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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

5 and > 25 and especially > 40 (obesity) Diabetes mellitus Type II Food content Steroid hormone therapy     www. in der DGGG e. Guidelines Breast Version 2015. polyfluoroalkyls) . sowie in der DKG e.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.Modifiable Risk Factors for Breast Cancer © AGO e.V.1      Less breast feeding BMI < 18.ago-online. V.V.

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. V.Prevention by Changing Pregnancy Related Factors © AGO e.V. Oxford / AGO LoE / GR Guidelines Breast Version 2015.1     www. sowie in der DKG e.ago-online. in der DGGG e.5–2 years) 2b B 2b B 2b B 3a B .

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) .de Maintaining normal weight 2a B ++ (BMI at 18.Prevention by Changing Lifestyle Factors: Body Mass Index / Diet © AGO Oxford / AGO LoE / GR e. sowie in der DKG e.V.V. V. in der DGGG e.1   www.ago-online. Guidelines Breast Version 2015.

V.ago-online. sowie in der DKG e. V.1 Preference of a healthy diet 2b B + 2a B 2a B + + 2a 3a 2a 2a 1b +/+/-* +/+ Dietary components    www. Guidelines Breast Version 2015.de Fat reduced food (unsaturated > saturated fatty acids) Reduced consumption of red meat Supplementation of vitamins. 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 . minerals.V. in der DGGG e.Prevention by Changing Lifestyle Factors: Diet © AGO Oxford / AGO LoE / GR e.

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

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

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

LoE / GR Guidelines Breast Version 2015.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.ago-online.de  (no enhanced breast cancer risk with estrogen only therapy. Oxford / AGO in der DGGG e. sowie in der DKG e.V. but increased risk for endometrial cancer) . maybe even risk reduction. V.V.

de Metaanalyse 16 Studien Nelson HD: JAMA 2002 Chlebowski SABCS 2010 .6) 1.ago-online.9) Thrombosen Med.4 (1.2) E-Mono EPC > E 1.V.7J Million Women EPC > E Art der Anwendung egal Einnahmedauer > 5 Jahre Tibolon RR 1.1-1.0-1. in der DGGG e.95-1.4 (1.5) II 2321 1.1 J (0.3 WHI: JAMA 2002 (1.1 (1.7) 1.4-3. sowie in der DKG e.084 110 1.9) Schlaganfälle 2.8 (1.2-1.1-1. Alter 67 J keine sekundäre Prävention Newkg.3) Lungenembolien 2.6) koronare Events 1. follow-up EPIC 1.5-2. 2.4-2.3 (1.21-1.40 Newkg. V.153 747 person- Int J Cancer 2010 years o 1.Prevention Hormone (EGC) in der Post-MP © AGO e.6) HERS I 2763 1. wie WHI + Cholzystektomien open-label.1 WHI N MC-RR(95%CI) Weitere Aussagen ~ 27 000 1.6-1.45 (1.1 J.2 Hulley S: JAMA 2002 RCT.2-1.V.66 (1.1 (1. Guidelines Breast Version 2015.8) Beral V: Lancet 2003 ~ 50% HRT 4. med. wie WHI + www. 4.

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

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

including 118 964 women with breast cancer from 117 epidemiological studies. 2012 Nov.: Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. BMC Cancer 2013 Dec 9.01. menopause.cancer. Modified from American Cancer Society 2014 (http://www.org/cancer/breastcancer/detailedguide/breastcancer-risk-factors) downloaded 01.13:584. and breast cancer risk: individual participant meta-analysis.Non Modifiable Risk Factors for Breast Cancer (3/13) No further information References: 1. 2. .13(11):1141-51. Lancet Oncol. Collaborative Group on Hormonal Factors in Breast Cancer: Menarche. 3.2015) Ritte et al.

cancer. Modified from American Cancer Society 2010 (http://www.Modifiable Risk Factors for Breast Cancer Risk (4/13) No further information References: 1.105(8):515-25.12.2013) Gaudet MM et al: Active smoking and breast cancer risk: original cohort data and meta-analysis. . J Natl Cancer Inst. 2. 2013 Apr 17. last revised 31.org/cancer/breastcancer/detailedguide/breastcancer-risk-factors.

2013. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries. Breast Cancer Res Treat. 4. 2008 Jul. Breast Cancer Res. Li CI: Reproductive factors and risk of estrogen receptor positive. Lord SJ: Breast cancer risk and hormone receptor status in older women by parity. Lancet 2002. 2005.17(7):1723-30.360:187-95. and HER2-neu overexpressing breast cancer among women 20-44 years of age.12(3):R35 Martin RM: Breast-feeding and cancer: the Boyd Orr cohort and a systematic review with meta-analysis. 2. triple-negative. including 50302 women with breast cancer and 96973 women without the disease. J Natl Cancer Inst.97:1446-57. age of first birth. . 3. and breastfeeding: a case-control study.Prevention by Changing Pregnancy Related Factors (5/13) No further information References: 1. 2010. Collaborative Group on Hormonal Factors in Breast Cancer. 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.137:579-87. Cancer Epidemiol Biomarkers Prev. 5.

