG e.de . V.V.1 Standard therapy in endocrine responsive tumors:  Endocrine therapy  Chemotherapy followed by endocrine therapy (dependent on individual risk and tumor biology) 1a A ++ 1a A ++ www.

V.ago-online. Oxford / AGO LoE / GR in der DGGG e.V.V.de  . sowie in der DKG e.1   Endocrine responsive & doubtful: Endocrine therapy 1a A ++ Endocrine therapy sequentially after CT 2b C ++ Non-responsive: No endocrine therapy 1a A ++ www.Adjuvant Endocrine Therapy © AGO e. Guidelines Breast Version 2015.

General Principles in Adjuvant Endocrine Therapy AGO ++ © AGO e. V. N+ status at presentation)  Duration.ago-online.1 www..V. Guidelines Breast Version 2015.V. sowie in der DKG e.g.de .  Standard treatment duration 5 years  Treatment up to 10 years may be considered based on the individual risk of relapse (e. choice & sequence of AI or Tam mainly rely on menopausal status and side effects  Switch to another endocrine treatment (Tam or AI) is better than to stop  AI as first treatment preferably in postmenopausal patients at high risk and lobular cancers  So far no evidence for AI > 5 yrs in der DGGG e.

in der DGGG e.1 AGO  Tamoxifen* 5-10 yrs.Premenopausal Patients Adjuvant Endocrine Therapy © AGO Oxford / LoE / GR e.ago-online. 1a A ++  GnRHa alone 1a B + (only if relevant contraindications for Tam) In patients with ovarian function (within 8 mo. + TAM 5 yrs. + AI 5 yrs.) after adjuvant chemotherapy (exploratory retrospective analysis suggests higher benefit in younger age)**: www. V. 1b B +/- 1b B +/- OFS (ovarian function suppression) * * Treat as long as tolerable and premenopausal Switch to AI optional when patient turned postmenopausal # increased side effects may impair compliance.V. sowie in der DKG e. High compliance to TAM ist more effective. Guidelines Breast Version 2015.V.de  #OFS (ovarian function suppression)  #OFS 5 yrs. ** Duration of treatment may be prolonged to up to 10 yrs using TAM . than addition of GNRH or treatment with GNRH+AI with impaired compliance. 5 yrs.

Guidelines Breast Version 2015.V.de .1  AI alone 1c A --  AI after GnRHa (induced amenorrhea) 5 D --  Upfront AI in patients with chemotherapyinduced amenorrhea (CIA. TIA) 4 C -- EAT in perimenopausal pts. with validated postmenopausal status after 5 yrs. V.V.ago-online. of Tam 2b B +  www. in der DGGG e.Premenopausal Patients Adjuvant Endocrine Therapy © AGO Oxford / AGO LoE / GR e. sowie in der DKG e.

Postmenopausal Patients
Adjuvant Endocrine Therapy
© AGO

Oxford / AGO
LoE / GR

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

AI for 5 yrs.

Preference in lobular inv. cancers

1a

A

+

2b

B

+

Sequential therapy for 5 -10 yrs.

++

Tam followed by AI (2-5 yrs.)*

1a

A

AI (2-5 yrs.)* followed by Tam

1b

C

1a

A

Preference in N+
www.ago-online.de

Tamoxifen 20 mg/d for 5-10 yrs.
*Duration

of AI  5 yrs.

++

Ovarian Protection and Fertility Preservation
in Premenopausal Patients
Receiving Adjuvant Chemotherapy (CT)
© AGO

e. V.

Oxford / AGO
LoE / GR

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Ovarian Function Protection
CT + GnRHa (Interaction with CT unclear)

1b

B

+/-

Fertility preservation counselling

4

C

+

Fertility preservation with
assisted reproduction therapy

4

C

+

(GnRHa application > 2 weeks prior to chemotherapy)

Impairment of CT – effect cannot be excluded!
www.ago-online.de

Testing Ovarian Reserve
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Assessment of ovarian reserve in

Oxford / AGO
LoE / GR

infertile patients

(>6-12 mths without conception)*

5

C

+

Tests for fertility assessment

Anti-Müllerian Factor

3b

B

+/-

Antral follicle count

3b

B

+/-

www.ago-online.de

* Tests are suggested for women > 35yrs and infertility for 6-12 months;
the tests do not predict failure to conceive, but they allow to counsel that
the window of opportunity to conceive may be shorter than anticipated
and infertility treatment may be considered.

Contraceptive Options for Premenopausal
Women after Diagnosis of Breast Cancer
© AGO

Oxford / AGO
LoE / GR

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1




Barrier methods
Sterilization (tubal ligation / vasectomy)
Non-hormonal intrauterine devices (IUDs)
Levonorgestrel-releasing IUDs
 Removal in newly diagnosed patients

www.ago-online.de




Timing methods
Injectable progestin-only contraceptives
Progestin-only oral contraceptives
Combined oral contraceptives

5
5
5
5

D
D
D
D

+
+
+
-

4

D

+/-

5
5
5
5

D
D
D
D

-

No trial included women after diagnosis of breast cancer,
non-estrogen containing devices do not increase the risk to
develop primary breast cancer

Ovarian Function Preservation – Comparison of
Randomized Trials
ZORO

PROMISE

Munster et al. - US

POEMS

Patient number

60 (60 HR-)

281 (50 HR-)

49 (13 HR-) of 124

218 (218 HR-)

in der DGGG e.V.
sowie
in der DKG e.V.

Age median

38 years

39 years

39 years

Premenop. < 50 years

Treatment

goserelin

triptorelin

triptorelin

goserelin

Guidelines Breast
Version 2015.1

Start of treatment >2 weeks prior to cht

>1 week prior to cht

> 1 week prior to cht

> 1 week prior to cht

Primary Endpoint menstruation at
month 6 after
chemotherapy

rate of early
menstruation rate within Ovarian failure at 2 yrs
menopause at month
2 years after cht
after cht
12 after chemotherapy

Primary objective to detect 30%
absolute increase of
menstruation rate

to detect at least 20%
absolute reduction in
early menopause

Multivar. analysis age as only
independent
predictive factor

treatment as only
independent predictive
factor

Resumption of
83% with LHRH vs.
menses at month 80% w/o
12 in HR- cohort

93% with LHRHa vs.
74% w/o

Median time to
6.1 with LHRHa vs.
restoration of
6.8 w/o; p=0.30
menses (months)

not reached with LHRH 5.8 with LHRH vs. 5.0
vs. 6.7 w/o; p=0.07
w/o; p=0.58

n.d.

Cyclophosph.
dose

4080 vs. 4008 mg

n.a.

© AGO

e. V.

www.ago-online.de

4600 vs. 4700mg

to detect 20%
difference in
amenorrhea rate - from
10% to 30%
n.d.

74% with LHRH vs.
68% w/o

n.r.

Treatment as only
Independent predicitve
factor

78% with LHRH vs.
75% w/o; at 2 years;
22% with LHRH vs. 8%

Metaanalysis of GnRHa for Prevention
of Premature Ovarian Failure
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.

Autor

Jahr

Odds Ratio
(95%CI)

Ereignisse Ereignisse
GnRHa
Kontrolle

Guidelines Breast
Version 2015.1

www.ago-online.de

Vorteil GnRHa / Vorteil Kontrolle

nach Del Mastro et al. Cancer Treat Rev 2014

TEXT /SOFT Joint Analysis
5 yrs
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

TEXT
Premenopausal
Patients with HR+ BC
≤ 12 wks after surgery
(N = 2672)

SOFT

www.ago-online.de

Premenopausal
patients with HR+ BC
≤ 12 wks after surgery
(if no chemo) or
≤ 8 mos after chemo
(N = 3066)

Tamoxifen 20 mg/day
+ OFS* (n = 1328)

Joint Analysis

Exemestane 25 mg/day
+ OFS* (n = 1332)

Tamoxifen + OFS*
(n = 2344)

Tamoxifen 20 mg/day
+ OFS* (n = 1016)

Exemestane + OFS*
(n = 2346)

Exemestane 25 mg/day
+ OFS* (n = 1014)

Tamoxifen 20 mg/day

*OFS
 TEXT: triptorelin 3.75 mg IM
every 28 days for 6 mos, then
optional bilateral oophorectomy or
irradiation
 SOFT: choice of method

Median follow-up: 5.7 yrs
Nach Pagani O, et al. N Eng J Med, 371(2) 2014

Aromatase Inhibitors in
Adjuvant Therapy
© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

www.ago-online.de

Overview over Published Trials: Upfront and Extended Therapy
Trial

Source

ATAC

ATAC Trialists´
Group 2010

AI

Indication

Pts

A

upfront
vs T

6241

BIG 1-98

BIG 1-98
Collaborative
Group 2011

L

upfront2
vs T

4922

NCIC CTG
MA.27

Goss 2010

E

upfront vs A

Extended

Adjuvant

MA 17

Goss 2005

L

ABSCG6a

Jakesz 2007

NSABPB33

Mamounas
2008

F/U
mo

DFS/BCFS/TTR/
TTDR/CBC

120

HR + patients:
DFS HR 0·86, p=0·003
TTR ·0,79, p=0·0002
TTDR 0·85, p=0·02

OS

Side Effects

Remarks

HR 0.87
p=0·4

SAE T>A
gyn AE T>A
VE T>A
SE A>T

only anastrozole vs
tamoxifen, combination arm
stopped after first analysis;
ER+PR-=ER+PR+
(Cuzick 2010)
QoL (Cella 2006)

97

DFS = 0·86
P = 0,007

P = 0,048

7576

49

EFS HR 1,02
DDFS HR 0,95

ns

extended after 5y T
vs P

5170

30

DFS HR 0.58, p<0.01
TTDR HR 0.60, p<0.01
CBC HR 0.63, p=0.13

HR 0,61 in
N+, p=0,04

A

extended after 5y T
vs Nil

856

62

DFS HR 0.642 p=0.031

ns

E

Extended after 5y T
Vs P

30

DFS HR 0,68 p=0,07
RFS HR 0,44 p= 0,004

SAE T=L
gyn AE T>L
TE T>L
CE L>T
SE L>T
Osteoporosis A>E
El. liver enzymes E>A
Hyperlypidaemia A>E

L>T in particular in case of
N+

Randomization for Celecoxib
cancelled

Therapy

1598

ns

CE L=P
SE L>P

QoL (Whelan 2005)
Lipids  (Wasan 2005)

SE E=P
after 6 Mo

Grad 3 AE E>P
9%vs3%, p=0,03
Profit from E particular in
N+

A anstrozole; gyn AE, gynecological adverse event; BCFS, breast cancer-free survival; CBC, contralateral breast cancer; CE, cardiac events; CVE,
cardiovascular events; Cx, chemotherapy; DFS, disease-free survival; RFS relapse-free survival; E, exemestane; ER, estrogen receptor; HR, hazard
ratio; L, letrozole; OS, overall survival; P, placebo; PR, progesterone receptor; Qol, quality of life; Rx, radiotherapy; SAE, serious advesrse event; SE,
skeletal event; T, tamoxifen; TE, thromboembolism; TTR, time-to-recurrence; TTDR, time-to-distant-recurrence; VE, vascular event; (?) according to
retrospective analysis. * only HR positive population

Aromatase Inhibitors in Adjuvant Therapy
Overview over Published Trials: Switching/Sequential trials
Trial

© AGO

e. V.

Source

AI

Pts

F/U
mo

DFS/BCFS/TTR/
TTDR/CBC

OS

Side
Effects

Remarks

HR, 0.86;
95% CI,
0.75 to
0.99; P =
.04).

gyn AE T>A
TE T>E
SE E>T
diarrhea E>T

Random after 2-3y T, only pts.
relapse-free after 2-3 y T were
included
Random after 2-3y T, only pts.
relapse-free after 2-3 y T were
included

4599

91

DFS HR 0.76, ITT p<0.01
DFS HR 0,75, ER+/u
BCFS HR 0.76, ITT, s
BCFS HR 0,75, ER+/u
TTDR HR 0.83, ITT, s
TTDR HR 0,82 ER+/u, s

448

64

EFS HR 0.57, p<0.01
RFS HR 0.56, p=0.01

ns

SAE T>A

IES

Bliss JM

E

switch after 2-3y T
vs T

ITA

Boccardo 2006

A

switch after 2-3y T
vs T

ABCSG 08
ARNO95

Jakesz 2005

A

switch after 2y T
vs T

3224

28

DFS HR 0.59, p<0.01
TTR HR 0.60, p<0.01
TTDR HR 0.61, p<0.01

ns

TE T>A
SE A>T

ABCSG -08

Jakesz 2005

A

switch after 2y T
vs T

2529

31

DFS HR 0.61, p=0.01
TTDR HR 0.68, p=0.11
CBC HR 0.45, p=0.07

ns

TE T>A
SE A>T

Analysis of switch data only,
random upfront

ARNO 95

Kaufmann
2007

A

switch after 2y T
vs T

979

30

DFS HR 0.66, p=0.049

HR 0,53,
p=0.045

SAE T>A 30,8
vs 22,7 %

No chemotherapy, random after
2 y T; only pts relapse-free after
2 y T were included

1548

L

switch after 2y T vs.
Let
swtch after 2y L vs.
Let.

97

disease-free survival;
87·5%, 87·7%, 85·9%
ns

89·9%,
88·7%,
88·1%
ns

SE L>T
VE L = T

Comparison of switch L/T or
T/L vs. L

n.a.

DVT;
endometrial >
switch
Musculoskeleta
l problems
hyperlipidaemi
a > E mono

n.a.

dito

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Indication

BIG 1-98

Regan et al
2011

TEAM

Van de Velde
2011

N-SAS
BC03

Aus Japan

1540

E

TEAM: E alone vs
Tam switch after 2 –
3 y to E

4868
4898

60

A

Tam 5 y vs
Tam A switch
after 1 – 4 y Tam

706

42

A

switch (2-3y T)

hazard ratio 0·97, 95%
CI 0·88-1·08; p=0·60)

www.ago-online.de

Metaanalysis
ARNO95
ABSCG8
ITA

2010

Jonat 2006

4006

DFS: 0.69 P = 0.14

RFS 0.54 P = 0.06

DFS HR 0.59, p<0.01

HR 0.71,
p=0.04

with heterogeneity

A, anastrozole; gyn AE, gynecological adverse event; BCFS, breast cancer-free survival; CBC, contralateral breast cancer; CE, cardiac events; Cx, chemotherapy; DFS, disease-free survival; E,
exemestane; ER, estrogen receptor; HR, hazard ratio; ITT, intent to treat; L, letrozole; OS, overall survival; P, placebo; PR, progesterone receptor; Qol, quality of life; Rx, radiotherapy; s, significant; SAE
serious advesrse event; SE, skeletal event; T tamoxifen; TE, thromboembolism; TTR, time-to-recurrence; TTDR, time-to-distant-recurrence; u, unknown; VE, vascular event; (?) according to
retrospective analysis.

Assessment of Ovarian Reserve

© AGO

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

Tests recommended to assess ovarian reserved (according to ACOG
Committee Opinion No. 618: Ovarian Reserve Testing. Obstetrics &
Gynecology 2015 ;125 : 268–273
Test

Details

FSH (follicle
• Serum level on cycle day 2–3
stimulating
• Variation between cycles possible
hormone) plus • High FSH value is associated with poor response
estradiol
to ovarian stimulation
Anti Müllerian
Hormone
(AMH)

• No specific timing for the test
• Stable value within and between menstrual cycles
• Low AMH value is associated with poor response
to ovarian stimulation

Antral follicle
count
(AFC)

• Number of visible follicles (2–10 mm) during
transvaginal ultrasound
• Performed on cycle days 2–5
• Number of antral follicles correlates with ovarian
response to stimulation

www.ago-online.de

All the tests do not predict failure to conceive, but they allow to counsel that
the window of opportunity to conceive may be shorter than anticipated.

10 yrs versus 5 yrs Breast Cancer Mortality in ER+
Rate ratio per period in aTTom and ATLAS
5 yrs. vs. 10 yrs Tamoxifen

© AGO

10 yrs. vs. 5 yrs. Tam
aTTom Trial
(n=6934 ER+)

10 yrs. vs. 5 yrs. Tam
Atlas Trial
(n=10543 ER+)

10 yrs. vs. 5 yrs. Tam
aTTom + Atlas
combined
(n=17477 ER+)

Years 5-9

1.08 (0.85-1.38)

0.92 (0.77-1.09)

0.97 (0.84-1.15)

Years 10+

0.75 (0.63-0.90)
p = 0.07

0.75 (0.63-0.90)
p = 0.002

0.75 (0.65-0.86)
p = 0.00004

0.88 (0.74-1.03)
p = 0.1

0.83 (0.73-0.86)
p = 0.004

0.85 (0.77-0.94)
P= 0.001

e. V.

in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2015.1

n
www.ago-online.de

All years

nach Grey et al ASCO 2013
J Clin Oncol 31, 2013 (suppl. Abstr 5)

Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients (2/20)

No further information

No references

Assessment of Steroid Hormone Receptor Status (3/20)

No further information

References:
Statement 1
1.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).: Effects of chemotherapy and hormonal therapy for
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472):
1687-717, 2005
2.
Colleoni M et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive
breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006.
3.
Harvey JM, Clark GM, Osborne CK, et al.: Estrogen receptor status by immunohistochemistry is superior to the
ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17 (5):
1474-81, 1999.

Adjuvant Endocrine Therapy – Assessment of Menopausal Status (4/20)

No further information

References:
1.
2.
3.

4.
5.

6.
7.

Ortmann O, et al: Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast. 2009
Feb;18(1):2-7
Clemons M, et al: Identifying menopause in breast cancer patients: considerations and implications. Breast Cancer
Res Treat. 2007 Aug;104(2):115-20.
Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, Freeman EW, Gracia CR, DeMichele A.
Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast
cancer survivors. Cancer. 2010 Feb 1;116(3):592-9.
Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M, Ginsburg E. Ovarian reserve in women who
remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril. 2010 Jul;94(2):638-44.
Anders C, Marcom PK, Peterson B, Gu L, Unruhe S, Welch R, Lyons P, Behera M, Copland S, Kimmick G, Shaw
H, Snyder S, Antenos M, Woodruff T, Blackwell K. A pilot study of predictive markers of chemotherapy-related
amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest. 2008 Apr-May;26(3):28695
Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and
bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab. 2011 May; 96(5):1336-43.
Su HI, Chung K, Sammel MD, Gracia CR, DeMichele A. Antral follicle count provides additive information to
hormone measures for determining ovarian function in breast cancer survivors. Fertil Steril. 2011 Apr;95(5):1857-9

Adjuvant Endocrine Therapy (5/20)

No further information

References:
1.

2.

3.

4.

5.
6.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and
other factors to the effi cacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011
Aug 27;378(9793):771-84. doi: 10.1016/S0140-6736(11)60993-8. Epub 2011 Jul 28
Thürliman B et al: Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine
responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. Breast Cancer Res
Treat. 2009; 113:137-44
Goldhirsch A, Winer EP, Coates AS et al. Personalizing the treatment of women with early breast cancer: highlights
of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 Ann Oncol
2013;24:206-2223
Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years
of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast
cancer.J Clin Oncol. 2011 May 1;29(13):1657-63. doi: 10.1200/JCO.2010.32.2933. Epub 2011 Mar 21.
Pagani O1,et al.Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014
Jul 10;371(2):107-18. doi: 10.1056/NEJMoa1404037. Epub 2014 Jun 1.
Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be
sequential instead of concurrent: initial results from Intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol
2002;21:37a (abst 143

Adjuvant Endocrine Therapy (6/20)

No further information

References:
1.
2.

3.

4.

5.

6.

Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of randomised trials. Lancet 2005;365:1687-717.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and
other factors to the effi cacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011
Aug 27;378(9793):771-84. doi: 10.1016/S0140-6736(11)60993-8. Epub 2011 Jul 28
Fisher B, Anderson S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptornegative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol
2001;19:931-42.
Jaenicke F, Prechtl A, Thomssen C, et al. Randomized adjuvant chemotherapy trial in high-risk, lymph nodenegative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator
inhibitor type 1. J Natl Cancer Inst 2001 20;93:913-20.
Hutchins L, Green S, Ravdin P, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast
cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of Intergroup
Trial INT 0102; Proc Am Soc Clin Oncol 1998;17:1a (abstr. 2).
Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years
of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast
cancer.J Clin Oncol. 2011 May 1;29(13):1657-63. doi: 10.1200/JCO.2010.32.2933. Epub 2011 Mar 21.

General Principles of Adjuvant Endocrine Therapy AGO ++ (7/20)

Further information:
Voting: 18/7

References:
1.
2.

3.

4.

5.

6.

Metzger O, Giobbie-Hurder A, Mallon E et al. Relative effectiveness of letrozole compared with tamoxifen for
patients with lobular carcinoma in the BIG 1-98 trial. SABCS 2012, S1-1
Davies C, Hongchao P, Godwin J et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus
stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet
2013;381:805-806
Hackshaw A1, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years
of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast
cancer.J Clin Oncol. 2011 May 1;29(13):1657-63. doi: 10.1200/JCO.2010.32.2933. Epub 2011 Mar 21.
Cuzick J1, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of
anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial.
Lancet Oncol. 2010 Dec;11(12):1135-41. doi: 10.1016/S1470-2045(10)70257-6. Epub 2010 Nov 17.
Higgins MJ1, Liedke PE, Goss PE.Extended adjuvant endocrine therapy in hormone dependent breast cancer: the
paradigm of the NCIC-CTG MA.17/BIG 1-97 trial. Crit Rev Oncol Hematol. 2013 Apr;86(1):23-32. doi:
10.1016/j.critrevonc.2012.09.013. Epub 2012 Oct 30.
Regan MM1, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I,
Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group;
International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for
postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial

7.
8.

9.

10.

11.
12.

13.

14.

at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S1470-2045(11)70270-4. Epub
2011 Oct 20.
Ingle JN. Overview of adjuvant trials of aromatase inhibitors in early breast cancer. Steroids. 2011 Jul;76(8):765-7.
doi: 10.1016/j.steroids.2011.02.021. Epub 2011 Mar 4.
van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi
Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and
exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. doi:
10.1016/S0140-6736(10)62312-4.
Baum M et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun
22;359:2131-9. Erratum in: Lancet 2002;360:1520.
Coates AS et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal
women with endocrine responsive early breast cancer: update of study BIG 1-98 J Clin Oncol, pub ahead January
2007
Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy
in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262-71.
Jakesz R1, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, Mlineritsch B, Tausch C, Stierer M, Hofbauer F,
Renner K, Dadak C, Rücklinger E, Samonigg H; Austrian Breast and Colorectal Cancer Study Group.Extended
adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized
Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007 Dec 19;99(24):1845-53. Epub
2007 Dec 11.
Mamounas EP1, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB,
Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr,
Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant
tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin
Oncol. 2008 Apr 20;26(12):1965-71. doi: 10.1200/JCO.2007.14.0228. Epub 2008 Mar 10.
Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: A randomized, placebo-controlled trial
of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:6931-40.

15.

Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in
postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG
MA.17L). Ann Oncol 2005;16:707-15.

Premenopausal Patients - Adjuvant endocrine therapy (8/20)

Further information and references:
Tamoxifen* 5-10 yrs.
1.

2.

3.

4.

2.
3.

A ++

Voting: 100% acceptance

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472):
1687-717, 2005.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and
other factors to the effi cacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011
Aug 27;378(9793):771-84. doi: 10.1016/S0140-6736(11)60993-8. Epub 2011 Jul 28
Davies C, Hongchao P, Godwin J et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus
stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet
2013;381:805-806
Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with
lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): 1828-33, 1996.

GnRHa alone
1.

1a

1a

B

+

Voting: 100% acceptance

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for
early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472):
1687-717, 2005.
Walshe JM et al: Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol
24: 5769-5779, 2006.
Swain SM, Jeong JH, Wolmark N. Amenorrhea from breast cancer therapy--not a matter of dose. N Engl J Med.
2010 Dec 2;363(23):2268-70

4.
5.

Goel S et al: LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane
Database Syst Rev. 2009 Oct 7;(4):CD004562.
Cuzick J et al: Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal
patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised
adjuvant trials. Lancet 2007; 369:1711-23.

in patients with ovarian function (within 8 mo.) after adjuvant chemotherapy (Exploratory retrospective analysis
suggests higher benefit in younger age)
OFS (ovarian function suppression) 5 yrs. + TAM 5 yrs.
1b B
+/Voting: 100% acceptance
OFS 5 yrs. + AI 5 yrs.
1b B
+/Voting: 100% acceptance
1.

2.

3.
4.

5.

Pagani O, Gelber S, Colleoni M et a. Impact of SERM adherence on treatment effect: International Breast Cancer
Study Group Trials 13-93 and 14-93. Breast Cancer Res Treat. 2013 Nov;142(2):455-9. doi: 10.1007/s10549-0132757-x. Epub 2013 Nov 7.
Ganz PA, Land SR, Geyer CE Jr, Cecchini RS, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff JA,
Vogel VG, Erban JK, Livingston RB, Perez EA, Mamounas EP, Wolmark N, Swain SM. Menstrual history and
quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B30 trial. J Clin Oncol. 2011 Mar 20;29(9):1110-6
Goel S et al: LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane
Database Syst Rev. 2009 Oct 7;(4):CD004562.
Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Prada GA, Burstein
HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP,
Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS,
Goldhirsch A, Gelber RD; the SOFT Investigators and the International Breast Cancer Study Group. Adjuvant
Ovarian Suppression in Premenopausal Breast Cancer. N Engl J Med. 2014 Dec 11. [Epub ahead of print]
Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA,
Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer
EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G,

6.

Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study
Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul
10;371(2):107-18. doi: 10.1056/NEJMoa1404037. Epub 2014 Jun 1.
Gnant M et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009 Feb
12;360(7):679-91.

Premenopausal Patients – Adjuvant Endocrine Therapy (9/20)

Further information and refeernces:
AI alone
1.
2.
3.

1c

A

--

Voting: 100% acceptance

Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea:
caution and suggested guidelines. J Clin Oncol. 2006 Jun 1;24(16):2444-7
Ortmann O, et al: Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast. 2009
Feb;18(1):2-7
Dieudonné AS, Vandenberghe J, Geerts I, Billen J, Paridaens R, Wildiers H, Neven P. Undetectable antimüllerian
hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral
aromatase inhibitor. Menopause. 2011 Jul;18(7):821-4.

AI after GnRHa (induced amenorrhea) 5
1.
4.

5.

D

--

Voting: 100% acceptance

Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea:
caution and suggested guidelines. J Clin Oncol. 2006 Jun 1;24(16):2444-7
Dieudonné AS, Vandenberghe J, Geerts I, Billen J, Paridaens R, Wildiers H, Neven P. Undetectable antimüllerian
hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral
aromatase inhibitor. Menopause. 2011 Jul;18(7):821-4.
Goss PE et al: Outcomes of women who where premenopausal at diagnosis of early stage breast cancer. Cancer Res
69(Suppl.1);2009:487s(#13)

Upfront AI in patients with chemotherapyinduced amenorrhea (CIA, TIA) 4
C

--

Voting: 100% acceptance

1.

Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea:
caution and suggested guidelines. J Clin Oncol. 2006 Jun 1;24(16):2444-7

EAT in perimenopausal pts. with validated
postmenopausal status after 5 yrs. of Tam
1.
2.

2b B

+

Voting: 100% acceptance

Smith IE et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea:
caution and suggested guidelines. J Clin Oncol. 2006 Jun 1;24(16):2444-7
Goss PE et al: Outcomes of women who where premenopausal at diagnosis of early stage breast cancer. Cancer Res
69(Suppl.1);2009:487s(#13)

Postmenopausal patients – adjuvant endocrine therapy (10/20)

Further information and references:

.

AI for 5 yrs
Preference in lobular inv. Cancers
1.

2.
3.
4.

5.
6.

1a
2b

A
B

+
+

Voting: 100% acceptance
Voting: 100% acceptance

Baum M et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun
22;359:2131-9. Erratum in: Lancet 2002;360:1520.
Cuzick J et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year
analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. Epub 2010 Nov 17.
BIG 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early
breast cancer. N Engl J Med 2005;353:2747-57.
Coates AS et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal
women with endocrine responsive early breast cancer: update of study BIG 1-98 J Clin Oncol, pub ahead January
2007
Cella D et al. Five years quality of life follow up of adjuvant endocrine therapy for postmenopausal women in the
ATAC trial. Proc ASCO 2005, Abstract 577.
Duffy S. Gynecological adverse events including hysterectomy with anastrozole tamoxifen: Data from the ATAC
('Arimidex', Tamoxifen, Alone or in Combination) trial. J Clin Oncol 2005;23(Suppl.):58S, Abs 723.

Sequential therapy for 5 -10 yrs.
Tam followed by AI (2-5 yrs.)*
1a
AI (2-5 yrs.)* followed by Tam 1b

++
A
C

Voting: 100% acceptance

Ingle JN. 4.23(Suppl. Jakesz R.97:1262-71. Godwin J.16:707-15. J Clin Oncol 2005. 3. Samonigg H. Extended adjuvant treatment with anastrozole: results from the Austrian Breast an Colorectal Cancer Study Group Trial 6a (ABSCG 6a). 3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Burstein HJ. Assessment of quality of life in MA. placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. et al. Greil R. American Society of Clinical Oncology technology assessment an the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. published online 2012 Early Breast Cancer Trialists' Collaborative Group. 1a A ++ Voting: 100% acceptance Davies C. Wasan KM. Davies C. Abs 527 Mamounas E et al. 2. 4. et al. Hudis C.Benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen intent to treat analysis of the NSABP-B33. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA. J Clin Oncol 2005. 1. 6. 5. 2011 .1.23:619-29. Whelan TJ. et al. 2.17. Goss PE. a randomised trial. Pritchard PH. Lancet. Tamoxifen 20 mg/d for 5-10 yrs. 349: 1793-1802 Goss PE. Ingle JN. Hongchao P. Lancet 2005. Winer EP. et al.):10S.23:6931-40. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Goss PE. J Clin Oncol 2005.365:1687-717. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials. et al. J Natl Cancer Inst 2005. Breast Cancer Res and Treat 2006.17: A randomized. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS. Lancet. 100 (suppl1):abstract 49. et al. a randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer N Engl J Med 2003.17L). Ann Oncol 2005. 378:771-84. Goss PE et al. Martino S. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA. Godwin J et al.

Mallon E et al. a randomised trial. Giobbie-Hurder A. S1-1 Davies C.381:805-806 . Hongchao P. Lancet 2013. Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. Metzger O. 6.5. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS. SABCS 2012. Godwin J et al.

Poggio F. Lambertini M. Catzeddu T. Scialla J. Maass N. Pronzato P. early breast cancer patients. 3. (2006) Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young. 13. D'Alonzo A. Bighin C. Moore H: Preventing chemotherapy-related amenorrhea using leuprolide during adjuvant chemotherapy for early-stage breast cancer. Bruzzi P. 2008 Mar. 7. Ceppi M. Cancer 106: 514-523 Fox K. Breast Cancer Res Treat. Peccatori F.108(1):1-7. (2006) Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma. Demeestere I. Ortmann O. Levaggi A. 6. Fischer D. Ann Oncol 17: 74-78 Gerber B. 2007. Felberbaum R. Canavese G. Conrad B.Ovarian Protection and Fertility Preservation in Premenopausal Patients Receiving Adjuvant Chemotherapy (CT) (11/20) Further information and references: Ovarian Function Protection CT + GnRHa (Wechselwirkung mit CT unklar) 1b B (GnRHa application > 2 weeks prior to chemotherapy) 1. Del Mastro L. Reimer T. Fehm T. Tham YL: The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. German Breast Group Investigators. Amiconi G et al. Giraudi S.Effect of luteinizing hormonereleasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. 2003. Rezai M. Am J Clin Oncol. Sommer HL. 2. Boni L et al.29(17):2334-41. J Clin Oncol. 5. 4. Stehle H. +/Voting: 100% acceptance Gerber B: Controversies in preservation of ovary function and fertility in patients with breast cancer. von Minckwitz G. 30:126-32 Recchia F. Epub 2011 May 2 Del Mastro L. 2011 Jun 10. Saggio G. Mehta K. Gonadotropin-releasing hormone analogues for the prevention of . Proc Am Soc Clin Oncol 22. Loibl S.

Fertility and cancer: psychological support in young women who contemplate emergency assisted reproductive technologies (ART) prior to chemo. author reply 1760-1. Besse D.2010.4414/smw.12. 2011 Jul 20. Reprod Biomed Online. Almog B. [Epub ahead of print]. Gerber B. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. Kupka MS et al.40(5):675-83. Cancer Treat Rev. Xu P. J Clin Oncol.1016/j.13075.306(3):269-76. 4 C + Voting: 100% acceptance 4 C + Voting: 100% acceptance Lawrenz B. Del Mastro L. Carter WB. Shehata F et al.ctrv. JAMA.000 patients: patient's characteristics. Ismail-Khan R. Bellavia M.140:w13075. Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer. 2011 Oct 26. Shalom-Paz E. Cox CE. Lacevic M. Fertility preservation in >1. Fertility preservation for breast-cancer patients using IVM followed by oocyte or embryo vitrification. Epub 2013 Dec 8. Jauckus J. 2010 Oct. 5. [Epub ahead of print] Loibl S. Gonadotropin-releasing hormone analogue for premenopausal women with breast cancer.21(4):566-71. JAMA. 2010 Dec 1. Swiss Med Wkly.and/or radiation-therapy. . Arch Gynecol Obstet. Wunder D.chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Moore AP. 3. 2014 Jun. 2. doi: 10. Gross-King M.306(16):1760. doi: 10. Epub 2010 May 13.001. Michelotti A et al. Fertility preservation counselling* Fertility preservation with assisted reproduction therapy 1. Minton SE. 4. Munster PN. Boni L. de Ziegler D. 6.2013. efficacy and risks of applied preservation techniques. 2012 Jan 9. 2010 Jul 16. spectrum.

Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer.95(5):1857-9. Matro J. Sammel MD. Antral follicle count provides additive information to hormone measures for determining ovarian function in breast cancer survivors. Behera M. Lyons P. Blackwell K. 5. Abusief M. Green J. Kimmick G. Ruddy KJ. Antenos M. 2010 Jul. Sammel MD.26(3):28695 Anderson RA. DeMichele A. Shaw H. Gu L. 618: Ovarian Reserve Testing. Cancer Invest. Chung K. 2008 Apr-May. Cancer. Su HI. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. Freeman EW. Schapira L. Snyder S. DeMichele A. Fertil Steril. Obstetrics & Gynecology 2015 . Anders C. 2011 May.125 : 268–273 Su HI. 96(5):1336-43. Gracia CR. J Clin Endocrinol Metab. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. 3. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. 6. 2010 Feb 1. Welch R. Unruhe S. 2011 Apr. Velders L. Gelber S. Gracia CR.116(3):592-9. Stankiewicz C. Partridge AH. Cameron DA. Copland S. 2. . ACOG Committee Opinion No. 4. Meyer M.94(2):638-44. Woodruff T. Peterson B. Ginsburg E.Testing ovarian reserve (12/20) No further information References: 1. Marcom PK. Fertil Steril.

1200/JCO. Obstet Gynecol. Havrilesky LJ. 3. Contraception.Contraceptive Options for Premenopausal Women after Diagnosis of Breast Cancer (13/20) No further information References: 1. J Clin Oncol.2013. Giersch JM et al. . doi: 10. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. 2. Backman T. 2005 Oct.69(5):353-60. 2013 Nov 20.9021. Epub 2013 Oct 21. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. 2004 May. Moormann PG.106(4):813-7.48. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Strom BL.31(33):4188-98.

Ovarian Function Preservation (14/20) No further information No references .

Metaanalysis of GnRH for Prevention of Premature Ovarian Failure (15/20) No further information No references .

TEXT/SOFT Joint Analysis (16/20) No further information No references .

Aromataseinhibitors in Adjuvant Therapy (17/20) No further information No references .

Aromataseinhibitors in Adjuvant Therapy – Overview over Published Trials (18/20) No further information No references .

Assessment of Ovarian Reserve (19/20) No further information No references .

10 Yrs versus 5 yrs Breast Cancer Mortality in ER+ (20/20) No further information No references .

1 Adjuvant Cytotoxic and Targeted Therapy . V.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. in der DGGG e. Guidelines Breast Version 2015. sowie in der DKG e.V.V.

ago-online.V.  Version 2002: Möbus / Nitz  Versionen 2003–2014: Harbeck / Jackisch / Janni / Loibl / von Minckwitz / Möbus / Müller / Nitz / Schneeweiss / Simon / Solomeyer/ Stickeler / Thomssen / Untch  Version 2015: Schütz / Lux Guidelines Breast Version 2015. sowie in der DKG e. V.V.1 www.Adjuvant Cytotoxic and Targeted Therapy © AGO e.de . in der DGGG e.

V.1 If chemotherapy is indicated due to tumor biology. Guidelines Breast Version 2015. carboplatinum-containing regimen • Dose dense & escalated in case of high tumor burden ++ ++ + + TNBC  Conventionally dosed AT-based chemotherapy  Dose dense & escalated ++ + .and “high risk”  Conventionally dosed AT-based chemotherapy  Dose dense & escalated in case of high tumor burden  Followed by endocrine therapy ++ + ++ HER2+ www.and “low risk”:  Endocrine therapy without chemotherapy ++ HR+/HER2. consider systemic treatment before surgery (neoadjuvant) AGO ++ HR+/HER2.Subtype-specific General Systemic Strategies © AGO e.de  Trastuzumab plus • Sequential A/T-based regimen with concurrent T + H • Anthracycline-free. sowie in der DKG e. in der DGGG e.V.ago-online. V.

V.ago-online. sowie in der DKG e.de  Dose-dense in case of high tumor burden .1   Anthracycline / taxane based chemotherapy 1a A ++ If anthracyclines cannot be given  Docetaxel plus cyclophosphamide 1b B +  Paclitaxel mono weekly 1b B +/-  CMF 1a A +/- 1a A ++ www.V. Guidelines Breast Version 2015. in der DGGG e.Adjuvant Chemotherapy without Concurrent Trastuzumab: Overview © AGO Oxford / AGO LoE / GR e.V.

V.V. Guidelines Breast Version 2015. V. sowie in der DKG e.de Anthracycline-free regimen  DC D75 C600 x4 1b B +  Pac mono P80 q1w x 12 1b B +/-  CMF C600M40F600 q3w x 6 1a A +/- . in der DGGG e.Recommended Regimens for Adjuvant Chemotherapy © AGO e.1 Oxford / LoE / GR AGO Anthracycline / taxane based regimen  EC  Pw E90C q3w x 4  P80 qw1 x 12 1ba B ++  DAC D75A50C q3w x 6 1b A ++  AC  Pw A60Cq3w x 4  P80qw1 x 12 1b A ++  AC  D A60C q3w x 4  D100 qw3 x 4 1b A ++  EC  D E90C q3w x 4  D100 qw3 x 4 1ba B ++ www.ago-online.

de Dose-dense regimen  AC q3w / Pac q1w x 12 1b A ++  *EC q3w Pac q1w x 12 1b B ++  EC q3w / Pac q2w 1ba A +  EC q2w / Pac q1w 1b B +  ACPac / AC-Pac q2w 1b A + A ++ Dose-dense and dose-escalated regimen (N  4+)  E-Pac-C q2w * Extrapolated from doxorubicin trials 1b .1 www. Guidelines Breast Version 2015.ago-online. sowie in der DKG e. in der DGGG e. V.V.Dose-dense and/ or Dose-escalated Adjuvant Chemotherapy in Case of High Tumor Burden © AGO Oxford / AGO LoE / GR e.V.

de  Capecitabine containing regimen in TNBC 1a B +/-  Platinum containing regimen in TNBC 5 D +/-  5.ago-online.1 www. V.V.V. in der DGGG e. sowie in der DKG e.Fluorouracile added to EC/AC 1ba A -- . Guidelines Breast Version 2015.Adjuvant Chemotherapy other Drugs © AGO Oxford / AGO LoE / GR e.

sowie in der DKG e. Guidelines Breast Version 2015. V.Adjuvant Treatment with Trastuzumab I © AGO e.V.ago-online.de .1  Node-positive disease  Node-negative disease 1a A ++ (whenever chemotherapy is considered as adequate)  > 10 mm 1a A ++  > 5–10 mm 2b B +  ≤ 5 mm 2b B +/- www. Oxford / AGO LoE / GR in der DGGG e.V.