2014 Oct. physical activity. 2009 Mar 18. Ann Oncol. doi: Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. PLoS One. 5.106(3):djt465. Cheraghi Z: Effect of body mass index on breast cancer during premenopausal and postmenopausal periods: a metaanalysis. 3. 2014 Mar. Brinton LA: Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results. nutrition. . 4. J Mol Endocrinol.7(12):e51446. 2012.101(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. World Cancer Research Fund and American Institute for Cancer Research: Food. 2013 Nov 26. J Natl Cancer Inst. 6. Simpson ER: Obesity and breast cancer: role of inflammation and aromatase. J Natl Cancer Inst.Prevention by Changing Life Style Factors: Body Mass Index / Diet (6/13) No further information References: 1. AICR. 2007.25(10):1901-14. 2. and the prevention of cancer: a global perspective. Washington DC.51(3):T51-9.

4. 7. Am J Clin Nutr. Zhao YM. 2010 Sep. Brennan SF: Dietary patterns and breast cancer risk: a systematic review and meta-analysis.22 Suppl 2:S30-7.. Eliassen AH. BMJ. Farvid MS. 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. BMJ. Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study. Chlebowski RT: Nutrition and physical activity influence on breast cancer incidence and outcome. Am J Clin Nutr.. Trichopoulou A: Conformity to traditional Mediterranean diet and breast cancer risk in the Greek EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Chen WY. Rossi RE: The Role of Dietary Factors in Prevention and Progression of Breast Cancer. 2. 5. Breast Cancer Res Treat.92(3):620-5. 2014 Dec.Prevention by Changing Life Style Factors: Diet (7/13) No further information References: 1. Breast. Yang J. 2009 Mar 18. Li D. 2013 Jun 27.34(12):6861-6875. Anticancer Res. 3. Zheng JS. Hu XJ. 2014 Jun 10.348:g3437 .139(1):163-76. 6. Cho E. Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. Willett WC.91(5):1294-302.346:f3706. 8. J Natl Cancer Inst. 2010 May. 2013 Aug.101(6):384-98. 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. 2013 May.

J Natl Cancer Inst 2010.2014. McDonald JA: Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence. . doi: 10.579. 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.122(8):1832-41. 2003 May. 4. Bagnardi V: Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis.1038/bjc. Br J Cancer.Prevention by Modifying Life Style Risk Factors: Alcohol (8/13) No further information References: 1. 2014 Nov 25.79(2):265-76. Int J Cancer. Gerber B: Nutrition and lifestyle factors on the risk of developing breast cancer. 2013 Sep. 5.5(3). Breast Cancer Res Treat. 3. [Epub ahead of print] Li CI: Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: The Women’s Health Initiative Observational Study. 2. 2008 Apr 15.

Dossus L: Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort. J Natl Cancer Inst. 2.134(8):1871-88. 2013 Apr 17. 3. . 2013 Jul.865 Norwegian women.105(8):515-25 Bjerkaas E: Smoking duration before first childbirth: an emerging risk factor for breast cancer? Results from 302. Gaudet MM: Active smoking and breast cancer risk: original cohort data and meta-analysis. 2014 Apr 15. Int J Cancer. Cancer Causes Control.24(7):1347-56.Prevention by Modifying Life Style Risk Factors: Smoking (9/13) No further information References: 1.

J Natl Cancer Inst.188:125-39. Breast Cancer Res Treat. Physical activity and breast cancer: review of the epidemiologic evidence and biologic mechanisms. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. 2009 Mar 18. Zhang D. 2003 May. 4. Breast Cancer Res Treat. Breast Cancer Res Treat. 6. 2011. 2013 Feb. Friedenreich CM. 5.101(6):384-98.137(3):869-82. 3. Cummings SR: Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk. Chlebowski RT: Nutrition and physical activity influence on breast cancer incidence and outcome.22 Suppl 2:S30-7. . 2013 Feb.79(2):265-76 2. Recent Results Cancer Res. Kang S. Wu Y. Breast.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.137(3):869-82. 2013 Aug. Wu Y: Physical activity and risk of breast cancer: a meta-analysis of prospective studies.

JAMA (2003) 289: 3243–3253. J Natl Cancer Inst 2010. Cochrane Database Syst Rev. Saether S: The risk of breast cancer linked to menopausal hormone therapy. De P: Breast cancer incidence and hormone replacement therapy in Canada.: Breast cancer and hormone-replacement therapy in the Million Women Study. 5. 8. 102: 1489 – 95 7. Reeves GK: Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and metaanalysis.7:CD004143. Tidsskr Nor Laegeforen (2012) 132: 1330–1334 6. 362: 419 – 27. Lancet 2003. Lancet Oncol (2006) 7: 910–918. 2012 Jul 11. 2013 Oct 2. 4. JAMA. Chlebowski RT: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. .310(13):1353-68.Prevention by Modifying Life Style Risk Factors: Hormone Therapy in Postmenopausal Women (11/13) No further information References: 1. Marjoribanks J: Long term hormone therapy for perimenopausal and postmenopausal women. Beral V. Manson JE: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. Chlebowski RT: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. 3. JAMA (2010) 304: 1684–1692 2.

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

Cancer Epidemiol Biomarkers Prev. Havrilesky LJ. 631–650. J Clin Oncol. Moorman PG. No. Vol. . 2.22(11):1931-43.16.:Hormonal contraception and risk of cancer. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. cervical. 2010 Gierisch JM:Oral contraceptive use and risk of breast.6 pp. Gierisch JM. 3.31(33):4188-98. colorectal.Prevention by Modifying Life Style Risk Factors: Oral contraception (13/13) No further information References: 1. 2013 Nov. 2013 Nov 20. and endometrial cancers: a systematic review. Cibula D. Human Reproduction Update.