Adjuvant Treatment with Trastuzumab II © AGO Oxford / AGO LoE / GR e.ago-online. in der DGGG e. V. Guidelines Breast Version 2015.de  For 1 year For 2 years For 0.V.1 Start of treatment Simultaneously with taxanes  Sequentially up to 3 months after chemotherapy  1a A ++ 1b B + 1b 1b 1b A A A ++ +/- Duration   www.5 years * Loading dose .V. sowie in der DKG e.

ago-online. physical examination (edema.Adjuvant Trastuzumab cardiac Monitoring for CHF © AGO e. Guidelines Breast Version 2015. sowie in der DKG e. in der DGGG e.V. hepatomegaly)  Echocardiography (alternative to MUGA) Assessment of LVEF During trastuzumab www. V.1 Oxford LoE: 5 GR: D AGO: ++ Before start of trastuzumab  History.V.de Regular assessment of  Heart rate increase > 15% above individual base level  Body weight increase ≥ 2 kg/week 3 monthly assessment of LVEF .

sowie in der DKG e.V. in der DGGG e.de Radiotherapy concurrent with Trastuzumab * Study participation recommended . Guidelines Breast Version 2015.ago-online. pN0    With docetaxel and carboplatin 1b A 2ba B 1b A ++ +/+ With anthracyclines With taxanes dose-dense 2b 2b B B +/+* 2b B + www.1 Simultaneously  With paclitaxel / docetaxel after AC / EC  With P q1w 12 x without A in pT < 3 cm.V. V.Adjuvant Treatment with Trastuzumab: Schedules © AGO Oxford / AGO LoE / GR e.

de (delayed adjuvant treatment) 5 1b D B -  Lapatinib + Trastuzumab 1ba B -  Pertuzumab 5 D -  Bevacizumab 1b B -- a . Oxford / AGO LoE / GR in der DGGG e. sowie in der DKG e. Guidelines Breast Version 2015.1  Lapatinib  www. V.V.ago-online.Adjuvant Therapy with Other Targeted Agents © AGO e.V.

Adjuvant Cytotoxic and Targeted Therapy (2/12) No further information No references .

Winer EP. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. 24:2206–2223. how and which one? Breast Care (Basel). Coates AS et al. 2014 Jul. Ann Oncol 2013. . Schmidt M. Chemotherapy in early breast cancer: when.9(3):154-60. Goldhirsch A.Subtype-specific general systemic strategies (3/12) No further information: References: 1. 2.

Mackey D. Hobday TJ. Harbeck N. Albain KS. Barlow WE. Boehm KA. Sandbach J. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. McGregor BA. Thomssen C. Moore HC. J Clin Oncol. Srkalovic G. Lew DL. Kreipe HH.33(1):58-64. Weiss E. Lisboa B. Moore TD. Budd GT. Wallwiener D. SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer. Burton GV. Hartmann A. Chew HK. Livingston RB. O'Shaughnessy J. Mennel RG. 2014 Aug.Paclitaxel mono weekly (1b B +/-) . Jänicke F. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. Kiechle M. Savin MA. Mohrmann S. McIntyre KJ.25(8):1551-7. Bordelon JH. Hyman WJ. Augustin D. Hortobagyi GN. 2015 Jan 1.Docetaxel plus cyclophosphamide (1b B +) Vote result of the AGO recommendation: 100% 1. Nitz U.Adjuvant Chemotherapy without concurrent trastuzumab: overview (4/12) Further information and references: Statement: Anthracycline/ taxane based chemotherapy (1a A ++) Vote result of the AGO recommendation: 100% 1. Salim M. Möbus V. Jones S. Scholz M. Asmar L. Pippen JE. Blum JL. Holmes FA. 2009 Mar 10. Kirby RL. Cho JK. Sattler D. Ann Oncol. Rinn KJ. Stewart JA. Statement: If anthracyclines cannot be given . Gralow JR. Erber R. Isaacs C. Kuhn W. Statement: If anthracyclines cannot be given . Huober J. Du Bois A. Gluz O. Riedel S. Kreienberg R. 2. Muss H. Clin Oncol. Böhmer S. Hoffmann G. Richards DA. Meyer WG. Kates RE. Vukelja SJ. Flaherty LE.27(8):1177-83.

O'Reilly S. pii: mdu564. 2014 Dec 8. Rossi E. Jones V. Shulman LN. 2014 Aug 1. de Matteis A. Wang M. Are dose-dense and triplet chemotherapy regimens optimal adjuvant therapy in the majority of women with node-positive early breast cancer? J Clin Oncol. Kimmick G. Sparano JA. Vassalli L. Norton L. Sledge GW Jr. O'Regan R. Simoncini E. Perez EA.33(3):290.Vote result of the AGO recommendation: 100% 1. Morabito A. methotrexate. and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. Riccardi F. Lauria R. Di Maio M. Wolff AC. . Valagussa P. Gravina A. Becker HP. Forestieri V. Amoroso V. Zambetti M. Montanino A. Cirrincione CT. Landi G. Bonadonna G. Wood WC. De Placido S.32(22):2311-7. Sharratt P.358(16):1663-71 Statement: If anthracyclines cannot be given . Daniele B. N Engl J Med. Berruti A. D'Aiuto M. Ferrari L. Ann Oncol. Burstein HJ. Sigala S. Perez EA. De Laurentiis M. Should adjuvant weekly Paclitaxel be considered less efficacious than anthracyclines plus cyclophosphamide for lower-risk patients with early-stage breast cancer? J Clin Oncol. 2014 Feb 20. J Clin Oncol.32(6):605-6. Perrone F. Moliterni A. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Barni S. 1995 Apr 6. Brambilla C. Botti G. Pacilio C.CMF (1a A +/-) Vote result of the AGO recommendation: 100% 1. Labonia V. Saphner T. Gori S. Di Rella F. 2008 Apr 17. Tinessa V. Daniele G. Winer EP. Moylan EJ. 2. Nuzzo F. Piccirillo MC. Colantuoni G. Connell LC. Hudis CA. N Engl J Med. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). Berry DA. 2015 Jan 20. Martino S. De Maio E. 2. Pedersini R. Schneider CJ. Signoriello S. 3. Martino S. Gallo C. Iodice G. Muss H. [Epub ahead of print] Adjuvant cyclophosphamide.332(14):901-6 Statement: Dose-dense in case of high tumor burden (1a A ++) Vote result of the AGO recommendation: 100% 1. Shapiro CL. Davidson NE.

Moebus V. Breast. Kurbacher C. Kreienberg R. Lemos Duarte I. and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. Thomssen C. Runnebaum IB. Schneeweiss A. . du Bois A. 2010 Jun 10. 3. Hinke A. Untch M. Nitz U. Passos Lima CS. Lueck HJ. Konecny GE. Dose-dense chemotherapy versus conventional chemotherapy for early breast cancer: a systematic review with meta-analysis.2. paclitaxel. Deeke Sasse A. Huober J. J Clin Oncol.28(17):2874-80. 2012 Jun. von Minckwitz G. Jackisch C. Harbeck N. da Silveira Nogueira Lima JP.21(3):343-9. Intense dosedense sequential chemotherapy with epirubicin. Kuhn W.

node-positive breast cancer: the NSABP B-38 trial. Brufsky AM. 2014 Statement: Anthracycline/ taxane based regimen DAC D75A50C q3w x 6 (1b A ++) Vote result of the AGO recommendation: 100% 1. doi: 10. Barlow WE. Biggs DD. Mamounas EP. Zapas JL. Fehrenbacher L. 2013 (suppl. Costantino JP. Robidoux A. Levine EA. Martino S. Rastogi P.31(26):3197-204. Sledge GW.Recommended Regimens for Adjuvant Chemotherapy (5/12) Further information and references: Statement: Anthracycline/ taxane based regimen EC  Pw E90C q3w x 4  P80 qw1 x 12 (1ba B ++) Vote result of the AGO recommendation: 100% 1. Statement: Anthracycline/ taxane based regimen AC  Pw A60Cq3w x 4  P80qw1 x 12 (1b A ++) Vote result of the AGO recommendation: 100% . Donnellan PP. Saphner T. Moore HCF. Zhao F. S3-03.1275. Swain SM. Wolmark N. SABCS. Atkins JN. 2013 Sep 10. 2. Wood WC. Budd GT. Geyer CE Jr.1200/JCO. Wolff AC. Azar CA. Epub 2013 Aug 12. J Clin Oncol 31:51s. Northfelt DW. abstr CRA1008) Sparano JA. Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer. Polikoff JA. Ligibel J. Tang G. Davidson NE.48. et al: S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer.2012. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable. Perez EA. Provencher L. J Clin Oncol. Paik S.

Savin MA. Statement: Anthracycline-free regimen Pac mono 80 mg q1w x 4-6 (1b B +/-) Vote result of the AGO recommendation: 100% 1. Norton L. Muss H.1. Louis Fehrenbacher. Sedlacek. Jones S. Winer EP. O'Regan R. Cirrincione CT. Holmes FA.Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28 J Clin Oncol 2005. 23:3686-3696. Barry Lembersky. Kirby RL. Meyer WG. Statement: Anthracycline/ taxane based regimen AC  D A60C q3w x 4  D100 qw3 x 4 (1b A ++) EC  D E90C q3w x 4  D100 qw3 x 4 (1ba B ++) Statement: Anthracycline-free regimen DC D75 C600 x4 (1b B +) Vote result of the AGO recommendation: 100% 1. Shulman LN.32(22):2311-7. Becker HP. Berry DA. Sandbach J. Hudis CA. Muss H. Vukelja SJ. Asmar L. Shapiro CL. and Norman Wolmark. Bordelon JH. McIntyre KJ. John Bryant. 2009 Mar 10. Mennel RG. Schneider CJ. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). Mamounas. Lawrence Wickerham. Boehm KA. Riedel S. J Clin Oncol. Scot M. Martino S. Statement: Anthracycline-free regimen CMF 600/40/600 mg q3w x 6 (1a A +/-) . Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. Bernard Fisher. Eleftherios P. Pippen JE. Burstein HJ. Atilla Soran. Blum JL. Greg Yothers. Kimmick G. O'Shaughnessy J. 2014 Aug 1. Clin Oncol. Richards DA. Mackey D. Perez EA.27(8):1177-83. Hyman WJ. D.

Landi G. Botti G. De Maio E. Labonia V. Lauria R. Gallo C. Colantuoni G. Perrone F. de Matteis A. Signoriello S. De Laurentiis M. Pacilio C. Iodice G. Montanino A. [Epub ahead of print] . Gori S. De Placido S. Nuzzo F.Vote result of the AGO recommendation: 100% 1. Di Rella F. Morabito A. Ann Oncol. Forestieri V. D'Aiuto M. Daniele G. Di Maio M. Rossi E. 2014 Dec 8. Gravina A. Piccirillo MC. Barni S. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. pii: mdu564. Tinessa V. Riccardi F. Daniele B.

Bramwell V. Burnell M. Agarwal R. et al. Br J Cancer 2009.100:305e10.28:77e82.Dose-dense and/ or dose-escalated adjuvant chemotherapy in case of high tumor burden (6/12) Further information and references: Statement: Dose-dense regimen AC q3w / Pac q1w x 12 (1b A++) *EC q3w Pac q1w x 12 (1b B ++) Vote result of the AGO recommendation: 100% 1.97:1724e33 Jones RL. Statement: Dose-dense regimen EC q3w / Pac q2w (1ba A +) EC q2w / Pac q1w (1b B +) Vote result of the AGO recommendation: 100% 1. Chua S. O'Brien M. Caroti C. Cyclophosphamide. 3. Contu A. 2. Baldini E. Venturini M. et al. Walley B. J Clin Oncol 2010. Levine MN. Del Mastro L. Gelmon K. A randomized pilot phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer. Ashley S. Aitini E. J Natl Cancer Inst 2005. epirubicin. and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk nodenegative breast cancer. Dosedense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. Statement: Dose-dense regimen ACPac / AC-Pac q2w (1b A +) Vote result of the AGO recommendation: 100% . et al. Walsh G. Chapman JA.

Mamounas EP. Atkins JN. Lueck HJ. J Clin Oncol. Polikoff JA. Winer EP. Robidoux A. Untch M. 2010 Jun 10. du Bois A. Huober J. Runnebaum IB. Thomssen C. Zapas JL. Tang G. Statement: Dose-dense and dose-escalated regimen (N ≥ 4+) E-Pac-C q2w (1b A ++) Vote result of the AGO recommendation: 100% 1. Berry DA. 2013 Sep 10. Hudis C. Levine EA. Rastogi P. Schneeweiss A. Provencher L. Intense dosedense sequential chemotherapy with epirubicin. paclitaxel.Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. Nitz U. and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. Konecny GE. Jackisch C. Harbeck N. . node-positive breast cancer: the NSABP B-38 trial. Hinke A. Northfelt DW. Costantino JP. Kreienberg R. J Clin Oncol 2003. et al. Brufsky AM. Kuhn W. Cirrincione C. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable.31(26):3197-204. Citron ML. Biggs DD. Paik S. Moebus V.1. Geyer CE Jr. Swain SM.28(17):2874-80. Fehrenbacher L. Wolmark N. Negative Trial 1. Donnellan PP. Azar CA. Gradishar WJ. von Minckwitz G. J Clin Oncol. Kurbacher C.21:1431e9.

2012 Jan 1. Du Y. Kataja V. Bono P. Jiang Y. docetaxel. Epub 2011 Nov 21.1200/JCO. Asola R. Nyandoto P. Kellokumpu-Lehtinen PL. Tondini C. Huovinen R.Adjuvant Chemotherapy Other Drugs (7/12) Further information and references: Statement: Capecitabine containing regimen in TNBC (1a B +/-) Vote result of the AGO recommendation: 100% 1. Zhou L.2011. Aitini E.30(1):11-8.-) Vote result of the AGO recommendation: 100% 1. Boni C. Jukkola-Vuorinen A. and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. in . Barni S. Bruzzi P. 2. J Clin Oncol. Statement: 5. Parisi AM. Leinonen M. De Laurentiis M. Yin W. Lu J. Del Mastro L. Adjuvant capecitabine. Lindman H. Shao Z. Montemurro F. Kokko R. Ahlgren J. Di Blasio B. Joensuu H. De Placido S.35. Gamucci T. doi: 10. Lambertini M. Poikonen P. PLoS ONE 2012 7(3): e32474. Auvinen P. Yan L. Bighin C. Zhou Q. Pastorino S. cyclophosphamide. Garrone O. Puglisi F.Fluorouracile added to EC/AC (1ba A . Durando A. Cognetti F.4639. all given every 3 weeks or 2 weeks. Colantuoni G. First efficacy results of capecitabine with anthracycline-and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis. Helle L. Turletti A. Paija O. Villman K. Pajunen M. Valle E. Olmeo N. Nilsson G. epirubicin and cyclophosphamide (FEC) followed by T. Statement: Platinum containing regimen in TNBC (5 D +/-) Vote result of the AGO recommendation: 100% No References available. Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil. Shen Z. Tanner M.

Final results of the Gruppo Italiano Mammella (GIM)-2 randomized phase III study
. . San Antonio Breast Cancer Symposium 2013. S5-06.node-positive early breast cancer (BC) patients (pts).

Hillenbach C. [Epub ahead of print] Statements: >10 mm/> 5-10 mm/ <= 5mm . Gelber RD. Bell R. Elliott R. Suter TM. Wardley A. Harbeck N.Adjuvant treatment with trastuzumab I (8/12) Further information and references: Statements: Node-positive and node-negative disease Vote result of the AGO recommendation: 100% 1. Bell R. Herceptin Adjuvant (HERA) Trial Study Team. Suto T. N Engl J Med. Procter M. Smith I. Wilcken N. Stroyakovskiy D. Lancet.369(9555):29-36.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.353(16):1659-72. Suter TM. Untch M. Vindevoghel A. randomised controlled trial. Rüschoff J. McFadden E. Goldhirsch A. Untch M. Inbar M. Láng I. Bergh J. Leyland-Jones B. Herceptin Adjuvant (HERA) Trial Study Team. Piccart-Gebhart MJ. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. Baselga J. Cameron D. Cameron D. 2005 Oct 20. Smith I. Smith I. Lancet. Procter M. Wist E. Barrios CH. Otero-Reyes D. Dowsett M. 2. Kaufmann M. Köhne CH. Piccart-Gebhart MJ. HERA study team. 2007 Jan 6. 2013 Sep 21. Heinzmann D. Gelber RD. McFadden E. Jackisch C. Guillaume S. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Goldhirsch A. Melichar B. Gianni L. Andersson M. 2014 Nov 17. Sánchez Rovira P. Mallmann P. Steger G. Ward C. Lichinitser M. Semiglazov V.382(9897):1021-8. Iwata H. Piccart-Gebhart MJ. Kim SB. Dowsett M. Untch M. Gelber RD. Dolci MS. Mariani G. Lum BL. Ann Oncol. Bell R. Lohrisch C. Jackisch C. Jackisch C. Huang CS. Gianni L. Straehle C. de Azambuja E. Baselga J. Nitz U. Cameron D. Brunt AM. Dal Lago L. Greatorex V. Gelmon K. Lopez RI. Weber HA. Thomssen C. Ismael G. Andersson M. Coleman R. Weber HA. Dowsett M. 4. Leyland-Jones B. pii: mdu524. Song S. Procter M. Baselga J. Goldhirsch A. 3. Feyereislova A. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Pivot X.

Litton JK. Rakkhit R. Berry DA. Buchholz TA. Sahin A. Piccart-Gebhart M. Ravdin PM. Hanrahan EO. Broglio KR. Epub 2009 Nov 2.27(34):5700-6. Hortobagyi GN High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive.1. Guray M. Larsimont D. Theriault R. Cardoso F. Gonzalez-Angulo AM. J Clin Oncol. Meric-Bernstam F. Feoli F. Valero V. Peintinger F. Stranzl H. 2009 Dec 1. node-negative tumors 1 cm or smaller. .

Baselga J. N Engl J Med. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. Geyer CE Jr. Kataja V. Jeong.369(9555):29-36. Journal of . 2. Elomaa I. Jenkins RB. A. FinHer Study Investigators. P. J. Procter M. Mariani G. Gelber RD. Greatorex V. E. Romond EH. Piccart-Gebhart MJ. Kellokumpu-Lehtinen PL. Kokko R. Lohrisch C. E. Davidson. Wilcken N. Gianni L. Romond. Leyland-Jones B. Pajunen M. Sánchez Rovira P. Dowsett M. Barrios CH. Dolci MS.353(16):1673-84. Asola R. Untch M. Procter M. Guillaume S. J. Dakhil SR. Vogel VG. McFadden E. Fehrenbacher L. Suto T. HERA study team. S. Ingle JN. Jyrkkiö S. 4. Suman. Joensuu H. E. Dowsett M. Bergh J. H. Lichinitser M.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Kaufman PA. Gelmon K. Geyer. Yothers G. Mamounas. Wolmark N. P. Martino S. Bono P. Inbar M. Rauhala M. Feyereislova A. Cameron D. NCCTG/NSABP. Lopez RI. Wardley A. Perez EA. Leinonen M. Smith I. Salminen T. Perez. V. Lancet. Alanko T. Helle L. 2005 Oct 20. 2007 Jan 6. Rüschoff J. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Goldhirsch A. Suter TM. Untch M. N Engl J Med. 5. Turpeenniemi-Hujanen T. Wolmark. Tarkkanen M. Flander M. Lingle WL. Andersson M. Piccart-Gebhart MJ. Bell R. Kutteh LA. Isola J. C. Johansson K. Davidson NE. Ingalsuo S. Mallmann P. Huang CS. Nitz U. Swain SM. Brown AM. N. Bell R. Cameron D. Iwata H. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. Goldhirsch A. Straehle C. Paik S. Ward C. Mamounas EP.354(8):809-20. Bryant J. Martino. Jackisch C. Pisansky TM. Herceptin Adjuvant (HERA) Trial Study Team. Kaleva-Kerola J. Visscher DW. Coleman R.Adjuvant treatment with Trastuzumab II (9/12) Further information and references: Statement: Start of treatment Vote result of the AGO recommendation: 100% 1. Kaufmann M. Tan-Chiu E. Steger G. Wist E. Smith I. Suman VJ. Gelber RD. Kauffman.353(16):1659-72. Láng I. E. Utriainen T. Baselga J. A. N Engl J Med. Thomssen C. E. Jääskeläinen AS. 2005 Oct 20. Harbeck N. 3. N. Klein PM. 2006 Feb 23. Hemminki A.

No. Vera J.1056/NEJMoa0910383. Procter M. J Clin Oncol 29:4491-4497. Leinonen H. 2011 Oct 6. Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer.365(14):1273-83.6. Visco F. as adjuvant treatments of breast cancer: final results of the FinHer Trial. Untch M. Buyse M. Chan A. Robert N. 2007 ASCO Annual Meeting Proceedings Part I. Press M. Helle L. Salminen T. PLoS One. Tabah-Fisch I. Fluorouracil. Lancet. Otero-Reyes D. Dal Lago L. Jiang Y. JoAnne Zujewski. Epub 2013 Jul 18. Turpeenniemi-Hujanen T. Suman. Huusko M. Asola R. Pisansky. 7. Shao Z. Gianni L. Pajunen M. Liu MC. 2013 Sep 21. Edith A. Epub 2011 Jun 9. Smith I. Peter A. Nancy E. Leyland-Jones B. 8. 2007: 512 Joensuu H.1016/S01406736(13)61094-6. Pienkowski T. and cyclophosphamide with either docetaxel or vinorelbine. Yin W. Leinonen M. randomised controlled trial. Eiermann W. Statement: Duration Duration Trastuzumab 1 year Vote result of the AGO recommendation: 100% Duration Trastuzumab 2 year . Beiyun Chen. Alanko T. Lu J. Mackey J. Jackisch C. Kaufman. Julie R. Köhne CH. Herceptin Adjuvant (HERA) Trial Study Team. Valero V. J Clin Oncol. Thomas M. Bendahmane B. Gelber RD. Adjuvant trastuzumab in HER2positive breast cancer. Shen Z. 10. Suter TM. Riva A. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Martin M. 2011 Slamon D. Isola J. Auvinen P. Lindsay MA. Kataja V. with or without trastuzumab. Piccart-Gebhart MJ. Crown J. Baselga J. Bono P. von Minckwitz G. Vindevoghel A. Möykkynen K.6(6):e21030. and Robert B. Breast Cancer International Research Group. Bee V. 18S (June 20 Supplement). doi: 10.382(9897):1021-8. Kellokumpu-Lehtinen PL. Pawlicki M. Jyrkkiö S. N Engl J Med. Cameron D. Brunt AM. de Azambuja E. Song S. Visscher. Ingle. Andersson M. Kokko R.27(34):5685-92. doi: 10. epirubicin. 2011. Dakhil. 2009 Dec 1. Heinzmann D. Jenkins. Alvaro Moreno-Aspitia. Gralow. Vol 25. 9. Utriainen T. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. Daniel W. Goldhirsch A. Dowsett M. Clinical Oncology. Davidson. Epub 2009 Nov 2. Shaker R. Perez. Ingalsuo S. James N. Glaspy J. Weber HA. McFadden E. Sauter G. Pinter T. Bell R.

Song S. Köhne CH. Suter TM. Bell R. Kerbrat P. Brunt AM. Weber HA. PHARE trial investigators. de Azambuja E. 2013 Sep 21. McFadden E. Tubiana-Mathieu N. . Gianni L. Fumoleau P. Vindevoghel A. Jackisch C. Leyland-Jones B. Serin D. Pauporté I. Lancet Oncol. Baselga J. Jouannaud C. Untch M. Catala S. Herceptin Adjuvant (HERA) Trial Study Team. 2. Procter M. 3. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Pierga JY. Romieu G. Andersson M.14(8):741-8. Dowsett M.5 years Vote result of the AGO recommendation: 1 +/ 23 +/-/ 6 -/ 1 -1. randomised controlled trial. Piccart-Gebhart MJ. Lancet. Gelber RD. Lortholary A. Otero-Reyes D. Jacquin JP. Heinzmann D. Rios M. Dal Lago L. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Espié M.Vote result of the AGO recommendation: 100% Duration Trastuzumab 0. Goldhirsch A. 2013 Jul. Cany L. Abadie-Lacourtoisie S. Kramar A. Khayat D. Smith I.382(9897):1021-8. Pivot X. Bachelot T. Debled M. Cameron D.

Dakhil SR. 2. J Clin Oncol. Klijn JG. Muscholl M. Knap M. Davidson NE. Perez EA. Rodeheffer RJ. Perez EA.22(2):322-9. Epub 2008 Feb 4. Provencher L. Delgado D. Côté MA. Verma S.25(25):3859-65. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. Gnant M. Clemons M. Winer EP. Procter M. van Veldhuisen DJ. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. Ageev FT. Iwata H. Sawyer MB. Muehlbauer S. Gelmon KA. Sledge GW. Gralow JR. J Clin Oncol. Groetz J. J Clin Oncol. Hitre E. Gersh BJ. Rodeheffer R.15(1):24-35. Bergh J. Gelber RD. Carlomagno C. Perren T. 4. Kaufman PA. Bighin C. 2007 Sep 1. Jaffe AS. Spence A. Suman VJ. Dent S. 2008 Mar 10.26(8):1231-8.Adjuvant trastuzumab – Cardia mMnitoring for CHF (10/12) Further information and references: Statement: Cardiac Monitoring Vote result of the AGO recommendation: 100% 1. Passalacqua R. Ingle JN. 3. 5. Suter TM. Epub 2007 Jul 23. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Clinical cardiac tolerability of trastuzumab. 2008 Feb. Mackey JR. Hudis CA. Martino S. . 2004 Jan 15. Curr Oncol. Paterson A. PiccartGebhart MJ.

Winer EP. Moy B. Baselga J. . Carey LA. Adjuvant paclitaxel and trastuzumab for node-negative. Carey LA. Perez. Andersson M. Beiyun Chen. 2011 Goldhirsch A. A phase II study of adjuvant paclitaxel (T) and
trastuzumab (H) (APT trial) for node-negative.372(2):13441. Dang CT. Yardley DA. Peter A. Wolff AC. Shaker R. Marcom PK. Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer. Smith I. Nancy E. Köhne CH. Hudis CA. Ellis M. Ellis M. Gelber RD. HER2-positive breast cancer. Albain
KS. N Engl J Med. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Jackisch C. Dakhil. JoAnne Zujewski. Ingle. Krop IE. Guo H. Tolaney SM. Barry WT. Gianni L. Gralow. de Azambuja E. Winer EP. Hudis CA. Dal Lago L. Julie R. Pisansky.382(9897):1021-8. Rugo HS. Cameron D. Shapira I. Moy B. Suter TM.
Partridge AH. 2013 Sep 21. Marcom PK. Procter M. 2. Dowsett M. McFadden E. Alvaro Moreno-Aspitia.Adjuvant treatment with trastuzumab: Schedules (11/12) Further information and references: Statement: with paclitaxel/docetaxel after AC/EC Vote result of the AGO recommendation: 100% 1. Davidson. S1-04 Tolaney SM. Untch M. Visscher. Wolff AC. Vera J. Burstein HJ. Krop IE. 2. SABCS 2013. Albain KS. Suman. J Clin Oncol 29:4491-4497. Bell R. Lancet. Herceptin Adjuvant (HERA) Trial Study Team. Vindevoghel A. Overmoyer BA. Shapira I. Yardley DA. James N. and Robert B. Thomas M. Brunt AM. Daniel W. Partridge AH. Guo H. Otero-Reyes D. Piccart-Gebhart MJ. Overmoyer BA. Edith A. randomised controlled trial. Dang CT. Kaufman. Leyland-Jones B. Burstein HJ. Weber HA. 2015 Jan 8. Heinzmann D. Song S. Barry WT. Statement: P q1w12 without A in pT < 3 cm pN0 Vote result of the AGO recommendation: 100% 1. HER2-positive
breast cancer (BC). Jenkins. Rugo HS.

Pisansky. Forbes J. Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial . Solin. E. Winer. A. carboplatin. Jagiello-Gruszfeld A.29(2):149-56. Valero V. J Clin Oncol. 2. Eric P. Fumoleau P. Crown J. J. Dueck. Statement: with taxanes dose-dense Vote result of the AGO recommendation: 100% See references slide 8. Marks. Norman Wolmark. Eiermann W. Perez. L. Mackey JR. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel. Y. Piccart-Gebhart. Taupin H. Hortobagyi. Trastuzumab can be administered concurrent to adjuvant radiotherapy of the breast or thoracic wall. Statement: radiotherapy concurrent with trastuzumab Vote result of the AGO recommendation: 100% 1. Albain. Kathy S.Statement: with docetaxel and carboplatin Vote result of the AGO recommendation: 100% 1. Martine J. Edith A. and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. Perez. Pegram MD. 2012: pp 2179-2182 Statement: with anthracyclines Vote result of the AGO recommendation: 100% See references slide 8. M. T. Roche H. 2011 Jan 10. von Minckwitz G. L. A. J. No 18 (June 20). Rolski J. Press MF. Harold J. Hudis. Halyard. M. Sauter G. L. Martin M. Gabriel N. Vol 30. Pierce. Pienkowski T. Larry Norton. Burstein. Clifford A. Mrsic-Krmpotic Z. B. Buyse M. Slamon DJ. Riva A. Choosing the Best Trastuzumab-Based Adjuvant Chemotherapy Regimen: Should We Abandon Anthracyclines? Journal of Clinical Oncology.

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Patel T. Fumoleau P. Lang I. Moy B. trastuzumab. Tenner KS. NCCTG 063D) comparing one year of antiHER2 therapy with lapatinib alone (L). Santillana S. Northfelt D. 2013 Apr.14(1):88-96.138(2):427-35. Moreno-Aspitia A1. de Azambuja E. McCullough AE. Piccart-Gebhart M. Untch M. Smith IE. Rodeheffer R. their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Gelber RD. Lancet Oncol. First results from the phase III ALTTO trial (BIG 02-06. Piccart-Gebhart M. Johnson D. Santillana S. Dakhil S. Perez EA. Gelber RD. Perez EA. Untch M. 3. Martin M. Dueck A. O'Shaughnessy J. Jackisch C. Boyle F. Jackisch C. Chavarri-Guerra Y. Goldhirsch A. RC0639: phase II study of paclitaxel. Zujewski JA. ASCO. Xu B. Breast Cancer Res Treat. Baselga J. Perez EA. Franco S. Williams LS. phase 3 trial. Wolff A. 2. Baselga J. Goldhirsch A. TEACH investigators. Ejlertsen B. Jenkins RB. Pritchard K. Kaufmann M. ASCO. Viale G. Gradishar W. de Azambuja E. 2014 Statement: with Lapatinib + Trastuzumab Vote result of the AGO recommendation: 100% 1. their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Dueck AC. Finkelstein DM. and lapatinib as adjuvant therapy for early stage HER2-positive breast cancer. First results from the phase III ALTTO trial (BIG 02-06. Pritchard KI. Pritchard K.Adjuvant Therapy with Other Agents (12/12) Further information and references: Statement: with Lapatinib Vote result of the AGO recommendation: 100% 1. Goss PE1. Dueck A. NCCTG 063D) comparing one year of antiHER2 therapy with lapatinib alone (L). Gomez H. Kahanic S. Holmes AP. Ghanem-Cañete I. 2013 Jan. Boyle F. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised. Boyle F. trastuzumab alone (T). Wolff A. Aktan G. Smith I. Buzdar AU. Lang I. Piccart-Gebhart M. Lindquist D. Colon-Otero G. Palmieri FM. Smith I. trastuzumab alone (T). Viale G. Rappold E. Xu B. Zujewski JA. controlled. Gomez H. 2014 . Holmes AP.

Press. Lipatov O. Parmar M. Deurloo RJ. G. Lancet Oncol. Cameron D. D. Cottu P. phase 3 trial. Pienkowski T. M. L.Swain. Statement: Bevacizumab Vote result of the AGO recommendation: 100% 1. Suter TM.Costantino. No final results available. Mackey J.Bee-Munteanu. S. S. N.Steger.Eiermann. Im SA. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised. Pivot X. Henschel V. M. A.Wolmark. V. T. M. Im YH.Crepelle-Flechais.Provencher.Slamon.Paterson. E. Y-H.Im.Henschel.Im. Chan A. Brown J.Verma. J. Laeufle R. Bubuteishvili-Pacaud L. Harvey V. SABCS 2013 . SA. Pallaud C. Bell R.Statement: Pertuzumab Vote result of the AGO recommendation: 100% Trials are ongoing.Thirlwell.Crown. J.Martin. J. 2013 Sep. Steger GG. C.Mamounas. Dent R. Toi M.Geyer. Jackisch C.Schwartzberg.14(10):933-42.Robert. S-B. BETH: A Randomized Phase III Study Evaluating Adjuvant Bevacizumab Added to Trastuzumab/Chemotherapy for Treatment of HER2+ Early Breast Cancer. L.Pienkowski.Kim. N. Hall PS. Romieu G. V.Mackey. M.Buyse. 2. W. A.

Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.V. in der DGGG e.V.1 Neoadjuvant (Primary) Systemic Therapy . sowie in der DKG e. Guidelines Breast Version 2015. V.

sowie in der DKG e. in der DGGG e.V.Neoadjuvant Systemic Therapy © AGO e.  Version 2002: Costa  Versions 2003–2014: Bauerfeind / Blohmer / Dall / Fersis / Göhring / Harbeck / Heinrich / Huober / Jackisch / Kaufmann / Loibl / Lux / von Minckwitz / Müller / Nitz / Schneeweiss / Schütz / Solomayer / Untch  Version 2015: Friedrich / Schneeweiss Guidelines Breast Version 2015.V. V.1 www.de .ago-online.

de Trastuzumab plus • Sequential A/T-based regimen with concurrent T + H • Anthracycline-free.  in der DGGG e.V.and “high risk”   ++ HR+/HER2. carboplatin-cont.1  In case of indication for chemotherapy. consider neoadjuvant approach Endocrine therapy without chemotherapy   Conventionally dosed AT-based chemotherapy Dose dense & escalated in case of high tumor burden Followed by endocrine therapy ++ + ++ HER2+  www.Subtype-specific General Systemic Strategies © AGO e.and “low risk”:   AGO ++ ++ + + TNBC    Conventionally dosed AT-based chemotherapy Dose dense & escalated Plus Carboplatin in case of family history for BC/OC or gBRCA alteration ++ + . V.ago-online.V. sowie in der DKG e. regimen Dose dense & escalated in case of high tumor burden •  ++ HR+/HER2. Guidelines Breast Version 2015.

Guidelines Breast Version 2015. primary) and adjuvant systemic therapy 1a A Pathological complete response is associated with improved survival in particular subgroups 1b A Can achieve operability in primary inoperable tumors 1b A ++  Improved options for breast conserving surgery 1b A ++  Allows individualization of therapy according to mid-course treatment effect 1b B +* Allows individualization of post-neoadjuvant management according to refined risk assessment after neoadjuvant treatment and surgery 2b B +/-*    www. sowie in der DKG e.ago-online.Neoadjuvant Systemic Chemotherapy Clinical Benefit © AGO e. V.V.V. in der DGGG e.1 Oxford / AGO LoE / GR Survival is similar after neoadjuvant (preoperative.de  * Study participation recommended .

1 www. V.Neoadjuvant Systemic Chemotherapy Indications © AGO Oxford / AGO LoE / GR e.ago-online.V. in der DGGG e.V. Guidelines Breast Version 2015. sowie in der DKG e.de  Inflammatory breast cancer 2b B ++  Inoperable breast cancer 1c A ++  Large operable breast cancer primarily requiring mastectomy and adjuvant chemotherapy with the goal of breast conservation 1b B + If similar postoperative adjuvant chemotherapy is indicated 1b A +  .

1  Young age B 1a A +  cT1 / cT2 tumors o. in der DGGG e.V.de .V.Neoadjuvant Systemic Chemotherapy Response Prediction I © AGO e. Factor CTS LoEOx2001 GR AGO Guidelines Breast Version 2015. V. N0 o. G3 B 1a A ++  Negative ER and PgR status B 1a A ++ Triple negative breast cancer (TNBC) B 1a A ++   Positive HER2 status B 1a A ++  Non-lobular tumor type B 1a A +  Early clinical response B 1b A + www.ago-online. sowie in der DKG e.

Neoadjuvant Systemic Therapy Response Prediction II © AGO e. Guidelines Breast Version 2015.V.V.ago-online. in der DGGG e.1 Factor Multigene signature III C B +/- Ki-67 I B A + Tumour infiltrating lymphocytes I B B + PIK3CA mutation II B B +/-    www. sowie in der DKG e. V.de LoE2009 CTS GR AGO  .

ago-online.1 Standard regimens used in the adjuvant setting with a duration of at least 18 weeks 1a A ++  AC or EC  D q3w or P q1w 2b A ++  DAC 2b B ++  AP  CMF 1b A +  Taxane followed by anthracycline sequence 1a A +  Dose-dense regimen (e. V. E -P-CMF. in der DGGG e.V.g.V.Neoadjuvant Systemic Chemotherapy Recommended Regimens and Schedules © AGO Oxford / AGO LoE / GR e. E-P-C) 1b B +*  Platinum in TNBC 1a A +/- 2b B +  www.de  In case of family history of BC/OC or BRCA alteration *Study participation recommended . Guidelines Breast Version 2015. sowie in der DKG e.

(BCRT 2014) Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 5 q3w x4 – FEC q3w x4 Phase II TNBC ± Cb: 61% vs.Superior Carboplatin Containing Regimens in the Neoadjuvant Setting © AGO e. 26% .ago-online. et al.1 www. sowie in der DKG e. Guidelines Breast Version 2014. et al. (Lancet Phase II Oncol 2014) NPLD 20mg/m² qw x18 + TNBC ± Cb: Paclitaxel 80mg/m² qw x18 53% vs.de Author Study Regimen pCR rate Sikov WM.5 qw x18 (ypT0 ypN0) + Bev 15mg/kg q3w x6 Ando M. in der DGGG e. V. Sixto et al.V.V. (JCO 2015) CALGB 40603 Phase II Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 6 q3w x4 – dd AC q2w x4 TNBC ± Cb: 54% vs 41% (ypT0/is ypN0) von Gepar Minckwitz G. 37% + Carboplatin AUC 1.

Neoadjuvant Systemic Chemotherapy Recommended Methods of Monitoring of Response © AGO e. V.V.1 www.de  Breast ultrasound 2b B ++  Palpation 2b B ++  Mammography 2b B ++  MRI 2b B +  PET(-CT) 2b B +/-  Clip tumour region 5 D ++ . Oxford / AGO LoE / GR in der DGGG e. Guidelines Breast Version 2015.ago-online. sowie in der DKG e.V.

de   Trastuzumab in combination with chemotherapy Lapatinib in combination with chemotherapy 1b A ++ 1a B - Lapatinib + Trastuzumab in combination with chemotherapy 1a B +/- Pertuzumab + Trastuzumab in combination with chemotherapy 1a B +* Two anti-HER2 agents without chemotherapy 2b B +/- Anti-HER2 agent in combination with endocrine treatment 2b C +/- * Study participation recommended .1     www.V. in der DGGG e. sowie in der DKG e.Neoadjuvant Targeted Therapy in HER2 Positive Tumors © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015. V.ago-online.V.

V.1 Bevacizumab in combination with chemotherapy In hormone receptor positive BC 1b B - In TNBC 1b B +/-   www. in der DGGG e.Neoadjuvant Targeted Therapy in HER2 Negative Tumors © AGO Oxford / AGO LoE / GR e.V.ago-online.de . sowie in der DKG e. Guidelines Breast Version 2015.V.

sowie in der DKG e.ago-online.Neoadjuvant Systemic Therapy Procedures in Case of Early Response © AGO e.e. Oxford / AGO LoE / GR in der DGGG e. V.V.V. ≥ 18 weeks of treatment 1b A ++ In case of response after 2 cycles of DAC in HR positive breast cancer consider 8 instead of 6 cycles of DAC 2b C  www. Guidelines Breast Version 2015.1 In case of early response following 6 to 12 weeks of neoadjuvant chemotherapy: Complete all chemotherapy before surgery i.de  + .

1 www. Guidelines Breast Version 2015. V. sowie in der DKG e.V.V. followed by surgery  Continuation of NST with non cross-resistant regimen  AC or EC x 4  D x 4 or Pw x 12  DAC x 2  NX x 4 In case of progressive disease:  Stop of NST and immediate surgery or radiotherapy  Additional adjuvant chemotherapy with non cross-resistant regimen 2b C ++ 2b B + 2b B + 1b B + 4 D ++* 4 D +/-* * Study participation recommended . in der DGGG e.Neoadjuvant Systemic Therapy Procedures in Case of No Early Response © AGO Oxford / AGO LoE / GR e.de In case of no change:  Completion of NST.ago-online.

de  Mark previous tumor region 5  Surgery 2b C ++  Microscopically clear margins 5  Tumor resection in the new margins  Sentinel node biopsy (see chapter “Surgery”) D ++ D ++ 3b C + .ago-online. V.V. Guidelines Breast Version 2015.1 www. Oxford / AGO LoE / GR in der DGGG e.Local/Regional Procedure after Neoadjuvant Therapy © AGO e. sowie in der DKG e.V.

de cN-Status (before NST) pN-Status (before NST) cN-Status (after NST) Surgical procedure cN0 pN0(sn) - nihil 1a A + cN0 pN+(sn) analogue ACOZOG ycN0 ALND 3 B +/- cN0 pN+(sn) not analogue ACOZOG ycN0 ALND 2b B + ycN0 SNB ALND 2a 2b B B +/+ ycN+ (CNB/FNA) ALND 2b B ++ cN+ cN+ (CNB/FNA) . sowie in der DKG e.V.Surgical Procedure of the Axilla Before or After NACT © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015.1 SLNB before or after NACT in cN0 SLNB before NACT SLNB after NACT 2b 2a B B + +/- Further surgical procedures depending on SLNB www.ago-online. V. in der DGGG e.V.

de D 2b C + +/- In case of pCR  Multicentric lesions 2b C +/-  cT4a-c breast cancer 2b B +/- .ago-online. in der DGGG e.V.Neoadjuvant Systemic Therapy Indications for Mastectomy © AGO Oxford / AGO LoE / GR e.1  Positive margins after repeated excisions 3b C ++  Radiotherapy not feasible 5 ++  In case of clinical complete response  Inflammatory breast cancer  www. Guidelines Breast Version 2015. sowie in der DKG e. V.V.

1  Surgery  4 C ++ 2b B ++ After the nadir of the leucocyte count (2 to 4 weeks after last course of chemotherapy) www. in der DGGG e. V.Neoadjuvant Systemic Therapy Timing of Surgery and Radiotherapy © AGO e. sowie in der DKG e.de  Radiotherapy after surgery 2–3 weeks after surgery BCS .ago-online. Oxford / AGO LoE / GR Guidelines Breast Version 2015.V.V.

Adjuvant Systemic Therapy after Neoadjuvant Systemic Treatment © AGO e.1    Endocrine treatment in endocrine responsive disease Complete trastuzumab treatment for 1 year in HER2-positive disease In case of insufficient response 1a A ++ 2b B ++ www. Oxford / AGO LoE / GR in der DGGG e.V.de 3  Experimental therapies in clinical trials 5  Further chemotherapy C D + . V.V. Guidelines Breast Version 2015.ago-online. sowie in der DKG e.

sowie in der DKG e.Neoadjuvant Endocrine Therapy in Patients with Endocrine-responsive Breast Cancer © AGO e. adjuvant endocrine therapy) . in der DGGG e.1  Premenopausal patients  www. N status. level of Ki-67.ago-online.V.V.de Who are inoperable Optimal duration of neoadjuvant endocrine therapy is unknown No long term results for neoadjuvant endocrine therapy (vs. V.  Postmenopausal patients:  Oxford / AGO LoE / GR Who are inoperable and can / will not receive chemotherapy 2a B +  Optimizes the option for breast conserving therapy 1b A +  Aromatase inhibitors (for > 3 months) 1aa B +  Aromatase inhibitor + lapatinib (HER2+ BC) 2b B +/- and can / will not receive chemotherapy 5 C +  Tamoxifen 2b C +  Aromatase inhibitors + LHRH 1b C +/-  Concurrent chemo-endocrine therapy 1b A -  Prognostic factors during/after NST: quantitative ERexpression. T status 1b B + Guidelines Breast Version 2015.

Neoadjuvant (Primary) Systemic Therapy (2/20 and 3/20) Further information and references: Systematic review of published evidence: PUBMED 1999-2015 ASCO 1999-2015 SABCS 1999-2015 ECCO/ESMO 1999-2015 .

J Clin Oncol 2012: 30. 4. 2474 Pathological complete response is associated with improved survival in particular subgroups Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. et al.Neoadjuvant Systemic Chemotherapy . Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. et al. J Clin Oncol 2011: 29. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. methotrexate. J Clin Oncol 2009: 27. 3. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide. as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. and fluorouracil. 2. 3. 2672 Van der Hage JA.Clinical Benefit (4/20) Further information and references: Survival is similar after neoadjuvant (preoperative. methotrexate. primary) and adjuvant systemic therapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 2. 4224 Rastogi P. 778 Gianni L et al. 2474 Untch M. 1796 . as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. Gianni L et al. et al. J Clin Oncol 2009: 27. et al. Fisher B. J Clin Oncol 1998: 16. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide. J Clin Oncol 2001: 19. 3351 Von Minckwitz G. and fluorouracil. J Clin Oncol 2008: 26. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.

Von Minckwitz G. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer.051 patients with infiltrating lobular breast carcinoma. 348 Kaufmann M. Rest Enthaltungen . 1796 Allows individualization of post-neoadjuvant management according to refined risk assessment after neoadjuvant treatment and surgery Abstimmungsergebnis der AGO-Empfehlungen: 9+.4. 3883 Loibl S. Neoadjuvant systemic treatment of breast cancer. Breast Cancer Res Treat 2014: 144. Ann Surg Oncol 2012: 19. et al. Cortazar P. Response and prognosis after neoadjuvant chemotherapy in 1. Ann Surg Oncol 2012: 19. 164 Berruti A. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. et al. 153 Can achieve operability in primary inoperable tumors Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 6. 2. 1508 Allows individualization of therapy according to mid-course treatment effect Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. Kaufmann M. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. J Clin Oncol 2014: 32. et al. 14+/-. et al. Makhoul I. Lancet 2014: 384. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. et al. J Clin Oncol 2012: 30. 5. 1508 Improved options for breast conserving surgery Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Surg Oncol 2011: 103. et al.

methotrexate. et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. and 5-fluorouracil (CMF) in stage III breast cancer: GOCS experience. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. 1956 Von Minckwitz G. and cyclophosphamide (FAC) compared with cyclophosphamide. J Clin Oncol 2012: 30. 2. doxorubicin.Breast Cancer Res Treat 2014: 143. et al. Nottingham Clinico-Pathological Response Index (NPRI) after Neoadjuvant Chemotherapy (Neo-ACT) Accurately Predicts Clinical Outcome in Locally Advanced Breast Cancer. 313 Berruti A. 4. 3. J Clin Oncol 2011: 29. Sixteen years follow-up results of a randomized phase II trial of neoadjuvant fluorouracil. 4414 Mittendorf EA. J Clin Oncol 2007: 25. 2014 [Epub ahead of print] . 5. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.1. et al. et al. 6. 1796 Leone JP. J Clin Oncol 2014: 32. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. Symmans WF. 3883 Abdel-Fatah TM. et al. Clin Cancer Res.

Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 1927 Dawood S. 2.Neoadjuvant Systemic Chemotherapy Indications (5/20) Further information and references: Inflammatory breast cancer Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Kaufmann M. Ann Surg Oncol 2012: 19. Kaufmann M. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol 2011: 22. et al. 1927 Kaufmann M. 2. et al. 1927 Dawood S. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 2007: 18. 1508 . Ann Oncol 2011: 22. 2. Ann Oncol 2007: 18. Kaufmann M. 515 Large operable breast cancer primarily requiring mastectomy and adjuvant chemotherapy with the goal of breast conservation Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol 2007: 18. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. 515 Inoperable breast cancer Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al.

radiological. 887 . 2.If similar postoperative adjuvant chemotherapy is indicated Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. et al. 138 Loibl S. Neoadjuvant chemotherapy: early response as a guide for further treatment: clinical. Treatment of breast cancer during pregnancy: an observational study. Untch M. and biological. Lancet Oncol 2012: 13 . J Natl Cancer Inst Monogr 2011: 43.

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9. 1183-1192 De Azambuja E. open-label. De Azambuja E. 2. multicentre. Neoadjuvant treatment with docetaxel plus lapatinib. trastuzumab. 1139 Bonnefoi H. 4. 1137 Bonnefoi H. or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. et al. Br J Cancer 2014: 110. et al. 3. randomised phase 3 trial. Lancet Oncol 2014: 15. Neoadjuvant treatment with docetaxel plus lapatinib. 1137 Lapatinib in combination with chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 3. randomised phase 3 trial. et al. GBG 44): a randomised phase 3 trial. 2. et al. or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial. 106(9): [EpuB ahead of print] Lapatinib + Trastuzumab in combination with chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1.144 Robidoux A. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label. et al. phase 3 trial and their association with pathological complete response. 5. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. et al. 135 . et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised. Ann Oncol 2014 [Epub ahead of print] Nagayama A. trastuzumab. open-label. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label. Untch M et al. Lancet Oncol 2013: 14. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto. et al. J Natl Cancer Inst 2014. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised. Ann Oncol 2014 [Epub ahead of print] . 1183-1192 Alba E. Lancet Oncol 2012: 13. Lancet Oncol 2014: 15. multicentre. phase 3 trial and their association with pathological complete response. Lancet Oncol 2013: 14. Robidoux A.

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randomized.1. phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive. 1050 . et al. placebo-controlled. 2. Rimawi MF. human epidermal growth factor receptor 2negative. Double-blind. operable breast cancer. SABCS 2014 (S6-02) Guarneri V. et al. multicenter. J Clin Oncol 2014: 32.

Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012: 366. 5. 3. et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. Von Minckwitz G. 3. N Engl J Med 2012: 366. 171. et al. et al. J Clin Oncol 2015: 33. 299 Bear HD. Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance). 2. results from the geparquinto study (GBG 44). N Engl J Med 2012: 366. 91. 2. 13 . 2363 Sikov WM. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers.Neoadjuvant Targeted Therapy in HER2 Negative Tumors (12/20) Further information and references: Bevacizumab in combination with chemotherapy in hormone receptor positive Abstimmungsergebnis der AGO-Empfehlungen: 13+/-. Ann Oncol 2014: 25. et al. Von Minckwitz G. 310 Von Minckwitz G. et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. Ann Oncol 2014: 25. 2978 Von Minckwitz G. 4. Annals Oncol 2013: 24. et al. N Engl J Med 2012: 366. et al. 13+/-. 310 Gerber B. 299 Bear HD. 2363 Bevacizumab in combination with chemotherapy in TNBC Abstimmungsergebnis der AGO-Empfehlungen: 2+/-.

Dose-dense doxorubicin. controlled. ≥ 18 weeks of treatment Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. J Clin Oncol.e. Von Minckwitz G. 552 Kaufmann M. and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized. 2. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. 542 Von Minckwitz G. 2013: 31. docetaxel. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. Ann Surg Oncol 2012: 19. 3623-30 . et al. 3. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. et al. et al. 3506 Von Minckwitz G. 1508 In case of response after 2 cycles of DAC in HR positive breast cancer consider 8 instead of 6 cycles of DAC Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. J Natl Cancer Inst 2008: 100. 4. J Clin Oncol 2001: 19. et al. et al. Von Minckwitz G. open phase IIb study. J Natl Cancer Inst 2008: 100.Neoadjuvant Systemic Therapy Procedures in Case of Early Response (13/20) Further information and references: In case of early response following 6 to 12 weeks of neoadjuvant chemotherapy: Complete all chemotherapy before surgery i. Response-guided neoadjuvant chemotherapy for breast cancer.

et al. J Natl Cancer Inst 2008: 100. J Clin Oncol 2002: 20. Kaufmann M. et al. et al. followed by surgery Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 542 Continuation of NST with non-cross-resistant regimen AC or EC x 4  D x 4 or Pw x 12 Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 4165 Bear HD. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. 3. 2. J Clin Oncol 2006: 24. Bear HD. 1456 Von Minckwitz G. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. 2019 DAC x 2  NX x 4 Abstimmungsergebnis der AGO-Empfehlungen: 45/0 . Ann Surg Oncol 2012: 19. 1508 Smith IC. J Clin Oncol 2003: 21. et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer.Neoadjuvant Systemic Therapy Procedures in Case of No Early Response (14/20) Further information and references: In case of no change: Completion of NST. et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. 2.

Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 1508 Additional adjuvant chemotherapy with non-cross-resistant regimen Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. 2011 . Von Minckwitz G. et al. Mittendorf EA. Ann Surg Oncol 2012: 19. J Clin Oncol. 1956.1. et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 29. 2013: 31. 3623-30 In case of progressive disease: Stop of NST and immediate surgery or radiotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Response-guided neoadjuvant chemotherapy for breast cancer. Kaufmann M.

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3. Cancer 2010: 116. 2. 2. Kühn T. Kaufmann M. Lancet Oncol 2013 Boughey JC et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Surg Oncol 2012: 19. et al.2. et al. 1508 Sentinel node biopsy (see chapter “Surgery”) Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Cancer 2010: 116.. Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. 1455-1461 . Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol 2012: 19. 1184 Kaufmann M. et al. JAMA 2013: 310. 1508 Tumor resection in the new margins Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 1184 Kaufmann M. Kaufmann M. 1927 Kaufmann M. multicentre cohort study. Ann Oncol 2007: 18. et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. et al. 3. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective. et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.

Ann Oncol 2011: 22. 1508 In case of clinical complete response: Inflammatory breast cancer Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Kaufmann M. Dawood S. 1508 Dawood S. Ann Oncol 2011: 22. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.Neoadjuvant Systemic Therapy . et al. et al. 2. 515 Radiotherapy not feasible Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol 2012: 19. et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 515 Multicentric lesions Abstimmungsergebnis der AGO-Empfehlungen: 45/0 . et al. Ann Surg Oncol 2012: 19. Kaufmann M. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.Indications for Mastectomy (17/20) Further information and references: Positive margins after repeated excisions Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1.

1. Ataseven B.134 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. Impact of Multifocal or Multicentric Disease on Surgery and Locoregional. Ataseven B. Ann Surg Oncol 2014 [Epub ahead of print] . Ann Surg Oncol 2014 [Epub ahead of print] cT4a-c breast cancer Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Impact of Multifocal or Multicentric Disease on Surgery and Locoregional.134 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. Distant and Overall Survival of 6. Distant and Overall Survival of 6. et al. et al.

Ring A. 2. 4540 Radiotherapy after surgery 2–3 weeks after surgery BCS Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. Is radiotherapy an option for early breast cancers with complete clinical response after neoadjuvant chemotherapy? Int J Radiat Oncol Biol Phys 2011: 79.Neoadjuvant Systemic . 1452-145 . et al. et al. 4540 Daveau C. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 2003: 21. Ring A. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 2003: 21.Therapy Timing of Surgery and Radiotherapy (18/20) Further information and references: Surgery after the nadir of the leucocyte count (2 to 4 weeks after last course of chemotherapy) Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1.

Adjuvant Systemic Therapy after Neoadjuvant Systemic Treatment (19/20) Further information: Endocrine treatment in endocrine responsive disease Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Complete trastuzumab treatment for 1 year in HER2-positive disease Abstimmungsergebnis der AGO-Empfehlungen: 45/0 In case of insufficient response further chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Experimental therapies in clinical trials Abstimmungsergebnis der AGO-Empfehlungen: 45/0 No references .

anastrozole. 2. 244 Mathew J.review of literature. and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. 2342 Aromatase inhibitors (for > 3 months) Abstimmungsergebnis der AGO-Empfehlungen: 45/0 . Tamoxifen. Randomized phase II neoadjuvant comparison between letrozole. tamoxifen. Cancer 2007: 110. et al. et al. 339 Ellis MJ. Neoadjuvant endocrine treatment in primary breast cancer . Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. 5. J Clin Oncol 2005: 23. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. 1527 Smith I. or both in combination: the Immediate Preoperative Anastrozole. et al. Ann Oncol 2001: 12. 3.Neoadjuvant Endocrine Therapy (20/20) Further information and references: Postmenopausal patients: Who are inoperable and can / will not receive chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. J Clin Oncol 2011: 29. Semiglazov VF. et al. Breast 2009: 18. et al. or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. Eiermann W. 4. et al. 244 Optimizes the option for breast conserving therapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Cancer 2007: 110. 5108 Semiglazov VF. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole.

2342 Aromatase inhibitor + lapatinib (HER2+ BC) Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Premenopausal patients: Who are inoperable and can / will not receive chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Tamoxifen Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Aromatase inhibitors + LHRH Abstimmungsergebnis der AGO-Empfehlungen: 45/0 Concurrent chemo-endocrine therapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Ann Oncol 2001: 12. 339 Ellis MJ. et al.review of literature.review of literature. anastrozole. tamoxifen. 3. and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. 4. et al. et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole. J Clin Oncol 2011: 29. Mathew J. Eiermann W. 5108 Mathew J. Breast 2009: 18. et al. 2. Neoadjuvant endocrine treatment in primary breast cancer . or both in combination: the Immediate Preoperative Anastrozole. et al. Tamoxifen. 339 .1. or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. 1527 Smith I. Breast 2009: 18. Randomized phase II neoadjuvant comparison between letrozole. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. J Clin Oncol 2005: 23. Neoadjuvant endocrine treatment in primary breast cancer .

level of Ki-67. et al. Von Minckwitz G. docetaxel. hormone receptorpositive breast cancer patients--a phase II trial. et al. J Clin Oncol 2001: 15. Eur J Cancer 2014: 50.2. Efficacy of six month neoadjuvant endocrine therapy in postmenopausal. J Natl Cancer Inst 2008: 100. 3506 Fontein DB. Dose-dense doxorubicin. controlled. T status Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Ellis MJ. and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. 3. open phase IIb study. N status. 1380 . et al. 2190 Prognostic factors during/after NST: quantitative ER-expression.

V. Guidelines Breast Version 2015.1 Adjuvant Radiotherapy . sowie in der DKG e.V.V. in der DGGG e.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.

V.1 www. sowie in der DKG e. Guidelines Breast Version 2015.de  Versions 2002–2014: Souchon / Blohmer / Friedrichs / Göhring / Janni / Möbus / Seegenschmiedt  Version 2015: Thomssen / Kühn / Untch / Scharl Budach / Wenz / Souchon .V.ago-online. in der DGGG e.Adjuvant Radiotherapy (RT) © AGO e.V.

Guidelines Breast Version 2015.V.V.de  If agreement had not been reached in any statement.1  The recommendations on adjuvant radiotherapy for breast cancer are based on a consensus discussion between experts of the AGO and DEGRO  For technical details of radiotherapy we recommend to refer to the corresponding updated DEGRO practical guidelines 2014 www. the corresponding DEGRO view is written in blue colour . sowie in der DKG e.V.Preliminary Note © AGO e.ago-online. in der DGGG e.

Guidelines Breast Version 2015.Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer): . or hypofractionated RT with sequential boost > 65 years Low risk: consider hypofractionated RT without boost (15-16 fractions) High risk: RT as for 40-65 years Elderly Individual counseling including omission of radiotherapy according to individual risk after geriatric assessment Any age If radiotherapy of the regional lymph nodes is included.V.1 AGO ++ <40 years Conventional RT (25-28 fractions) with integrated or sequential boost 40 – 65 years Conventional RT with integrated or sequential boost.V.V.Whole Breast Irradiation – © AGO LoE 1b B e.ago-online.de (lymph node areas) Study participation recommended . sowie in der DKG e. in der DGGG e. conventionally fractionated RT (25-28 fractions) www.

V.59–0.V. 95% CI 0.042) (START B: Haviland JS et al.ago-online.94).8. Lancet Oncol 2013. in der DGGG e. and breast oedema). sowie in der DKG e. A benefit with regard to metastasis-free survival and overall survival has not been found yet. breast irradiation for breast conserving therapy is able to reduce the risk of a local recurrence by about 8% over 10 years. Guidelines Breast Version 2015.Additional Information with Regard to Effects of Breast Radiotherapy (BCT) © AGO e.“  In 1 of 5 trials: “There were significantly fewer distant relapses up to 10 years in the 40 Gy group (HR 0. p=0. .“ (HROS=0.V. telangiectasia. which contributed to the significantly higher rates of diseasefree survival and overall survival in the 40 Gy group compared with the 50 Gy group.74. 14: 1086–94)  Elderly patients should be advised about the following :  In older patients with pT1-2 (=<3 cm) pN0 hormone receptorpositive breast cancer.1 www.de  Hypofractionation:  „Some normal tissue effects were less common after the 15 fraction regimen than the control schedule (breast shrinkage.

de  Omission of radiotherapy in low risk* elderly patients if adjuvant endocrine treatment (e. G1-2. Tam 5-yrs) is consequently performed* Oxford / AGO LoE / GR AGO1 1b A + DEGRO1 1b C +/- Increase in local recurrence.g.V. negative resection margin (width >1 mm) 1 different interpretation of published data by AGO and DEGRO .1 www.Radiotherapy in Elderly Patient Life Expectancy less than 10 Years © AGO e. decrease in toxicity *Age ≥ 70 year.ago-online. pT1. HER2-negative. Guidelines Breast Version 2015.V. sowie in der DKG e. no influence on OS. HR positive. pN0. in der DGGG e.V.

Guidelines Breast Version 2015.) Tamoxifen Tamoxifen plus Radiotherapy Hazard Ratio Local recurrence 90% (85%-93%) 98% (96%-99%) HR=0.s. Tamoxifen + RT Time:1994-1999. 0.32.71%) 67% (62% .) Hughes KE et al J Clin Oncol 2013. since 8/1996 only pT1cN0 ER/PR+ or unknown allowed © AGO e.98%) 98% (96% .V.42.17 to 1. 0. n. in der DGGG e.48. n. 31:2382-2387 .97%) 95% (92% .s) Overall survival 66% (61% . sowie in der DKG e.18.s.99%) HR=0.77 to 1.de @10 yrs (95% C.97%) HR=1. P < .BCS >=70y <4 cm cN0: Tamoxifen vs.95 (95% CI.V.) Distant metastasis-free 95% (91% .50 (95% CI.I.72%) HR=0.63 to 2.20 (95% CI. 0. 0.ago-online.07 to 0. n.001) Mastectomyfree 96% (93% .1 www.V.18 (95% CI.

V.de  Postoperative partial breast irradiation as sole radiotherapy modality * Study participation recommended.Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) – Partial Breast Irradiation © AGO e. IORT during first surgery.V. age >50 y.ago-online. no extensive DCIS. non-lobular. no survival benefit) Oxford / AGO LoE / GR 1b B +  < 40 years 1b B ++  40-60 years 1b B ++  > 60 years. if G3 or >pT1 2b B +/- 2a B +  IORT using 50 kV (pT1 pN0 R0 G1-2.1  Boost-RT (improves local control. **no long term data . HR+) 1b B +/-*  IOERT 1b B +/-*  Interstitial brachytherapy 1b B +/-*  Intracavity balloon technique 2b B -*  APBI (IMRT)** 2b B -*  Intraoperative irradiation (IORT/IOERT)  As boost-irradiation followed by WBI  As sole radiotherapy modality www. in der DGGG e. sowie in der DKG e.V. Guidelines Breast Version 2015.

92).1% (57.6%) 24. p<0.81).4%) Boost (n=2.66 (0.661) No boost (n=2.7% (7. p=0.s.96%) 10.2 y) acc.0) HR=0.42–1.I.46–1.04).8–16.4% (14.5–17. Guidelines Breast Version 2015.4) 16. Cumulative Risk of Ipsilateral Breast Tumour Recurrence www.1%) HR=0.0% (9.4% (14. 16: 47–56 .66 (0.5) 19.V.04).9%) 13.3–14. to: Bartelink et al.0% (25.7) HR=0.019 (Median F/U 17.69 (0.7–24.0) 61.9–33.) Overall Survival (=-1.3–63.I. in der DGGG e.0%) 9.19) n. p=0.de All patients 12.0–14.8–46.003 41–50 years (=5.8) HR=0.52–0.7% (5.Boost vs no Boost: EORTC 22881-10882 Trial © AGO e.4) 12.7% (56. p=0.45–0.3) HR 1.1–18.) 59.6–64.56 (0.1 @20 yrs (95% C.65 (0.0001 ≤40 years (=11.05 (0.3) 13.5% (9.92–1.2) HR=0.8–14.98). p=0.34–0.3% (6. Lancet Oncol 2015.007 51–60 years (=2.4–18.2% (9.657) Hazard Ratio (95% C.4% (14.020 >60 years (=3.ago-online. sowie in der DKG e.V.V.8) 36.

go to Further information.V.V.ago-online. high risk AGO1 1–3 tumor infiltrated Lnn.1 www.de      > 3 tumor infiltrated lymph nodes (Lnn. low risk* AGO1 1–3 tumor infiltrated Lnn. in der DGGG e.) 1–3 tumor infiltrated Lnn.Postmastectomy Radiotherapy (PMRT)** to the Chest Wall © AGO Oxford / AGO LoE / GR e. sowie in der DKG e. **Study participation recommended .V. Guidelines Breast Version 2015. (every risk) DEGRO1 T3 / T4  pT3 pN0 R0 (and no additional risk factors)  If R0 is impossible to reach (for invasive tumor)  In young pts with high risk features  After neoadjuvant chemotherapy (NACT) based on the initial stage prior to NACT (cN+. cT3/4a-d)  Omission of RT if ypT0 ypN0 after NACT** 1a 1a 5 1a 1a 2b 1a 2b A A D A A B A B ++ + +/+ ++ +/++ ++ 2a 2b B B + +/- The indications for PMRT and regional RT are independent of adjuvant systemic treatment 1a A 1 different interpretation of published data by AGO and DEGRO *For definition of risk.

g. cN0. SLN pos. Guidelines Breast Version 2015.V. in der DGGG e. sowie in der DKG e. (see chapter surgery) 2a B - Extracapsular tumor spread (ECS) 2b B -- Axillary micrometastases or isolated cells found in regional lymph nodes 1b B -- .ago-online.Radiotherapy of the Axilla © AGO Oxford / AGO LoE / GR e.1 www.de Tumor residuals after axillary dissection 5 D ++ Sentinel node negative 1b B -- Axillary dissection not indicated e.V.V.

Guidelines Breast Version 2015. RT of chest wall not planned 5 5 D D +/-* +/++* +/-* +/- 1b D ++ Axillary dissection or RT of the axilla. if >=3 pos. SLN  Axillary dissection 1b B  Radiotherapy of the axilla 1b B ++ + *Study participation recommended . RT of chest wall indicated and ACOSOG Z011-criteria not met or Mastectomy.ago-online. If 1-2 pos.Axillary Intervention in Patients with Positive Sentinel Lymph Nodes © AGO Oxford / AGO LoE / GR e.V.V.V.1 Axillary dissection or RT of the axilla. RT of chest wall indicated and ACOSOG Z011-criteria fulfilled  No axillary treatment www. in der DGGG e. sowie in der DKG e.de  Mastectomy. SLN:  BCT and ACOSOG Z011-criteria fulfilled 1b B  No axillary treatment 1b B  BCT and ACOSOG Z011-criteria not met 1b B  Mastectomy.

adj. go to Further information . centr.V. PMRT) DEGRO1 Internal mammaria lymph node region (IMC)  pN1-pN2 and HR pos. if radiotherapy of the internal mammaria lnn. if cardiac risk factors are present or if trastuzumab is given 1 Oxford / AGO LoE / GR 1b 1b 2b 2b 2b A A B B B ++ ++ + +/+ 2a 2b 2b B B A +/+/+ 1ba B 1ba B + +/- 2b -- A different interpretation of published data by AGO and DEGRO *For definition of risk.ago-online. who had systemic chemoth.CT)  IMC-RT. chain is indicated (see below)  After NACT/NAT (indications as for PMRT) AGO1  After NACT/NAT if cN+ (indications acc.V.de Supra-/infraclavicular lymphatic regions   pN2a  Level III involved  pN1a high risk* AGO1  pN1a low risk* AGO1  pN1a (every risk) DEGRO1  pN0 high risk. tumors (HR+.1 www. in der DGGG e.Radiotherapy (RT) of Other Locoregional Lymph Node Areas © AGO e. sowie in der DKG e.  pN0 high risk w.V. Guidelines Breast Version 2015./med.

V. ECCO Amsterdam 2013 .88 (0.de * missing data on 40 patients Poortmans et al.84 .Multivariate Analysis of Overall Survival: Effect of Radiotherapy of the Internal Mammaria Lymph Nodes © AGO (median follow-up 10.1.39) Chemotherapy 954 1.9 yrs) e.V. sowie in der DKG e.76 – 1.91 (0.06) Both (endocrine th.59 .01) www.63 .72 (0.1.94) Total 4004 0.V. and chemotherapy) 1200 0.05 (0.1.ago-online.32) Endocrine therapy 1185 0.55 – 0.1 Adjuvant treatment n* Hazard ratio (95%CI) No adjuvant reported 625 0. in der DGGG e. Guidelines Breast Version 2015.82 (0.

de Trastuzumab* concurrent with radiotherapy 2b B + Tamoxifen concurrent with radiotherapy 2b B + AI (letrozole.Concomitant Use of Systemic Therapy with Radiotherapy © AGO e.ago-online.V. tumors parasternal RT should generally be avoided. Oxford / AGO LoE / GR in der DGGG e.1    www.V. anastrozole) concurrent with radiotherapy 2b B + *in HER2 pos.V. no concurrent trastuzumab in parasternal RT . Guidelines Breast Version 2015. sowie in der DKG e.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: metaanalysis of individual patient data for 10. 2011 Nov 12. Ewertz M.Adjuvant Radiotherapy – (2/15) Further information: Search Strategy Search Terms: Radiotherapy Breast Cancer Source: Pubmed 1/2010 – 1/2015 References (Overviews): Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.801 women in 17 randomised trials. Wang Z. McGale P. Mannu G.378(9804):1707-16. Correa C. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Whelan T. Lancet. Taylor C. Wang Y. Correa C. Duane F. 1. Wang Y. Whelan T. Peto R. Darby S. 1. Pierce L. Gray R. Cutter D. Taylor C. Godwin J. Davies C. Lancet. Ewertz M. Gray R. Darby S. Clarke M. McGale P.383(9935):212735. 2014 Jun 21. Peto R. EBCTCG (Early Breast Cancer Trialists' Collaborative Group). Arriagada R. . Cutter D.

McGale P. Solin L. Bijker N.2010(41):162-77. 2010. Taylor C. Darby S. Peto R. J Natl Cancer Inst Monogr. Correa C. 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). . Davies C. Clarke M.Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. Wang Y.

Sauer R. Fietkau R.V. Wenz F. Dunst J.Preliminary Note (3/15) Further information: AGO – Arbeitsgemeinschaft für Gynäkolgische Onkologie e. 2014 Aug. Harms W.190(4):342-51. Souchon R. Fussl C. Sautter-Bihl ML. Strahlenther Onkol. Sperk E. Harms W.190(8):705-14. Souchon R. DEGRO . Sedlmayer F. Fietkau R. Piroth MD. Sautter-Bihl ML. Budach W. Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO). Sauer R. References: DEGRO practical guidelines for radiotherapy of breast cancer IV: radiotherapy following mastectomy for invasive breast cancer. Feyer P. DEGRO practical guidelines: radiotherapy of breast cancer III--radiotherapy of the lymphatic pathways. Feyer P. Haase W. Budach W. 2014 Apr. Dunst J. 1. .V. 1.Deutsche Gesellschaft für Radioonkologie e. Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO). Haase W. Sedlmayer F. Strahlenther Onkol. Fussl C. Piroth MD. Wenz F.

1.189(10):825-33. Fastner G. Haase W. Wenz F. Budach W. 2013 Oct. Harms W. Sautter-Bihl ML. Sauer R. Strahlenther Onkol. Dunst J. Souchon R. Sedlmayer F.DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer. . Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO). Feyer P. Fietkau R.

Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) . Haviland JS1. References: 1. Dobbs HJ. Shelley W. Buchholz TA. hypofractionation is opened for specific patient groups as recommended in this slide. Owen JR. 2013 Oct. Treatment of these patients in ongoing clinical trials is recommended. Fyles A. Lukka H. 4.11(3):231-40. Julian JA. START Trial Management Group. Parpia S. for concerns with long term toxicity (data are not yet sufficient). Pignol JP. Mills J. Bliss JM. Gulavita S. Haviland JS. Freeman C. Grimard L. . Levine MN. 2010 Mar. Although some data showed that also integration of boost irradiation into hypofractionation protocol is feasible. Barrett J. Whelan TJ. Perera F. Comparison of patient-reported breast. Bowen J. arm. Long-term results of hypofractionated radiation therapy for breast cancer. Dewar JA.362(6):513-20. Yarnold JR. Hopwood P.Whole Breast Irradiation (4/15) Further information: Basically. Mills J. Sydenham MA. Lancet Oncol. N Engl J Med. Magee BJ. Simmons S. START Trialists' Group. and shoulder symptoms and body image after radiotherapy for early breast cancer: 5year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. However. Yarnold JR. data on hypofractionation in PMRT and BCT are valid for all subgroups and age groups. Sumo G. 2010 Feb 11. MacKenzie R. 2. Agrawal RK.14(11):1032-4. Lawton PA. Haffty BG1. Venables K. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Schneider K. Barrett-Lee PJ. Lancet Oncol. Hopwood P1. Bliss JM. Hypofractionated breast radiation: preferred standard of care? Lancet Oncol.14(11):108694. 3. it is not accepted as a standard. 2013 Oct.

Virani S3. Shaitelman SF1. Wilkinson JB. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: long-term hospital-related morbidity from cardiac causes.20(2):131-46. Wai ES4. Chambers S.106(1):15-20.88(4):786-92. Cuttino LW. Levine MN. White JR. Woodward WA. Shah C. Pond GR. Shortened radiation therapy schedules for early-stage breast cancer: a review of hypofractionated whole-breast irradiation and accelerated partial breast irradiation. 2013 Jan. 7. Khan AJ. Pritchard KI. Pignol JP. Vicini FA. 2014 Mar 15. McBride ML2. Int J Radiat Oncol Biol Phys. Ann Oncol. Chan EK1. Babiera GV. Parpia S. Julian TB. Tyldesley S6. 6. Gohla G. Bane AL1. Allen Li X. Woods R2. 8. 2014 MarApr. Arthur DW. Fyles AW. Nichol A4. Freedman GM. Speers C5.25(5):992-8. Whelan TJ. Vicini FA. Bloom ES. Arthur DW. Accelerated fractionation with a concurrent boost for early stage breast cancer. .5. Freedman GM. Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy. Breast J. 2014 May. Radiother Oncol.

Yarnold JR. 14: 1086–94 Elderly patients should be counseled about: Absolute benefit of WBRT in older women with pT1-2 (up to 3 cm) pN0. Hopwood P. . Bliss JM. Agrawal RK. Sydenham MA. START Trialists' Group. 95% CI 0. Barrett J. p=0.74. metastasis-free survival and overall survival has been observed. telangiectasia.94). Barrett-Lee PJ.59– 0.14(11):108694. Haviland JS1. 2013 Oct.8. References: 1. Simmons S.“ (HROS=0. Lancet Oncol 2013.042) START B: Haviland JS et al.“ In 1 of 5 trails: “There were significantly fewer distant relapses up to 10 years in the 40 Gy group (HR 0.Additional Information with Regard to Effects of Breast Radiotherapy (BCT) (5/15) Further information: Additional information with regard to effects of radiotherapy in breast conservation (BCT) Hypofractionation: „Some normal tissue effects were less common after the 15 fraction regimen than the control schedule (breast shrinkage. Venables K. Dobbs HJ. Lawton PA. No advantage with regard to secondary mastectomy. Dewar JA. Lancet Oncol. and breast oedema). HR-positive breast cancer after BCS and endocrine therapy is small (2-8 % after ten yrs) and decreases with increasing age. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. which contributed to the significantly higher rates of disease-free survival and overall survival in the 40 Gy group compared with the 50 Gy group. Owen JR. Magee BJ. Mills J.

on behalf of the PRIME II investigators. Dixon JM. Lancet Oncol. J Clin Oncol. Hughes KS. Muss HB. Smith BL. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. Schnaper LA. Available online 28 January 2015 . Bellon JR. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Winer EP. Hudis CA. Schnaper LA. Wood WC. McCormick B. Hughes KS. 2013 Jul 1.2. 2015 Jan 27. Kunkler IH. Jack WJ. Berry DA. Can older women with early breast cancer avoid radiation? The Lancet Oncology. 3.31(19):2382-7. 4. Cameron DA. Williams LJ. Cirrincione CT.

We would suggest that in this older population. 3. Williams LJ. Kunkler IH. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. Wood WC. Jack WJ. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.Radiotherapy in Elderly Patient Life Expectancy less than 10 Years (6/15) Further information: Hughes KS et al. Lancet Oncol. on behalf of the PRIME II investigators. 2. References: 1. Berry DA. dictate survival. Bellon JR. Smith BL. and the biology of the tumor dictates the rate of IBTR. not specific breast cancer treatments. J Clin Oncol. Winer EP. 2015 Jan 27.6 yrs. not the length of life. Can older women with early breast cancer avoid radiation? The Lancet Oncology. Dixon JM. McCormick B. Schnaper LA.31(19):2382-7. Cameron DA. comorbid conditions. Schnaper LA. Hughes KS. Hughes KS. Muss HB. 2013 Jul 1.. 2013: N=636 eligible: WE+Tam RT vs WE + Tam med F/U 12. Cirrincione CT. Available online 28 January 2015 . Hudis CA.

not the length of life. not specific breast cancer treatments. dictate survival. Muss HB. 2013 Jul 1. Bellon JR. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. Hudis CA. Berry DA. We would suggest that in this older population.BCS >=70y <4 cm cN0: Tamoxifen vs.31(19):2382-7. comorbid conditions. Cirrincione CT. Schnaper LA. Tamoxifen + RT (7/15) Further information: Hughes KS et al.6 yrs. 2013: N=636 eligible: WE+Tam RT vs WE + Tam med F/U 12. Wood WC. J Clin Oncol. Winer EP. Smith BL. the biology of the tumor dictates the rate of IBTR. . Hughes KS. McCormick B. Reference: 1.

ipsilateral second cancer or death due to breast cancer. Bartelink et al. Collette L.doi. Van Limbergen E. Lancet Oncol 2014. Morgan D. Dubois JB. Supplementary appendix.I. According to the publication. Remouchamps V.Partial Breast Irradiation Boost-RT (improves local control. published online Dec 9. Rodenhuis C. 95%-C. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Struikmans H. http://dx. Fourquet A.1016/S1470-2045(14)71156-8.04. Poortmans P. Bongartz R. Mirimanoff RO. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Elkhuizen P. 0. Miralbell R.Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) – Partial Breast Irradiation (8/15) Further information: The primary objective of this trial was Overall Survival. Collette S. Weltens C. Reference: 1. Bartelink H. References to the statements: Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) . No significant benefit by boost irradiation was observed with regard to Time to First Recurrence neither in the entire study cohort nor in any of the age-defined subgroups (HR=0. no survival benefit) (LoE 1a A AGO+) 1. A reproducible benefit was observed with regard to Time to Ipsilateral Breast Tumour Recurrence as shown above. Maingon P. Jager J. the endpoint “Time to First Recurrence” is the time from randomization to first relapse defined as a loco-regional or distant relapse. Oei B.81-1.org/10. Whole-breast irradiation with or without a boost for patients .94. Kirova Y. Schinagl D. Horiot JC. p=0-09).

IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer--results of a case series after 5-year follow-up. Kirova Y. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis. Jager J. Fussl C. Deutschmann H. Peintinger F. Collette L. Radiother Oncol. 2013 Aug. Miralbell R. Weltens C. 2. Menzel C. Farmini A. Mirri A. Maingon P. 2015 Jan. Zehentmayr F.treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Poortmans P.136(5):1193-201. Horiot JC. Schinagl D. Hager E. Fastner G. Remouchamps V. Collette S. Fischer T. if G3 or >T1 (LoE 2b B AGO+/-) Antonini et al. 2015 Mar 1. Fourquet A.16(1):47-56. Ziegler I. .108(2):279-86. Van Limbergen E. Morgan D. 2015 Jan. Boost-RT in pts <40 years (LoE 1b A AGO++) Boost-RT in pts 40-60 years (LoE 1b B AGO+) 1. Lancet Oncol. Greil R. Elkhuizen P. Fastner G. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Reinartz G. Valentini V. Mirimanoff RO. Merz F. Radiotherapy and Oncology 82 (2007) 265–271 Intraoperative irradiation (IORT/IOERT) As boost-irradiation followed by WBI (LoE 2a B AGO+) 1. Oei B. Ciabattoni A. Orecchia R. Reitsamer R. Sedlmayer F. Reitsamer R. Bongartz R. Struikmans H. Boost-RT in pts >60 years. Int J Cancer. Lancet Oncol. Fischer T. Dubois JB. Sedlmayer F. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Bartelink H. Lemanski C.16(1):47-56. Deutschmann H. Stierle C. Rodenhuis C. Kopp P.

14(13):1269-77. Tobias JS4. Leonardi MC. Wenz F. Sütterlin M13. Eiermann W. Rotmensz N. Maisonneuve P. Lancet. Flyger HL7. Kraus-Tiefenbacher U. Veronesi P. Viale G. Lancet Oncol. Gentilini O. Falzon M. Wenz F2. Zurrida S. Sütterlin M. Esserman L9. Kraus-Tiefenbacher U. Williams NR. Veronesi U1. IOERT as sole radiotherapy modality (LoE 1b B AGO+/-) 1. Roncadin M15. Lazzari R. Sperk E2. Metaxas M12. non-lobular. Metaxas M. Vaidya JS1. Alvarado M9. Keller A. 2. Matthews A20. Keshtgar M. Keshtgar M6. Ballardini B. Dewar J. Brown D14.3. prospective. Flyger HL. 2010 Jul 10. Matthews A. Tobias JS. Falzon M18. Ann Surg Oncol. 2014 Feb 15. Pigorsch S. Orecchia R. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Massarut S. 2013 Dec. Thompson A14. Harris E19. Cattani F. Baum M. Massarut S8. HR+) (LoE 1b B AGO+/-) 1. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Galimberti V. Joseph DJ5. As sole radiotherapy modality IORT using 50 kV (pT1 pN0 R0 G1-2. IORT during first surgery. Pigorsch S17. Vaidya JS. Alvarado M. Bulsara M3. Potyka I12. Lancet. Saunders C. . age >50 y. Esserman L. Baum M12. doi: 10. Corica T. Wenz F. Intra M.376(9735):91-102. TARGIT trialists' group. Sangalli C. Brew-Graves C12. Welzel G. Williams NR12. Bulsara M.383(9917):603-13. Sütterlin M. Blank E1. Holtveg HM7. Eiermann W11. Corica T5.1245/s10434-010-1265-z. non-inferiority phase 3 trial.17 Suppl 3:352-8. 2010 Oct. Joseph DJ. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international. Single-center long-term follow-up after intraoperative radiotherapy as a boost during breast-conserving surgery using low-kilovoltage x-rays. randomised. Holtveg HM. Caldarella P. Dewar JA16. Roncadin M. Luini A. Bohrer M. no extensive DCIS. Saunders C10.