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

V.Breast Cancer Risk and Prevention © AGO e.de . V. sowie in der DKG e. Guidelines Breast Version 2015.1  Versions 2003–2014: Schmutzler with Albert / Blohmer / Fehm / Kiechle / Maass / Mundhenke / Rody / Thomssen  Version 2015: Schmutzler / Schmidt www.V. in der DGGG e.ago-online.

sowie in der DKG e. V.V. Guidelines Breast Version 2015.V.Principles in Prevention © AGO e. do no harm!“ (Primum nil nocere) .ago-online.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. in der DGGG e.

or at least one woman affected by breast cancer < 36 yrs.V.1 www.ago-online.Who Should be Tested for BRCA1/2 Mutations? © AGO Oxford LoE: 2b e. Guidelines Breast Version 2015. in der DGGG e. first < 51 yrs. one < 51 yrs. 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. sowie in der DKG e. V.000 families tested by 2013 . 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.V.

sowie in der DKG e.ago-online.de C + . V. in der DGGG e. Guidelines Breast Version 2015.BRCA1/2 Testing in Patients with TNBC (irrespective of family history) © AGO e.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.V.

V.875 in 2014.1 BRCA1/2 mutation frequency: 24% (OC only: 35%. Guidelines Breast Version 2015.Recruitment of the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) © AGO e. Leipzig) national DNA-biobank (center Cologne) *Institute for Medical Genetics. Statistics and Epidemiology.V. exp.ago-online. 18. sowie in der DKG e.de    since 1996. Leipzig Leipzig Würzburg Heidelberg Tübingen Regensburg Ulm München 6 . BC/OC: 42%) Kiel Berlin Hannover Münster Göttingen Dresden Düsseldorf Köln/Bonn www.000 new families in 2015 in der DGGG e. 15 centres national database (IMISE*. +3. V.

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

ATM. PALB2 . 5p12. CDH1.0) (BRCA1/2) disease risk Guidelines Breast Version 2015.0) (RAD51C. PTEN….) low risk variants / modifiers (OR/HR <1.1 moderately penetrant risk genes (OR 1. high risk genes (OR >5.ago-online.State of the Art Unexplained Heritability: Oligogenic Traits and Genetic Heterogeneity © AGO e. V.5 . SLC4A7. CHEK2. 2q35. MAP3K1…) www. sowie in der DKG e.5) (FGFR2.V. TOX3. in der DGGG e. 11q15.de minor allele frequency . NBN.5. BRIP1.V.

V. in der DGGG e.de Lynch mismatch repair MLH1.ago-online. V. MSH2. 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.V. PMS2 up to twofold increased risk compared to general population5 Endometrial: ~ 25-60 % Ovary: up to 25 % Recommendation: genetic counselling: GCP .Non BRCA-associated Hereditary Cancer Syndromes with Increased Risk for Breast Cancer © AGO e. sowie in der DKG e. Guidelines Breast Version 2015.

V.ago-online.100 BRCA1/2 negative risk families: 670 breast only. Guidelines Breast Version 2015. V.5%) . 2010 www. 430 breast and ovarian cancer  6 deleterious mutations in BC/OC families only ( 1.Third Moderate to High Risk Gene Identified within the GC-HBOC © AGO e.V.de  1. in der DGGG e.1 Nature Genetics April 18. sowie in der DKG e.

illumina.com/documents/products%5Cdatasheets%5Cdatasheet_trusight_cancer.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. 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 . sowie in der DKG e. 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/tests/breastnext in der DGGG e.1 http://www. V.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.und Ovarialkarziom (30 genes) Guidelines Breast Version 2015.ago-online.de ATM BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 MRE11A MUTYH NBN PALB2 PTEN RAD50 RAD51C STK11 TP53 CEGAT CAN02: Brust.ambrygen.pdf www.centogene.V.V.de/Tumorerkrankungen_171.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. BROCA 40 gene panel © AGO (cross-cancer.labmed. http://web.edu/tests/genetics/BROCA Commercially Available.cegat.washington.

V. unpublished) Strategy: Validation in large cohort. 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. sowie in der DKG e. Song et al. 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. in der DGGG e.V.TruRisk™ BC/OC Gene Panel (34 genes) by the German Consortium GC-HBOC © AGO e.. 2014) 12 BC/OC ´research genes´ (validation in cooperation with the ENIGMA consortium) 8 candidate BC/OC genes (GC-HBOC.ago-online.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.

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

V. in der DGGG e.1 www. sowie in der DKG e. 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 .ago-online.de  Distinct genetic subtypes of breast cancer may show distinct clinical features.Genetically Defined Subtypes are Distinct Tumor Entities © AGO e.V.V. Guidelines Breast Version 2015.

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

1% CDKN2A/B rs1011970 17% 1.4% MAP3K1 rs889312 28% 1.3% CASP8 rs1045485 13% 0.Low risk Variants from Genome Wide Association Studies (GWAS) Locus © AGO SNP Häufigkeit e.08 5x10-11 0.4% 5p12 rs10941679 26% 1.10 7x10-10 0.2% ZMIZ1 rs704010 39% 0.01% .3% 8q24 rs13281615 40% 1.ago-online.2% ZNF365 rs10995190 15% 0.24 5x10-87 1. Guidelines Breast Version 2015.09% COX11 rs6504950 27% 0.08 7x10-8 0.07% ANKRD16 rs2380205 43% 0.12 4x10-23 0.9 2x10-8 0.88 4x10-15 0.5% SLC4A7 rs4973768 46% 1.6% TOX3 rs3803662 25% 1.2% LSP1 rs3817198 30% 1.5% 11q15 rs614367 15% 1.1 www.92 3x10-8 0.1% 2q35 rs13387042 51% 1.12 3x10-34 0. in der DGGG e.V.94 2x10-7 0.20 5x10-16 0. sowie in der DKG e.09 2x10-15 0. V.01% RAD51L1 rs999737 24% 0.98 4x10-7 0.2% 1p11.11 3x10-20 0.11 4x10-23 0.de TOTAL BCAC FRR (%) Odds Ratio P-trend FGFR2 rs2981582 38% 1.2% ESR1 rs2046210 33% 1.95 10-8 0.10 8x10-15 0.2 rs11249433 39% 1.21 8x10-52 1.V.

CDKN2A/B. LSP1.ago-online. 12p11. 3p24. in coop with the GC-HBOC 2013: Combined genotype distribution of 10 variants in 11. 12q24.de BRCA2 carriers at the highest tertile of the score distribution were at significantly higher risk than women at he lowest tertile (HR = 4. 19p13.Low Risk Variants as Modifiers © AGO e.. LSP1. Clin Cancer Res.2 to 14. 2013: combined genotype distribution of 7 low-risk SNP in 909 BRCA2 carriers www. 6q25.02)´ first ´proof of principle´ Associations are breast cancer subtype specific Garcia-Closas et al.3. P = . in der DGGG e. TOX3. 8q24. TERT)  5% of BRCA1 carriers at lowest risk (28–50%) compared to the 5% at highest risk (81–100%) Prospective Mavaddat et al. in coop with GC-HBOC 2013: Combined genotype distribution of 14 variants in 8.. 5q11. Guidelines Breast Version 2015.705 BRCA1 mutation carriers (1q32.221 BRCA2 mutation carriers (FGFR2.1. ESR1.. 10q25. 2q35. sowie in der DKG e. RAD51L1. 11q13)  Couch et al.V.1 Retrospective Gaudet et al.5. 2008 .1. 95%. ZNF365.V. TOX3. CI = 1. 5p12. 12p11. V.

V. V.or polygenic trait of moderate and low risk genes and alleles. 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 -++ .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. Potential multiplicative effects that may be relevant for risk stratification and the provision of clinical prevention strategies remain to be elucidated.  Clinical genetic testing for RAD51C. sowie in der DKG e. Moderate risk genes such as RAD51C exhibit very low mutation detection rates and may be associated with specific tumor subtypes. in der DGGG e.g. Guidelines Breast Version 2015.de The remaining cancer susceptibility is most likely be transmitted by an oligo. e.Current Clinical Impact of Other Risk Genes © AGO e. Low risk variants confer only small risk elevations and also seem to be associated with specific tumor subtypes.V. CHEK2 and/or other moderate risk genes.ago-online.

V. sowie in der DKG e.1 www.V.Requirements for the Introduction of New Diagnostic or Predictive Genetic Testing © AGO e.V. in der DGGG e.ago-online.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 . Guidelines Breast Version 2015.

V.1 www.Non Directive Counseling for the Uptake of Preventive Measures © AGO e.ago-online.g.g. in der DGGG 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 . e.de  According to the Genetic Diagnostic Law  According to the Medical Devices Act. V. sowie in der DKG e. Guidelines Breast Version 2015.V. risk assessment requires professional training and expertise  Communicate absolute risks within a manageable timeframe  Communicate competing risks. e.

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

V.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. sowie in der DKG e. V. Guidelines Breast Version 2015. Oxford / AGO LoE / GR in der DGGG 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.

lower than in women from BRCA1/2 positive families www.Modified Surveillance Program for BRCA-neg. V. Guidelines Breast Version 2015.V.V. however. Women at Moderate to High Risk or Survivors of Hodgkin Disease © AGO e. sowie in der DKG e.de  Referral to centres of the GC-HBOC or cooperating centres for the evaluation of structured surveillance and follow-up . in der DGGG e.ago-online.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.

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

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

in der DGGG e. sowie in der DKG e.V.ago-online.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.de + Overall prognosis has to be considered *Study participation recommended . Guidelines Breast Version 2015. V.V.Risk-reducing Interventions for BRCA1/2 Mutation Carriers Affected by Breast Cancer © AGO Oxford / AGO LoE / GR e.

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

Contralateral Cancer Risk in 6235 BRCA1/2 Positive and Negative Patients (retrospektive) © AGO e.de .ago-online. Guidelines Breast Version 2015.1 www. in der DGGG e. V.V.V. sowie in der DKG e.

V. Limited prospective cohort studies with short follow-up time Oxford / AGO LoE / GR Guidelines Breast Version 2015.1 Breast conserving therapy: Adequate local tumor control (10 years observation) www.de 2a B + Systemic therapy according to sporadic breast cancer 3a B + BRCA1 mutation status is predictive for chemotherapy 3b B response + Carboplatin (vs. Docetaxel) in MBC 2ba B + PARP inhibitor in breast cancer 2b D +/-* + Overall prognosis has to be considered *Study participation recommended . V.Therapy of BRCA1/2-associated Breast Cancer+ © AGO e.ago-online. sowie in der DKG e.V. in der DGGG e.

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

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

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

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 .