Postoperativ partial breast irradiation as sole radiotherapy modality
Interstitial brachytherapy
(LoE 1b B AGO+/-)
1.

Aristei C, Palumbo I, Capezzali G, et al. Outcome of a phase II prospective study on partial breast irradiation with
interstitial multi-catheter highdose rate brachytherapy. Radiother Oncol 2013;108:236-241.

Intracavity balloon technique (LoE 1b B AGO-)
1.

Am J Surg. 2007 Oct;194(4):456-62. Five-year results: the initial clinical trial of MammoSite balloon brachytherapy
for partial breast irradiation in early-stage breast cancer. Benitez PR1, Keisch ME, Vicini F, Stolier A, Scroggins T,
Walker A, White J, Hedberg P, Hebert M, Arthur D, Zannis V, Quiet C, Streeter O, Silverstein M.

APBI (IMRT) (LoE 1b B AGO-*)
1.
2.

3.

Lehman M, Hickey BE, Francis DP, See AM. Partial breast irradiation for early breast cancer. Cochrane Database
Syst Rev. 2014 Jun 18;6:CD007077.
Eur J Cancer. 2015 Jan 17. pii: S0959-8049(15)00002-7. Accelerated partial breast irradiation using intensitymodulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled
trial. Livi L1, Meattini I2, Marrazzo L3, Simontacchi G1, Pallotta S3, Saieva C4, Paiar F1, Scotti V1, De Luca Cardillo
C1, Bastiani P5, Orzalesi L6, Casella D6, Sanchez L6, Nori J7, Fambrini M8, Bianchi S9.
J Clin Oncol. 2013 Nov 10;31(32):4038-45. Interim cosmetic and toxicity results from RAPID: a randomized trial of
accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. Olivotto
IA1, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, Kong I, Cochrane B, Nichol A, Roy I, Germain I, Akra
M, Reed M, Fyles A, Trotter T, Perera F, Beckham W, Levine MN, Julian JA.

Boost vs no Boost: EORTC 22881-10882 Trial (9/15)

Further information:
Primary objective of this trial was Overall Survival. A reproducible benefit was observed with regard to Time to Ipsilateral
Breast Tumour Recurrence as shown above. No significant benefit by boost irradiation was observed with regard to Time
to First Recurrence neither in the entire study cohort nor in any of the age-defined subgroups (HR=0.94; 95%-C.I. 0.811.04; p=0-09). According to the publication, the endpoint “Time to First Recurrence” is the time from randomization to
first relapse defined as a loco-regional or distant relapse, ipsilateral second cancer or death due to breast cancer.

Reference:
1.

2.

Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, Schinagl D, Oei B, Rodenhuis C, Horiot JC,
Struikmans H, Van Limbergen E, Kirova Y, Elkhuizen P, Bongartz R, Miralbell R, Morgan D, Dubois JB,
Remouchamps V, Mirimanoff RO, Collette S, Collette L; European Organisation for Research and Treatment of
Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients
treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
Lancet Oncol. 2015 Jan;16(1):47-56.
Bartelink et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery
for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Supplementary appendix. Lancet Oncol
2014; published online Dec 9. http://dx.doi.org/10.1016/S1470-2045(14)71156-8.

Postmastectomy Radiotherapy (PMRT)** to the Chest Wall (10/15)

Further information:
The interpretation of the current EBCTCG publication (2014) should take into account, that this meta-analysis is highly
influenced by the Danish radiotherapy trials (Overgaard et al. 1997, 1999).
Strong evidence on definition of low risk criteria with regard to the group of 1-3 tumor infiltrated axillary Lnn is lacking.
Different definitions are discussed eg.
Kyndi et al. 2013: Low risk of locoregional recurrence, if at least 3 out of 4 favourable criteria are present:
• Hormone receptor receptor status positive,
• Grad I,
• HER2 negative,
• Tumor <2 cm).
Truong et al. 2005: High risk of locoregional recurrence
• If younger age (<45 yrs; HR=3.44) and one of the following factors:
• High proportion of positive nodes (>25%; HR=2.00),
• Medial tumour location (HR=2.46) or
• Negative ER-Status (HR=2.02) and,
• If age 45+ yrs and
• high proportion of positive nodes (>25%).
Also Grading (G3) and vessel invasion, are sometimes considered as criteria of high risk for locoregional recurrence.
However, from the current literature a unique definition cannot be concluded. Since EBCTCG overview demonstrates a
broad benefit in patients with 1-3 tumor infiltrated axillary lymph nodes, the NCCN guidelines are stating: “Strongly
consider postchemotherapy radiation therapy to chest wall plus infraclavicular and supraclavicular areas; if radiation
therapy is given, strongly consider internal mammary node radiation therapy.”

References:
1.

2.

3.

4.

5.
6.

7.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT,
Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who
receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997 Oct
2;337(14):949-55.
Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC,
Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breastcancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.
Lancet. 1999 May 15;353(9165):1641-8.
Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1-T2
tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant
radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1337-47.
Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.
Kyndi M, Overgaard M, Nielsen HM, Sørensen FB, Knudsen H, Overgaard J. High local recurrence risk is not
associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup
analysis of DBCG 82 b&c. Radiother Oncol. 2009 Jan;90(1):74-9.
NCCN Guidelines for Treatment of Cancer by Site
“http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast” download 2014

References according to the statements:
Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with > 3 tumor infiltrated lymph nodes (Lnn.) (LoE1a A
AGO++):
1.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with 1–3 tumor infiltrated lymph nodes (Lnn.) high risk
(LoE 1a A AGO+):
1.

2.

3.

4.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Wenz F, Sperk E, Budach W, Dunst J, Feyer P, Fietkau R, Haase W, Harms W, Piroth MD, Sautter-Bihl ML,
Sedlmayer F, Souchon R, Fussl C, Sauer R; Breast Cancer Expert Panel of the German Society of Radiation
Oncology (DEGRO). DEGRO practical guidelines for radiotherapy of breast cancer IV: radiotherapy following
mastectomy for invasive breast cancer. Strahlenther Onkol. 2014 Aug;190(8):705-14.
Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT,
Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who
receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997 Oct
2;337(14):949-55.
Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC,
Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-

5.

6.
7.

8.

cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.
Lancet. 1999 May 15;353(9165):1641-8.
Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1-T2
tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant
radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1337-47.
Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.
Kyndi M, Overgaard M, Nielsen HM, Sørensen FB, Knudsen H, Overgaard J. High local recurrence risk is not
associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup
analysis of DBCG 82 b&c. Radiother Oncol. 2009 Jan;90(1):74-9.
NCCN Guidelines for Treatment of Cancer by Site
“http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast” download 2014

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with 1–3 tumor infiltrated lymph nodes (Lnn.) low risk
(LoE 5 D AGO+/-):
1.

2.

3.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Wenz F, Sperk E, Budach W, Dunst J, Feyer P, Fietkau R, Haase W, Harms W, Piroth MD, Sautter-Bihl ML,
Sedlmayer F, Souchon R, Fussl C, Sauer R; Breast Cancer Expert Panel of the German Society of Radiation
Oncology (DEGRO). DEGRO practical guidelines for radiotherapy of breast cancer IV: radiotherapy following
mastectomy for invasive breast cancer. Strahlenther Onkol. 2014 Aug;190(8):705-14.
Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1-T2
tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant
radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1337-47.

4.
5.

6.

Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.
Kyndi M, Overgaard M, Nielsen HM, Sørensen FB, Knudsen H, Overgaard J. High local recurrence risk is not
associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup
analysis of DBCG 82 b&c. Radiother Oncol. 2009 Jan;90(1):74-9.
NCCN Guidelines for Treatment of Cancer by Site
“http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast” download 2014

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with T3 / T4 breast cancer (LoE 1a A AGO++):
1.

2.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Valli MC; Association of Radiotherapy and Oncology of the Mediterranean arEa (AROME). Controversies in locoregional treatment: post-mastectomy radiation for pT2-pT3N0 breast cancer arguments in favour. Crit Rev Oncol
Hematol. 2012 Dec;84 Suppl 1:e70-4.

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with pT3 pN0 R0 breast cancer (and no additional risk
factors) LoE 2b B AGO+/- ):
1.

2.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Boutrus R, Taghian AG; Association of Radiotherapy and Oncology of the Mediterranean arEa (AROME). Post
mastectomy radiation for large node negative breast cancer: time for a second look. Crit Rev Oncol Hematol. 2012
Dec;84 Suppl 1:e75-8.

3.

Valli MC; Association of Radiotherapy and Oncology of the Mediterranean arEa (AROME). Controversies in locoregional treatment: post-mastectomy radiation for pT2-pT3N0 breast cancer arguments in favour. Crit Rev Oncol
Hematol. 2012 Dec;84 Suppl 1:e70-4.

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. with if R0 is impossible to reach (for invasive tumor)
(LoE 1a A AGO++):
1.

2.

3.
4.
5.
6.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.
Freedman GM, Fowble BL, Hanlon AL, Myint MA, Hoffman JP, Sigurdson ER, Eisenberg BL, Goldstein LJ, Fein
DA. A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged
fifty or younger. Int J Radiat Oncol Biol Phys. 1998 Jun 1;41(3):599-605.
Truong PT, Olivotto IA, Speers CH, Wai ES, Berthelet E, Kader HA. A positive margin is not always an indication
for radiotherapy after mastectomy in early breast cancer. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):797-804.
Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.
Rowell NP. Are mastectomy resection margins of clinical relevance? A systematic review. Breast. 2010
Feb;19(1):14-22.
Rowell NP. Radiotherapy to the chest wall following mastectomy for node-negative breast cancer: a systematic
review. Radiother Oncol. 2009 Apr;91(1):23-32.

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in young pts with high risk features (LoE 2b B AGO++):
1.

Garg AK, Oh JL, Oswald MJ, et al. Eff ect of postmastectomy radiotherapy in patients <35 years old with stage II-III
breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy. Int J Radiat Oncol Biol
Phys 2007; 69: 1478–83.

2.

3.

4.
5.

Cardoso F, Loibl S, Pagani O, et al.; European Society of Breast Cancer Specialists. The European Society of Breast
Cancer Specialists recommendations for the management of young women with breast cancer. Eur J Cancer
2012;48:3355-77.
Dragun AE, Huang B, Gupta S, Crew JB, Tucker TC. One decade later: trends and disparities in the application of
post-mastectomy radiotherapy since the release of the American Society of Clinical Oncology clinical practice
guidelines. Int J Radiat Oncol Biol Phys 2012;83:e591-6.
Mallon PT, McIntosh SA. Post mastectomy radiotherapy in breast cancer: a survey of current United Kingdom
practice. J BUON 2012;17:245-8.
van der Sangen MJ, van de Wiel FM, Poortmans PM, et al. Are breast conservation and mastectomy equally
effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort
of 1,451 patients aged ≤ 40 years. Breast Cancer Res Treat 2011;127:207-15.

Postmastectomy Radiotherapy (PMRT) to the Chest Wall in pts. after neoadjuvant chemotherapy (NACT) based on the
initial stage prior to NACT (cN+, cT3/4a-d) (LoE 2a A AGO+):
1.

2.

3.

Wright JL, Takita C, Reis IM, Zhao W, Saigal K, Wolfson A, Markoe A, Moller M, Hurley J. Predictors of
locoregional outcome in patients receiving neoadjuvant therapy and postmastectomy radiation. Cancer. 2013 Jan
1;119(1):16-25.
Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Buzdar AU, Valero V, Perkins GH, Schechter NR,
Hunt KK, Sahin AA, Hortobagyi GN, Buchholz TA. Postmastectomy radiation improves local-regional control and
survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and
mastectomy. J Clin Oncol. 2004 Dec 1;22(23):4691-9.
Hoffman KE, Mittendorf EA, Buchholz TA. Optimising radiation treatment decisions for patients who receive
neoadjuvant chemotherapy and mastectomy. Lancet Oncol. 2012 Jun;13(6):e270-6.

Omission of Postmastectomy Radiotherapy (PMRT) to the Chest Wall after NACT in case of ypT0 ypN0 after NACT
(LoE 2b B AGO+/-):
1.

2.

3.

Wright JL, Takita C, Reis IM, Zhao W, Saigal K, Wolfson A, Markoe A, Moller M, Hurley J. Predictors of
locoregional outcome in patients receiving neoadjuvant therapy and postmastectomy radiation. Cancer. 2013 Jan
1;119(1):16-25.
Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Buzdar AU, Valero V, Perkins GH, Schechter NR,
Hunt KK, Sahin AA, Hortobagyi GN, Buchholz TA. Postmastectomy radiation improves local-regional control and
survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and
mastectomy. J Clin Oncol. 2004 Dec 1;22(23):4691-9.
Hoffman KE, Mittendorf EA, Buchholz TA. Optimising radiation treatment decisions for patients who receive
neoadjuvant chemotherapy and mastectomy. Lancet Oncol. 2012 Jun;13(6):e270-6.

Indications for Postmastectomy Radiotherapy (PMRT) to the Chest Wall and regional RT are independent of adjuvant
systemic treatment (LoE 1a A)
1.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.

Further references:
Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality:
meta-analysis of individual patient data for 8135 women in 22 randomised trials.

1.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Lancet. 2014 Jun 21;383(9935):212735.

DEGRO practical guidelines for radiotherapy of breast cancer IV: radiotherapy following mastectomy for invasive breast
cancer.
2.

Wenz F, Sperk E, Budach W, Dunst J, Feyer P, Fietkau R, Haase W, Harms W, Piroth MD, Sautter-Bihl ML,
Sedlmayer F, Souchon R, Fussl C, Sauer R; Breast Cancer Expert Panel of the German Society of Radiation
Oncology (DEGRO). Strahlenther Onkol. 2014 Aug;190(8):705-14.

Radiotherapy of the Axilla (11/15)

No further information

References:
References related to the statements:
Tumor residuals after axillary dissection (LoE 2b B, AGO ++)
1.

Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms Langversion 3.0,
Aktualisierung 2012 AWMF-Register-Nummer: 032 – 045OL Leitlinie. Herausgeber: Leitlinienprogramm
Onkologie der AWMF, Deutschen Krebsgesellschaft e.V. und Deutschen Krebshilfe e.V.

Sentinel node negative (LoE 1b B, AGO --)
1.

2.
3.

Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, Ashikaga T, Weaver DL, Mamounas EP,
Jalovec LM, Frazier TG, Noyes RD, Robidoux A, Scarth HMC, Wolmark N. Sentinel-lymph-node resection
compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer:
overall survival fi ndings from the NSABPB-32 randomised phase 3 trial. Lancet Oncol 2010; 11: 927–33.
Helms G, Kuhn T, Moser L, Remmel E, Kreienberg R. Shoulder-arm morbidity in patients with sentinel node biopsy
and complete axillary dissection: data from a prospective randomised trial. Eur J Surg Oncol 2009; 35: 697–701.
Kuehn T, Bembenek A, Decker T, et al, for the Consensus Committee of the German Society of Senology. A
concept for the clinical implementation of sentinel lymph node biopsy (SLNB) in breast cancer patients with special
regard to quality assurance. Cancer 2005; 103: 451–61.

4.
5.

Lyman GH, Giuliano AE, Somerfi eld MR, et al. American Society of Clinical Oncology guideline
recommendations for sentinel lymph node biopsy in early stage breast cancer. J Clin Oncol 2005; 23: 7703–20.
Galimberti V, Manika A, Maisonneuve P, Corso G, Salazar Moltrasio L, Intra M, Gentilini O, Veronesi P, Pagani G,
Rossi E, Bottiglieri L, Viale G, Rotmensz N, De Cicco C, Grana CM, Sangalli C, Luini A. Long-term follow-up of
5262 breast cancer patients with negative sentinel node and no axillary dissection confirms low rate of axillary
disease. Eur J Surg Oncol. 2014 Oct;40(10):1203-8.

Axillary dissection not indicated e.g. cN0, SLN positive (see surgical chapter) (LoE 2a B, AGO -)
1.

Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
LM, Morrow M. Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel
Node Metastasis. A Randomized Clinical Trial. JAMA. 2011;305(6):569-575

Extracapsular tumor spread (ECS) (LoE 2b B, AGO --)
1.

2.

Stranzl H, Ofner P, Peintinger F. Postoperative irradiation in breast cancer patients with one to three positive axillary
lymph nodes. Is there an impact of axillary extranodal tumor extension on locoregional and distant control?
Strahlenther Onkol. 2006 Oct;182(10):583-8.
Stranzl H, Mayer R, Ofner P, Peintinger F, Prettenhofer U, Hackl A. Extracapsular extension in positive axillary
lymph nodes in female breast cancer patients. Patterns of failure and indications for postoperative locoregional
irradiation. Strahlenther Onkol. 2004 Jan;180(1):31-7.

Axillary micrometastases or isolated cells found in regional lymph nodes (LoE 3b B, AGO --)
1.

Pernas S1, Gil M, Benítez A, Bajen MT, Climent F, Pla MJ, Benito E, Guma A, Gutierrez C, Pisa A, Urruticoechea
A, Pérez J, Gil Gil M. Avoiding axillary treatment in sentinel lymph node micrometastases of breast cancer: a
prospective analysis of axillary or distant recurrence. Ann Surg Oncol. 2010 Mar;17(3):772-7.

2.

Yegiyants S, Romero LM, Haigh PI, DiFronzo LA. Completion axillary lymph node dissection not required for
regional control in patients with breast cancer who have micrometastases in a sentinel node. Arch Surg. 2010
Jun;145(6):564-9.

Axillary Intervention in Patients with Positive Sentinel Lymph Nodes (12/15)

Further information:
The optimal management of patients with a positive axillary lymph node status (pSN1) remains unclear. Future studies
(e.g. INSEMA) are urgently needed.

References related to the statements:
1-2 pos SLN: BCT: no further treatment to the Axilla (criteria according ACOSOG Z011) (LoE 1b B, AGO+/-)
1.

2.

3.

Giuliano AE, Hunt KK, Ballmann KV, Bartsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
L, Morrow M. Axillary dissection vs no axillary dissection in women with breast invasive cancer and sentinel node
metastasis. A randomised clinical trial. JAMA 2011;305(6):569-575.
Galimberti V1, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, Baratella P, Chifu C, Sargenti M, Intra M,
Gentilini O, Mastropasqua MG, Mazzarol G, Massarut S, Garbay JR, Zgajnar J, Galatius H, Recalcati A, Littlejohn
D, Bamert M, Colleoni M, Price KN, Regan MM, Goldhirsch A, Coates AS, Gelber RD, Veronesi U; International
Breast Cancer Study Group Trial 23-01 investigators. Axillary dissection versus no axillary dissection in patients
with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013
Apr;14(4):297-305.
Jagsi R, Manjoet C, Moni J, Ballmann K, Laurie F, Buchholz TA, Giuliano A, Haffty BG. Radiation field design in
the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 2014;Nov 10;32(32): 3600-6

1-2 pos SLN: BCT: Axillary dissection (LoE 1b B, AGO +/-)
1.

2.

Giuliano AE, Hunt KK, Ballmann KV, Bartsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
L, Morrow M. Axillary dissection vs no axillary dissection in women with breast invasive cancer and sentinel node
metastasis. A randomised clinical trial. JAMA 2011;305(6):569-575.
Jagsi R, Manjoet C, Moni J, Ballmann K, Laurie F, Buchholz TA, Giuliano A, Haffty BG. Radiation field design in
the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 2014;Nov 10;32(32): 3600-6

1-2 pos SLN: BCT: radiotherapy of the axilla (LoE 1b B, AGO +/-)
1.

Donker M, Tienhoven G, Straver ME, Meijnen P, van der Velde JH, Mansel RE, Catagliotti C, Westenburg AH,
Klinkenbigt JHG, Orzalesi L, Boum WH, van der Mijte HCG, Nienwerhuijzen GAP, Keltkamp SC, Staets L, Duez
NJ, de Graf PW, van Daten T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JWS, Belkacemi Y, Petignat P,
Schinagl DAX, Coens C, Messina CGM, Bogaerts J, Rutgers EJT. Radiotherapy or surgery of the axilla after a
positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS) a randomised, multicenter open label,
phase 3 non inferiority trial. Lancet Oncol 2014;15:1333-10

1-2 pos SLN: Mastectomy: If RT of chestwall is indicated, axillary dissection or radiotherapy of the axilla (LoE 1b B,
AGO +)
1.

Donker M, Tienhoven G, Straver ME, Meijnen P, van der Velde JH, Mansel RE, Catagliotti C, Westenburg AH,
Klinkenbigt JHG, Orzalesi L, Boum WH, van der Mijte HCG, Nienwerhuijzen GAP, Keltkamp SC, Staets L, Duez
NJ, de Graf PW, van Daten T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JWS, Belkacemi Y, Petignat P,
Schinagl DAX, Coens C, Messina CGM, Bogaerts J, Rutgers EJT. Radiotherapy or surgery of the axilla after a
positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS) a randomised, multicenter open label,
phase 3 non inferiority trial. Lancet Oncol 2014;15:1333-10.

1-2 pos SLN: Mastectomy: If RT of chestwall is indicated, no axillary treatment (criteria ACOSOG Z011) (LoE 5 D,
AGO+/-)
EXPERT OPINION, extrapolated from:
1.
Giuliano AE, Hunt KK, Ballmann KV, Bartsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
L, Morrow M. Axillary dissection vs no axillary dissection in women with breast invasive cancer and sentinel node
metastasis. A randomised clinical trial. JAMA 2011;305(6):569-5753.
2.
Galimberti V1, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, Baratella P, Chifu C, Sargenti M, Intra M,
Gentilini O, Mastropasqua MG, Mazzarol G, Massarut S, Garbay JR, Zgajnar J, Galatius H, Recalcati A, Littlejohn
D, Bamert M, Colleoni M, Price KN, Regan MM, Goldhirsch A, Coates AS, Gelber RD, Veronesi U; International
Breast Cancer Study Group Trial 23-01 investigators. Axillary dissection versus no axillary dissection in patients
with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013
Apr;14(4):297-305.
1-2 pos SLN: Mastectomy: If RT of chestwall is not planned, axillary dissection or radiotherapy of the axilla (LoE 5
AGO++)
EXPERT OPINION, extrapolated from:
1.
Donker M, Tienhoven G, Straver ME, Meijnen P, van der Velde JH, Mansel RE, Catagliotti C, Westenburg AH,
Klinkenbigt JHG, Orzalesi L, Boum WH, van der Mijte HCG, Nienwerhuijzen GAP, Keltkamp SC, Staets L, Duez
NJ, de Graf PW, van Daten T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JWS, Belkacemi Y, Petignat P,
Schinagl DAX, Coens C, Messina CGM, Bogaerts J, Rutgers EJT. Radiotherapy or surgery of the axilla after a
positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS) a randomised, multicenter open label,
phase 3 non inferiority trial. Lancet Oncol 2014;15:1333-10.

>=3 positive SLN: Axillary LN dissection (LoE 1b B, AGO ++)
1.

2.

3.

Giuliano AE, Hunt KK, Ballmann KV, Bartsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
L, Morrow M. Axillary dissection vs no axillary dissection in women with breast invasive cancer and sentinel node
metastasis. A randomised clinical trial. JAMA 2011;305(6):569-575.
Donker M, Tienhoven G, Straver ME, Meijnen P, van der Velde JH, Mansel RE, Catagliotti C, Westenburg AH,
Klinkenbigt JHG, Orzalesi L, Boum WH, van der Mijte HCG, Nienwerhuijzen GAP, Keltkamp SC, Staets L, Duez
NJ, de Graf PW, van Daten T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JWS, Belkacemi Y, Petignat P,
Schinagl DAX, Coens C, Messina CGM, Bogaerts J, Rutgers EJT. Radiotherapy or surgery of the axilla after a
positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS) a randomised, multicenter open label,
phase 3 non inferiority trial. Lancet Oncol 2014;15:1333-10.
EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.

>=3 positive SLN: Radiotherapy of the axilla (LoE 1b B, AGO +)
1.

2.

Giuliano AE, Hunt KK, Ballmann KV, Bartsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall
L, Morrow M. Axillary dissection vs no axillary dissection in women with breast invasive cancer and sentinel node
metastasis. A randomised clinical trial. JAMA 2011;305(6):569-575.
Donker M, Tienhoven G, Straver ME, Meijnen P, van der Velde JH, Mansel RE, Catagliotti C, Westenburg AH,
Klinkenbigt JHG, Orzalesi L, Boum WH, van der Mijte HCG, Nienwerhuijzen GAP, Keltkamp SC, Staets L, Duez
NJ, de Graf PW, van Daten T, Marinelli A, Rijna H, Snoj M, Bundred NJ, Merkus JWS, Belkacemi Y, Petignat P,
Schinagl DAX, Coens C, Messina CGM, Bogaerts J, Rutgers EJT. Radiotherapy or surgery of the axilla after a
positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS) a randomised, multicenter open label,
phase 3 non inferiority trial. Lancet Oncol 2014;15:1333-10.

3.

EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F,
Ewertz M, Gray R, Mannu G, Peto R, Whelan T, Wang Y, Wang Z, Darby S. Effect of radiotherapy after
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Jun 21;383(9935):2127-35.

Radiotherapy (RT) of Other Locoregional Lymph Node Areas (13/15)

Further information:
The definition of high risk and low risk pN1a is different with regard to that in PMRT and that in RT of supra- and
infraclavicular lymphatic regions. A proposal by Yates et al. assigns patients as following:
Low risk, if the following conditions are given: G1 with 1-3 positive LN; or G2 with 2 positive LN; or G3 plus 1 positive
LN (10 years supraclavicular recurrence rate <10%).
High risk if the following conditions are given: G3 plus 2-3 positive LN; or G2 plus 3 positive LN (10 years
supraclavicular recurrence rate 21%).

References:
1.

2.

Yates L, Kirby A, Crichton S, Gillett C, Cane P, Fentiman I, Sawyer E. Risk factors for regional nodal relapse in
breast cancer patients with one to three positive axillary nodes. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):2093103.
Viani GA, Godoi da Silva LB, Viana BS. Patients with N1 breast cancer: who could benefit from supraclavicular
fossa radiotherapy? Breast. 2014 Dec;23(6):749-53.

References related to the statements:
Supra-/infraclavicular lymphatic regions
RT to Supra-/infraclavicular lymphatic regions if  pN2a (LoE 1b A; AGO++)

1.

2.
3.

Whelan TJOI, Ackerman I, Chapman JW, Chua B, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ,
Manchul L, Craighead P, Nolan MC, Bowen J, McCready DR, Pritchard KI, Leine MN, Parulekar W, Parulekar W:
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol ASCO
Annual Meeting Proceed (Post-Meeting Edition) 2011:29.
Budach W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a
meta-analysis of randomized trials. Radiat Oncol. 2013 Nov 14 ;8:267.
P. F. Nguyen-Tan, L. Vincent, F. Methot et al., “The incidence of supraclavicular failure in patients with T1-2 breast
cancer an four or more positive nodes treated by conservative surgery and tangential breast irradiation without
regional nodal irradiation,” International Journal of Radiation Oncology Biology Physics, vol. 42, supplement 1, p.
249, 1998.

RT to Supra-/infraclavicular lymphatic regions if Level III involved (LoE 1b A; AGO
1.

2.

++)

Whelan TJOI, Ackerman I, Chapman JW, Chua B, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ,
Manchul L, Craighead P, Nolan MC, Bowen J, McCready DR, Pritchard KI, Leine MN, Parulekar W, Parulekar W:
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol ASCO
Annual Meeting Proceed (Post-Meeting Edition) 2011:29.
Budach W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a
meta-analysis of randomized trials. Radiat Oncol. 2013 Nov 14 ;8:267.

RT to Supra-/infraclavicular lymphatic regions if pN1a high risk (LoE 2b B; AGO+)
1.

2.

Whelan TJOI, Ackerman I, Chapman JW, Chua B, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ,
Manchul L, Craighead P, Nolan MC, Bowen J, McCready DR, Pritchard KI, Leine MN, Parulekar W, Parulekar W:
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol ASCO
Annual Meeting Proceed (Post-Meeting Edition) 2011:29.
Budach W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a
meta-analysis of randomized trials. Radiat Oncol. 2013 Nov 14 ;8:267.

RT to Supra-/infraclavicular lymphatic regions if pN1a low risk
1.

2.

(LoE 2b B; AGO+/-)

Whelan TJOI, Ackerman I, Chapman JW, Chua B, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ,
Manchul L, Craighead P, Nolan MC, Bowen J, McCready DR, Pritchard KI, Leine MN, Parulekar W, Parulekar W:
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol ASCO
Annual Meeting Proceed (Post-Meeting Edition) 2011:29.
Budach W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a
meta-analysis of randomized trials. Radiat Oncol. 2013 Nov 14 ;8:267.

RT to Supra-/infraclavicular lymphatic regions if pN0 high risk, if radiotherapy of the internal mammaria lnn. chain is
indicated (see below) (LoE 2a B; AGO+/-)
1.

2.

Whelan TJOI, Ackerman I, Chapman JW, Chua B, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A, Pierce LJ,
Manchul L, Craighead P, Nolan MC, Bowen J, McCready DR, Pritchard KI, Leine MN, Parulekar W, Parulekar W:
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol ASCO
Annual Meeting Proceed (Post-Meeting Edition) 2011:29.
Budach W, Kammers K, Boelke E, Matuschek C. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a
meta-analysis of randomized trials. Radiat Oncol. 2013 Nov 14 ;8:267.

RT to Supra-/infraclavicular lymphatic regions after NACT/NAT (indications as for PMRT) (LoE 2b B; AGO+/1.
2.

3.

Bernier J. Post-mastectomy radiotherapy after neodjuvant chemotherapy in breast cancer patients: A review. Crit
Rev Oncol Hematol. 2015 Mar;93(3):180-189.
Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, GeyerJr CE, et al. Predictors of locoregional
recurrence after neoadjuvantchemotherapy: results from combined analysis of national surgicaladjuvant breast and
bowel project B-18 and B-27. J Clin Oncol 2012;30:3960–6.
Buchholz TA, Tucker SL, Masullo L, Kuerer HM, Erwin J, Salas J, et al.Predictors of local-regional recurrence after
neoadjuvant chemotherapyand mastectomy without radiation. J Clin Oncol 2002;20:17–23.

Internal mammaria lymph node region (IMC)
RT to Internal mammaria lymph node region (IMC) if pN1-pN2 and HR positive in patients who had systemic
chemotherapy
1ba
B
+
1.

2.

3.

4.

Hennequin C, Bossard N, Servagi-Vernat S, Maingon P, Dubois JB, Datchary J, Carrie C, Roullet B, Suchaud JP,
Teissier E, Lucardi A, Gerard JP, Belot A, Iwaz J, Ecochard R, Romestaing P. Ten-Year Survival Results of a
Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy. Int J Radiation Oncol Biol Phys
2013; 86 (5): 860-866.
Chang JS, Park W, YB Kim, Lee IJ, Keum KC, Lee CG, Choi DH, Suh CO, Huh SJ. Long-term Survival Outcomes
Following Internal Mammary Node Irradiation in Stage II-III Breast Cancer: Results of a Large Retrospective Study
With 12-Year Follow-up. Int J Radiation Oncol Biol Phys, 2013; 86 (5): 867-872.
Poortmans PSH, Kirkove C, Budach V, Maingon P, Valli MC, Collette S, Fourquet A, Bartelink H, Van den Bogaert
W: Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10
years results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. EJC 2013,
47(Suppl 2).
Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.

RT to Internal mammaria lymph node region (IMC) if pN0 high risk with central/medial tumors
1.

2.

1ba

B

+/-

Hennequin C, Bossard N, Servagi-Vernat S, Maingon P, Dubois JB, Datchary J, Carrie C, Roullet B, Suchaud JP,
Teissier E, Lucardi A, Gerard JP, Belot A, Iwaz J, Ecochard R, Romestaing P. Ten-Year Survival Results of a
Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy. Int J Radiation Oncol Biol Phys
2013; 86 (5): 860-866.
Chang JS, Park W, YB Kim, Lee IJ, Keum KC, Lee CG, Choi DH, Suh CO, Huh SJ. Long-term Survival Outcomes
Following Internal Mammary Node Irradiation in Stage II-III Breast Cancer: Results of a Large Retrospective Study
With 12-Year Follow-up. Int J Radiation Oncol Biol Phys, 2013; 86 (5): 867-872.

3.

4.

Poortmans PSH, Kirkove C, Budach V, Maingon P, Valli MC, Collette S, Fourquet A, Bartelink H, Van den Bogaert
W: Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10
years results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. EJC 2013,
47(Suppl 2).
Jagsi R. Postmastectomy radiation therapy: an overview for the practicing surgeon. ISRN Surg. 2013 Sep
11;2013:212979.

Multivariate Analysis of Overall Survival: Effect of Radiotherapy of the Internal Mammaria Lymph Nodes (14/15)

No further information

References:
1.

Poortmans P, Struikmans H, Kirkove C, Budach V, Maingon P, Valli MC, Collette L, Fourquet A, Bartelink H, Van
den Bogaert W. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast
cancer: 10 years results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22922/10925.
Eur J Cancer, 2013; 49 (Suppl. 3): abstr. #2BA.

no concurrent trastuzumab in parasternal RT) 1.19:1110-6. Chung C. 5. Breast Cancer Res Treat. 3. Belkacemi and J. [Monocentric evaluation of the skin and cardiac toxicities of the concomitant administration of trastuzumab and radiotherapy].13:276-80. Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. Campana F. Piccart-Gebhart MJ. 4. et al. 2014 Nov. Fourquet A. Dueck AC. et al. et al. 6. Dinh P. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. . Keves M. Stuart D. Gligorov. Beuzeboc P. Ann Oncol 2008.94:119-20 (Letter to the editor). Facts and controversies in the use of trastuzumab in the adjuvant setting.2009:307894. Case Report Med 2009. Cardoso F. Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study. Kirova YM. Concurrent trastuzumab — internal mammary irradiation for HER2 positive breast cancer: “It hurts to be on the cutting edge”. Vincent-Salomon A.27:2638-44. Halyard MY. Gobillion A. J Clin Oncol 2009. Belin L. Ozsahin M. Belkacémi Y. Gligorov J. Pisansky TM. Nat Clin Pract Oncol 2008.Concomitant Use of Systemic Therapy with Radiotherapy (15/15) No further information References: Trastuzumab* concurrent with radiotherapy (LoE2b B AGO+) (*in HER2 pos tumors parasternal RT should generally be avoided. Jacob J. Radiother Oncol 2010.5:645-54. Kirova YM. de Azambuja E. Caussa L. Granger B. 2. Radiation recall reaction induced by adjuvant trastuzumab (Herceptin). Dendale R. Cancer Radiother 2009. Pierga JY.148(2):345-53. 7.

. . et al. Gligorov J. Castadot P. Magné N. Radiotherapy for invasive breast cancer: Guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de Vence. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Lancet Oncol.15:1169-78 Winzer KJ. 3. Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy. Braun M. Anticancer Res 2011. Magné N. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Lancet Oncol. Am J Clin Oncol 2011. Rolles M. 2009 Jan. 2. 4. 3. Radiotherapy. 2009 Jan. Colleoni M. Karlsson P. 5. Eur J Cancer 2010.8. Macdermed D. Castadot P. Risk of ipsilateral breast tumor recurrence in patients treated with tamoxifen or anastrozole following breast-conserving surgery with or without radiotherapy. Crit Rev Oncol Hematol 2011. Tsoutsou PG. et al.46:95-101. 2. Toillon RA. Lancet Oncol 2010. Macdermed D. and personalised medicine.31:367-371.34:245-8 Ishitobi M. et al. et al.10(1):53-60. Cole BF. 4.79:91-102 Valakh V. et al. et al. Chargari C1.80:398-402. Chargari C1. Belkacémi Y. Influence of concurrent anastrozole on acute and late side effects of whole breast radiotherapy. Werts ED. antihormonal therapy. Optimal sequence of implied modalities in the adjuvant setting of breast cancer treatment: an update on issues to consider. Nakahara S. Belkacemi Y. Radiother Oncol 2009.90:122-126 Tamoxifen concurrent with radiotherapy (LoE 2b B AGO +) 1. Sauerbrei W. Radiation therapy and tamoxifen after breast-conserving surgery: updated results of a 2 x 2 randomised clinical trial in patients with low risk of recurrence.11:215-216. Recht A. on behalf of the Association of Radiotherapy and Oncology in the Mediterranean area (AROME). Shaffer R. Acute cardiotoxicity with concurrent trastuzumab and radiotherapy including internal mammary chain nodes: A retrospective single-institution study.10(1):53-60. Toillon RA.. German Breast Cancer Study Group (GBSG). Int J Radiat Oncol Biol Phys 2011. Oncologist 2010.. Cutuli B. Fourquet A. et al. International Breast Cancer Study Group. AI (letrozole. Komoike Y. Tyldesley S. Trombetta MG. anastrozole) concurrent with radiotherapy (LoE 2b B AGO +) 1.

. Kirova YM. Dendale R. Campana F. Identifying patients at risk for late radiation-induced toxicity. Bontemps P. De La Lande B. et al. Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. Belin L. Ozsahin M. Crit Rev Oncol Hematol 2012. Sozzi WJ. Gobillion A. Azria D. Pernin V.11:258-265. Azria D. 2015 Feb 3:20140800.5. Romieu G. Br J Radiol. Lancet Oncol 2010. Belkacemi Y. Bollet M. Missohou F. Betz M. Reynaud-Bougnoux A. Denis F. Levy C. Peignaux K. Baumann P. Bourgier C. 6. Lemanski C. Late toxicities and outcomes after one year of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple negative non-metastatic breast cancer. Fourquet A. Cottu P.84 Suppl 1:e35-41 Other compounds (bevacizumab) 1.

V. sowie in der DKG e. in der DGGG e.V.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e.1 Therapy Side Effects . Guidelines Breast Version 2015.V.

V. sowie in der DKG e. in der DGGG e.V.ago-online.  Versions 2004–2014: Albert / Bischoff / Brunnert / Costa / Friedrich / Friedrichs / Gerber / Göhring / Huober / Jackisch/ Lisboa / Müller / Nitz / Schmidt / Souchon / Stickeler / Untch  Version 2015: Lück/Dall Guidelines Breast Version 2015.de .1 www.Therapy Side Effects © AGO e.V.

0 . CTCAE v4.nih.1 Grade Information required 0 none 1 mild 2 moderate 3 severe 4 life threatening organs involved type of toxicity time interval after treatment effect on general health status treatment required recovery achieved www. Common Toxicity Criteria.html .ago-online.gov/ftp1/CTCAE/About. NHI.Toxicity Assessment © AGO Acute Toxicity e. USA.Bethesda. According to WHO1 or NCI-CTC2 Guidelines Breast Version 2015.V.nci.V.V. N0 48 (1979) (WHO offset Publications. (2010) http://evs. sowie in der DKG e. Geneva) NCI.de Long-Term Toxicity No general assessment scale 1 WHO 2 Handbook for reporting results of cancer treatment. in der DGGG e.

Alopecia Mucositis/ Stomatits Cardiac Toxicity Renal Toxicity Cyclophosphamide ++ ++ + + + ++ Methotrexate ++ + + ++ + ++ 5-Fluorouracil ++ ++ ++ + Carboplatin Cisplatin ++ + ++ +++ Capecitabine + + + Gemcitabine ++ + + Epi-/Doxorubicin ++ ++ +++ ++ + Pegliposomal Doxorubicin + + + ++ (+) Liposomal Doxorubicin + + + ++ (+) Mitoxantrone ++ ++ + + + Paclitaxel nab-Paclitaxel ++ + + + +++ +++ + Docetaxel ++ + +++ ++ Vinorelbine ++ (+) + Eribulin ++ + + + Hepatic Toxicity + ++ +++ + + + .ago-online.V. Toxicity e.Cytotoxic Anti-Cancer Drugs Acute Toxicity I © AGO Haematol. in der DGGG e.V. Guidelines Breast Version 2015.V.de Nausea/ Vomit.1 www. sowie in der DKG e.

Dexraxozane Epi-/Doxorubicin + Liposomal Doxo.Cytotoxic Anti-Cancer Drugs Acute Toxicity II © AGO Allergy Bladder e. Obstipation . nails! Thrombophlebitis.V. sowie in der DKG e. in der DGGG e. + + Pegliposomal Doxo.V.1 Cyclophosphamide + Methotrexate + + Neurotoxi Cutane Tox + + + ++ 5-Fluorouracil Carboplatin Cisplatin Diarrhea + + ++ ++ +++ Capecitabine Gemcitabine www. Guidelines Breast Version 2015. Fluid retention.. Edema Paravasate. + +++ Mitoxantrone Paclitaxel nab-Paclitaxel +++ + ++ ++ Docetaxel ++ + Vinorelbine Eribulin ++ ++ ++ + + Myalgia Myalgia + Myalgia.de Flue-like Synd.ago-online.V.