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

Slettedahl S. Eccles DM. Olswold C. Miron P. 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.1200/JCO. Nevanlinna H. Tapper WJ. Toland AE. Pilarski R. Brauch H. . Fasching PA. J Clin Oncol. 1. Pelttari LM. Yao S. Guidugli L. Wang X. Couch FJ. Slamon DJ. Epub 2014 Dec 1. Shapiro CL. Hart SN. Janni W. Cox A. Pankratz VS. Klemp J.57. Konstantopoulou I. Fountzilas G.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. Godwin AK. Vratimos A. 2015 Feb 1. Davila JI. Ekici AB. Olson JE. Hallberg E. Sharma P.2014. Beckmann MW. Cross SS. Durcan L. Slager SL.33(4):304-11. doi: 10.1414. Garber J. Fostira F. Yannoukakos D. Ambrosone C. Rack B. Vachon CM.

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 .

2006. Risks of less common cancers in proven mutation carriers with lynch syndrome. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res May 15. Masciari et al. Breast Cancer Res Treat.18(2):400-7 Benusiglio et al. Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome. J Med Genet.. 2012 Jun. 12. 5. 3209 Engel et al. 4.133(3):1125-30 Tan et al.. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. 2013 Jul. 2012 Jan 15. 2.. 2012 Dec 10.Non BRCA-associated Hereditary Cancer Syndromes with Increased Risk for Breast Cancer (9/32) No further information References: 1. Clin Cancer Res. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Clin Oncol...50(7):486-9 Hearle et al.30(35):4409-15 . 3.

2012 Jul 1. Ramser J. Schindler D. Endt D. Hum Mol Genet.569. doi: 10.: Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Deissler H. doi: 10. Eirich K. Osorio A. Schindler D. Neveling K. Schmutzler R. Nature Genetics May. Benitez J. Erven V.1038/ng. Kiechle M. 2. Epub 2012 Mar 26 . Hellebrand H. de la Hoya M. Meindl A. Wichmann HE.21(13):2889-98. Fernández F. Wiek C. Wappenschmidt B. Meindl A. Kast K. Freund M. Epub 2010 Apr 18. Caldés T. Niederacher D.Third Moderate to High Risk Gene Identified within the GC-HBOC (10/32) No further information References: 1. Engel C.: Germline mutations in breast and overian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Lichtner P. Kubisch C.1093/hmg/dds115.42(5):4104. Schmutzler RK. Müller-Myhsok B. Mathew CG. Schaal H. Hartmann L. Honisch E. Hanenberg H.

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 .

Nordestgaard BG. Anton-Culver H. PLoS Genet. Li J. Giles GG. Blomqvist C. Reed MW. doi: 10. Breast Cancer Res. (2011) 13:R110. Nevanlinna H. Severi G. Van't Veer LJ. Sherman M. Morrison J. Pharoah P. Broeks A. Margolin S.42. van Leeuwen FE. Shah M. Tollenaar RA. Dörk T. Cox A. (2008) 4:e1000054. Tollenaar RA. Broeks A. Richesson DA et al.7336. Ziogas A. Mannermaa A. Hall P. Barrowdale D. Eccles D. Couch FJ. Domchek SM. Marme F.1200/JCO. Weischer M. 2. Kataja V. Couch FJ. Liu J. Hooning M. and increased risk of a second breast cancer. Børresen-Dale AL.Genetically Defined Subtypes are Distinct Tumor Entities (14/32) No further information References: 1. Phillips KA. Collée JM. John EM. Burwinkel B. Knight JA.25(1):64-9. J Clin Oncol. Wang Q. 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. Bojesen SE. . Bolla MK. Meyer A. Beckmann MW. Ekici AB. Figueroa J. Lindblom A. Easton DF. Leunen K. Garcia-Closas M. Czene K. Hall P. Andrulis IL. Hopper JL. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. Fasching PA. Flyger H. Nevanlinna H. Kristensen VN.30(35):4308-16. Bogdanova N. Cornelisse CJ. 4. Kriege M. Cross SS. Schmidt MK. van Hien R. Muranen TA. Glendon G. Epub 2006 Nov 28. Garcia-Closas M. breast cancer-specific death. Dunning AM. Epub 2012 Oct 29. Christiaens MR. 3. Grenaker Alnæs G. Olson JE. Sohn C. Nevanlinna H et al. Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. Smit VT. Seynaeve C. Wang X. Lambrechts D. J Clin Oncol. Peterse JL. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death. Pooley K. Devilee P. Mulligan AC. Miron A. Kosma VM.2012. Baglietto L. 2007 Jan 1. 2012 Dec 10. Van't Veer LJ. Southey MC. Schmidt MK. de Kemp SR.

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

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

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

2012. .with breast cancer associated with early death. 2012 Dec 10.1200/JCO.42. doi: 10.7336. Epub 2012 Oct 29.30(35):4308-16. and increased risk of a second breast cancer. breast cancer-specific death. J Clin Oncol.

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

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

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

Al-Foheidi M.1007/s11899-012-0128-z. new treatments. and prognosis of breast cancer after Hodgkin's lymphoma.1186/1471-2407-12197. Vlastos G. Usel M. Veit-Rubin N. Kast K.12:197.108(19):323-30. Curr Hematol Malig Rep.2011-0451. 3. Elmasri OA. characteristics. Rapiti E.1634/theoncologist. Bouchardy C. Epub 2011 May 13. Rhiem K. Vinh-Hung V.0323. Darrington DL.17(6):783-91. doi: 10. Benhamou S. 2012 May 28. 2012 Sep. Risk of second breast cancer in female Hodgkin's lymphoma survivors: a meta-analysis. 2012. doi: 10. Hereditary breast and ovarian cancer: new genes. Review.3238/arztebl. Abouelkhair KM. Dtsch Arztebl Int. doi: 10. doi: 10. Meindl A. Risk.7(3):200-7. Epub 2012 May 15 . new concepts. Ibrahim EM. 2.Definition of Women at Moderate to High Risk (21/32) No further information References: 1.2011. Oncologist. Kazkaz GA. 4. Appropriate surveillance for late complications in patients in remission from Hodgkin lymphoma. 2011 May. BMC Cancer. Vose JM. Schmutzler RK. Ditsch N.

Evans DG. Rhiem K. 5. new treatments. MRI breast screening in high-risk women: cancer detection and survival analysis.3238/arztebl. Ditsch N. doi: 10. Schmutzler RK Hereditary breast and ovarian cancer: new genes. Maxwell AJ. 4. Warren RM. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. 3. 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. J Cin Oncol 2001: 19: 3524-3531 Kriege et al. Gadde S. Schmutzler RK. new concepts. Dtsch Arztebl Int. Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. Breast Cancer Res Treat. Eeles R. Efficacy of MRI and mammography for breast cancer screening in women with a familial or genetic predisposition. Evans DG. Lim Y. 6. Kesavan N.0323. Comparison of breast magnetic resonance imaging. MARIBS Group. Radiology (2000) 215:267-279 Warner et al. Kuhl C.1007/s10549-014-2931-9. Ingham S.108(19):323-30. Epub 2011 May 13.2011. Hereditary breast and ovarian cancer: new genes. new concepts. doi: 10. and ultrasound for surveillance of women at high risk for hereditary breast cancer. . Dtsch Arztebl Int. Ditsch N. 2011 May. Massat NJ. et al. Epub 2011 May 13. Radiology (2009) 252:35868. Thompson DJ. N Engl J Med 2004: 351: 427-437 Leach MO et al. Gilbert FJ. Kwan-Lim G.3238/arztebl. Epub 2014 Apr 1. Leach MO. Eeles RA.108(19):323-30. 7. Rhiem K. Kast K.2011. 2. Duffy SW. 2011 May. Kast K. Howell A. 2014 Jun. Meindl A.0323. Hurley E. doi: 10.145(3):663-72.Surveillance Program for Women with deleterious BRCA-mutations (22/32) Further information and references: 1. new treatments. mammography.

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

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. Rhiem K. Ditsch N. 2004).2011.108(19):323-30. Radiology 2000: 215:267-279 3.Modified Surveillance Program for BRCA-neg.3238/arztebl. Dtsch Arztebl Int. Schmutzler RK. Meindl A. Kriege et al. new treatments. new treatments.0323. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. et al. and ultrasound for surveillance of women at high risk for hereitary breast cancer. Epub 2011 May 13. London: national Collaborating Centre for Primary Care/University of Sheffield. Dtsch Arztebl Int. Kuhl C. These guidelines are in close agreement with the NICE-guidelines on Great Britain (McIntosh A et al. new concepts. Kast K. Ditsch N. . 2011 May. Warner et al. doi: 10.0323. J Cin Oncol 2001: 19: 3524-3531 4. Comparison of breast magnetic resonance imaging. 2.108(19):323-30. Efficacy of MRI and mammography for breast cancer sreening in women with a familial or genetic predisposition. Epub 2011 May 13. 2011 May. Leach MO et al. mammography. Women at Moderate to High Risk or Survivors of Hodgkin Disease (23/32) Further information and references: 1.: Clinical Guidelines and evidence review for the classification and care of women at risk of familial breast cancer. Rhiem K.3238/arztebl. doi: 10.2011. Kast K. Schmutzler RK Hereditary breast and ovarian cancer: new genes. new concepts. N Engl J Med 2004: 351: 427-437 5. Hereditary breast and ovarian cancer: new genes.

Hamilton LJ Clin Radiol 2004 ) . Kaas R et al. Kuhl. Int J Cancer 2002. NEJM 2004. Roentgenology 2006. 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. 2000 ). Warner et al. Am J. Schmutzler et al. 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. JAMA 2004. Eur Radiol 2004. Kriege et al. However. Tilanus-Linthorst M et al.

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

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

Premalignant lesions of the breast develop especially over the age of 40 (Hoogerbrugge N et al.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. Prophylactic surgery should be preceeded by interdisciplinary counselling and. if possible. A recent cohort study proved a breast cancer specific. The German Consortium for Hereditary Breast and Ovarian Cancer has developed guidelines for prophylactic surgery. Lancet Oncology 2006). Eur J Cancer 2006). ovarian cancer specific and overall survival benefit for PBSO (Domchek et al.de) .deutsche-krebshilfe. genetic testing within a familial breast cancer centre (addresses are deposited at www.