V.ago-online. sowie in der DKG e. in der DGGG e.1 www.V. Guidelines Breast Version 2015.de .ASCO Guidelines PNP © AGO e.V.

V. resp. dose.) 2b B  Liposome encapsulated anthracyclines (doxorubicin) induce less cardiotoxicity 1b B  Anthracycline.V.1  Equivalent cardiotoxicity of doxorubicin and epirubicin at recommended dose levels (450–500 and 900–1000 mg/m² cum. Guidelines Breast Version 2015. sowie in der DKG e.de  Obesity  Hypertension  Hypercholesterolemia  Pre-existing cardiac diseases (incl.ago-online.or trastuzumab-associated cardiotoxicity may occur earlier/more frequently: 2b B  Elderly patients www. borderline LVEF)  Diabetes mellitus  Monitoring of cardiac function before / during / after treatment: Echocardiography (LVEF or SF in %) 3b C + . in der DGGG e.Long-Term Toxicity Cardiotoxicity © AGO Oxford / AGO LoE / GR e.V.

in der DGGG e. sowie in der DKG e.V.V.V.de .1 Regarding cardiac toxicity  Trastuzumab simultaneous to radiotherapy  Trastuzumab simultaneous to epirubicin  Trastuzumab simultaneous to doxorubicin  Anthracycline simultaneous to radiotherapy 2b 2b 2b 2c B B B C + +/- Regarding lung and breast fibrosis  Tamoxifen simultaneous to radiotherapy 3 C  Chemotherapy simultaneous to radiotherapy 1b B +/- www. Guidelines Breast Version 2015.ago-online.Feasibility of Treatment Combinations Considering Toxicities © AGO Oxford / AGO LoE / GR e.

V. in der DGGG e.1 www.de .ago-online. sowie in der DKG e. Guidelines Breast Version 2015.Side Effects of Trastuzumab/Pertuzumab Algorithm in Case of Cardiac Toxicity © AGO e.V.V.

1      www.de  With regard to solid tumours.15 years 2a Anthracycline-containing regimens increase the risk of MDS and leukaemia to 0.ago-online.V. in der DGGG e. sowie in der DKG e.5-1% 2b Radiotherapy increases the risk of leukaemia by 0. Guidelines Breast Version 2015.4 % within 10 .2–1.V.2–0.2–0.7 % within 8 to 10 years 2a PARP-inhibitors are associated with an increased risk of AML and MDS to 0.V.Secondary Malignancies I © AGO e.4% in patients treated with anthracyclinecontaining chemotherapy 2b Tamoxifen approximately doubles the risk for developing endometrial cancer 2b . chemotherapy induced secondary malignancies are rare events Oxford LoE 2a Alkylating agents increase the risk of leukaemia dosedependently to a total of 0.

 Guidelines Breast Version 2015.V. in der DGGG e.1  The risk of developing secondary cancers is low if modern radiation techniques are applied and should not deter the use of radiotherapy when indicated 2b Radiotherapy may moderately enhance the risk of ipsilateral lung cancer and angiosarcoma appearing 5–10 years after treatment 1a  www. sowie in der DKG e.de Enhanced risk especially among ever smokers 2b .Secondary Malignancies II (after Radiotherapy) © AGO Oxford LoE e.ago-online.V.V.

but delays conception to a less fertile period www. CIA) .V.1  CRA may be permanent or temporary  Depends on CTX regimen used  CRA is an (imperfect) surrogate for menopause and fertility  Adjuvant endocrine therapy induces reversible amenorrhea.Chemotherapy Related Amenorrhea (CRA) © AGO Oxford LoE e. Guidelines Breast Version 2015. sowie in der DKG e. in der DGGG e.de  Risk of CRA increases with age / treatment duration 2b  Ovarian reserve of women who remain premenopausal after CTX is reduced 2b CRA is associated with improved outcome (DFS/OS) 1b  Synonyma: Chemotherapy / Treatment induced Amenorrhea (TIA.ago-online.V.V.

Guidelines Breast Version 2015. in der DGGG e.1  Fatigue frequently present in breast cancer patients (30–60%)   2a B Exclusion of somatic reasons (anemia. co-morbidity.V. tumor burden.ago-online.(Therapy Related) Fatigue © AGO Oxford / AGO LoE / GR e.V. medication) for fatigue 1a A ++ A ++ Psycho-social interventions specifically addressing fatigue are efficient in reducing fatigue www.V. sowie in der DKG e.de   1a Physical exercise with ambiguous effects regarding fatigue 1b D + Methylphenidate might improve fatigue 1a + D .

V. Guidelines Breast Version 2015.V.ago-online.V.de Sleep disturbances are a common problem of breast cancer patients during and after therapy (20–70%) 2a Behavioral therapies demonstrated efficacy in the treatment of insomnia and improved the quality of life 1b A B ++ . in der DGGG e.(Therapy Associated) Sleeping disturbance © AGO Oxford / AGO LoE / GR e.1   www. sowie in der DKG e.

V.de Depression is an often reported adverse event in breast cancer patients (20–30%) 2a B  Psychological interventions are effective to improve mood. in der DGGG e.ago-online.1 www.  Guidelines Breast Version 2015. but not survival in distressed and depressed patients 1b A  Antidepressents have shown to improve depression in breast cancer patients 1b A Regular exercise participation can prevent depression among breast cancer survivors 2b B  + . sowie in der DKG e.V.(Therapy Associated) Depression © AGO Oxford / AGO LoE / GR e.V.

ago-online.V.de  Therapy-related cognitive deficits (chemobrain frequently described (16–75%)) 2a B  Cognitive-behavioral therapy is beneficial for cognitive function 2b B  Methylphenidate might improve cognitive function in patients with cancer 3a C .V. Guidelines Breast Version 2015.(Therapy Associated) Cognitive Impairment © AGO Oxford / AGO LoE / GR e. sowie in der DKG e.V.1 www. in der DGGG e.

Side-effects and Toxicity of Endocrine Agents © AGO Visual Disturbances e. Guidelines Breast Version 2015.de SERMs Osteoporosis CerebroVascular Events * (+) Fracture + + + SERD + + GnRHa + + AIs Goserelin + Arthralgia Myalgia Flush Dysfunctional Bleeding* Endometrial Changes Deep Venous Thrombosis (+) + + + (+) (+) + + + + (+) (+) + SERD Cognitive functions + AI 3rd Gen* SERMs Cardiac risk (+) Lipid Profile Impaired (+) .V.1 www.V. in der DGGG e.ago-online.V. sowie in der DKG e.

1    www. DB) 10–30% 1b Gastrointestinal side effects (oral BPs) 2–10% 2b In adjuvant bisphosphonate therapy.de  Renal function deterioration due to IV-amino-BP 1b Osteonecrosis of the jaw (ONJ) mostly under IV-BP and DB therapy (appr. 2%) 1b Acute phase reaction (IV Amino-BPs.ago-online. major side effects were observed rarely (except APR) . Guidelines Breast Version 2015.V. in der DGGG e. sowie in der DKG e.V.Side-Effects and Toxicity of Bone Modifying Agents (BMA) Bisphosphonates (BP) and Denosumab (DB) © AGO Oxford LoE e.V.

ago-online.V. avoid any elective dental procedures.V. ONJ was rare . use oral bisphosphonate In adjuvant bisphosphonate therapy.1 Oxford LoE: 4 GR: C AGO: +  During bisphosphonate treatment.V. if feasible (LoE 2b) www. prophylactic antibiotics are recommended (LoE 2b)  Optimize dental status before start of bisphosphonate treatment. sowie in der DKG e. in der DGGG e.de  Inform patients about ONJ risk and educate about early symptom reporting  In case of high risk for ONJ.Recommendations for Precautions to Prevent Osteonecrosis of the Jaw (ONJ) © AGO e. Guidelines Breast Version 2015. which involve jaw bone manipulations – if interventions are inevitable.

v. + + 0 0 + Pamidronate 90 mg i.v. in der DGGG e. sowie in der DKG e.de Hypocalcemia .v.v. + + 0 0 + Zoledronate 4 mg i.o.Frequent Side Effects of Bone Modifying Agents (BMA) © AGO e.V.1 www. Diarrhea ONJ Clodronate 1500 i. 0 + 0 0 0 Clodronate 1600 p. + 0 0 0 + Zoledronate 4 mg i.v.ago-online. 0 0 + 0 0 Amino Ibandronate 6 mg i.V. q6m 0 0 0 0 0 Denusomab 120 mg sc q4w 0 0 0 + + Guidelines Breast Version 2015. GI-SE React. 0 0 + + 0 Non-A Ibandronate 50 mg p.o.V. Drug Acute Renal Upper Phase Tox.

de  Skin rash. bleeding.V.ago-online.Key-Toxicities – Antibodies / Antibody-drug-conjugates © AGO Oxford / AGO LoE / GR e. sowie in der DKG e. in der DGGG e. Trastuzumab Guidelines Breast Version 2015. pneumonitis 2b B .V. proteinuria. diarrhea.1   Cardiotoxicity in the adjuvant setting (0. left ventricular dysfunction. headache. mucositis 2b B T-DM1  Thrombocytopenia.8–4.V. hepatotoxicity pyrexia.0%) Troponin I might identify patients who are at risk for cardiotoxicity 1b A 2b B Bevacizumab  Hypertonus. 1a A Pertuzumab www.

neutropenia .V. myelosuppression cdk4/6 inhibitors (palbociclip.V. fatigue Oxford / AGO LoE / GR 1b A 2b B 3 C 3 C Everolimus  Pneumonitis. hyperglycemia. skin rash. stomatitis. in der DGGG e.Small Molecules © AGO e. Thrombocytopenia PARP-inhibitors (olaparib)  www.de Fatique. infections. LEE011)  myelosuppression.1 Lapatinib  Diarrhea. Guidelines Breast Version 2015.V. sowie in der DKG e. skin rash.ago-online.

Therapy Side Effects (2/22) Further information: Screened data bases: Pubmed 2007 .ca NCCN (National Comprehensive Cancer Network . Cochrane data base (2013) Screened guidelines: NCI (National Cancer Institute .cancer. SABCS 2010 – 2013.gov ASCO (American Association of Clinical Oncology.org CMA (Canadian Medical Association .cmaj. ASCO 2010 – 2013.2013. 2012): http://www.nccn.org No references . Practice Guidelines. 2012): http://www. 2012) http://www.asco. 2012): http://www.

WHO Handbook for reporting results of cancer treatment.Toxicity Assessment (3/22) Further information: Acute toxicity and in most cases 100 day mortality rates are well documented in the majority of phase III trials. Bethesda. This implies that toxicities concerning liver. Most trials end five or ten years after the last patient in. 2. published 2010). Other toxicities like fatigue. http://evs. Geneva) NCI.nih.html .0 (CTCAE. depression. such that late and very late effects are rarely documented.gov/ftp1/CTCAE/About. Toxicities are graded according to WHO or NCI standards. kidney heart or skin are well documented and graded. USA. Acute Toxicity according to WHO1 or NCI-CTC2: References: 1. menopausal symptoms or impairment of cognitive function are systematically underreported by these tools. Common Terminology Criteria for Adverse Events v4.nci. N0 48 (1979) (WHO offset Publications.

Recht A: Side effects of adjuvant treatment of breast cancer. Twelves C et al. 2001 Azim HA Jr.: Long-term toxic effects of adjuvant chemotherapy in breast cancer. Ann Oncol. Petrelli F et al: Mortality. 2012 Sep.135(2):335-46 Jim HS et al: Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. 4. Shapiro CL.22(9):1939-47. 2012 Oct 10. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. O'Shaughnessy J. de Azambuja E. J Clin Oncol.Cytotoxic Anti-Cancer Drugs – Acute Toxicity I (4/22) No further information References: 1. Loesch D et al. Bines J. 6. Awada A.377:914-23 Kaufmann PA. 2. 5. 2011. and cardiovascular toxicity of adjuvant anthracycline and taxane chemotherapy in breast cancer: a meta-analysis. abstract S6-6 . Piccart MJ. 3. Lancet. Breast Cancer Res Treat. N Engl J Med 344:1997-2008. leukemic risk. 2011 Sep. Colozza M. Phase 3 open label randomized multicenter study Eribulin Mesylate versus Capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclirns and taxanes SABCS 2012.30(29):3578-87 Cortes J.

Cytotoxic Anti-Cancer Drugs – Acute Toxicity II (5/22) No further information References: see slide 4 .

ASCO Guidelines PNP (6/22) No further information No references .

In this trial patients were randomized to CAF or to CMF.6%).01). Limited data are available on long-term cardiac safety of A based regimens. 180 patients from an potential sample of 1176 patients entered. In terms of long. 0%.5 % of patients from the FE50C arm and in 1.4%. decrease > 15%: 2. As patients with breast cancer are getting older and as survival rates improve long term cardiotoxicity is of growing interest. FAC: The Southwest Oncology Group evaluated long term cardiotoxcity from patients randomized to protocol S8897. There was no significant difference in the proportion of women with an LVEF less than 50 % at 5 to 8 years (CAF vs. Delayed (> 1 month after the end of chemotherapy) symptomatic cardiotoxicity was reported in 1. .8 % of patients. French FEC: The FASG reports ten year follow –up data in patients receiving either FE50C or FE100C from FASG 05. Similar data were presented recently by Perez et al. Cardiotoxicity: Early cardiotoxicity of anthracyclines has been well established in clinical trials. CMF: 8% vs. In 2992 patients completed AC 5% had LVEF decrease disallowing trastuzumab (decrease below normal: 2. but not in the 10 to 13 year sample. CMF: 3% vs. p=0.term toxicity cardiotoxicity and secondary acute leukemia/MDS are clinically relevant.1 % of patients from the FE100C arm. 5%. AC: Among patients treated with four cycles of AC on NSABP B31 17 % of patients developed asymptomatc cardiac disease defined as the decline in left ventricular ejection fraction of more than 10 % to an ejection fraction of less than 55 %. p=0. In summary early and delayed cardiotoxicity was reported in 4. However in an exploratory analysis the mean LVEF in the doxorubicin group was statistically significantly lower in the 5 to 8 year sample (p=0.3 % and in 4. A was given on day 1 and 8.16).68) or at 10 to 13 years (CAF vs. in N9831 trial.Long-Term Toxicity Cardiotoxicity I (7/22) Further information: Anthracycline (A) based standard chemotherapy regimens as used in the adjuvant therapy of breast cancer are associated with a relatively low acute toxicity and treatment related mortality rates < 1 %.

93). only 0. and heart disease for patients > 65 years treated with doxorubicin compared with patients who received no chemotherapy were 2. because these patients are per se younger. Preexisting heart disease was beside of afro-american race the most important risk factor for cardiac failure after A-exposure.338 women from the SEER’S database. investigating cardiac affects of A-chemotherapy.6 % respectively in rates of chronic heart failure between anthracycline based chemotherapy and other adjuvant chemotherapy or no chemotherapy.26 for women aged 66 to 70 treated with a compared other chemotherapy. had subsequently less .g. The first one by Doyler et al. in which lower doses af anthracyclines are used. 2. cardiac failure.7 % when comparing anthracycline treated patients to the other or no adjuvant chemotherapy groups.10 to 2.21% in controls (p=0. with absolute differences of 5. 1. with less comorbities and a higher risk of recurrence. A containing regimens outside clinical trials in the elderly There are 2 important studies from the SEER database in older women. Similarly as in the previous study anthracycline–treated women were younger.3%. The adjusted hazard ratio was 1.004).027).44).9 % and 9. and 1. E+ therapy was associated with 1. with less comorbidity and had more advanced diseases than women who received non anthracycline based regimens. For women aged 71 to 80 adjuvant chemotherapy was not associated with chronic heart failure.The second analysis from the FASG trials compared E+ and E. where trials in which total doses of anthracycline was reduced by substitution of taxane. analyzed data from 31478 patients. In these analysis age > 65 years old and body mass index > 27 were significant predictors of cardiac toxicity.26 to 1.25 to 1. 1. These data have been confirmed in the Cochrane analysis. Taxanes and cardiac safety Data on cardiac safety in anthracycline-taxane sequential trials are in favour of taxane-based combinations. 5575 of them received A-based chemotherapy (18%).36% decrease in LVEf after 7 years vs.35 (95% CI. 1. p=0.4% vs.38 (95% CI. 1.48 (95% CI. respectively The relative risk remained elevated 5 years after diagnosis. E. The hazard ratios for cardiomyopathy. This study highlights bias of all studies.52). After ten years the increased risk of chronic heart failure was amplified rather than attenuated. In this age group at five years of follow-up the observed absolute differences were of 1 % and 4. the PACS 01 trial reported significantly lower incidence of cardiac toxicity in the 3xFEC-3xDoc arm than in the 6xFEC arm (0. Pinder et al reported data from a total of 43.(antihormontherapy or nil) regimens in 3577 breast cancer patients.

Trastuzumab and cardiac safety Most studies have excluded elderly patients (> 60 or 65 years) or patients with other risk factors (cardiovascular diseases. van Dalen EC Different anthracycline derivates for reducing cardiotoxicity in cancer patients. 2010. although the negative synergistic cardiac effect of Herceptin should be considered separately of anthracycline cardiac side effects. obesity. reported 5 cardiac events in 510 patients treated by 4 cycles of AC and only 1 in 506 patients in the 4xTC arm in the US Oncology study. There are only limited data on cardiac safety of A-free regimens in adjuvant setting in breast cancer. Cochrane Database Syst Rev. than standard A-based regimens (OR=0.(3):CD005006. In the BCIRG 006 study there were also significantly less patients with >10% decrease of LVEF value in the Taxotere/Carboplatin/Herceptin (TCH) arm than in AC-TH arm (8% vs. leukemic risk.cardiac events. Petrelli F: Mortality. hypertension) from studies including trastuzumab. 32% of HER2+ EBC patients treated with trastuzumab are 'over-60'. These patients have an increased cardiovascular risk profile and develop trastuzumab related cardiotoxicity commonly.(5):CD005006. dose. Breast Cancer Res Treat. References: Statements “Equivalent cardiotoxicity of doxorubicin and epirubicin at recommended dose levels (450–500 and 900–1000 mg/m² cum. Jones et al.135(2):335-46 .3%).14-0. 2010 Mar 17. In clinical practice. “Anthracycline.)” “Liposome encapsulated anthracyclines (doxorubicin) induce less cardiotoxicity” 1. and cardiovascular toxicity of adjuvant anthracycline and taxane chemotherapy in breast cancer: a meta-analysis. which is reversible after cessation of trastuzumab.or trastuzumab-associated cardiotoxicity may occur earlier/more frequently…” 1. 2012 Sep. Review. Update in: Cochrane Database Syst Rev. 17.95)). resp. Also with regard to other risk factors there is an increased risk of trastuzumab related cardiotoxicity during treatment.37 (95%CI: 0.

Bellet M. Azim HA Jr. Simoncini E. Piccart MJ. Vidal M. De Mattos-Arruda L. Di Cosimo S. Ewer SM. Doyler JJ: Chemotherapy and cardiotoxicity in older breast cancer patients: a population based study. Gerber B: Adjuvant therapy for women over age 65 with breast cancer. 2. Saura C. Pinder MA: Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. Gori S. Bovelli D. Baselga J.: Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Cioffi G. Tuccia F. Carreras MJ. Annals of Oncology 2006. Gómez P. ICARO (Italian CARdio-Oncologic) Network. 2011 Aug 9. N Engl J Med. J Clin Oncol 2007.” 1. Lestuzzi C. Colozza M. 2006. Slamon D: Breast Cancer International Research Group. Sautter-Bihl ML. 2011 Oct 6. Sánchez-Ollé G. Tarantini L. 25:3808-3815 Fumuleau P: Long term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group Results. 2011 “Monitoring of cardiac function before / during / after treatment: Echocardiography (LVEF or SF in %)” Ewer MS. Pérez J. 3. Souchon R.365(14):1273-83 . 2. Nat Rev Cardiol.7(10):564-75.2. 2010 Oct. 34:8597-8605. Review. Pulignano G. Serrano C. J Clin Oncol. 2012 Dec. Ann Oncol. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. 3.22(9):1939-47. Tabernero J. 2011 Sep. Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis. Bines J. Long-term toxic effects of adjuvant chemotherapy in breast cancer.23(12):3058-63. Cortés J. Adjuvant trastuzumab in HER2-positive breast cancer. Ceccherini R. Further references: 1. 4. de Azambuja E. Ann Oncol. Ann Oncol. “Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. 17:85-92. Muñoz-Couselo E. Faggiano P. Dtsch Arztebl Int 108:365-371.

5. Ann Oncol.. 2011. Oncology (Williston Park). Leonard R. Aapro M. Brain EG. Cochrane Database Syst Rev. Lluch A: Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper. Ann Oncol. 2007 Oct 17. Verma S: Is cardiotoxicity being adequately assessed in current trials of cytotoxic and targeted agents in breast cancer? Ann Oncol. 8.22(5):1011-8. Leonard RC: Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet).(4):CD004421. 9.23(3):227-34. Bernard-Marty C. Batist G. Erdkamp F. 2010 Nov. 10. Krzemieniecki K. Hershman: Anthracycline cardiotoxicity after breast cancer treatment. Ferguson T: Taxanes for adjuvant treatment of early breast cancer.21(11):2153-60. 2009 Aug. 6. Costa RB: Efficacy and cardiac safety of adjuvant trastuzumab-based chemotherapy regimens for HER2-positive early breast cancer. 2009 Mar. 7. 2011 May. Epub 2010 Nov 22.18(4):218-24. . Breast.22:257-67.

the cumulative incidence was 1. RT with H did not increase relative frequency of cardiac events (CEs) regardless of treatment side. De Fendi LI. Simultaneusly given tamoxifen to radiotherapy might increase the risk of Grade 1 lung fibrosis (p = 0. Dueck AC: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. 2. Adjuvant trastuzumab in the treatment of Her2 positive early breast cancer: a metaanalysis of published randomized trials. respectively. concurrent adjuvant RT and H for early-stage BC was not associated with increased acute AEs (Halyard al. Halyard MY.01) and might increase the risk of late lung sequelae (OR = 2.120-5.7 years. With AC-TH-H. The cumulative incidence of CEs with AC-T-H was 2. At a median follow-up of 3. Therefore the results of the ongoing CONSeT-trials has to be awaited.326. 2009). 1503 patients were irradiated. p = 0.Feasibility of Treatment Combinations Considering Toxicities (8/22) Further information: The frequency of adverse events for patients with HER-2 positive early breast cancer was examined in a randomized study with a median follow-up time of 3.7% with or without RT. Reported data regarding the influence of tamoxifen given simultaneously to radiotherapy are diverging. Stefano EJ.7 years (range. 2009 Viani GA.025). 0 to 6.J Clin Oncol 27: 2638-2644.5 years). Afonso SL. References: Statements “Trastuzumab simultaneous to radiotherapy” 1.442. Soares FV. Radiotherapy (RT) was administered either without or with concurrent trastuzumab (H). 95% CI 1. However other reports did not confirm such an connection. Thus. BMC Cancer 2007.9% with or without RT. 7:153-164 . Pisansky TM.7% v 5.

Jackisch C. Le Floch O.: Adjuvant trastuzumab in HER2positive breast cancer.“Trastuzumab simultaneous to epirubicin” 1. Chan A. Untch M. Tabah-Fisch I. Buyse M. and Epirubicin (HERCULES) trial. Press M. Tjulandin S. Liu MC. 2006. Meerpohl HG. Glaspy J. Tesch H. Azria D. Kreienberg R. Catalani O. Crown J. Rezai M. Phys. Bosset JF. Jonat W. Huober J. . du Bois A. Muscholl M. Serin D. Bauerfeind I. Eidtmann H.28(12):2024-31. Valero V. Fourquet A.28(9):1473-80. Pienkowski T. Müller V. Lindsay MA. Thomssen C. Toledano A.365(14):1273-83 “Anthracycline simultaneous to radiotherapy” 1. Riva A. Fasching PA. Dan Costa S. Loibl S. 2010 Apr 20. Kaufmann M. Firstline trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin. Jackisch C. Breteau N. 2010 Mar 20. Eiermann W. Thomssen C. Breast Cancer International Research Group. “Trastuzumab simultaneous to doxorubicin” 1. Blohmer JU. Visco F. Pinter T. Hanusch C. Bee V. Int J Radiation Oncology Biol. Pauschinger M. Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conserving surgery enhances late toxicities: long-term results of the ARCOSEIN multicenter randomized study. Harbeck N. Untch M. Lichinitser M. 65: 324-332. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. Sauter G. N Engl J Med. Garaud P. du Bois A. von Minckwitz G. Gerber B. Lehle M. Pawlicki M. Robert N. J Clin Oncol. Martin M. Cyclophosphamide. Slamon D. J Clin Oncol. Coumbos A. Hilfrich J. Mackey J. Kühn T. Body G. Mehta K. Manikhas AG. 2. 2011 Oct 6. Calais G. Lück HJ. Bendahmane B. von Minckwitz G.

Int J Radiat Oncol Biol Phys. De Fendi LI.7(1):217. Feyer P. Guardino AE. 2011 Jul 15. On the interaction of adjuvant radiotherapy and tamoxifen treatment for breast cancer. Gupta D.The CONSET trial is launched. Welzel G. Cserháti A. Trastuzumab-Related Cardiotoxicity: Calling Into Question the Concept of Reversibility. Thurzó L. Trombetta MG. Munshi A. 2011 Jan. 2. Carlson RW. Werts ED. Labban G. 3. Telli ML. Stefano EJ. Kelemen G. Organgruppe "Mammakarzinom" der DEGRO. Am J Clin Oncol. Radiat Oncol. Siebenlist K. Borgmann K.50(1):154-5. Mai S. 3. [Epub ahead of print] Varga Z. 2011 Jun. Adjuvant trastuzumab in the treatment of Her2 positive early breast cancer: a metaanalysis of published randomized trials. 2007. Acta Oncol. Kaminsky A. Further references: 1. Influence of concurrent anastrozole on acute and late side effects of whole breast radiotherapy. 7:153-164 . Strahlenther Onkol. BMC Cancer 2007. Khalid MK.“Tamoxifen simultaneous to radiotherapy” 1. Sperk E. 4. 2007 Oct.34(3):245-8. Kahán Z. Afonso SL. Journal of Clin Oncol. Simeonova A. Hoeller U. 2012 Dec 18. Factors of influence on acute skin toxicity of breast cancer patients treated with standard external beam radiotherapy (EBRT) after breast conserving surgery (BCS). 25: 3525-3533 Viani GA. Kraus-Tiefenbacher U. Soares FV. Parda D. Wenz F. Sfintizky A. 2.183(10):535-44.: Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients. Valakh V. Boda K. Concurrent versus sequential radiotherapy and tamoxifen in breast cancer . Hunt SA. Souchon R.80(4):1109-16.

Ludke A. Trastuzumab-associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab. Signs and symptoms are similar to those observed in patients who develop anthracyclineinduced cardiomyopathy and include tachycardia. 2011 Fall.Side Effects of Trastuzumab and Pertuzumab: Algorithm in Case of Cardiac Toxicity (9/22) Further information: Cardiotoxicity has been reported to occur with trastuzumab when administered alone and in combination with antineoplastic agents. Jassal DS. Exp Clin Cardiol. In the Cleopatra trial 808 pts with metastatic breast cancer were randomized to docetaxel and trastucumab and placebo or to docetaxel and trastuzumab and pertuzumab. and there is no evidence that the toxicity is dose related. and medically manageable. nonspecific. However. which may ultimately progress to congestive heart failure (Keefe. References: 1. Trastuzumab-induced cardiac dysfunction: A 'dual-hit'. in neither trial cardiotoxicity was increased through the addition of pertuzumab to trastuzumab both in the absence or presence of taxane containing chemotherapy. The risk of cardiotoxicity with trastuzumab has been reported to be 4% with monotherapy and 27% when administered in combination with an anthracycline and cyclophosphamide. . 2002 Zeglinski M. LVEF dysfunction (any grade) was more frequently seen in the placebo group than in the pertuzumab group (8.16(3):70-4.4%).8% and 1. 2. 2002). An algorithm based on LVEF changes is presented to aid in the question whether continuation of trastuzumab is safe and feasible or whether discontinuation is warranted.3% vs 4. Keefe DL: Trastuzumab-associated cardiotoxicity. There are also data for trastuzumab and pertuzumab from phase 2 trials and randomized phase 3 trials. Cancer 95:1592-1600. Singal PK. and exertional dyspnea. particularly anthracyclines.2% of the patients in the placebo and pertuzumab arms respectively. palpitations. Left ventricular ejection fraction (LVEF) should be measured at baseline and at regular intervals. LVEF dysfunction of grade 3 or higher was reported in 2. severe and life-threatening damages are rare and the majority of reported cardiac effects are mild to moderate.

Nat Clin Pract Oncol.5(6):324-35. Pertuzumab plus Trastuzumab plus Docetaxel for metastatic breast cancer. Popat S. Cortes J. 2008 Jun. Smith IE. Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects. Kim S-B et al. 4. 366:109-119 . N Engl J Med 2012. Baselga J.3.

with highest age-specific relative risk for AML in the 30.2 Risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) Women with a prior breast cancer were ~2. The occurance of a second non-breast cancer was associated with a decrease in overall survival (HR 3.15 to 4. acute myeloid leukemia and homonal therapy with uterine cancer (HR 1. bladder. ACP) the risk to develop grade 4 hematologic toxicity.2 For women > 65 years receiving polychemotherapy (CAF.31.1.7). non Hodgkin’s lymphoma.1 to 34.27).5). radiotherapy was associated with increased risk of soft tissue sarcoma (HR 3.04). ovary.8.6). 95%CI 5. 95%CI 3. uterine cancer. Compared with the general female dutch population.77 to 4.2 than RR 2.4%.7 to 4.60) and chemotherapy with decreased risk for all secondary non-breast cancers. acute myeloid leukemia.78.46 to 8.1-3 Patients younger than 50 years. to have discontinued treatment for toxicity or to die of acute myeloid leucemia/MDS was significantly elevated. kidney.000 women-years (13.1-5 .6 (95%CI 9. stomach. melanoma.98. radiotherapy was associated with increased lung cancer risk (HR 2.to 49-age group. chemotherapy with increased risk of melanoma. rectum.3 Granulacyte colony-stimulating factor (G-CSF) increased the risk of developing AML/MDS. 95%CI 7.7 to 17.1.7.Secondary Malignancies I (10/22) Further information: Approximately one in every 20 breast cancer patients deveolped a second non-breast primary tumour within 10 years following a breast cancer diagnosis (10 years cumulative incidence rate 5. 95%CI 1.1 Mitoxoantrone-based chemotherapy was associated with a higher leukemic risk than with anthrazyclines (RR 16.1 Standard incidence ratios were elevated for cancers of esophagus.40 to 2. Epirubicin and doxorubicin had a similar risk. these breast cancer patients had a 22% increased relative risk in second non-breast primary cancers and an absolute excess risk of 13 cases per 10.1 to 5. 95%CI 1.6 times more likely to develop AML than the total femal Australien population. 95%CI 1.43.20).2 Patients 50 years and older. uterus. soft tissue sarcomas. lung. colon. 95%CI1.

100 mg/m2) and cyclophosphamide i. A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia.7 % (95 % confidence interval [CI]. antihormonal therapy). About two-third of the patient population received epirubicin-based adjuvant chemotherapy while slightly lower than one-third received CMF-like regimens. The incidence of secondary leukemia was very low: 0. The group concluded that CEF chemotherapy for breast cancer carries a small increased risk of sAL compared with CMF which has to be taken into account when discussing treatment options with patients who are at a lower risk of breast cancer death. q3w. As for leukemia. 0 % to 1. node negative patients The rates of acute leukemia had not changed since the original report when updated 10-years results have been reported in 2005. Canadian CEF comprises epirubicin doses of 120 mg/m2.3 % for those patients treated with adjuvant epirubicin and <0. data of 3653 women are available. two who had received AC. 75.7 %) among the 231 treated with AC. two acute lymphoblastic leukemia): Seven among women treated with CEF. 0 % to 4. 0. Using competing risk statistics.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years. epirubicin (50. 0. and 1. .v.3 % (95 % CI.9%.Details to chemotherapy regimes: French FEC The French Adjuvant Study Group reviewed their 16-year experience with their FEC regimen of 5-Fluorouracil.5 to 3. Canadian FEC The National Cancer Institute of Canada Clinical Trials Group analysed the risk of secondary acute leukemia (sAL) following adjuvant therapy with regimens containing epirubicin The analysis were performed to assess the conditional probability of sAL in 1545 women having received adjuvant (n = 1477) or neoadjuvant (n = 68) chemotherapy in four National Cancer Institute of Canada Clinical Trials Group trials from 1990 to 1999. g. which were followed for a median of 104 months. The conditional probability for breast cancer death at 8 years for the whole group treated with epirubicin-containing regimens in all four trials was approximately 34. e.1 % for those treated with other adjuvant therapies (CMF-like. Of note. the conditional probability of sAL was 1. and one following CMF. Cumulative epirubicin doses mostly were below 600 mg/m2. The leukemia risks associated with epirubicin-containing regimens (CEF or EC) and other regimens as doxorubicin and cyclophosphamide (AC or CMF) were registered.3 %) among the 678 who received CMF.4 % (95 % CI.

41 %) for patients treated with standard AC. and the data indicated that G-CSF may also be independently correlated with increased risk. B-16. Breast radiotherapy appeared to be associated with an increased risk of AML/MDS.21 % (95 % CI. Occurrence of AML/MDS was summarized by incidence per 1.63 % to 1. although the incidence of AML/MDS was small relative to that of breast cancer relapse. AML/MDS in older patients In summary Conclusion for FEC and :AC secondary AML/MDS rates correlate with regimens employing intensified doses of cyclophosphamide requiring. J Clin Oncol 26: 1239-46. B-18.62 %). Patients who received breast radiotherapy experienced more secondary AML/MDS than those who did not (RR = 2. by age. 1200 mg/m2 q 21 days x 4. and B25). Results:The incidence of AML/MDS was sharply elevated in the more intense regimens. compared with 0. 0.01 % (95 % confidence interval [CI]. Louweman M et al.11 % to 0. Six distinct AC regimens have been tested and are distinguished by differences in cyclophosphamide intensity.000 patient-years at risk and by cumulative incidence. Schaapveld M. References for statements 1-4: 1. and 2400 mg/m2 q 21 days x 4. B-23. 2400 mg/m2 q 21 days x 2. 0. 1200 mg2 q 21 days x 2. . cumulative incidence of AML/MDS at 5 years was 1. B-22. Materials and Methods:Six complete NSABP trials have investigated AC regimens (B-15.(2008) Risk of primary nonbreast cancers after breast cancer treatment: a dutch population-based study.38. In patients receiving two or four cycles of C at 2400 mg/m2 with granulocyte colony-stimulating factor (G-CSF) support. but data are inconsistent (see slide 10/20). In all regimens. Rates were compared across regimens.006). G-CSF support and to a smaller extent which were characterized by increased rates of subsequent AML/MDS. Visser O. A was given at 60 mg/m2 q 21 days x 4. cumulative dose and by the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. C was given as follows: 600 mg/m2 q 21 days x 4 ("standard AC").US – AC Purpose: We reviewed data from all adjuvant NSABP breast cancer trials that tested regimens containing both doxorubicin (A) and cyclophosphamide (C) to characterize the incidence of subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). P = . and by treatment with or without breast radiotherapy.

Gambotti L et al. Fritschi L(2009) Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers. Jensen M. Catali B et al. Smith R(2003) Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome: review of the literature and the National Surgical Adjuvant Breast and Bowel Projekt Experience. Peto R. Muss H. Berry D. 6. and granulocyte colonystimulating factor: risik factors for leukemia and myelodsplastic syndrome after breast cancer. Ann Oncol 20: 103-9. 89 programmes during 1977-2001. . Neugut A. Baade P. Andersson M. 82. Ingle J. Hershman D. J Natl Cancer Inst 99: 196-205 Reference for Statement Tamoxifen and endometrial cancer 1. Beadle G. radiotherapy. Kirova Y. Jacobson J et al. 3. De Rycke Y. mitroxntrone. Dowsett M. Darby S. Suzan F. J Clin Oncol 25: 3699-704. Taylor C. Cirrincone C et al. Pan HC. 2011 Aug 27. Le Deley M.(2008) Second malignancies after breast cancer: the impact of different treatment modalities. Clin Breast Cancer 4: 273-9. Godwin J. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Cutter D.(2007) Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stmulating factors during breast cancer adjuvant chemotherapy.(2007) Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B experience. 5. B J Cancer 98: 870-4. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. McGale P.(2007) Anthracyclines. Engholm G. Storm H(2008) Risk of secondary primary cancer among patients with early operable breast cancer registered or randomised in Danish Breast Cancer cooperative Group (DBCG) protocols of the 77. Ann Oncol 47: 755-64.2. 8. 4. J Clin Oncol 25: 292300. Gray R. Davies C. 7.378(9793):771-84. Clarke M. Wang YC.

2. 95%CI 1. radiotherapy was associated with an increased lung cancer risk (HR 2. EBCTCG (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15 year survival: an overview of randomised trials. The RR were 1.33 to 1.4) according the results of the nested breast cancer cohort study population of the Connecticut Tumor Registry. Gilbert E et al.(2008) Risk of primary non-breast cancers after breast cancer treatment: a dutch population-based study. Visser O.45 (95%CI 1. B J Cancer 102: 220-6. Curtis R.6-8 The risk of lung cancer was elevated for ever-smokers who receive PMRT (HR18. But the pattern of risks observed were consistend with the general literature on radiation carcinogenesis. J Clin Oncol 18: 229-35.43.46 to 8.6-8 References: 1. Berrington de Gonzalez A.9-45. Overall risks were generally lower for patients treated in recent years (1993 +). 3. Jassem J(2011) Complications of Breast cancer Radiotherapy.31.60) and patients older than 50 years were more likely to develop soft tissue sarcoma (HR 3. Lancet 366: 2087-3106. lung. bone and soft tissue sarcoma) with no evidence of elevated risk for sites receiving medium (05. Schaapveld M.(2010) Second solid cancers after radiotherapy for breast cancer in SEER cancer registries. 95%CI 1.9 Gy) or low doses (< 0. patients younger than 50 years.5 Data are inconsistent for an elevated risk of AML/MDS after radiation exposure.5 Gy). Radiotherapy treatment assuming standard protocol with 50Gy tumour dose and beem energy 6 MV photons. oesophagus. 95%CI 7. Louweman M et al. 4. . Senkus-Konefka E.58) for high dose second cancer sites (1 +Gy.9.-0.Secondary Malignancies II (11/22) Further information: Radiotherapy increased the risk of sarcoma and lung cancer. J Clin Oncol 26: 1239-46.04).1 According to the cohort data of the SEER registries 1973 to 2000 risk for second cancers was dose dependend. risks were higher for sites that should have received higher doses and also higher for young age at exposure.15 to 4. Results of a Dutch population-based study. pleuro.

Neugut A(2008) Effect of breast cancer radiotherapy and cigarette smoking on risk of secundary lung cancer. Clin Breast Cancer 4: 273-9 . Catali B et al. Hershman D. radiotherapy. 8. Le Deley M.(2008) Second malignancies after breast cancer: the impact of different treatment modalities. Suzan F.(2007) Anthracyclines. B J Cancer 98: 870-4. De Rycke Y. J Clin Oncol 26: 392-8. Jacobson J. 6. mitroxantrone.5. Desai M. and granulocyte colonystimulating factor: risik factors for leukemia and myelodsplastic syndrome after breast cancer. Kaufman E. Kirova Y. Smith R(2003) Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome: review of the literature and the National Surgical Adjuvant Breast and Bowel Projekt Experience. 7. J Clin Oncol 25: 292300. Gambotti L et al.

2. N Engl J Med 362: 2053-65. 3. 4.not a matter of dose. Swain S. Stehle H et al: Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. in particular when the tumor was ER-positive. Fertil Steril 94: 138-43. von Minckwitz G. Gimenes D. CIA) Preservation of ovarian function is an important issue in the population of breast cancer patients especially in the patient younger than 40. Druz M. Geyer CJ et al. Jeong J. New Engl J Med 353: 2268-70 . Especially in younger patients the restitution of menses after 2 years is greater than 90 %. early stage breast cancer) amenorrhoe in premenopausal women was associated with improved dissease-free and overall survival regardless of treatment.4 The dose of drug delivered was not a key factor explaining the differnces.(2010) Longer therapy. node-positive.3. Fanelli M(2010) Fertility preservation in women with breast cancer undergoing adjuvant chemotherapy: a systematic review. J Clin Oncol 29:2334-2341.4 References: 1. The effects are more pronounced the older the patient and the longer the chemotherapy. Up to now neither data for ovarian protection with e.g. Data from the NSABBP B-30 trial (sequential versus concurrent ACT.1 After modern taxananthracyclin containing chemotherapy the risk of CRA is markedly lower compared to older chemotherapy regimens.2 However one third of the patients probably will be infertile after chemotherapy.Chemotherapy Related Amenorrhea (CRA) (12/22) Further information: Synonyma: Chemotherapy / Treatment induced Amenorrhea (TIA. GnRH analogues nor cryopreservation of ovarian tissue are convincing. Gerber B. doxorubicin-docetaxel in women with operable. iatrogenic amenorrhoe. Wolmark N (2010) Amenorrhoe from the breast cancer therapy . and survival in early breast cancer. The treatment compromising most oftenly fertility is chemotherapy. Jeong J. 2011 Swain S.

Geyer CE Jr. .29(9):1110-6.5. J Clin Oncol. Ganz PA. Land SR. et al:. Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. 2011 Mar 20.

2005) as well as physical exercise (McNeely et al. This symptom is typically underreported and under-treated and might adversely affect quality of life (Bower. Behavioral and psychological interventions (Stanton et al. Bower et al. 2006. 2006). has not yet been evaluated.(Therapy Related) Fatigue (13/22) Further information: Fatigue is a commen side effect during and after antineoplastic therapy. Recent studies suggest an inflammatory basis for persistent fatigue in breast cancer survivors like increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue (Bower et al. Contrary to what was expected. However. adverse effects of cancer treatment. Anemia might contribute to a subset of cancer patients presenting with fatigue (Cella et al. Blaney 2012). It was shown in a meta-analysis by the Cochrane Collaboration that psychosocial interventions specifically addressing fatigue proved efficient (Goedendorp et al. 2008). . 2011) have demonstrated efficacy in reducing fatigue among breast cancer patients and survivors. which are used broadly in daily praxis. In terms of pharmacological treatments for fatigue in a palliative setting. However the effectiveness of glucocorticoides. psychosocial factors. 2010). These authors concluded that improvements in fatigue were ambiguous and that strategies for behaviour change should underpin these interventions (Markes et al. including direct effects of cancer. physical activity did not mediate the effect of cognitive behavioural therapy on fatigue in this study (Goedendorp et al. Studies of long-term breast cancer survivors suggest that approximately one quarter to one third experience persistent fatigue for up to 10 years after cancer diagnosis (Bower et al. 2006). 2010). 2010). Another Cochrane Collaboration meta-analysis for physical exercise and fatigue only found statistically non-significant improvements for participants in the exercise intervention groups compared to control (non-exercising) groups. 2006). Especially in breast cancer incidence of moderate to severe fatigue ranges between 30 and as high as 60% (Lawrence 2004. a study using methylphenidate (Ritalin™) in 112 cancer patients showed that this medication was not significantly superior to placebo after 1 week of treatment (Bruerat al. Several factors are thought to contribute to cancer-related fatigue. 2004). 2009) and the same authors reported a randomized controlled trial showing that cognitive behavioural therapy was effective in reducing cancer-related fatigue. a significant effect of methylphenidate against cancerrelated fatigue was confirmed in a meta-analysis performed by the Cochrane Collaboration (Peuckmann-Post et al. and comorbid medical conditions. comorbid physical symptoms.

2008 Bower JE. J Clin Oncol 23:6009-6018. and treatment of fatigue in cancer patients. 1. Issue 1. Miller K. Ganz PA.11:CD006145. Lowe-Strong A. Verhagen CAHHVM. 26:768-777. Byron-Daniel J. 4. Psychosocial interventions for reducing fatigue during cancer treatment in adults. doi: 10. J Natl Cancer Inst Monogr 32:40-50.: CD006953. Ganz PA. Epub 2011 Oct 6. Goedendorp MM. Irwin MR.CD006953. 2. facilitators and preferences in the context of fatigue. 2008 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. Desmond KA. 2011 Jan.1002/14651858.pub2 Stanton AL.. Psychooncology. Cochrane Database of Systematic Reviews 2009.: Exercise for the management of cancer-related fatigue in adults. 2012 Nov 14. Gracey JH. Art. randomized.Cochrane Database Syst Rev.1002/14651858. Cancer 106:751-758. Arevalo JM. Brain Behav Immun. Gielissen MFM. Cramp F. doi: 10. No. Kwan L. controlled trial with breast cancer patients.Stone: How common is fatigue in disease-free breast cancer survivors? A systematic review of the literature.References: Fatigue is frequently present… 1. quality of life and physical activity participation: a questionnaire-survey.CD006145. Cole SW : Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.. Bleijenberg G.Cancer survivors' exercise barriers. 2006 Lawrence DP. 2. Kupelnick B. et al: Fatigue in long-term breast carcinoma survivors: A longitudinal investigation. 2004 Psycho-social interventions… 1. et al: Outcomes from the Moving Beyond Cancer psychoeducational. Campbell A.pub3. Bower JE. DOI: 10. J Clin Oncol. 2005 Physical exercise…. Rankin-Watt J.2072. 2013 Jan. . 5.22(1):186-94.1002/pon. Minton . Ganz PA. 6. et al: Evidence report on the occurrence.25(1):147-50. Breast Cancer Res Treat 112: 5-13. 3. Blaney JM. assessment.

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behavioral symptoms in breast cancer survivors 2008. References: Sleep disturbances are a common problem…. 2008. 2010). Those with insomnia complaints had significantly more depression and fatigue than good sleepers (Palesh et al. Insomnia was approximately three times higher than the proportions reported in the general population. Indeed. 2005).R24#R24New data suggest that sleep disturbances.(Therapy Associated) Sleeping disturbance (14/22) Further information: Sleep disturbances are a common problem of breast cancer patients during and after therapy (20-70%) leading to disruption in women's quality of life and general ability to function (Bower. supporting their use among breast cancer patients (Berger et al. 2009). evening fatigue. especially found in chemotherapy treated patients (Bower et al. fatigue and depression may stem from distinct TNF-a mediated inflammatory processes. 2011. Empirical studies of benzodiazepines and benzodiazepine receptor antagonists indicate that they are effective in improving various aspects of sleep. In a recently published study examining 823 cancer patients treated with chemotherapy. 2001. although no trials have evaluated the efficacy of these medications in cancer populations. and depressive symptoms predicted baseline levels of subjective sleep disturbance. and depressive symptoms predicted the trajectory of subjective sleep disturbance (Dhruva et al 2012). a randomized controlled trial of behavioural therapy for women with insomnia caused or exacerbated by breast cancer found significant improvement in subjective sleep complaints. Ancoli-Israel et al. Liu et al 2012). Comorbidity. Comparative studies have shown that behavioral therapies are at least as effective and longer lasting than pharmacotherapy in treating insomnia (McChargue DE et al 2012. it was shown that 43% of the patients met the criteria for insomnia syndrome. including insomnia secondary to medical conditions. Berger et al. Savard et al. 60% of the patient sample reported that their insomnia symptoms remained unchanged from cycle 1 to cycle 2. Behavioral therapies have demonstrated efficacy in the treatment of insomnia. 2009). 2006). .htm . E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. as well as improvements in mood and quality of life (Savard et al.

2009 Savard J.44(2):215-28. and circadian rhythms prior to chemotherapy for breast cancer. Sadler GR. West C. 2006 Behavioral therapies have demonstrated efficacy…. J Pain Symptom Manage. Natarajan L. Liu L. 6. and after radiation therapy. Mills PJ. Berger AM. et al: Fatigue.20(2):245-52. and sleep disturbances share a common underlying mechanism? J Clin Oncol 29:35173522. Am J Psychiatry 159:5-11. 2012 Jul. Lee K. Park A. Perlis ML. Support Care Cancer 14:201-209. Ancoli-Israel S. et al: One-year outcomes of a behavioral therapy intervention trial on sleep quality and cancer-related fatigue. Fiorentino L. Predictors of adherence to a behavioral therapy sleep intervention during breast cancer chemotherapy. sleep. 5.: Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy. Visovsky CG. J Clin Oncol 27: 6033-6040.26(5):706-13 McChargue DE. J Clin Oncol. Parker BA. 2002 . 3. 2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. Dunn LB. Bower JE. Dimsdale JE. Highland KB. Aouizerat BE. depression. Mustian KM. Ganz PA. Irwin MR et al: Inflammation and behavioural symptoms after breast cancer treatment: do fatigue. Roscoe JA. Liu L. 2. 3. 2008 Ancoli-Israel S. Marler MR. 7. et al: Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer. Kuhn BR. Dhruva A. 26:768-777. 1. Rissling M. J Clin Oncol 28:292-298.1. 2012 Feb. 4. Swift PS.: A longitudinal study of measures of objective and subjective sleep disturbance in patients with breast cancer before. et al: Prevalence. Support Care Cancer.. Matthews EE. 2012 Aug. Wara W. Farr LA. Miaskowski C. Sankaranarayanan J. Simard S. Ivers H. et al: Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. demographics. Brain Behav Immun. Cooper BA. part I: Sleep and psychological effects. and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. J Clin Oncol 23:6083-6096. 2005 Smith MT. during. 2. Paul SM. Berger AM.2011 Palesh OG.

Meta-analysis of efficacy of interventions for elevated depressive symptoms in adults diagnosed with cancer. 2007).1371/journal. Pescatello LS. 2008). Depression negatively affects quality of life and there is also evidence of increased morbidity and. possibly. Craft LL. Hoyt MA. Steel JL. Huedo-Medina TB. References: Statements 1-4 1. Cuijpers P. The occurrence of depression in breast cancer patients is more strongly influenced by psychosocial and physical factors. even though the occurrence of a major depressive disorder might be lower. Spring B. Diefenbach M. 2006).pone. Brown JC. 2010). rather than severity of the disease or treatment regimen (Bardwell et al. Kilbourn KM. 2.(Therapy Associated) Depression (15/22) Further information: Depression is an often reported adverse event in breast cancer patients.0030955. . Hart SL. Berendsen M. In terms of treatment psychological interventions seem to be most effective distressed patients even though these interventions do not prolong survival. PLoS One. doi: 10. The majority of studies find that 20-30% of breast cancer patients experience elevated depressive episodes (Bower.1093/jnci/djs256. Depressed mood is correlated with fatigue and sleep disturbance in the context of breast cancer. Anderson DR. Mohr DC. even among those who were not depressed at study entry. Psychological distress and depressive symptoms are typically highest in the first 6 months after cancer diagnosis and then decline over time. 2012 Jul 3.104(13):990-1004. in particular paroxetine has been shown to be effective in reducing depressive symptoms in breast cancer patients. 2012. doi: 10. et al: The efficacy of exercise in reducing depressive symptoms among cancer survivors: a meta-analysis.7(1):e30955. mortality in depressed cancer patients (Gallo et al. Stanton AL. J Natl Cancer Inst. Regular exercise participation and tea consumption were shown in a population-based cohort study from Shanghai to play an important role in the prevention of depression among breast cancer survivors (Chen et al. Antidepressents have also shown to improve depression.

2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. 2008 Gallo JJ. Dimsdale JE. Tea Consumption. et al: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. Zheng Y. 2007 Bardwell WA.341:c4737. BMJ.c4737. J Clin Oncol 28: 991-998.3. J Clin Oncol. and Depression Among Breast Cancer Survivors. 2011 Mar.1097/YIC. doi: 10. Iovieno N. Int Clin Psychopharmacol. Bogner HR. 8. Lelgemann M.0b013e328340775e. Morales KH. Grouven U. et al: The effect of a primary care practice-based depression intervention on mortality in older adults: A randomized trial. et al: Exercise. Ann Intern Med 146:689-698. et al: Objective cancer-related variables are not associated with depressive symptoms in women treated for early-stage breast cancer. 2010 Oct 12. 7.1136/bmj.26(2):69-74. 6. doi: 10. 2006 . 5. Lu W. Ameral VE. Eyding D. et al: Antidepressants for major depressive disorder in patients with a comorbid axis-III disorder: a meta-analysis of patient characteristics and placebo response rates in randomized controlled trials. 26:768-777. 4. Tedeschini E. Natarajan L. Chen X. J Clin Oncol 24:2420-2427.

E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. DNA damage and telomere length. 2006). 2005). Considering adjuvant endocrine treatment. inflammation and cytokine dysregulation. 2007). among breast cancer patients during and after chemotherapy have been reported in 16 to 75% (Bower et al. often referred to as chemobrain. 2011). behavioral symptoms in breast cancer survivors 2008. and estrogen or testosterone reduction. 2010). Neuroimaging findings provide compelling evidence that chemotherapy has a negative effect on cognition in a subset of women and that these effects may persist for years after successful treatment (Silverman et al. as well as genetic polymorphisms (Ahles et al.htm R122#R122 Interestingly. Patients rated their own cognitive functions as improved after 6 months. 2007). are there several candidate mechanisms for chemotherapyinduced cognitive changes. These results again do not support that adjuvant chemotherapy is associated with cognitive side effects in breast cancer patients. neuropsychological tests did not reveal any differences in cognitive function between breast cancer patients after chemotherapy and healthy controls (Debess et al. 2010). 2007Stewart et al. Other potential treatment approaches include methylphenidate. the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes.(Therapy Associated) Cognitive Impairment (16/22) Further information Reports of cognitive deficits. 2008. whereas exemestane use was not associated with statistically significant lower cognitive functioning in postmenopausal patients with breast cancer (Schilder et al. A study on young premenopausal patients was able to clearly correlate chemotherapy-induced changes in cerebral white matter with impaired cognitive functioning (Deprez et al. In a current study examining 120 breast cancer patients treated with CMF. The biologic base for these changes is unclear. and standard neuropsychological test performance after treatment and at the 2-month and 6-month follow-ups (Ferguson et al. Cognitive behavioral therapy might lead to significant improvements in self-reported cognitive function. subjective cognitive complaints are typically not correlated with objective cognitive performance in breast cancer patients but are correlated with subjective reports of fatigue and depressed mood. tamoxifen use was associated with statistically significant lower functioning in verbal memory and executive functioning. including direct neurotoxic effects. which has been used to improve cognitive . Among breast cancer survivors who remain disease-free for more than a decade. In patients after treatment completion there is improvement in cognitive function over time. 2007). Vardy et al. However. although a subset of patients continued to show deficits for up to 10 years after treatment (Fan et al. quality of life.

htm . 26:768-777.function in patients with advanced cancer. Chait S. Faul LA. 2010 Schilder CM. Deprez S.30(29):3578-87. . J Clin Oncol 25:2455-2463. Small BJ. Clin Neuropsychol 20:76-89. 5. and basal ganglia activity in adjuvanttreated breast cancer survivors 5-10 years after chemotherapy. Bielajew C. Ewertz M: Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study. 2007 Silverman DH.htm . 4. 2. Seynaeve C. Popa MA. Rourke S. Phillips KM. Saykin AJ: Candidate mechanisms for chemotherapy-induced cognitive changes. Engebjerg MC. 2012 Oct 10.5640. Lee YH. J Clin Oncol. behavioral symptoms in breast cancer survivors 2008. Dy CJ. J Clin Oncol 2011 Dec 19. 2006 3.39. 8. 2008 Vardy J. Breast Cancer Res Treat 103:303-311. Collins B. Breast Cancer Res Treat 121:91-100. Smeets A et al: Longitudinal assessment of chemotherapy induced structural chan ges in cerebral white matter and its correlation with impaired cognitive function. doi: 10. et al: Altered frontocortical.2011. et al: A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer.:Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. 7. cerebellar. 2007 Stewart A. J Clin Oncol. behavioral symptoms in breast cancer survivors 2008. 9.R110#R110 References: Therapy-related cognitive deficits (chemobrain)… 1. 6. Jacobsen PB. et al: Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. Riis JØ. Nat Rev Cancer 7:192201.1200/JCO. 2007 Ahles TA. E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. Castellon SA. Tannock IF: Evaluation of cognitive function associated with chemotherapy: A review of published studies and recommendations for future research.R130#R130 E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. Jim HS. 2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. Amant F. J Clin Oncol 28:1294-300. (Epub ahead of print) Debess J. Beex LV. Hussin MG.

: Cognitive-behavioural stress management enhances adjustment in women with breast cancer. Lauche R. 3. [Epub ahead of print] Cramer H.: Mindfulness-based stress reduction for breast cancer-a systematic review and meta-analysis.: Chemotherapy and cognitive deficits: mechanisms. 2012 Oct. et al: Palliative uses of methylphenidate in patients with cancer: A review. and potential interventions. Groarke A. Saykin AJ.19. Houede-Tchen N. Dreisbach A. findings. and cognitive function in women after adjuvant chemotherapy for breast cancer: 1. 2007 Sep. Fan HG. Curr Oncol. Rozans M. et al: Fatigue. 2.and 2-year follow-up of a prospective controlled study.10. menopausal symptoms.12009.5(3):273-80.1016.19(5):e343-52. 1. Curtis R. 2. J Clin Oncol 23:8025-8032.3747/co. Ahles TA. 2012 Dec 4. Lertora JJ. 2005 Cognitive-behavioral therapy…. Palliat Support Care. Yi QL. J Clin Oncol 20:335-339. 2007 Methylphenidate might improve cognitive function…. Dobos G. Roth AJ. 1. Paul A. Ferguson RJ. doi: 10. doi: 10. Nelson CJ. Kerin M.1111/bjhp. Psychooncology 16:772-777. Nandy N. et al: Cognitive-behavioral management of chemotherapy-related cognitive change. 2002 . Br J Health Psychol.

55) was significantly lower in comparison to tamoxifen (Amir et al. Coates AS.34) and venous thrombosis (OR=0.Side-effects and Toxicity of Endocrine Agents I (17/22) Further information: In a metaanalysis on 19. . as well as the occurence of bone fractures (OR=1. treated with 3rd generation aromatase inhibitors the risk of developing cardiovascular adverse events was slightly higher in comparison to tamoxifen with an RR of 1.112(2):260-7. 105:75-89 Mouridsen H. 29:785-801. Bria E. 57155722 Gandhi S. Gligorov J. Cardiovascular safety profiles of aromatase inhibitors. 103 :1299-1309. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG1-98 trial. Breast Cahcer Res Treat 126 :221-226.34 translating into a minimal risk of 0. Amir E. Niraula S et al. 4. Drug Safety. JCO 2007. Breast Cancer Res Treat 2007.5%. References: 1. 7. Verma S. et al: Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer. Phillips KA.023 patients in 7 trials comparing aromatase inhibitors with tamoxifen.818 pts.: Aromatase inhibitors and cardiac toxicity: getting to the heart of the matter. Ribi K et al. 2006. Cognitive function in postmenopausal breast cancer patients one year after completeing adjuvant endocrine therapy with letrozol and/or tamoxifen in the BIG 1-98 trial. 2008 Jan 15. 25. Breast Cancer Res Treat 2007. Perez EA.26) for aromatase inhibitors was confirmed.47). Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients : asystemtatic review and méta-analysis. 2011 Cuppone F. J Natl Cancer Inst 2011 . Verma S. Rabaglio M et al. 106:1-9 Nabholtz JM. 5. while the OR for endometrial carcinoma (OR=0. Aldridge J. Cancer. 2011). Safety of aromatase inhibitors in the adjuvant setting. 6. (Cuppone F et al 2008) In an actual systematic review and metaanalysis of 30. the increased risk for developing cardiovascular disease (OR=1. Seruga B. Keshavia A. 2. 3.

8. Morris GJ. . 2006. 33(6):688-95. Semin Oncol. Pandya N. Toxicity of aromatase inhibitors.

1011. Bisphosphonates. Brufsky AM.1016/S1470-2045(12)70226-7. Wong et al 2012).: Bisphosphonates and other bone agents for breast cancer. Perez EA. Lad T. Wolmark N. Pavlakis N. Lancet Oncol. Paterson AH.Side-Effects and Toxicity – of Bone Modyfing Agents (BMA. 2012 Jul. Paterson AH. References: 1.0%.pub3. Stockler MR. 2010). An excess of renal AEs and acute-phase reactions occurred with zoledronic acid. Robidoux A. Although there amounting data. Zheng P.1002/14651858. with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. doi: 10. randomised trial. denosumab.19.CD003474.67% (RR= 1. Cochrane Database Syst Rev. P = . that bisphosphonates might have anticancer benefits for older postmenopausal women. Costantino JP.61) (Van den Wyngaert et al. Osteonecrosis of the jaw occurred infrequently (2.4%. Wong MH. doi: 10. Falkson CI. Pritchard KI. 3. placebo-controlled. Epub 2012 Jun 14. Gralow JR. Weir LM.39) (Stopeck et al. Anderson SJ. a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand. Fehrenbacher L. Swain SM. Curr Oncol. the routine use of bisphosphonates as adjuvant treatment for patients with early breast cancer is not recommended (Paterson et al 2012.: Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre.2:CD003474. Dakhil S.3747/co. 2011). . In terms of toxicity rates of adverse events (AEs) and serious AEs were similar between groups. 2012 Oct. In a pooled analysis of three randomized phase III trials of denosumab versus zoledronic acid in patients treated for metastatic cancer this occurrence rate for denosumab was confirmed with 1. Clemons M. hypocalcemia occurred more frequently with denosumab.: Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art.13(7):734-42. Geyer CE Jr. doi: 10. Denosumab) (18/22) Further information: A recently published randomized study compared denosumab. Baez-Diaz L. Gelmon KA. King KM. 1. Lembersky BC. zoledronic acid. Mamounas EP. 2.19(5):259-68. 2012 Feb 15.

Wouterds K.1093/jnci/djq516 Vahtsevanos K. et al. J Natl Cancer Inst. J Clin Oncol 27: 5356-5362. Adverse effects of bisphosphonates: current issues. Kyrgidis A. 6. 2009 Acute phase rea Gastrointestinal side effects… 1. Diel IJ. 2. J Clin Oncol 28: 5132-5139. Stockler R. Van den Wyngaert T. 2007 Pavlakis N. Verrou E. 7.4. 2011. 5:475-482. Body JJ. Grötz KA. 5. Lipton A. 2010 Pazianas M: Osteonecrosis of the Jaw and the Role of Macrophages. Stopeck AT. Huizing MT et al. 19:2035-40. double-blind study. Bergner R. Cochrane Database Syst Rev 2005 Jul 20:CD003474 . et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Schmidt R. RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem? Support Cancer Care. Bisphosphonates for breast cancer. J Support Oncol. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized. 2010 doi: 10.

95% CI. 2009 .6%.98893.5%.03 to 3. randomized controlled trials are needed to validate these results. given monthly reported an crude ONJ incidence of 8.9% in patients with multiple myeloma. Verrou E. Joseph AP: Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review. which turned out to be non-significant after adjustment for other variables. A study with 1. et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw.1%.4103/0973-029X. 95% CI. References: 1. 1. Before initiation of a bisphosphonate.94% to 18.006 intravenous doses of BP.43).621 patients who received 29. Sivakumar T. Nair BJ. Kyrgidis A. having ever received zoledronate (aOR = 28. 2012 May. Vahtsevanos K. doi: 10. history of dental extraction (aOR = 32. validated dental extractions and use of dentures are risk factors for ONJ development.02 to 60. Smoking. periodontitis. and 4.15 to 3. 1.02.Recommendations for Precautions to Prevent ONJ (19/22) Further information: The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.09. Multivariate analysis demonstrated that use of dentures (aOR = 2. 3. 2. and each zoledronate dose (aOR = 2.74 to 137. respectively. breast cancer. 18. however.02. 95% CI.56) were associated with increased risk for ONJ development. J Oral Maxillofac Pathol. Patients with breast cancer demonstrated a reduced risk for ONJ development. 95% CI. In conclusion.31). Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication. patients should have a comprehensive dental examination. 5.96).16(2):210-4.97. and prostate cancer. Varun B. J Clin Oncol 27: 5356-5362. and root canal treatment did not increase risk for ONJ in patients receiving BP.

Frequent Side Effects of Bone Modifying Agents (BMA) (20/22) Further information: Side-Effects and Toxicity – Bisphosphonates References: Go to slide 18-19/22! .

6 years.Key-Toxicities Antibodies/Antibody-drug-conjugates – Small Molecules (21/22) and (22/22) Further information: In the HERA trial. Thus. asymptomatic cardiac events were identified in four women in the combination-therapy group and in one woman in the monotherapy group. the incidence of discontinuation of trastuzumab because of cardiac disorders was low (5. The majority of these patients recover with appropriate treatment (Russell et al. a low ejection fraction at the start of paclitaxel treatment. 59 of 73 patients with a cardiac end point reached acute recovery. and trastuzumab treatment.001). The incidence of cardiac end points remains low even after longer-term follow-up and the majority of cardiac events resolved (Procter et al. 3. and all women had an LVEF value that was at or above the lower limit of the normal range on subsequent assessment.8% v 0.1% of trastuzumab-treated patients with symptomatic heart failure events after cessation of trastuzumab. All of these events in the combination-therapy group were considered to be related to treatment.and NCCTG 9831-trial trastuzumab-treated patients had a 2. 62% v 5%. 0. 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point. TIC occurred more frequent in patients with troponin elevation (TNI+. In the Phase III trial of Capecitabine with or without the oral tysosinkinase-inhibitor lapatinib which led to the approval of lapatinib in advanced HER-2 positive breast cancer.45% in the chemotherapy-alone arm.0% incidence of symptomatic heart failure events compared with 0. confirmed significant LVEF decreases. The usefulness of troponin I in the identification of patients at risk for trastuzumab induced cardiotoxicity (TIC) and in the prediction of LVEF recovery was investigated in 251 women treated with trastuzumab. Troponin increase identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.6% v 0.6%) In the trastuzumab group. . Complete or partial recovery was observed in 86. At a median follow-up of 3. of these 59 patients. 2010).1%). Independent predictors for cardiac events were age older than 50 years. the incidence of cardiac end points remained low. though it was higher in the trastuzumab group than in the observation group (severe CHF. P < . TNI was measured before and after each trastuzumab cycle. In the NSABP B-31.0%. 2010).

respectively References Cardiotoxicity…. 3. Robert N et al: Adjuvant trastuzumab in Her2-positive breast cancer. Oncologist 2009. Most adverse events were grade 1. fatigue. Grade 4 diarrhea occurred in two women in the combination-therapy group (1%). 2. 4. de Azambuja. Suter TM. Blackwell KL. One case each of grade 4 fatigue. and rash occurred more often in the group of women who received combination therapy. Expert. dyspepsia. Marquez A. Alba E. 1. and rash that was distinct from the hand–foot syndrome. 2010 Russell SD. et al: Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. Slamon D. Lawrence J. Zamorano J: Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations. Sengupta P. vascular or fatal events and febrile neutropenia. Perez-Isla L. et al: Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial.68). vomiting. left ventricular dysfunction (OR=2. J Clin Oncol 28: 3416-3421.14:1–11 . Rev Anticancer Ther 2009.76). 2011 Procter M. or 3. 2. 2010 Higa GM. Khandheria B. nausea. Abraham J: Biological mechanisms of bevacizumab-associated adverse events.25) and hemorrhagic events (OR=4. headache. Garcia-Saenz JA. and dizziness was reported in the monotherapy group. 5. while no increased incidence was found for gastrointestinal perforation.9:999–1007 Martin M. Eiermann W.The most common adverse events were diarrhea. Esteva FJ.07). the hand–foot syndrome. A systematic review and meta-analysis of five randomized phase III clinical trials that used bavcizumab alone or in combination with chemotherapy in metastatic breast cancer showed a statistically significant bevacizumab associated increased risk for proteinuria (OR=27. J Clin Oncol 28: 3422-3428. hypertension (OR=12. Diarrhea. N Engl J Med 365:1273-1283.

2011 (Epub ahead of print) Hamilton EP. Hall K: Managing adverse events in the use of bevacizumab and chemotherapy. Eidtmann H. Anadkat MJ: Prphylaxs and treatment of dermatologic adverse events from epidermal growth factor receptor inhibitors. 2010 Bevacizumab …. Ann Oncol 22:301-306. Balagula Y. et al: Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. Gralow J.Safety results of the GeparQuinto trial. Cortes J. Reichardt P. N Engl J Med 357: 2666-2676. Langer B. Karapanagiotu E. Jackisch C. 2. Wu PA. Loibl S et al:Integrating bevacizumab. Thomssen C. Eidtmann H. 2. Ramirez-Merino N et al: Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a metanalysis. Meerpohl HG. 25:159-169. Wang M. 1. Cardinale D. Blackwell KL: Safety of Bevacizumab in patients with metastatic breast cancer. Torrisi R. Br J Nurs 2009. Kuhn W. 6. Annals of Oncology Oct. Biodrugs. 5. et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. 58 Miller K. Blohmer JU. Hoffken K. everolimus. Colombo A. Heilman V. 2007 Lapatinib… 1. Muscholl M. 2011 . Harbeck N. Ebert A.18:351– 6. Calvo V. Boura P et al: Bevacizumab-induced hypertension. Oncology 80:314-325. 4. 3. Lacouture ME. 40:988–97 Troponin I…. Eur J Cancer 2004. 2011 Blowers E. and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer. J Clin Oncol 28: 3910-3916. Wallwiener D. Luck HJ: Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. 2011 Von Minckwitz G. Curr Opin Oncol 23:343-351. Emons G. 2011 Syrigos KN. Wiese W. Untch M. Pauschinger M. du Bois A.6.

Baselga J. 2. 2006 Pertuzumab 1. Forster J. 4. Blackwell K. N Engl J Med 2012. Olsen S. Pertuzumab plus Trastuzumab plus Docetaxel for metastatic breast cancer.366: 520-529 . Wu S.: Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis. 2012 Nov 8. Baselga J. Miles D. Diéras V. Guardino E. Rugo H et al. Olica C et al: Lapatinib plus capecitabine in women with Her2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. Oh DY. 2012 Sep. Sherill B. Campone M.135(2):347-54. 2010 Cameron D. N Engl J Med 355:2733-2743. Lu MW. Everolimus in postmenopausal hormone receptor positive advanced breast cancer. Kim S-B et al. EMILIA Study Group. 366:109-119 T-DM1 1. Pegram M. et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. Krop IE. Amonkar MM. Welslau M. Drucker AM. Lindquist D. Trastuzumab emtansine for HER2-positive advanced breast cancer. Verma S. Oncologist 15:924-934. Sherif B et al: Quality of life in hormone receptor-positive Her2-positive metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. 2010 Geyer CE. Fang L. Breast Cancer Res Treat. Gianni L. Lacouture ME. N Engl J Med 2012.3.367(19):1783-91. Casey M. Baselga J. N Engl J Med. Cortes J. 5. Dang CT. Oncologist 15:944-953. Everolimus: 1.

1 Supportive Care .V. sowie in der DKG e. in der DGGG e.Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. Guidelines Breast Version 2015. V.V.

Guidelines Breast Version 2015. sowie in der DKG e.V.ago-online.Supportive Care © AGO e.V.1 www. in der DGGG e.de  Version 2002: Diel  Versions 2003–2014: Bauerfeind / Bischoff / Costa / Dall / Diel / Fersis / Hanf / Heinrich / Jackisch / von Minckwitz / Möbus / Oberhoff / Rody / Schaller / Scharl / Schmidt / Schütz  Version 2015: Diel / Bischoff . V.

V.de In the German environment. in der DGGG e.V.onkosupport.Guideline Spectrum © AGO e.2012. sowie in der DKG e. announced 1. Rehabilitation und Sozialmedizin der DKG: http://www.ago-online.6. Guidelines Breast Version 2015. Supportive Maßnahmen in der Onkologie. The listing is clearly biased towards German and English language Special emphasis is put on aspects concerning breast cancer patients www.7. but underline that the listings of relevant guidelines do not claim to be complete. planned release: 30.V.interdisziplinäre Querschnittsleitlinie“.1 Specific national and international guidelines deal with various aspects of evidence-based supportive therapy of cancer patients We try to quote these guidelines wherever appropriate.de“ In preparation: multidisciplinary guidelines of the AWMF: „Supportive Therapie bei onkologischen Patientinnen .2015 . special interest is earnt by the publications of the „Arbeitsgem.

de  Indicated in asymptomatic anaemia  In dose-dense / dose-escalated CT (iddETC) 1a 1b B A +  Indicated in symptomatic anaemia  In the adjuvant setting  In the neoadjuvant/metastatic setting 1b 1b 1a A A A + + +/-  Treatment and secondary prophylaxis of chemotherapy induced anemia (CIA)  Improvement of outcome (DFS.1 www.ago-online. V. sowie in der DKG e.V.V. OS)  Treatment start at Hb-levels approaching < 10 g/dL  Target Hb 11–12 g/dL  Thromboembolic events are increased with ESAs 1a 1a 1a 1a 1a A B A A A + -+ + .Erythropoiesis-stimulating agents (ESAs) © AGO Oxford / AGO LoE / GR e. in der DGGG e. Guidelines Breast Version 2015.

sowie in der DKG e.o.000 IU 1 x /week s.de  Hb measurements weekly  Dose reduction at Hb-increase > 1g/dl within 2 weeks  Dose increase at Hb-increase < 1g/dl within 4-6 weeks Hb-levels after 9 weeks .1  Epoetin α and Darbepoetin are equieffective 1b A ++ 1a A ++ 1b B +  Darbepoetin: 2. q3w 1b A ++  In case of FID give IV iron supplementation 1a B +  p. iron supplementation 1a B +/-  STOP ESA-treatment in case of missing increases of 1b A ++  Dose:  Epoetin α: 150 IU/kg 3 x weekly s. or 40.c. weekly 1b A ++  Darbepoetin: 500 µg s.V. www.c. V.c.000 IU q3w s.c.25 µg/kg s.ago-online. in der DGGG e.  Epoetin α: 80.c.000 IU q2w s.Practical Use of ESAs © AGO Oxford / AGO LoE / GR e.c.V. Guidelines Breast Version 2015. or 120.

2015.1 www.V. 28: 4996–10 .and chemotherapy-induced anemia. J Clin Oncol 2010.org  Rizzo JD et al: ASCO/ASH/Clinical Practice Guideline update on the use of epoetin and darbepoetin in adult patients with cancer. V.nccn. in der DGGG e.ago-online. Gilreath JA et al: Cancer.Relevant Guidelines © AGO e. Available from: URL: http://www.de  Rodgers GM. Guidelines Breast Version 2015.V. NCCN Clinical Practice Guidelines in Oncology 2. sowie in der DKG e.

“ 2013 © AGO Oxford / AGO LoE / GR e.V.de * High risk definition: estimated duration of neutropenia < 100/µl > 7d .g. V.1  Avoidance of highly infection-risking behaviour or situations 5 D +  Prophylactic treatment in low risk patients 1a B -  Antibiotics 1a A ++  Anti-fungal agents (triazole) 1a B +/-  Virostatics in solid tumors 5 D -  Granulocyte colony-stimulating factors 1a A ++  Prophylactic treatment in high risk* patients (e.. in der DGGG e. sowie in der DKG e..V.g. BC) ASCO Practice Guideline „Antimicrobial Prophylaxis.ago-online. Guidelines Breast Version 2015.Prophylaxis of Infections NB Rarely Applicable to Patients with Solid Tumors (e. according to NCCN Guidelines) with www.

de High risk: Age >65 years Increased risk: Advanced disease (level I and II evidence) History of prior FN No antibiotic prophylaxis Other Factors: Poor performance (ECOG > 1) (level III and IV Female gender evidence) Haemoglobin <12 g/dL Liver. FN risk ≥20% FN risk 10-20% FN risk <10% Guidelines Breast Version 2015. renal or cardiovascular disease Nutritional status Reass ess at each cycle Step 3: Define the patient’s overall FN risk for planned chemotherapy regimen Overall FN risk ≥20% Prophylactic G-CSF recommended Overall FN risk <20% G-CSF prophylaxis not indicated .V.1 Step 2: Assess factors that may increase the risk of FN: www. in der DGGG e.V.ago-online.EORTC and ASCO G-CSF Guideline-Based FN Risk Assessment Step 1: Assess frequency of FN associated with the planned chemotherapy regimen © AGO e. sowie in der DKG e. V.

2013 .Relevant Guidelines © AGO e.V. Guidelines Breast Version 2015.V. sowie in der DKG e.ago-online.1 www.de Flowers et al: Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. V. J Clin Oncol 31: 794-810. in der DGGG e.

5%) mouth rinsing.ago-online. hexetidine.V. Aciclovir®  Local anaesthesia: Benzocaine PO . V.de  Desinfecting / antiphlogistic measures: Mouth rinsing with infusions of camomile or salvia. polyvidon-iodine.Mucositis Mucositis http://www. Local therapy with crystal violet solution 0. sowie in der DKG e. fluconazole  Local antiviral treatment Aminoquinuride / tetracaine-HCl .V.org/assets/documents/MukositisGuidelinesMASCC2006(dtV).or HD-melphalane. nystatine.pdf © AGO e. H.mascc. etheric oils.1 www.5% or tinctura myrrhei. mometasonfuroate + propylene glycol  Mucosa protecting measures (during / after application of chemotherapy): Sucking ice cubes (especially from pineapple juice) during 5fluorouracile. Guidelines Breast Version 2015.  Local antimycotic treatment: Amphotericine B. extracts of camomile. Calcium folinate (LeucovorinMundgel®) every 4–6 hrs for HD-methotrexate: do not start earlier than 24 hours after end of MTX-Infusion (otherwise potential loss of efficacy of MTX!). in der DGGG e. Dexpanthenole (Panthenol®-Solution.

in der DGGG e. Guidelines Breast Version 2015.ago-online.g. dose-dense CT) www. DAC.V.1  Primary prophylaxis for expected febrile neutropenia (FNP)  If expected risk for FNP 10–20% 1b B +/- 3b C + 1a A ++  Secondary prophylaxis during chemotherapy (previous FNP or neutropenia grade IV > 7 days) 1b B ++  Therapeutic usage for FNP 1a A +/-  Pegfilgrastim day 2 1b A ++  Lipegfilgrastim day 2 1b B +  Filgrastim/Lenograstim from day 2–3 until ANC > 2–3 x 109 1b A ++  In case of individual risk factors  If expected risk for FNP >20% (e. V.de  Start related to chemotherapy and duration .V. sowie in der DKG e.Granulocyte Colony-stimulating Factors © AGO Oxford / AGO LoE / GR e.

V.de Crawford et al: Myeloid Growth Factors.ago-online. Ann Oncol 21 (suppl 5): v248v251. sowie in der DKG e. 2010 . V. J Clin Oncol 24:3187-3205. in der DGGG e.1 www. 2013 Smith et al: 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors. Guidelines Breast Version 2015. 2006 Crawford et al: Hematopoietic growth factors.V. J Natl Compr Canc Netw:1266-1290.Relevant Guidelines © AGO e.

dgho-infektionen.de for 2 h in a patient with an ANC of <500 cells/mm3 or expected to fall to <500 cells/mm) Oxford / AGO LoE / GR  Clinical examination 5 D ++  Daily evaluation 5 D ++  Hospitalization of high risk patients 1b A ++  Homecare in low risk patients 1b A +  Differential blood count 5 D ++  Blood cultures 5 D ++  Imaging of lungs 3 C ++  Immediate initial empiric antibiotic therapy 1a A ++ 1b A ++ 2b B +/-  Empiric antifungal therapy 4–7d in case of failure of antibiotic therapy  G-CSF for treatment (not prophylactic) .ago-online.Management of Febrile Neutropenia c.de (H.V. Recommendations by Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. (DGHO) www. Guidelines Breast Version 2015. V.V. in der DGGG e.5°C or two consecutive readings of >38°C © AGO e. Link et al: erstellt 04/07) Definition (oral temperature of >38.V. sowie in der DKG e.f.1 www.

V.ago-online.1 www. Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. Guidelines Breast Version 2015.dgho-infektionen.de regularly issues such recommendations in German. (DGHO) www.Calculated Antibiotic Therapy in FN © AGO e.de Recommendations need to be regularly updated according to the changes in microbial sensitivity and resistance towards antiinfective treatments. in der DGGG e.V. .V.V. sowie in der DKG e.

Guidelines Breast Version 2015.onkosupport.ago-online.1 http://www.de/e974/e2538/e3782/e3494/ ASORS_AV_Paravasate-Guidelines_04-2010.de . V. sowie in der DKG e.Dexrazoxane © AGO e. in der DGGG e.V.V. liposomal) www.pdf Oxford / AGO LoE / GR  Treatment of anthracycline extravasation 2b B ++ 5 D ++  In cardiac risk patients  Consider alternative regimens (anthracycline-free.

in der DGGG e. Local cooling: ice packs for 15 min every 6 hrs.ago-online.V. for at least 3 days. Guidelines Breast Version 2015. IV 1–2 hrs Day 3: 500 mg/m² (max. 2000 mg). IV 1–2 hrs Day 2: 1000 mg/m² (max. V. allow it to dry on air.1 www. The interval may be extended to 6 hours from day 4 onward. 1000 mg). sowie in der DKG e. alternatively: 24 h continuous ice cooling 2.Paravasation Dexrazoxane © AGO e. Local application (with swab) of dimethylsulfoxid 99% (DMSO) every 3-4 hours for at least 3 days (better 14 days).de Day 1: 1000 mg/m² (max. following measures are recommended 1. .V. 2000 mg). IV 1–2 hrs Otherwise or if treatment with dexrazoxane is not indicated.

de © AGO e.1 www.onkosupport.org/antiemetic-guidelines www.V.mascc. in der DGGG e. sowie in der DKG e. V. Oxford / AGO LoE / GR Guidelines Breast Version 2015.V.Antiemetic Therapy http://www.de  After assessment of emetic potential of chemotherapy protocol 5 D ++  Neurokinin-1-receptor-antagonists 1b A ++  Dexamethasone 1a A ++  5-HT3-antagonists 1b A ++  Metoclopramide 3b C + .ago-online.