2012 Dec 7. J Clin Oncol 24: 2437-2443. Vasen HF. Rhiem K. 2. Neuhausen SL et al.14(6):R156. J Clin Oncol 27:5887-92. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. et al: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation Carriers. 2004 Metcalfe KA. Levin AM. et al: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. Lynch HT. Breast Cancer Res. Mooij TM. 3. 2015 Feb 1. Friebel TM. Friebel TM.136(3):668-77. 6. Graeser M. Collée JM. Ausems MG. Keymeulen KB. Rookus MA. Association of risk reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. Kets CM. Tollenaar RA. 5. HEBON. Isaacs C et al.Risk-reducing Interventions for BRCA1/2 Mutation Carriers Affected by Breast Cancer (26/32) No further information References: 1. Aalfs CM. et al: Predictors of contra-lateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: the Hereditary Breast Cancer Clinical Study Group. 2006 Metcalfe K. 7. 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. 2008 . Seynaeve C. Int J Cancer. Evans DG. Koppert LB. J Clin Oncol 22: 2328-2335.. 2009 Rhiem K. Pierce LJ. Ghadirian P. et al. Lancet Oncol (2006) 7: 223–229 Domchek SM. 4. Hooning MJ. Engel C. Singer CF. Lynch HT. Engel C. Heemskerk-Gerritsen BA. JAMA (2010) 304:967-75. Meijers-Heijboer HE.J Clin Oncol 26: 1093-1097. et al: Contra-lateral breast cancer in BRCA1 and BRCA2 mutation carriers. Domchek SM. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Lubinski J. Rebbeck TR. 8. Ghadirian P. Jansen L. Graeser MK.

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

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

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

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

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

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 .Risk Reduction for Ipsi.

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

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

1 www. Oxford LOE / in der DGGG e.V. Guidelines Breast Version 2015.Early Detection Mammography © AGO e. sowie in der DKG e.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. V.

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

Early Detection Clinical Examination © AGO e.V.ago-online. sowie in der DKG e. V. Guidelines Breast Version 2015. Oxford / AGO LOE / GR in der DGGG e.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.V.

Assessment of Breast Symptoms or Lesions © AGO Oxford / AGO LOE / GR e. Guidelines Breast Version 2015.V.de  MRI* 2b B +/-  Minimally invasive biopsy 1c A ++ * If clinical examination.V. V. in der DGGG e.ago-online. mammography and sonography do not allow a definite diagnosis .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. sowie in der DKG e.

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

V.4% [OR. 0. 3.001)]  Re-excision after initial breast conservation 11.87). 1.51 (P < 0.de  9 eligible studies (2 randomized trials. 1.71)  Overall mastectomy 25.6% versus 11. adjusted OR. 7 comparative cohorts)  3112 patients with BC  MRI versus no-MRI:  Initial mastectomy 16.4% versus 8. Guidelines Breast Version 2015.02 (P = 0.001).ago-online.2% [OR.22 (P < 0.V. adjusted OR. sowie in der DKG e. 257 .54 (P < 0.06 (P < 0. adjusted OR. Ann Surg 2013.95 (P = 0.MRI: Preoperative Staging © AGO e.001)] N Houssami et al.5% versus 18. in der DGGG e. 2. 1.001).V.1% [OR.1 www.

adjusted OR.008)]  Re-excision after initial breast conservation 10. 257 . 1.de  766 patients with invasive lobular cancer (ILC)  Initial mastectomy: 31. adjusted OR. 1.12 (P = 0.36 (P = 0. Guidelines Breast Version 2015.9% [OR.031).056).09)]  Overall mastectomy 43. V.1 www.V. in der DGGG e.56 (P = 0. 1. 0. 2.V. adjusted OR.56 (P = 0.12 (P = 0. Ann Surg 2013.0% [OR.2% [OR.0% versus 40.1% versus 24.64 (P = 0. sowie in der DKG e. 0.45).034)] N Houssami et al.MRI: Preoperative Staging in Lobular Invasive Breast Cancer © AGO e.ago-online.9% versus 18.

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

7 92 H/M 687 27 93 98.4 33 99. V.V.ago-online.1 M 594 97 77. sowie in der DKG e. Guidelines Breast Version 2015. in der DGGG e.V.1 MRT Autor Kriege 2004 Warner 2004 Hagen 2004 Leach 2005 Riedl 2007 Kuhl 2010 www.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) .4 89.MRI Screening in Women with High Familiar Risk © AGO e.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.

MRI Screening (High-risk) Problems © AGO e.V.de MRI in addition to mammography RR Assessment of benign lesions 3. sowie in der DKG e.1 www. Guidelines Breast Version 2015.43–4.86 Benign biopsies 1. V. in der DGGG e.ago-online.22–9.50 Benign surgical biopsies (MARIBS) False-negative MRI (MRISC) 2 22% .V.

ago-online. (%) Spec.V. sowie in der DKG e.de „Negative breast MRI findings should not be considered a sure marker of benignancy. Cases Overall accuracy (%) Sens. in der DGGG e.V. (%) 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.MRI and DCIS © AGO e.“ . V.3 - www.1 88 79. Study No.

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

” 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. 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. and that screening at best. The authors conclude “the imbalance suggests that there is substantial overdiagnosis. 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. 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. The estimate of overdiagnosis range from 1-10%. The population-based data from the United States (SEER-Cancer Statistics 1976 . . the relative risk reduction in breast cancer mortality from inivitation to mammography screening is estimated to be 20%. overdiagnosis and overtreatment. The chance for saving a woman’s life by population-based mammographic screening of appropriate quality is greater than that of over-diagnosis”. which were done a long time ago.2008) showed an increase in number of early-stage breast cancer. a marginal reduction at advanced stage. only has a small effect on the rate of death from breast cancer”. Professionals and women need to be infomed about the benefits and harms of cancer screening tests before making medical decisions.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 best “European” estimate of of breast cancer reduction is 25-31% for women invited for screening. They conclude: 1. false negatives. This includes clear and understandable information in absolute terms about false positives. and 28-38% for women actually screened.