Wirkstoffgruppe Substanz Dosierung Nebenwirkungen Potenzial Serotoninantagonisten Ondansetron 8 mg i. 5 mg p. Cisaprid Metoclopramid bis zu 120 mg/24h als Dauerinfusion od. Flush.v.transdermal 5 mg i. V.v. Kopfschmerzen.V. 25 mg i.v. 1-3 x/d Blutzuckerentgleisung. 1-3 x/d mäßig Prednisolon 100-250 mg i.o./24 h ( 6 Amp.ago-online. sowie in der DKG e.o.v.. 2 x 4-8 mg p. als Tropfen Dyskinesien hoch in der DGGG e. transiente Leberwerterhöhung mäßig Dexamethason 8-20 mg i. Diarrhoe Haloperidol 1-3 mg 4 x/d Sedation.o.v. od. Cytochrom-P-450Aktivierung mit Dosisreduktion von Dexamethason (2 x 8 mg).v.o. psychotische Reaktionen. 80 mg d 2-3 p.. Keine Kombination mit Astemizol.Supportive Therapy Antiemetics © AGO e.V. Diarrhoe. 6 Tbl.v. Tropisetron Granisetron Palonosetron Guidelines Breast Version 2015. 0. Terfenadin.1 NK 1-Antagonisten Dopaminantagonisten/ substituierte Benzamide Alizaprid www. oder p. Blutdruckanstieg fixe Kombinationsp artner (oral) NE 300 mg PA 0.de Phenothiazine/ bis zu 300 mg i. Depressionen. Flushsymptomatik Transaminasenanstieg Darmatonie in hoher Dosierung sehr hoch Aprepitant 125 mg d1. 1-3 mg i.v. Senkung der Krampfschwelle. sehr hoch Fosaprepitant 150 mg d1 i.) NEPA (Netupitant and Palonosetron) Angstreaktion.5 mg Butyrophenone Corticosteroide (Antidot:Biperiden) sehr hoch .

de) © AGO e.ago-online.de Morphine. buprenorphine (sublingual or transdermal).V. V.dgs-praxisleitlinien. bisphosphonats .Analgesia (Deutsche Gesellschaft für Schmerztherapie Praxisleitlinie Tumorschmerz 2014 www. in der DGGG e. WHO Step 1 Diclofenac resinate. paracetamole Mild opioids. WHO Step 2 Tramadol (preferentially „retard“-formulations) or tilidine / naloxone (also as „retard“-formulations) Strong opioids.1 Non-opioids. fentanyle (transdermal).V. as back-up levomethadone. hydromorphone. sowie in der DKG e. pregabaline. Additional drugs – „adjuvants“ Gabapentine. carbamazepine. ibuprofene and / or metamizole. WHO Step 3 www. oxycodone. The dose of opioids should be titrated step by step according to the analgetic effect. Guidelines Breast Version 2015. amitriptyline.

sowie in der DKG e. Guidelines Breast Version 2015. in der DGGG e. opioids  Loperamide. morphine IV.de Adsorbent agents  Carbo medicinalis. tinctura opii. Al-Mgsilicate hydrate Analgetics.ago-online. codeine.V. V.V.Diarrhea Diarrhea © AGO e. butylscopolamine Colitis pseudomembranosa  Metronidazols or (if not effective) vancomycine . caoline / pectine.1 www.

ago-online.de  Sennae.g. paraffin) Opioid-receptor-antagonists (in opioid-related constipation)  Methylnaltrexone .V. AGO +)  Oral radio-opaque material: ultima ratio e. Ricinus.V. Guidelines Breast Version 2015. V. sodium amidotrizoate  Sorbite Motility stimulating laxatives www.Constipation Constipation Important Side Effect of Opioid Treatment Swelling agents © AGO e. sowie in der DKG e. flaxseed (shredded) Osmotic laxatives  Macrogol > Lactulose (Cochrane review LoE 1a. sodium-picosulfate Emollients (Internal lubricants e.g. in der DGGG e. Bisacodyl.1  Psylium.

J Natl Compr Canc Netw 10:1284-1309. 2012 3Cardoso et al. should be a priority.”2  “Expert palliative care. Guidelines Breast Version 2015. 2012 2 Levy .”1  “Palliative care should be initiated by the primary oncology team and augmented by collaboration with an interdisciplinary team of palliative care experts.Palliative Care © AGO e.”3 1 Smith et al.1 www.V.V. sowie in der DKG e. V. including effective control of pain and other symptoms. 2012 et al. J Clin Oncol 30 880-887.ago-online. Breast 21:242-252.de  “…expert consensus that combined standard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden. in der DGGG e.

Supportive Care (2/ 22) No further information No references .

Guideline spectrum (3/22) Further information: Specific national and international guidelines deal with various aspects of evidence-based supportive therapy of cancer patients We try to quote these guidelines wherever appropriate.6. but underline that the listings of relevant guidelines do not claim to be complete.onkosupport.7.2012.2015 No references .de In preparation: multidisciplinary guideline of the AWMF: „Supportive Therapie bei onkologischen PatientInnen interdisziplinäre Querschnittsleitlinie“. planned release: 30. Rehabilitation und Sozialmedizin der DKG: http://www. special interest is earnt by the publications of Arbeitsgem. The listing is clearly biased towards German and English language. Special emphasis is put on aspects concerning breast cancer patients. Supportive Maßnahmen in der Onkologie . In the German environment. announced 1.

Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth. . More data are needed for the effect of these drugs on quality of life and tumour progression. updated in November 2007. extracting data from a total of 91 trials with 20.Erythropoesis-Stimulating Agents (ESAs) (4/22) Further information: Prior to 2007. head and neck. concluding that ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient’s clinical circumstances and preferences. to include the following key points: (a) ESAs should be used only to treat anemia that occurs in patients with cancer while they are undergoing chemotherapy. and (b) describe patterns of ESA treatment subsequent to the first ESA administration at Hb above 12 gm per dL. In 2012 a Cochrane review was published by Tonia et al. OBJECTIVE: To (a) assess the prevalence and predictors of ESA administrations at Hb levels above 12 gm per dL among patients with a diagnosis of solid or hematologic cancer or myelodysplastic syndrome who began their first regimen of conventional myelosuppressive chemotherapy between 2002 and 2006. the FDA changed the labeling of the ESAs to add boxed warnings. (b) treatment with ESAs should be stopped when chemotherapy ends. In January 2008. 2008.102 participants to perform a systematic review." A new black-box warning regarding this association was added to the labels of the ESAs in March 2008. In March 2007. and treatment was to be withheld if Hb exceeded 13 gm per dL. lymphoid. Whether and how ESAs affects tumour control remains uncertain. that ESA therapy should not be initiated in patients receiving chemotherapy at Hb levels of 10 gm per dL or higher. There is suggestive evidence that ESAs may improve QoL. the FDA specified that the increased risk of more rapid tumor growth or shortened survival was associated with ESAs when "administered in an attempt to achieve a Hb level of 12 gm per dL or greater. and non-small cell lung malignancies.. although many patients did not reach that level. cervical. the erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa were indicated for use in chemotherapy-induced anemia to achieve target hemoglobin (Hb) levels of approximately 12 grams per deciliter (gm per dL). and the FDA mandated further label changes on July 30. and (c) dosing ESAs to an Hb target of 12 gm per dL or greater has resulted in more rapid cancer progression or shortened overall survival in patients with breast.

Kaiser JF.Use of erythropoietin-stimulating agents in breast cancer patients: a risk review. 6.PMID: 19535656 [PubMed . DOI: 10. Ranganathan G. Biakhov M. Pienkowski T. Hyde C. 2. Bencardino K. Buono DL. DeSantis ER. [Epub ahead of print]PMID: 19821012 [PubMed . Blau CA. McBride R. Danova M. 2009 Jul 1. Mettler A.66(13):1180-5. :Use of erythropoietin-stimulating agents in breast cancer patients: a risk review. Nalysnyk L. Further references: Statement: An increased mortality and tumor progression by the use of ESF can not be safely ruled out 1. 3. Tinelli C. Manikhas G. 2009.fda. Delfanti S.pub5. Tsai WY. http://www.27(9):2353-61.:Chemotherapyinduced anemia in breast cancer patients treated with pegfilgrastim-supported dose-dense regimens.101(23):1633-41. Am J Health Syst Pharm. Erythropoi. Wu Y. Vercammen E.PMID: 19903808 [PubMed . Aravind S. Martin A.:Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer. Bohlius J. J Natl Cancer Inst. :Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: A descriptive study of a large outpatient oncology practice database.as supplied by publisher] Miller CP. Urban N.Clin Exp Med.31P2:2416-2432. Liu X. http://www. Lowe KA. Schwarzer G. 2000-2007.:Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. 2009 Dec 2. 7.: CD003407. Crouch Z. Tjulandin S. 2009 Sep. Cochrane Database of Systematic Reviews 2012. Henke M. Engert A.htm Leyland-Jones B. Pawlicki M. Dodwell D.pdf PREPARE-Studie. No. Stem Cells.fda. Seidenfeld J. Issue 12. Crouch Z. 2009 Jul 1. Weingart O. Am J Health Syst Pharm.66(13):1180-5. Mattern D. Valliant-Saunders K. 2009 Oct 10. Baselga J.gov/drugsatfda_docs/label/2010/103234s5199lbl. Review. Art. 5. Makhson A.accessdata.CD003407. Grasso D. Mariucci S. 2. Tonia T.etin or darbepoetin for patients with cancer. Rovati B. 3.indexed for MEDLINE] Hershman DL. Semiglazov V. Malin J.1002/14651858.References: 1.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116830.indexed for MEDLINE] Manzoni M. 4. Voznyi E. Neugut AI. Maintaining normal hemoglobin . Valuckas K. Epub 2009 Nov 10. Clin Ther. Roth A. Robert N. DeSantis ER.

3.2010. American society of clinical oncology/american society of hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. 28: 4996–10 Aapro MS. J Clin Oncol 2010. Hurley P. Rizzo JD. Brouwers M. 2.23(25):5960-72 Relevant Guidelines: 1. J Oncol Pract.levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. Temin S. Aktualisierung 2012 in Vorbereitung Rodgers GM: Cancer. 2010 Nov.org 4. Oncologist 2008. Rizzo JD et al: ASCO/ASH/clinical practise guideline/epoetin and darbepoetin/adult patients with cancer.000132. NCCN Clinical Practice Guidelines in Oncology 2011 Available from: URL: http://www. Somerfield MR. J Clin Oncol. Seidenfeld J. 5.and chemotherapy-induced anemia. doi: 10. Link H: Update 09/2007/EORTC guidelines/anemia management/erythro-poiesisstimulating agents. . 2005 Sep 1.1200/JOP.nccn. 13 (suppl 3): 33–6.6(6):317-20.

Rizzo JD et al: ASCO/ASH/clinical practise guideline/epoetin and darbepoetin/adult patients with cancer. 28: 4996–10 .Practical Use of ESAs (5/22) Further information: For practical use refer to relevant practice guidelines The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient’s clinical circumstances and preferences. J Clin Oncol 2010. References: 1.

org Rizzo JD et al: ASCO/ASH/Clinical Practice Guideline update on the use of epoetin and darbepoetin in adult patients with cancer.and chemotherapy-induced anemia. 2. NCCN Clinical Practice Guidelines in Oncology 2013 Available from: URL: http://www.nccn. Rodgers GM und Gilieath JA: Cancer. 28: 4996–10 . J Clin Oncol 2010.Relevant guidelines (6/22) No further information References: 1.

that chemotherapy for solid tumors rarely leads to the mentioned conditions. The guideline encourages the use of myeloid growth factor prophylaxis to render antimicrobial prophylaxis unnecessary. or nutritional supplements are not recommended because evidence is lacking of clinical benefits to patients from their use . the consensus was that this evidence was not strong enough to recommend prophylaxis. Latest update: in the latest ASCO Guideline on Antimicrobial Prophylaxis and Outpatient Management… (2013) the use of antimicrobial prophylaxis is only recommended for patients expected to have 100 neutrophils/_L for 7 days.21. unless other factors increase risks for complications or mortality to similar levels. leading to an overall reduction in total infections. Recent evidence has demonstrated non-significant but consistent. An oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis. The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by the Australian Consensus Guidelines 2011 Steering Committee because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. respiratory or surgical masks. However. fluoroquinolone prophylaxis significantly reduced the incidence of Gram-negative infections by about 80% compared with those without prophylaxis (relative risk=0. 0. Barza M. Engels EA. J Clin Oncol 1998. antibiotic prophylaxis of asymptomatic patients under chemotherapy should be restricted to high risk cases: one selective criterion could be expected duration of neutropenia of greater than 10 days (NCCN). Interventions such as footwear exchange. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. The authors clearly state. neutropenic diet. Lau J.12-0. protected environments. 95% CI. (ASCO absolute neutrophil count < 100/µl > 7days) N.16:1179-1187: In a meta-analysis that evaluated 18 trials (N=1408) in which fluoroquinolones were compared to either placebo or TMP/SMX.Prophylaxis of Infection (7/22) Further information: According to relevant guidelines.37).: Standard chemotherapy protocols such as used in breast cancer patients do not regularly justify antibiotic prophylaxis. improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis.B.

I. Lau J. Australian Consensus Guidelines 2011 Steering Committee.16:1179-1187 Slavin MA. et. Christopher R.45. Kenneth V. Prophylactic antimicrobial agents and the importance of fitness. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. Engels EA. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. Amelia A. Clare Karten. 2. Relevant Guidelines Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. Menichetti F. Ramsey ASCO Practice Guideline „Antimicrobial Prophylaxis..References: 1. Rolston. Kieren A. al.1200/JCO. Barza M.45. Douglas K. Wei A.2012. Cain MJ.ascopubs. al. N Engl J Med2005.org/cgi/doi/10.353:1052-1054.8661 published ahead of Print on January 14. Langston.353:988-998. Use of antibacterial prophylaxis for patients with neutropenia. Jerome Seidenfeld. Cullen M. Billingham SN. 3. Micozzi A. Gaunt C. Charise Gleason. et. and Scott D. Ritchie DS. J Clin Oncol 1998. 4. N Engl J Med 2005. Eric J. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. Booth DL.“ 2013 The latest version is at http://jco. Intern Med J. Australian Consensus Guidelines 2011 Steering Committee. 5.1200/JCO.353:977-987..8661 . Nicole M. Thursky KA.41(1b):102-9. N Engl JMed 2005. Bucaneve G. 2013 as 10. Marr. Flowers. Hawley. Bow. Baden LR. 2011 Jan. Mileshkin L. Lingaratnam S.2012. Kuderer.

EORTC and ASCO G-CSF Guideline-Based FN Risk Assessment (8/22) No further information No references .

J Clin Oncol 31: 794-810. Flowers et al. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. 2013 .Relevant guidelines (9/22) No further information References 1.

Mucositis (10/22) Further information: „Mukositis kann als schwere und dosislimitierende Nebenwirkung bei Chemotherapie und Strahlentherapie von Malignomen auftreten.mascc. Außerdem stellt die Mukositis bei neutropenischen Patienten einen zusätzlichen Risikofaktor für eine Sepsis dar.“ References: Relevant Guidelines http://www. sondern sie beeinträchtigt auch erheblich die Lebensqualität der Patienten. Die Pathogenese der Mukositis ist nicht vollständig geklärt.org/assets/documents/MukositisGuidelinesMASCC2006(dtV). Diagnostik.pdf . In Ausprägungen von Grad III und IV gefährdet die Mukositis nicht nur das kurative Therapieziel durch möglicherweise notwendige Therapieverschiebungen oder Therapieabbrüche. die mit erhöhter Letalität verbunden ist. Therapie und Prophylaxe werden bisher nicht standardisiert durchgeführt und sind hauptsächlich auf die Symptomkontrolle ausgerichtet.

and all-cause and infection-related mortality during chemotherapy in patients with breast cancer. of a decrease of all-cause mortality during chemotherapy and a reduced need for hospital care. In clinical practice. CSFs have shown evidence of benefit in the prevention of FN. was as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. neutropenic events are the main limiting factors towards achieving this aim. a Cochrane review sought to assess the effect of prophylactic colony-stimulating factors (CSFs) in reducing the incidence and duration of FN. Without stringent management FN is associated with significant morbidity and mortality. is the most serious manifestation of neutropenia usually requiring hospitalization and intravenous antibiotics. The authors concluded that „In patients with breast cancer receiving chemotherapy. There is evidence. The primary use of recombinant granulocyte colony-stimulating factors has reduced the incidence of febrile neutropenia during dose-dense adjuvant/neoadjuvant chemotherapy programs for breast cancer. a novel glyco-pegylated granulocytecolony stimulating factor. No reliable evidence was found for a reduction of infection-related mortality. a higher dose intensity of chemotherapy with CSFs or diminished rates of severe neutropenia and infections.Granulocyte Colony-stimulatingy Factors (11/22) Further information: The ability to deliver the planned dose and intensity of chemotherapy (the amount of drug administered/unit of time) is important for tumor control and survival. . severe neutropenia accompanied by fever. so called „febrile neutropenia (FN)“. A recent study demonstrated in high risk breast cancer that 6 mg lipegfilgrastim. pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis. Furthermore. though less reliable. The majority of adverse events reported from CSF use were bone pain and injection-site reactions but no conclusions could be drawn regarding late-term side effects.“ In a comparative effectiveness study. In 2012.

Del Re M.as supplied by publisher] Khan S. Elaesser R. Silvestris N. . 2008 Jan. Bias P. Zwahlen M. Breast Cancer Res Treat. Danesi R. Buchner A.16 Suppl 2:S111-7. 2008 Nov. Roberts RD. Birkmann J.1517/14728222. Bencardino K. Deeter R. Badre S. doi: 10. Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized. BMC Cancer.Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Smith I. Maiello E. Sundar S. Becker L.1002/14651858. Henk HJ.1186/1471-2407-13-11.2011. Colucci G. Brunetti AE. 8. Issue 10. Epub 2012 Mar 23. Cochrane Database of Systematic Reviews 2012. 2009 Mar 1.: CD007913. 2012 Apr. Arnedos M. Mariucci S. Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines.References: 1. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients.CD007913.pub2. [Epub ahead of print] Naeim A. Grasso D. multicenter. Eur J Cancer Care (Engl). Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF). Delfanti S. Eubank TD. Curry JM. Epub 2007 Dec 1. 5. 2013 Aug 14. active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy. Guarini A. Cancer Res. 7. Tinelli C.112(1):1-4. Ashley S. doi: 10.:Chemotherapyinduced anemia in breast cancer patients treated with pegfilgrastim-supported dose-dense regimens. 4.Expert Opin Ther Targets. Bondarenko I. Pisconti S. Renner P. Epub 2009 Feb 17. Li X. Delcuratolo S.652089. Art. Chia V. Khan M.Clin Exp Med. Cinieri S. Manzoni M. Marsh CB. 6. Gladkov OA.69(5):2133-40. 2013 Jan 8. Horneber M. Nuovo GJ. Kuppusamy P. Danova M. Dhadda A.13:11.17(1):19-25. [Epub ahead of print]PMID: 19821012 [PubMed . 2. 3. Fyfe D. 2009 Oct 10. Sutherland S. DOI: 10. BMC Cancer. Rovati B. De Vita F. Liu JP. Lombardi L. Impact of neutropenia on delivering planned chemotherapy for solid tumours. Azzariti A.13(1):386. Milazzo S. Routine prophylactic granulocyte colony stimulating factor (GCSF) is not necessary with accelerated (dose dense) paclitaxel for early breast cancer. No.

Charles A. Scott B.de/download/ll_o_04. Donnelly JP. Rodger J. Charles L. Walewski J. Howard Ozer. Mark R. Gary H. 2011 Jan. Pizzo.pdf Lyman GH. European Organisation for Research and Treatment of Cancer. 2011. Scott J. Christopher E. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. and Antonio C. Eur J Cancer. Philip A. Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. Smith (Chair). James L.krebsgesellschaft. Lee Schwartzberg. Bohlius J. Bennett. Tjan-Heijnen VC. ASORS erstellt wurde.2012 Panel Members Myeloid Growth Factors. Wozniak.pdf . Cross. George Demetri.Relevant Guidelines: ASCO: Thomas J. Cancer Treat Res. James O. Schiffer. Pettengell R. http://www. Antoinette J. Winn. Kearney N. Lyman GH. Stimulation der Granulopoese mit G-CSF Kurzgefasste interdisziplinäre Leitlinie 2008 der Deutschen Krebsgesellschaft. Wade. Lodovico Balducci.org/professionals/physician_gls/pdf/myeloid_growth. Jeffrey Crawford. Kleiner JM. Armitage. George Somlo.nccn. James Khatcheressian. Cameron DA.47(1):832. die unter der Veranwortung der ASO bzw. Wolff 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline J Clin Oncol 24:3187-3205 NCCN: NCCN Guidelines Version 1. Zielinski C. Dal Lago L. James C. http://www.157:145-65. Lyman. Aapro MS. Desch. Weber DC. Wade. Cantor. Somerfield.

Myeloid Growth Factors. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors.Relevant guidelines (12/22) No further information References: 1. 2010 . 2. J Natl Compr Canc Netw:1266-1290. J Clin Oncol 24:3187-3205. Ann Oncol 21 (suppl 5): v248-v251. Crawford et al. Hematopoietic growth factors. 2006 Crawford et al. 3. 2013 Smith et al.

Karim M. Leibovici L. Witebsky FG. 2011 Oct 20. Paul M. 4. 2. 5. A Cochrane review sought to evaluate the safety and effectiveness of adding colony stimulating factors (CSF) to antibiotic therapy when treating febrile neutropenia caused by cancer chemotherapy. After inclusion of 13 studies the authors concluded. Lu C. Gill FA. Yahav D. 3. The authors looked for all randomized controlled trials (RCTs) that compare CSF plus antibiotics versus antibiotics alone for the treatment of established febrile neutropenia in adults and children. Khan WA. that „ the use of CSF in patients with febrile neutropenia due to cancer chemotherapy does not affect overall mortality. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta. It was not clear whether CSF has an effect on infection-related mortality. Sepkowitz KA. but no later than 2 hours after onset of fever. Talcott JA.29(30):3952-4. Siegel RD. et al. 2011 Oct 20. J Antimicrob Chemother 2006.“ References: 1. Godley PA. Robichaud KJ. Loggers ET. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia.J Clin Oncol No place like home? Outpatient management of patients with febrile neutropenia and low risk.Management of Febrile Neutropenia (13/22) Further information: The most important treatment aspect is to initiate calculated antibiotic treatment as soon as possible. ..57:176-189 Pizzo PA.analysis of randomized controlled trials. J Clin Oncol. but reduces the amount of time spent in hospital and the neutrophil recovery period. Yeap BY. according to updated guidelines. Clark JA. Am J Med 1995. Feasibility of outpatient management of fever in cancer patients with low-risk neutropenia: results of a prospective randomized trial. Malik IA.29(30):397783 Freifeld AG. Am J Med 1982. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial.72:101-111.98:224-231. Fraser A.

1002/14651858. Scott J. Somerfield. James L. Winn. Smith (Chair). Mark R. James C. Wade. Issue 4. George Demetri. Lyman G. Wade. Wozniak. Charles L. Cantor.: CD003039. Link et al: erstellt 04/07) .dgho-infektionen. James Khatcheressian.nccn. James O. Art. Pizzo. Ann Oncol 2010. Jeffrey Crawford. Christopher E. Wolff 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline J Clin Oncol 24:3187-3205 NCCN: NCCN Guidelines Version 1. Cochrane Database of Systematic Reviews 2000. and Antonio C. Lodovico Balducci.org/professionals/physician_gls/pdf/myeloid_growth. 7.V. Howard Ozer.6. Schiffer. Philip A. Ann Oncol 2010. No. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Bennett. et al. Colony stimulating factors for chemotherapy induced febrile neutropenia. Scott B. de Naurois J. Gary H.21(Suppl 5):v252-6 Clark OAC. Novitzky-Basso I. Rodger J.CD003039. Antoinette J. Armitage. Novitzky-Basso I. DOI: 10. Relevant Guidelines: ASCO: Thomas J. Gill MJ.2012 Panel Members Myeloid Growth Factors. Gill MJ. Cross. Charles A. Lee Schwartzberg. Djulbegovic B. Desch. . (DGHO) www. http://www.21(Suppl 5):v252-6 Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. George Somlo. Clark LGO. Lyman. et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines.de (H.pdf de Naurois J. Castro AA.

but no later than 2 hours after onset of fever.V. according to updated guidelines. Link et al: erstellt 04/07) . (DGHO) www.dgho-infektionen. References: Relevant practice guidelines: Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e.Calculated Antibiotic Therapy in FN (14/22) Further information: The most important treatment aspect is to initiate calculated antibiotic treatment as soon as possible. Recommendations need to be regularly updated according to the changes in microbial sensitivity and resistance towards antiinfective treatments.de (H.

cumulative dose-dependent cardiotoxicity is nevertheless a significant side effect of this therapy resulting in reduced cardiac reserve or even frank cardiac failure. Cardiac monitoring should continue in patients receiving doxorubicin.“ References: 1. Consider use with metastatic BC and other malignancies. or metastatic setting with initial doxorubicin-based chemotherapy.20 to 0. Importantly. particularly in the breast cancer setting. No evidence was found for a difference in response rate or survival between the dexrazoxane and control group.29.Dexrazoxane (15/22) Further information: Anthracyclines are among the most active chemotherapeutic agents in cancer treatment. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants.41). 95% CI 0. the monoclonal antibody trastuzumab. Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting. The meta-analysis of dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) 0. A great number of studies review and discusses the relationship of cardiotoxicity and anthracycline use. both in the metastatic as well as in the adjuvant breast cancer setting. for patients who have received more than 300 mg/m(2) doxorubicin who may benefit from continued doxorubicin-containing therapy. . and explores available treatment options for the anthracycline-treated patients based on evidence from recent Phase III trials. Although infrequent. Although used in several types of malignancy. anthracyclines are most commonly used in breast cancer treatment. A Cochrane review investigated Cardioprotective interventions for cancer patients receiving anthracyclines and concluded: …“The nine included studies of dexrazoxane enrolled 1403 patients. Only for one adverse effect (abnormal white blood cell count at nadir) a difference in favour of the control group was identified. recent advances have also seen the increasing use of another cardiotoxic agent.

Epub 2008 Dec 20. 5. Miglietta L. Eidtmann H. Giaccone G. Cochrane Database Syst Rev. Wasserman TH. Giaretto L. Jones RL. Oncologist. Thigpen JT. Ceste M. 2008 Apr.112 Suppl 1:53-66. Emami B. 7. Testore F. Mouridsen HT. 8. Cohen GI.8(4):257-63 van Dalen EC. Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity. 2008 Nov. Hensley ML. Rasmussen A. 2008. Ferrero G. Knoblauch P. Mitchell RB. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.13(4):445-50. Parello G.27(1):127-45. 2007 Mar. Milanese S. Schuchter LM. Caron HN. Hagerty KL.18(3):546-50. Epub 2006 Dec . Gligorov J. J Clin Oncol. Lotz JP. Bosso G. Am J Cardiovasc Drugs. Kane RC. Green DM. Cardioprotective interventions for cancer patients receiving anthracyclines. Kremer LC. Manfredi R.2. Ann Oncol. Langer SW. McGuinn WD Jr. Epub 2008 Nov 17. Dagher R.6(10):1311-7. 3. 2008 Apr 16. Dickinson HO. Gradishar WJ. Buter J. 2009 Jan 1. 6. Lanfranco C.(2):CD003917. 2008 Dec. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. Dahlstrøm K. Rosti G. Optimal treatment strategies in postmenopausal women with hormone-receptor-positive and HER2-negative metastatic breast cancer. de Conciliis E. Ferro S. Cardioprotective effect of dexrazoxane in patients with breast cancer treated with anthracyclines in adjuvant setting: a 10-year single institution experience. de Wit M. Breast Cancer Res Treat. Pazdur R. von Hoff D. 4. Kewalramani T. Justice R. Jensen PB. Trotti A 3rd. Meropol NJ. Expert Rev Cardiovasc Ther. Simoni C.

Regine Mayer-Steinacker. Diagnostik und Therapie der zytostatikaassoziierten Paravasation . .Empfehlungen zu Diagnose.Was tun wenn‘s brennt? Im Focus Onkologie 2010.de/e974/e2538/e3782/e3494/ASORS_AV_Paravasate-Guidelines_04-2010. Karin Jordan download: http://www. Hans-Peter Lipp.onkosupport.Paravasation Dexrazoxane (16/22) Further information: Although indicated and approved for cardioprotection. dexrazoxane has been suggested as being helpful in the case of anthracyclin paravasation. References: Relevant practice guideline Zytostatika-induzierte Paravasate . The agent is administered systemically. Carsten Bokemeyer. Prophylaxe und Therapie [ PDF-Datei ] Arbeitsversion der ASORS Paravasate-Guidelines (Stand April 2010) Maike de Wit. Michael Untch. Jalid Sehouli. Markus Ruhnke.6:50-55. de Wit M. Petra Ortner.pdf Witte J. Prävention.

mascc. In patients with breast cancer treated with anthracycline plus cyclophosphamide chemotherapy and receiving the same antiemetic prophylaxis for acute emesis.org . nausea and vomiting induced by chemotherapy was an almost neglected research area. research was stimulated and has now resulted in the development of two new classes of antiemetics. a particular interest in initiating trials to investigate agents with potential anti-nausea effect. References: 1. dexamethasone was not superior to aprepitant but instead had similar efficacy and toxicity in preventing delayed emesis. Until the late 1970s. such as olanzapine. therefore. In a subsequent trial. single-dose intravenous fosaprepitant (150 mg) given with ondansetron and dexamethasone was noninferior to standard 3-day oral aprepitant in preventing CINV during OP and DP. but are less effective in the prevention of nausea. are updated every 6 months (as new data arise). dexamethasone and aprepitant is able to protect 66–78% of patients from emesis and 48– 49% from nausea during the first cycle of cisplatin-based chemotherapy. To encourage implementation. www. New antiemetics have been highly successful in the prophylaxis of emesis. Guidelines such as the MASCC antiemetic guidelines are only useful if they are continuously updated and implemented in the daily clinic. and are always accessible on the MASCC website. The combination of ondansetron. A large number of trials have fine-tuned antiemetic therapy and made evidence-based recommendations possible for the majority of patients receiving chemotherapy. There is. In women receiving cyclophosphamide/anthracycline-based chemotherapy for breast cancer. With the introduction of cisplatin. the corresponding figures are 76% and 33%. the serotonin and neurokinin antagonists. the MASCC guidelines have been translated into several languages. A systematic Review summarizes recommendations from the evidence-based guidelines developed by the Multinational Association of Supportive Care in Cancer (MASCC).Antiemetic Therapy (17/22) Further information: Nausea and vomiting are two of the most severe problems for patients treated with chemotherapy. the cytotoxin with the highest emetic potential.

Horgan KJ.97(12):3090-8. Caldwell KC. Tjulandin SA. Navari RM. [Epub ahead of print Grunberg SM. Younger J. Results from a randomized. Evans JK. Aprepitant Protocol 052 Study Group. Grunberg SM. 7. Keith B. de Wit R. Reines S. Krentzin M. Carides AD. for antiemetic efficacy in high-dose cisplatin treatment. Hesketh AM. double-blind. Dessì M. Aprepitant Protocol 054 Study Group. Yunus F. Support Care Cancer. placebo-controlled trial in Latin America. Warr DG. Epub 2006 Jun 9. Siebel M. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Trainor B. 2008 Aug 23. 3. Astara G. J Clin Oncol. Chang AY. Bertoli LF. double-blind. Ianus J. randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. (2006) Comparison of an aprepitant regimen with a multiple-day ondansetron regimen. Ann Oncol.8:84 Hesketh PJ. Whaley W. Lordick F. Wood M. Julie Ma G. Olivares G. Mantovani G. Morrica B. Macciocchi A. Tchekmedyian NS. Beck K. placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. . Ann Oncol 17: 4112–4119 Hesketh PJ. 8. 2003 Nov 15.:Oral ondansetron for the control of cisplatin-induced delayed emesis: a large. Bushey J. Madeddu C. Lepori S. Chawla SP. 2008 Dec 6. [Epub ahead of print] Aapro MS. 9. Arnaoutakis K. Hipple A. Weisberg T.17(9):1441-9. Massa E. A phase III. Grunberg SM.2. Crit Rev Oncol Hematol. Evans JK. Eldridge K. Lawson F. Roila F. Suarez T. et al. Support Care Cancer. Gralla RJ. randomized. doubleblind. Hayden M. 2008 Nov 27. 2006 Sep. Aprepitant as salvage antiemetic therapy in breast cancer patients receiving doxorubicin and cyclophosphamide. Palonosetron plus dexamethasone effectively prevents acute and delayed chemotherapy-induced nausea and vomiting following highly or moderately emetogenic chemotherapy in pre-treated patients who have failed to respond to a previous antiemetic treatment: Comparison between elderly and non-elderly patient response. 6. Garewal H. Horgan KJ. Madajewicz S. 4. 5. and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Anderson N. Nowd P. Beck TM. Effectiveness of a singleday three-drug regimen of dexamethasone. Cancer. Greenberg B. Muss H. palonosetron. :Systematic review of the clinical effect of glycocorticoids on nonhematolic malignancy BMC Cancer (2008). Loi C. Rodrigues-Pereira J. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational. Elmer ME.21(22):4112-9. both with dexamethasone. Sanz-Altamira P. [Epub ahead of print] Schmoll HJ et al. Epub 2003 Oct 14 Poli-Bigelli S. Burdette-Radoux S. Manikhas GM. 2003 Jun 15. Carides AD. Dugan M.

2013. multicenter. Roila F. double-blind study comparing placebo. Grunberg S. Rittenberg C. Wilkinson JR A multicentre. Paska W. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized. Siler D. Kirkegaard S. double-blind. Tonato M. DeVandry S. McQuade B. J Clin Oncol. Tonato M. . Antiemesis. 2011 Mar. Barbour SY. National Comprehensive Cancer Network. Chua D. randomized comparative trial of ondansetron versus placebo. Herrstedt J. Saito M. 2012 Apr.org/antiemetic-guidelines Antiemetische Prophylaxe gemäß MASCC.10(4):493-9. Stelts S. 14. Relevant Guidelines http://www. Ballatori E.10. die unter der Veranwortung der ASO bzw. Bradbury B.4547. Seitz JF. Roila F. Todaro B. Barbour S. Bria E. Epub 2013 Dec 9. Sorscher SM.2010. Espersen B. Kris MG.1200/JCO.32(2):101-6. Berger MJ.1200/JCO. 2012 Apr. McRae J. Hardwick JS.13(9):2408-16. Ruggeri B. Del Favero A.31. Michaud LB. Taylor A.und ASCO-Guidelines [ PDF-Datei (auf www. Herrstedt J. Ann Oncol. Ballatori E. doi: 10. Carides A. J Clin Oncol. double-blind study protocol--EASE. Goedhals L. 1996 Nov. Nabati L. J Natl Compr Canc Netw. 2014 Jan 10. Ondansetron Delayed Emesis Study Group. Morrow G. Support Care Cancer. Stucky-Marshall L. Bierman PJ.7859. Boice JA. Epub 2011 Mar 7. Urba SG.10(4):456-85. 1995 Sep. Lim D. Hesketh P. 15.19 Suppl 1:S25-32. ASORS erstellt wurde. 12. Noonan K. Kloth DD. Armstrong DK. J Clin Oncol. Einhorn LH. ondansetron and ondansetron plus dexamethasone for the control of cisplatininduced delayed emesis. Corticosteroids in the treatment of chemotherapy-induced nausea and vomiting.51. Olver I. 2011 Apr 10. Rugo HS.29(11):1495501. Ellis G. doi: 10.7(9):945-52 Kris MG. Ettinger DS. Dinis J.krebsgesellschaft. Beckford E. Stewart DJ. Consensus recommendations for the prevention of vomiting and nausea following highemetic-risk chemotherapy. J Natl Compr Canc Netw. Grunberg S. 11. Aprepitant versus dexamethasone for preventing chemotherapy-induced delayed emesis in patients with breast cancer: a randomized double-blind study.de) ] Kurzgefasste interdisziplinäre Leitlinie 2008 der Deutschen Krebsgesellschaft. Depierre A. 13. Maru A.mascc.

Prestrud AA. J Oncol Pract. 2011 Nov. Kris MG. . Temin S.7(6):395-8.Basch E. Lyman GH. Antiemetics: american society of clinical oncology clinical practice guideline update. Hesketh PJ.

Supportive Therapie: Antiemetics (18/22) No further information No references .

dgss.Analgesia (19/22) No further information References: Relevant guidelines Deutsche Gesellschaft zum Studium des Schmerzes.pdf . www.krebsgesellschaft.de/download/ll_n_02.org Schmerztherapie bei Tumorerkrankungen http://www.

2.. Wieland Voigt. 2010 January. frequency and guideline-based management Ther Adv Med Oncol. Catalano. A.. J.B. Ajani. Benson 3rd.A.Diarrhea (20/22) No further information References: Relevant Guidelines 1. R. Alexander Stein.. J. (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22: 2918–2926. Karin Jordan Chemotherapy-induced diarrhea: pathophysiology. Kornblau.A. Engelking. . Martenson Jr. 2(1): 51–63.. C.. et al.B. S.M.

relief of abdominal pain and the need for additional products. the use of parenteral methylnaltrexone for the management of constipation in palliative care patients was evaluated. Subcutaneous methylnaltrexone. except for relief of abdominal pain. Opioid therapy usually results in constipation and regular digestion should always be aimed at. when indoor heating begins and air humidity is consequentially reduced. Sufficient fluid uptake should be encountered by treating health care providers. form of stool. this is seen in both adults and children. On subgroup analysis.“ References: 1. an opioid-receptor antagonist. Polyethylene Glycol should be used in preference to Lactulose in the treatment of Chronic Constipation. The authors concluded. 6: 77–82. 2010. Eberhard Klaschik Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide Ther Clin Risk Manag.Constipation (21/22) Further information: Constipation is not infrequently encountered during chemotherapy. that „The findings of our work indicate that Polyethylene glycol is better than lactulose in outcomes of stool frequency per week. However.“ More recently. rigorous. the safety of this product is not fully evaluated. A Cochrane meta-analysis investigated differential efficacy of different agents. Particularly around the time in autumn and winter. . Katri Elina Clemens. that „Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioidinduced constipation and where conventional laxatives have failed. is now licensed for the treatment of opioidinduced constipation in palliative care when response to usual laxative therapy is insufficient. Large. the authors concluded. independent trials are needed.

Lactulose versus Polyethylene Glycol for Chronic Constipation. Drake R. Gootjes JR. 3. Issue 7. Zucco F. 4. European Consensus Group on Constipation in Palliative Care. Candy B. Thomas K. Issue 1. 2008 Oct. Ripamonti C. Zuurmond WW. Centeno C.2. Eugene B. Palliat Med. Goodman ML. Morgan J. Cochrane Database of Systematic Reviews 2010. Larkin PJ. Noguera A. . Nabal M. Jones L. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. The management of constipation in palliative care: clinical practice recommendations. Ellershaw JE. Elsner F. Nelson RL. Cochrane Database of Systematic Reviews 2011.22(7):796-807. Tookman A. Sykes NP. Lee-Robichaud H.

Palliative Care (22/22) Further information Growing evidence and and increasing awareness in international recommendations underlines the relevance of combined standard oncology care and palliative care. including effective control of pain and other symptoms. J Clin Oncol 30 880-887. Smith et al. Cardoso et al. J Natl Compr Canc Netw 10:1284-1309. It is evident that the access to palliative care. is important in the treatment of metastatic breast cancer patients. This should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden. References: 1. 2012 2. Breast 21:242-252. Levy et al. 2012 3. 2012 .

V. Guidelines Breast Version 2015.V.Diagnosis And Treatment Of Patients With Primary And Metastatic Breast Cancer © AGO e.1 Breast Cancer: Specific Situations . in der DGGG e. sowie in der DKG e.V.

1 www. in der DGGG e. Guidelines Breast Version 2015.ago-online. V.V. sowie in der DKG e.V.de  Versions 2005-2014: Dall / Fehm / Fersis / Friedrich / Gerber / Göhring / Harbeck / Huober / Janni / Loibl / Lück / Lux / Maass / Mundhenke / Oberhoff / Rody / Scharl / Schneeweiss  Version 2015: Solomayer / Harbeck .Breast Cancer: Specific Situations © AGO e.

de . Guidelines Breast Version 2015.V. in der DGGG e.1  Young patients  Pregnancy-associated BC  Elderly patients  Male patients  Inflammatory BC  Occult Primary [Carcinoma of unknown primary (CUP)]  Paget´s disease  Malignant Phyllodes Tumor  Sarcomas www. sowie in der DKG e.Breast Cancer: Specific Situations © AGO e.ago-online. V.V.

ago-online. in der DGGG e.1 www. V.V. Guidelines Breast Version 2015.de  Aggressive biological behavior 2a B  Benefit from chemotherapy 1b A ++  Benefit from endocrine therapy 1b A ++  Endocrine therapy (TAM). sowie in der DKG e.V.Breast Cancer in Young Women ≤ 35 Years © AGO Oxford / AGO LoE / GR e. if possible 5-10 y 1b B ++  Benefit from HER2 targeted therapy 2b B ++  Benefit from CT induced temporary amenorrhoea 2b B +/-  GnRHa as ovarian protection 2 weeks prior to CT 1b B +/-  Surgery like ≥ 35 y (in particular BCT) 2b B +  Stage II–III benefit from PMRT 2b C +  Genetic and fertility counseling 2b B ++ .

chest X-ray if indicated 5 D +/-  Surgery like in non-pregnant patients 4 C ++  Sentinel node excision (technetium only) 4 C + SNE during 1st trimester 5 D +/- Sensitivity and specificity not established (during lactation). V.V.de  * Participation in register study recommended . Guidelines Breast Version 2015.V.Breast Cancer During Pregnancy* or Breast Feeding © AGO Oxford / AGO LoE / GR e. breast feeding should be avoided for 24 hrs 4 C ++ Blue dye (has not been tested in pregnant animals or humans) 4 C --  www.ago-online.1  Breast imaging & biopsy like in non-pregnant 4 C ++  Staging: ultrasound. in der DGGG e. sowie in der DKG e.

1   www.V. V.Breast Cancer During Pregnancy* © AGO Oxford / AGO e. sowie in der DKG e. LoE / GR Guidelines Breast Version 2015. CMF)  Endocrine treatment HER2-neu targeted treatment Bisphosphonates 4 2b 2b 4 4 3a 4 C - B B D D C D ++ ++ + ---- * Participation in register study recommended .ago-online.de   Radiation therapy during pregnancy (Neo-)adjuvant chemotherapy only after first trimester (indication as in non-pregnant)  Anthracyclines: AC.V. EC  Taxanes  MTX (e. in der DGGG e.g.

de  Delivery should be postponed until sufficient fetal maturation (avoid iatrogenic prematurity) 2b Termination of pregnancy does not improve maternal outcome 3b Delivery mode like in healthy women. in der DGGG e. breast feeding may be contraindicated depending on drug toxicities 5 C ++ C C ++ D ++ * Participation in register study recommended .ago-online. 4 avoid delivery 3 weeks from prior chemotherapy If further systemic therapy is needed after delivery.V.1    www.Breast Cancer During Pregnancy* © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015.V. sowie in der DKG e. V.

V. in der DGGG e. V.de  Outcome not compromized 3a * Participation in register study recommended .1 LoE BC during pregnancy / lactation  Adequate treatment is essential 3a Pregnancy and lactation after BC www.ago-online. Oxford Guidelines Breast Version 2015.Pregnancy Associated Breast Cancer*: Outcome © AGO e. sowie in der DKG e.V.

that are measured). mental. etc. and psycho-social health Basic activities of daily living (dressing.V. good predictor over a 10year period) 12 prognostic indicators to estimate 4-year mortality risk Short screening tests (more qualitative evaluation) IADL (IADL = The Lawton Instrumental Activities of Daily Living Scale with 8 domains of function. V. bathing. access to support services Assessment tools:     Charlson Comorbidity Index (widely used.ago-online. G8 .V. Guidelines Breast Version 2015.de  Physical. social network. medication management.Geriatric Assessment © AGO e.1    No specific algorithm is available Ability to tolerate treatment varies greatly („functional reserve“) Comprehensive geriatric assessment (CGA) describes a multidisciplinary evaluation of independent predictors of morbidity and mortality for older individuals    www. meal preparation.) Living arrangements. sowie in der DKG e. in der DGGG e.

Guidelines Breast Version 2015.1  Clinical geriatric assessment 2b B ++  Treatment according to standard 2a C ++  Surgery similar to „younger“ age 2b B ++  Endocrine treatment (endocrine resp.de  < 70 years 1a A +  > 70 years (especially N+. hormone receptor positive and if endocrine therapy is planned (CAVE: increased risk local recurrence) .V.Treatment for Fit Elderly Patients (Life Expectancy > 5 yrs. in der DGGG e.ago-online. V. and Acceptable Comorbidities) © AGO Oxford / AGO LoE / GR e.V.) 1a A ++  Chemotherapy (standard regimens) www. sowie in der DKG e. ER/PgR-) 2a C +*  Radiotherapy 1a A +  Omit Radiotherapy after BCT in low risk 1b B + 2b C + with endocrine treatment**  Trastuzumab *Study participation recommended **Population > 70 y.

Rec pos) 1b  Hypofractionated radiotherapy 2b C +  No chemotherapy if >70 years and negative 2b C risk-benefit analysis +  www.ago-online. in der DGGG e. cN0. Substantial Comorbidities) © AGO Oxford / AGO LoE / GR e.de 2b C B ++ .1  Reduced standard treatment  Options extrapolated from trials in elderly: ++ No breast surgery (consider endocrine options) 2b C +  No axillary clearing (≥ 60 y. sowie in der DKG e. V. pN0.V. Rec pos) 2b B +  No radiotherapy ( ≥ 65 y.Treatment for Frail Patients (Life Expectancy <5 yrs. Guidelines Breast Version 2015. pT1.V.

V.V. sowie in der DKG e.de Diagnostic work-up as in women  Mammography  Ultrasound Standard-surgery: Mastectomy  C C B C + +/++ ++* C +*  BCT my be an option (tumor breast relation) 4  Sentinel-node excision (SNE) 2b B + 4 + Radiotherapy as in women (consider tumor breast relation!)  4 3b 2b 4 Genetic counselling if one additional relative affected (breast/ovarian cancer) Screening for 2nd malignancies according to guidelines C 2b B ++ GCP ++ *Participation in register study recommended .1    www. V.ago-online.Male Breast Cancer: Diagnostic Work-Up and Loco-Regional Therapy © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015. in der DGGG e.

V.Aromatase inhibitors (metastatic BC) 4 C +/- .Fulvestrant (metastatic BC) 4 C +/- 4 C ++ www.de  Palliative chemotherapy as in women *Participation in register study recommended .GnRHa and AI (metastatic BC) 4 C +* . in der DGGG e.V.ago-online.Male Breast Cancer: Systemic Therapy © AGO Oxford / AGO LoE / GR e. sowie in der DKG e.Aromatase inhibitors (adjuvant) 2b B -* .Tamoxifen 2b B ++ . Guidelines Breast Version 2015.V.1  Adjuvant chemotherapy as in women 2a B ++  HER2 targeted therapy 5 D +*  Endocrine therapy 4 D ++ .

in der DGGG e.1    www.addition of bevacizumab Mastectomy after chemotherapy  Breast conserving therapy in case of pCR  Sentinel excision only Radiotherapy Postoperative systemic therapy as in non-inflammatory BC Oxford / AGO LOE / GR 2c 2c 2c B B B ++ ++ + ++ 2b 2b B B ++ ++ 2b 2b 2c 2b 3b 2c B C B C C B + +/++ +/-++ 4 C ++ .g.V.V. detection rate < 75%) Preoperative chemotherapy  Regimens as in non-inflammatory BC  Anthracycline and taxane-based  In HER2 + disease.ago-online. V. cT4d) © AGO e. sowie in der DKG e. addition of trastuzumab and pertuzumab  In Her2 . addition of trastuzumab  In HER2 + disease. ≥ 1/3 of the breast affected) determine stage cT4d Staging Skin punch biopsy (at least 2.Primary Inflammatory Breast Cancer (IBC.de    In case of invasive BC and clinical signs of inflammation (e.  Guidelines Breast Version 2015.

V.ago-online.Axillary Metastasis in Carcinoma of Unknown Primary (CUP) © AGO Oxford / AGO LOE / GR e. V. Guidelines Breast Version 2015.g. HER2 5 D ++  Axillary dissection 3a C ++  Systemic treatment according N+ tumor 3a C ++  Mastectomy if breast MRI is negative 3a C -  Breast irradiation if breast MRI is negative 3b C +/-  Irradiation of regional lymph nodes according to breast cancer guidelines 3b B + . sowie in der DKG e. ENT investigation) 3 B ++  PET / PET-CT 3b B +/-  Gene expression profiling (e. in der DGGG e.V. thyroid sonography.1 www. PgR. CupPrint™) 2c B +/-  ER.de  Mammography / Breast ultrasound 3 B ++  Breast MRI 3 B ++  Staging (CT thorax / abdomen.

Paget´s Disease of the Breast © AGO Oxford / AGO LOE / GR e. sonography ++  4 D ++ 4 C + 5 D ++ 1c B 2b B ++ + Isolated Paget´s disease of the NAC:  Surgery must achieve R0 1c B  Surgical resection only.1 Histological verification  Mammography. V.V. invasive breast cancer. sowie in der DKG e. DCIS)  Therapy according to standard of the underlying disease Surgery must achieve R0  Wide excision (like DCIS) + radiotherapy  www. Guidelines Breast Version 2015. no adjuvant radiotherapy 4 D  Sentinel-node excision (SNE) 2b B ++ ++ -   MR of the breast if other imaging negative Paget´s disease with underlying disease (e.V. in der DGGG e.de  .g.ago-online.

ago-online.1      Complete (wide) local excision or MRM SNE / Axillary dissection in cN0 Staging Systemic adjuvant therapy (chemo. V. sowie in der DKG e.de   If T ≥ 2 cm (BCT) or T ≥ 10 cm (mastectomy) 2b 4 5 4 4 2b B C D C C C ++ -+/--+/- 4 4 C C ++ +/- 4 C ++ Treatment of local recurrence  R0 resection  Radiotherapy. in der DGGG e. chemotherapy after R1 resection Distant metastases (very rare)  Treatment like soft tissue sarcomas .V.V.Malignant and Borderline Phylloides Tumor © AGO Oxford / AGO LOE / GR e. endocrine) Adjuvant radiotherapy  www. Guidelines Breast Version 2015.

sowie in der DKG e.V. V. grade.ago-online.Sarcoma / Angiosarcoma of the Breast (Note: very aggressive!) © AGO e.V. Guidelines Breast Version 2015. Sonography to determine extent of disease  Preoperative MRI to determine extent of disease  Diagnosis by core biopsy  Diagnosis by FNB  Staging  Prognostic factors: size.de Oxford / AGO LOE / GR Adjuvant chemotherapy (anthracycline-based). size > 5 cm. radiotherapy  www. radiotherapy in case of high risk (grade II-III.1 Treatment of Primary Disease:  Mammography. chemotherapy after R1 resection 4 4 C C ++ +/- Distant Metastases / Unresectable Tumors:  Treatment like soft tissue sarcomas  Paclitaxel weekly / liposomal doxorubicin (in angiosarcoma)  Antiangiogenic treatment  Trabectidin (after anthracycline/ ifosfamide failure in leiomyosarcoma) 4 2b 4 2b C B C B ++ + +/+    Breast-conserving therapy if feasible Axillary dissection if cN0 Adjuvant chemotherapy. margins  Surgery with wide clear margins 3a 3a 3a 3a 4 3a 3a 3a 3a 3a C C C C D C C C C C -++ ++ -++ ++ ++ +/+/- 4 C +/- Treatment of Local Recurrence:  R0 resection  Radiotherapy. in der DGGG e. R1) .

Reviews Screened guidelines: .org/professionals/physician_gls/PDF/breast. No references . Meta-Analysis. ASCO 2005 – 2014. Randomized Controlled Trial.nccn.pdf This chapter of rare diseases cannot deliver references for every statements separately but is providing them where possible.NCCN: http://www. ECCO/ESMO (2005 – 2014). SABCS 2005 – 2014. Cochrane data base (2012). Practice Guideline. EBCC (2005 – 2014). Screened for: Clinical Trials.Breast Cancer: Specific Situations (2/18) Further information: Update January 2015 – Solomayer / Harbeck Update January 2014 – Fehm/Schneeweiss Update January 2013 – Fersis/Friedrich Update January 2012 – Lux/Lück Update Februar 2011 – Janni/Huober Update Januar 2010 – Mundhenke/Rody Screened data bases: Pubmed 2000 – 2014.

Breast cancer: Specific situations (3/18) No further information No references .

Pagani O. Cardoso F. It could be demonstrated that therapy induced amenorrhea might be of some benefit in premenopausal women but if this is especially true for pts<35 years has not been proven. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. Abulkhair O. Harbeck N. First international consensus guidelines for breast cancer in young women (BCY1). References: International Guidelines: There is now a bi-annual International Consensus Conference on Breast Cancer in Young women (BCY): 1. Radiotherapy seems to deliver additional benefit. Peccatori F. the FERTIPROTECT Project is a platform to gain information how and where to get information. Pagani O. 2012 Dec. Kelly CM. Meirow D. 2014 Jun.or endocrine therapy. 2. Kotti-Kitromilidou AM. Delaloge S.Breast Cancer in Young Women ≤ 35 years (4/18) Further information: Breast cancer in young women is rare and probably a specific entity of high risk for recurrence. Gentilini O. Graziottin A. Panizza P. Martincich L. Treatment with tamoxifen of up to ten years is beneficial. Penault-Llorca F. Therefore chemotherapy is almost always indicated. Costa A. Fourquet A. Harbeck N. Marotti L. Cardoso F. Eur J Cancer. Peccatori F. Aebi S. Delaloge S.48(18):3355-77 . Partridge AH. Kaufmann B. Azim HA Jr. European Society of Breast Cancer Specialists. Rodger A.23(3):209-20. Counselling for fertility protection should be offered and the patient needs to be informed about the possibility of compromised ovarian function due to adjuvant chemo. Freilich G. Breast. Gentilini OD. Loibl S. Loibl S. In Germany. Amant F.

2. Anders CK. De Laurentiis et al. 14: 594-599 (Review) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). J Clin Oncol 2008. J Natl Compr Canc Netw. 2000 Feb 19. Partridge et al. Zhang Y.41(10):1446-52. Foekens JA. Breast cancer in adolescents and young adults: a review with a focus on biology. 2013.Prognosis in young women 1. Women age < or = 35 years with primary breast carcinoma: Disease features at presentation. Strom EA. Eur J Cancer 2005. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. Acharya CR.26:3324-30. 7. Kroman N. Hsu DS. 2013. Chemotherapy in young women 1. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Natl Compr Canc Netw.320(7233):474-8.. 4. 3. Cancer 2005. . Schechter NR. Survival of young and older breast cancer patients in Geneva from 1990 to 2001. 5. J Clin Oncol 2008. Outlaw ED. Broadwater G. Oh JL.44–53. Tichy JR et al. 2013. Gonzalez-Angulo AM et al.11(9):1060-9. 8(5): e105–e110. Aebi S. et al . Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ. et al. Lancet 2005. 3.26 (1).11(9):1060-9.103: 2466-2472 Rapiti E.22 Suppl 2:S176-9. 8. Model Program to Improve Care for a Unique Cancer Population: Young Women With Breast Cancer J Oncol Pract. Management of breast cancer in very young women. The impact of young age on locooregional recurrence after doxorubicin-based breast conservation therapy in patients 40 years old or younger: How young is "young"? Int J Radiat Oncol Biol Phys 2006.65:1345-52. et al . Breast. Perkins GH. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Breast 2005. Bonnen M. Special issues related to the adjuvant therapy in very young women. 2. Freedman RA et al. Ann H. 2012.365: 1687–1717 M. et al. 6.

Partridge et al. J Clin Oncol 2013. 2007. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Effect of Luteinizing Hormone-Releasing Hormone Agonist on ovarian function after adjuvant breast cancer chemotherapy: by the GBG 37 ZORO study. LHRH-agonists in Early Breast Cancer Overview group Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Sainsbury R. Kaufmann M. 2.4. The effect of age on breast cancer outcomes in women with her-2 positive breast cancer: results from the HERA trial J Clin Oncol 2013. Davidson N.381. Lancet 2013.99:516–525 .953 women with early breast cancer. 31(suppl): abstr 5 Benefit from trastuzumab 1. 2. Ambroisine L. 2010.124:133–140. Davies et al. 2007. Smith I.2692–2698 Benefit from temporary amenorrhoea after adjuvant chemotherapy (chemotherapy induced or GnRHa-related) 1. C. Clin Oncol 2011.29 (17) 2334-2341 Adjuvant Breast Cancer Trials Collaborative Group.360 (7) 679–691 Gerber B et al. Jakesz R. Regan M. N Engl J Med 2009. Cuzick J. Huober J et al.44.805–816 Gray RG. Endocrine therapy in young women 1.369(9574):1711-23. Gnant et al. a randomised trial. HERA study team: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.369(9555):29-36 A.H. Breast Cancer Res Treat. J. Lancet. M. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial J Natl Cancer Inst 2007 . 3. 2. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS. et al. 3.Lancet.

Costantino. Kim M. et al. S. Lee JH. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage. 6. Lee JE.in particular BCT) 1. Impact of radiation dose on local control.69(5):1478-83. Bratta M. Albain KS. Porter DJ. Kim J. fibrosis and survival after breast conserving treatment: 10 year results of the EORTC trial 22881-10882. J. Hitre E. Minasian LM. Int J Oncol. N Engl J Med 2010 . Cancer Treat Rev 2013 in press Yang B et al.. Meyskens FL. Gomez HL. Ovarian function preservation with GnRH agonist in young breast cancer patients: does it impede the effect of adjuvant chemotherapy? Breast.M. Swain. Int J Radiat Oncol Biol Phys. Recchia F. Geyer Jr.P. Francis PA. Rosselli M. C.46(3):1354-60. ECOG. Boyle FM. de Bock GH et al. Barlow WE. Gelber RD. 5. 2015 Mar. Lee H. Fehrenbacher et al. . Phillips KA.2053–2065 Del Mastro L et al.100:S8-10]. Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy. Kim SW. J. Moore HCF. Nam SJ. Pajon. Eur J Cancer 2005. J Clin Oncol 32:5s. 2014 Oct. 25. 9. and survival in early breast cancer. Fabian CJ. Long-term results of European Organisation for Research and Treatment of Cancer Studies. iatrogenic amenorrhea.R. Lee SK. abstr LBA505) Surgery in young women (Surgery like ≥ 35y . LH-RH analogues in the treatment of young women with early breast cancer: Long-term follow-up of a phase II study. Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials Breast 2013. Br Cancer Res Treat 2006. 2014 (suppl. Necozione S. Longer therapy. Martino S. Kil WH.23(5):670-5. Partridge AH. 7. E. Poortmans PM. (362). Guerriero G. – Radiation boost therapy can reduce in-breast recurrence [Bartelink H. Struikmans H. 2007 Dec 1. 2. Jeong.. Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy.22(2):150-7. IBCSG.4.E. and CALGB (Alliance). Jun SY. Rea S. hormone receptor-negative breast cancer: An international Intergroup trial of SWOG. Dakhil SR. Horiot JC. Unger JM. 8. Garg AK et al. Goldstein LJ.H. Vallejos C. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: Systematic review and meta-analysis of randomized trials. Bae SY. L. Hortobagyi GN.

Peppercorn J. J Clin Oncol. Cao JQ et al. Schapira L. 2009 Dec. 8. Review. Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer. et al.20(6):e593-e601. Tamimi RM. Curr Treat Options Oncol. Jeruss JS. Clin Breast Cancer 2008. Przypyszny M. Gelber S.2012. Ruddy KJ. Menopause. Genetic and fertility counselling 1. Sampson E.17(3):162-72. 2010 Jul. Effect of Luteinizing Hormone-Releasing Hormone Agonist on ovarian function after adjuvant breast cancer chemotherapy: by the GBG 37 ZORO study. Rosenberg R.10(5-6):308-17. Maintaining fertility in young women with breast cancer. 2013. 2011. Clin Oncol 29 (17) 2334-2341 2011 Del Mastro L et al:Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the occurrence of chemotherapy-induced early meopause in premenopausal women with brest cancer JAMA 306 (3). Come SE. pii: S0960-9776(12)00252-4.and gravidity-matched controls.3. Cancer Control. Comparison of recurrence and survival rates after breast-conserving therapy and mastectomy in young women with breast cancer. Int J Radiat Oncol Biol Phys. 4. Curr Oncol. Prospective study of fertility concerns and preservation strategies in young women with breast cancer. Gelber SI. Yang B et al: Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: A meta-analysis of randomized controlled trials. 3. Mahmood U et al. Fertility and menopausal outcomes in young breast cancer survivors. Menopausal symptoms and fertility concerns in premenopausal breast cancer survivors: A comparison to age. Breast 2013 Jan 5.: Fertility and reproductive considerations in premenopausal patients with breast cancer. Gerber B. Ginsburg E. Winer.32(11):1151-6 . 6. Ginsburg ES. Partridge AH EP. Borges VF. 5. Partridge AH. 2.18:105–108 Lee MC etzt al.83(5):1387e93. 7. 4. (:65-69 Hulvat MC. 269-276 2011 Ruddy KJ et al. J. Meyer ME. 2014 Apr 10.

short nursing periods. low number of children. since the danger of too much radiation for the fetus can be overcome by appropriate protective measures. The life style of the industrialized western world is thus causing an increase in breast cancer incidence.Breast Cancer During Pregnancy or Breast Feeding (5/18) Further information: Study link: http://germanbreastgroup. Moreover. Pregnancy or nursing period are no reason for delaying appropriate diagnostic work-up of a suspicious lesion. breast cancer incidence is also increasing with age. mammography can also be used if needed. Pregnant breast cancer patients have an average age of about 32-38 years. and increasing age at first birth are significant risk factors.de/studien/adjuvant/brustkrebs-in-der-schwangerschaft. Another reason for the delayed diagnosis next to “simply not thinking about it” is the reluctancy to order appropriate imaging and diagnostic test during pregnancy. Thus. there is no reason to replace an indicated mammography by an . Breast ultrasound will not harm the fetus. late menopause. Early menarche. Thus. The same imaging techniques as in non-pregnant women are available.html The individual breast cancer risk is strongly influenced by endocrine factors. the position in the MRI may not be acceptable for most pregnant women. The average time interval between first symptoms and a definite diagnosis is about 5-15 months. This delayed diagnosis is most likely one of the main reasons for the fact that overall survival of pregnant breast cancer patients is worse than that of non-pregnant breast cancer patients even though their stage-adapted prognosis is similar. This fact urgently needs to be acknowledged and accepted by physicians since the diagnosis of breast cancer is frequently being delayed in pregnancy. As a consequence. MRI does not have the danger of radiation but experiences with pregnant breast tissue is limited and interpretation may be difficult. we not only recommend that pregnant or nursing women need to examine their breast on a regular basis but also that clinical examination of breasts and loco-regional lymph nodes should be part of routine medical care during pregnancy and nursing period. Moreover. the diagnosis is typically made at a later stage than outside of pregnancy. Given the increasing average age of pregnant women. Moreover. the co-incidence of a breast cancer diagnosis with the patient also being pregnant or nursing is becoming more frequent.

after organogenesis. the beginning of a radiation therapy may automatically be delayed by a few months thus allowing the pregnancy to reach (almost) full term by the end of chemotherapy. Thus. FEC. As in non-pregnant patients. Thus.So far. there is no evidence for major complications. this can be done by minimal invasive techniques such as core or vacuum biopsies under local anesthesia.MRI in pregnant patients. chemotherapy does not cause an increased rate of malformations. pregnancy is not a reason for withholding an indicated chemotherapy – the timing however. However. antimetabolites such as methotrexate (or 5-fluorouracil) should not be used due to their teratogenic potential. For anthracyclines. . therapy recommendations follow treatment outside of pregnancy with a few modifications: Therapeutic radiation of the breast is contraindicated during pregnancy so that a mastectomy would theoretically be the surgical method of choice. i. There is growing evidence that the use of taxanes is safe. after delivery. no major complications have been reported. but is not recommended at the moment. Physiological changes in pregnant or nursing breasts cause an increased false-positive rate in imaging procedures. every suspicious palpable tumor definitely needs to be submitted to a histological diagnosis. premature labour. Which is possible cytotoxic agent in pregnant metastatic breast cancer patients.e. premature delivery. one has to consider the individual teratogenic potential of the different chemotherapeutics and plan the delivery date accordingly. Dose-dense chemotherapy does not appear to increase the risk of fetal or maternal complications. EC and Epi weekly are safe combinations. After diagnosis. Indication for chemotherapy follows the guidelines for non-pregnant patients. chemotherapy can only be applied after the 12th week of pregnancy. and intrauterine fetal death. Undertreatment should be avoided. In general. should take the delivery date into account. It is important to make the pathologist aware of the concurrent pregnancy or nursing period in order to avoid pregnancy-associated diagnostic histological changes to cause any diagnostic difficulties or even false-positive findings. The same is probably true for vinorelbine. Yet. radiation therapy is of course possible and thus breast conserving therapy is a valid option in breast cancer during pregnancy. In addition. Yet. An open biopsy is only indicated in situations where minimal invasive procedures may not allow a definite diagnosis. there is an increased risk for growth retardation. thus increasing again the danger of a delay in diagnosis. since adjuvant chemotherapy may be indicated in most cases anyway. Little is known about gonade development of and about the risk for malignancy in the children who were subjected to chemotherapy while still in utero. pregnant women as well as their physicians may be more reluctant towards an open biopsy than towards a minimal invasive procedure. Treatment with trastuzumab in HER2-positive tumours in pregnant women cannot be recommended. After the first trimester. in pregnant or nursing women. In conclusion. Among the most frequently used chemotherapeutics in breast cancer.

termination may be considered if therapy options for the mother are severely compromised by the pregnancy. Termination of pregnancy does not improve the prognosis of the breast cancer and thus is not considered a therapeutic option. nursing is not recommended during chemotherapy due to excretion of many chemotherapeutics into the milk. since maternal side effects (e. Rack B. Prognosis is not improved by cessation of nursing.g. Moreover. The delivery should not be planned for the immediate three weeks following a chemotherapy cycle. hematotoxicity) may increase the maternal risk for delivery-associated complications. Wildiers H. Ann Oncol. the placental excretion function disappears after delivery and the newborn may not be able to metabolize potential chemotherapy remainders. Giermek J. fetal underdevelopment. Moreover. embryolethality. Thus. Cancer. Ring AE. 2013. . Yet. Neven P. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis. Nekljudova V. Linn SC. depending on gestational age. Yet. Harbeck N. treatment and follow-up. Van Calsteren K. Amant F. von Minckwitz G. nursing should be stopped before surgery on order to reduce volume of the breast and its blood flow. so that bisphosphonates are contraindicated in pregnancy. Schlehe B. Untch M. References: 1. There is neither evidence of direct damage to the fetus due to breast cancer nor of metastases into the fetus.Results of studies of bisphosphonates in pregnant animals have shown maternal toxicity. Bontenbal M. Witteveen PO. However. rare placental metastases have been described. social and ethical aspects next to medical issues. religious. hypocalcaemia and skeletal retardation. Diagnosis of a malignancy during pregnancy causes extreme burden and conflicts for the pregnant women and their families touching on emotional. fatigue. Peccatori FA et al. Han SN. Fehm T.24 Suppl 6:vi160-70 Outcome information (GBG registry): 1. Most pregnant cancer patients want to “live long enough to see their child grow up”. Westenend PJ. Müller V. decisions about continuing the pregnancy and about treatment should not only consider medical arguments but also take psychological as well as emotional needs of the pregnant patient into account.

Annane K et al. Ann Oncol. Harbeck N.010. Arch Gynecol Obstet 2005 Ahn BY et al.. Treatment of breast cancer during pregnancy: an observational study. Cancer. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis. Kaufmann M. Statement: Surgery like in non-pregnant patients 8. Giermek J. J Ultrasound Med 2003. 4. Müller V.09.. Van Calster B. Van Calsteren K. evidence-based review and recommendations. 2012 Sep.2.1016/j.198:785-792. Nekljudova V. Infiltrative breast cancer during pregnancy and conservative surgery.ejca. 6. 27: 623-632 Hogge JP et al. Statement: Breast imaging & biopsy like in non-pregnant 1. Rationale for a diagnostic chain in gestational breast tumor diagnosis. Lenhard M. 2. Fehm T. Gziri MM. Imaging strategies in the pregnant cancer patient. Thomssen C. Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study. 5: 272283. Van Calster B. 491-497 Nicklas AH et al. von Minckwitz G.. Loibl S. Deckers S. Wang PI. AJR Am J Roentgenol 2012. chest X-ray if indicated 7. Heyns L. Loibl S. Van Calsteren K. Semin Oncol 2000. Rack B. Linn SC. Amant F. Breast J 1999. Bock K. et al. et al..46:3158-3168. Peccatori FA et al. Han SN. Lancet Oncol. doi:10. Breast cancer in pregnancy: Recommendations of an international consensus meeting. Schlehe B. treatment and follow-up.13(9):887-96. Eur J Cancer 2010. Halaska MJ. 2013 Jul 10. Schwedler K. Imaging of pregnant and lactating patients: part 2.31(20):2532-9. Bontenbal M. et al. Ring A. Westenend PJ. J Clin Oncol. Amant F. 20: 442-444 .2010. Imaging and management of breast masses during pregnancy and lactation. 5. 3. 2013.24 Suppl 6:vi160-70 Statement: Staging: ultrasound. Pregnancy and lactation-associated breast cancer: mammographic and sonographic findings. Fetal Diagn Ther 2005.

. 23: 5225-5229 7. von Minckwitz G. Dupont EL. Ahr A.. Cox CE. Economy KE. Conte PF. Meade TL. 17: 855-861 Statement: „Sentinel node biopsy“ during pregnancy 1. In: Kaufmann M. Safety of sentinel node biopsy in pregnant patients with breast cancer. Petrek JA. Meyers MP. Anticancer Res 2003. 2008 May-Jun. et al. 29: 545-548 8. 2014 Aug. Kuerer H et al. Costa SD. Gelber S et al. Scharl A. Ronce M. Springer. 2.21(8):2506-11. Ben Brahim E. Cancer 1991. Hasson DM. 9: 237-240 5. Rhei E. Gadducci A. Nardini V. Dominici L. Conservative surgery and chemotherapy for breast cancinoma during pregnancy. Mayer EL. Breast J. The lactating breast: MRI findings and literature review. Talele AC. Fanuchi A. Göhring U-J: Malignome in der Schwangerschaft. Cosio S. 2002 pp 509 6. 15: 13481351 Khera SY. Gynecol Obstet Fertil 2001. Pregnancy-associated breast cancer patients can safely undergo lymphatic mapping. 19: 1671-5 . Breast carcinoma during pregnancy. Heidelberg. Driss M. Tung NM. Farah F et al. Calvillo KZ. Ann Oncol 2004.14(3):250-4 Reviews 1. Dukoff R. Gentilini O et al. Scharl A (eds) Die Gynäkologie. Genazzani AR. 3. 131: 108-110 Berry DL et al. Troyan S. Placental metastasis of breast cancer. Sentinel lymph node biopsy in pregnant women with breast cancer.9. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and a review of the literature. 3.106(2):237-46... 2006 Jan 15. Gropper AB1. Rogatko A: Prognosis of pregnancy associated breast cancer. Effect of pregnancy on overall survival after diagnosis of early stage breast cancer. Breast J 2003. Mrad K. 10. Schapira L. Ann Surg Oncol. Cancer. 67: 869-872 4. Loibl S. Yeh ED. Kiluk JV. Berman CG. Sophie E. JCO 2001. Surgery 2002. Management of breast cancer during pregnancy using a standardized protocol J Clin Oncol 1999. Partridge AH. Meisel JL. McGrath Chemotherapy for breast cancer in pregnancy: evidence and guidance for oncologists 2. Slanetz PJ. Kopa DB. Edmister WB.

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2014 (suppl. Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Mayer K. Amant F. Nekljudova V. Epub 2012 Jun 27. J Clin Oncol 2005. 2008 Apr. Statement: Anthracyclines: AC.Breast Cancer During Pregnancy (6/18) No further information References: Statement: Radiotherapy during pregnancy 1. Luebbe K. Witzel I. Cancer. Weiss C. 6. Amant F. abstr 1071) Ring et al. Breast carcinoma during pregnancy. 3. 2012 Jun. Kal HB et al.106(2):237-46. Radiotherapy during pregnancy: fact and fiction. Parokonnaya A. Lancet Oncol 2005. Chemotherapy for breast cancer during pregnancy: An 18-Year experience from five London teaching Hospitals. Being Pregnant and Diagnosed with Breast Cancer.. 23: 4192-4197 Mir O et al. Ann Oncol. et al. Peccatori F et al.19(4):607-13. J Clin Oncol 32:5s. von Minckwitz G. Von Minckwitz G. Han SN.7(3):204-209. Gyapong S. 6: 328-333 (Review) Statement: (Neo-)adjuvant chemotherapy only after first trimester (indication as in non-pregnant): 1. Müller V. Han S. EC 4. MacMillan K. . Schneeweiss A. Neoadjuvant chemotherapy for patients with breast cancer during pregnancy (BCP). Rezek D. Loibl S. Mundhenke C. Breast Care (Basel). Loibl S. Aug 20 [epub ahead of print] Loibl S. 2006 Jan 15. 2. Weekly epirubicin in the treatment of gestational breast cancer (GBC). Strobel S. 5. Breast Cancer Res Treat 2008.. Vogt D. Waldhoer C. Schreiber K.

Ronce M. Maternal and neonatal outcomes of dose-dense chemotherapy for breast cancer in pregnancy. 3.7. Obstet Gynecol.g. De Placido S. Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil. Chrysikos D.23:3016-3023. 2012 Dec. Clin Breast Cancer 2013. von Minckwitz G.13:16-23. 23: 5225-5 Loibl S. 4. Statement: MTX (e. Sergentanis TN. Omission of 5FU based on the same evidence as in non-pregnant patients (GIM2 study) . Gilmandyar D. Final results of the gruppo Italiano mammella (GIM)-2 randomized phase III study.19(4):607-13. epirubicin and cyclophosphamide (FEC) followed by T. Amant F et al. in node-positive early breast cancer (BC) patients (pts). SABCS 2013: S5-06 Statement: Taxanes 1. Mir O et al. Cardonick E et al. et al. 8. Treatment of breast cancer during pregnancy: an observational study. CMF . Bruzzi P. Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Ann Oncol 2012. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and a review of the literature. Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature. Taxanes for breast cancer during pregnancy: a systematic review.13:887-896.see also chapter on adjuvant chemotherapy: Cognetti F. Conte PF. Somer RA. Gadducci A.120(6):1267-72. Han SN. Lancet Oncol 2012. 9. Cosio S. Loibl S et al.13:256-264. et al. Anticancer Res 2003. 5. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. et al. Treatment of breast cancer during pregnancy: an observational study. Nardini V. Lancet Oncol. 10. 2008 Apr. Genazzani AR. all given every 3 weeks or 2 weeks. Lancet Oncol 2012. Fanuchi A. Zagouri F. 2012 13(9):88796. Cardonick E. 2. Ann Oncol.

Cunha GR. New Engl J Med 2001. 23: 4192-4197 Statement: Endocrine treatment 7. Gynecol Oncol. 8. Aebi S.137(2):349-57.Breast cancer during pregnancy: medical therapy and prognosis. Trastuzumab administration during pregnancy: a systematic review and meta-analysis. Statement Trastuzumab during pregnancy 10. Davies et al. Clark K. 14. 105: 642-643 (Case Report) 12. Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01). a randomised trial. Zagouri F et al. Isaacs RJ. Lancet 2013. 5(7):733-41. Fanale MA et al. Are monoclonal antibodies a safe treatment for cancer during pregnancy? Immunotherapy 2013. C. Breast Care 2008. 1987. J Clin Oncol 2005. 2008.178:45-55. Clemons M. Goss P: Estrogen and the risk of breast cancer.6. Taguchi O. 16. 2012. Sarno MA et al. Treatment of metastatic breast cancer with trastuzumab and vinorelbine during pregnancy. 344: 276-285 15. Loibl S. Robboy SJ Teratogenic effects of clomiphene.80:405-408. Obstetrics and Gynecology 2005. Recent Results Cancer Res. 17.805–816. 6: 354-356 (Case Report) 11. tamoxifen. 2013 Jan. Hunter W.381. 3:171-176. Watson WJ.18:1132–1143. Nishizuka Y. 2001. New Therapeutic Options for Breast Cancer during Pregnancy. . Ring et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS. 9. Tamoxifen as systemic treatment of advanced breast cancer during pregnancy — case report and literature review. Chemotherapy for breast cancer during pregnancy: An 18-Year experience from five London teaching Hospitals. Azim HA Jr et al.133(1):387-91. (table overview of trastuzumab cases) 13. Namikawa R. Herceptin (Trastuzumab) therapy during pregnancy: Association with reversible anhydramnios. Breast Cancer Res Treat. Clin Breast Cancer 2005. Loibl S. and diethylstilbestrol on the developing human female genital tract Hum Pathol.. Breast Cancer Res Treat.

379(9815):570-9. Hodge S. Pregnancy outcome following in utero exposure to bisphosphonates. Ramirez MM. Neven P. Barnett CM. Amant F.Statement Bisphosphonate during pregnancy 18. Levy S. Murthy RK.16(6):3414. Outcomes of children exposed in utero to chemotherapy for breast cancer. Matsui D. Fayez I. Bone. 2009 Mar. Moretti M. Review. 2012 Feb 11. 2014 Dec 30. Han JY. Breast Cancer Res. Lancet. Breast cancer in pregnancy. Rimes SA. Valero V. Hortobagyi GN. Litton JK. General information: Chemotherapy during pregnancy 1. Van Calsteren K. Loibl S. 19. . Ito S. Aiello J. Taguchi N. Milbourne A. Theriault RL. Koren G.44(3):428-30.

treatment and follow-up. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis.Breast cancer during pregnancy (7/18) Further information: These statements are derived from common sense and literature cannot fully be assigned. References: In general 1. Cancer. Neven P.379(9815):570-9. Loibl S. Han SN. Avoid delivery  3 weeks from prior chemotherapy 5. von Minckwitz G.. Lancet Oncol 2012. Loibl S. et al. 2013. et al. Van Calsteren K. Loibl S. von Minckwitz G.13:887-896. Breast cancer in pregnancy. Han SN.24 Suppl 6:vi160-70. Statements: Delivery mode like in non-pregnant. 3. Lancet Oncol 2012. 17: 855-861 . Management of breast cancer during pregnancy using a standardized protocol J Clin Oncol 1999. Ann Oncol. Amant F. Statements: Delivery should be postponed until sufficient fetal maturation since termination of pregnancy does not improve maternal outcome 4. 2. 2012 Feb 11. Lancet. Peccatori FA et al. Treatment of breast cancer during pregnancy: an observational study. Berry DL et al.13:887-896. Treatment of breast cancer during pregnancy: an observational study.

antiemetics and growth-factors in human milk: how should we counsel cancer patients about breastfeeding? Cancer Treat Rev. Chemotherapy. 7. Williams Obstetrics lecture book Pistilli B et al.Statements: If further systemic therapy is needed after delivery. . breast feeding may be contraindicated depending on drug toxicities 6. 2013. targeted agents.39(3):207-11.

Hiatt RA. Russell-Edu W.1200/JCO. Senie RT. Rowell S. 67: 869-872 Loibl S. Møller B. if treated adaequately 1. et al. 7. Petrek JA. Obstet Gynecol. Azim HA Jr. 2. van Dijk T. .112(1):71-8 Stensheim H. 4. Data investigating this topic are inconsistent incorporating pregnant patients and PABC. 6. Pregnancy after breast cancer is safe and does not compromise the outcome. Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study J Clin Oncol. Cancer. Desai M. 2006 Jan 15. Kranick JA. Santoro L. doi:10. et al. Evidence of poorer survival in pregnancy-associated breast cancer. 2010 Jul-Aug. J Clin Oncol 2009.. however.Pregnancy Associated Breast Cancer: Outcome (8/18) Further information: The outcome of pregnant breast cancer patients do not seem to be inferior to those being non pregnant. 5. 2013. References: Statement: Breast cancer during pregnancy / lactation: Outcome not compromized. Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies. Petrek JA.. Is pregnancy after breast cancer safe? Breast J. Cancer Treat Rev 2012.27:45-51.4110.106(2):237-46 Rodriguez et al. Cancer 1991. Breast carcinoma during pregnancy.17. larger case series including also patients with advanced disease prosposed additional effects. 2008 Jul. A healthy mother effect might be the reason. A recent study however demonstrated a poorer survival for PABC.2008.38:834-842. Fosså SD.16(4):404-11. 3. Amant F et al.31(20):2532-9. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. Dukoff R. Rogatko A: Prognosis of pregnancy associated breast cancer. Schaefer C. von Minckwitz G. Most investigations did not report on the applied therapy which might be a confounding factor.

Valachis A. Peccatori FA. 11. Polyzos NP. 3. 2. p=0. Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer. 10. Tsalis K. J Clin Oncol 2013. Del Mastro et al. Eur J Cancer.96.7(3):210-214. Kroman N. JCO 2001. Oncologist.65(12):786-93.47(1):74-83. Epub 2006 Jul 13.47(4):545-9 Azim HA Jr et al.18(4):369-76. Pesce LL.44 – 0.350(9074):319-22. . Review articles 1. 19: 1671-5: IBCSG-participants . Epub 2010 Oct 11. 2008.31:73-79. Epub 2012 Jun 27. Azim HA Jr. Review. 2011 Jan. around. Pagani O. Gelber S et al. Tsali L. Dimitriadis C. Infertility and pregnancy after breast cancer: current knowledge and future perspectives. Cancer Treat Rev. 2010 Dec.matched pair analysis: 94 patients pregnant after treatment (RR 0. Litton JK et