The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer. Nyström L et al. Hsiu-Hsi Chen T. Lynch JW. Albert U. Duffy SW. 17:25-30 Duffy SW. 183:1991-2001 Ciatto S The overdiagnosis nightmare. 9. Heijnsdijk EA. J Med Screen 2011. 13. Moss S.1002/ijc. Int J Cancer2014. Olsen Ae. Absolute numbers of lives saved and overdiagnosis in breast cancer screening. Altland H.9:34 De Gelder R. 8. J Med Screen 2012.135:339-354 Armstrong K. 367:1998-2005 Broeders M. J Med Screen 2010. Berlin. Moye E. Duffy S. 1:31-38 Duffy S. 5. Alexander M. Recommendations on screening for breast cancer in average-risk women aged 40-74 years. et al. Williams S. Welch H. Farshid G. Duda V et al 2008 update of the guideline early detection of breast cancer in Germany. et al. 19(Suppl 1):5-13 . Effect of three decades of screening mammography on breast-cancer incidence. Clin Oncol 2009. Epidemiol Rev 2011. van Ravesteyn NT et al Interpreting overdiagnosis estimates in population-based mammography screening. Houssami NA. Olsen AH et al Absolute numbers of lives saved and overdiagnosis in breast cancer screening. 2. 17(1):25-30 Euroscreen Working Group. The impact of mammography screening on breast cancer mortality in Europe: a review of observational srudies. from a randomized trial and from the Breast Screening Programme in England. Hiller JE. N Engl J Med 2012. from a randomised trial and from the Breast Screening Program in England: Benefits and harms of breast screening. Breast Cancr Management 2012. A time for caution BMC Women’s Health 2009. 4. Ann intern Med 2007 Apr 3. Tabar L. et al. 7. 18:210-212 Bleyer A. Long-term benefits of breast screening. 3. 10.146(7):512-526 Beckmann KR. J Med Screen 2010.References: 1. Reynolds EE Screening mammography in women 40-49 years of age : a systematic review for the American College of Physicians. 19(Suppl 1):14-25 Canadian Task Force on Preventive Health Care. Ming-Fang Yen A. 11.29124 Beral V.33:112-121 Duffy S. CMAJ 2011. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. 12. J Med Screen 2012. Tabar L. DOI: 10. Roder DM A novel case-control design to estimate the extent of overdiagnosis of breast cancer due to organized population-based mammography screening. 6.

Imhof-Tas M. 23. Miccinesi G et al. Tabar L. 25.BMJ 2010. den Heeten GJ. Duffy S. Otto SJ. Gotsche PC Breast cancer mortality in organised mammography screening in Denmark: comparative study. Dershaw DD.) European Guidelines for Quality Assurance in Mammography Screening and Diagnosis. 26.S. van Doorne-Nagtegaal. The benefits and harms of breast cancer screening: an independent review. Breast Care 2011. Ann Intern Med 2009. 20. 17. Hacker A. 151:727-737 Paap E. Holland R. 21.J Am Coll Radiol 2010. beast MRI. Verbeek ALM. Review Heywang-Köbrunner SH . Bougatsos C. 15. Preventive Services Task Force. Lehman CD.). Törrberg S. 19(Suppl 1):42-56 Tabar L. Broeders MJM Breast cancer screening halves the risk of breast cancer death: A case referent study. Chen THH et al Swedish Two-County Trial: Impact of mammography screening on breast cancer mortality during 3 decades. Lancet 2012. 6:119-207 Independent UK Panel on Breast Cancer Screening.14. 340:1-6 Kalager M.K. de Koning HJ. Lee JM. Tyne. De Wolf C. 19.15/1: 45-56 . Reduction in Breast Cancer Mortality from the Organized Service Screening with Mammography: Cancer Epidemiol Biomarkers Prev 2006. van der Steen A.Karsa L. and other technologies for the detection of clinically occult breast cancer. v. HJ. Chen THH. Radiology 2011. Lee CI Imaging-based screening: Understanding the controversies. Am J Roentgenol 2014. 22. 380(1778):1786 Joergensen KJ. de Munck L. Overdiagnosis in mammography screening for breast cancer in Europe: a literature review. Chan B. Holland R. J Med Screen 2012. breast ultrasound. Zelen M. Humphrey L. Kopans D et al Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography. 16. Puthaar E (eds. Zahl PH. Olsen O Is screening for breast cancer with mammography justifiable? Database Syst Rev 2011 Jan 19(1): CD001877. Sedlacek S Advantages and disadvantages of mammography screening.203:952-956 Lee CH. Vitak B. Naik A. Gotsche PC. 18. Botterweck AAM. Langmark F et al Effect of screening mammography on breast cancer mortality in Norway N Engl J Med 2010. Screening for breast cancer: an update for the U.7(1):18-27 Nelson H.23:439-444 Perry N. Broeders M. et al. Office for Official Publications of the European Communities. 4th ed. Pandharipande PV.260:658-663 The Swedish Organized Service Screening Evaluation Group (Duffy W. Luxembourg 2006Puliti D.363(13): 1203-1209 Lam DL. The Breast 2014.

Radiology 2011.27. Yaffee MJ. 258(1):98-105 . Mainprize JG Risk of radiation-induced breast cancer from mammographic screening.

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

Dashevsky BZ. covering a wide range of alternative scenarios.11 (0. To estimate overdiagnosis within the “Age-Trial” Markov-modelling was performed and yielded the following results (Gunsoy N.7% of screen-detected cancers. Heijnsdijk EA.104: 1214-1220 .8 years (0.66-1. respectively. Arleo EK. 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. overdiagnosis was estimated as 0.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. 2.19) years. de Koning HJ Population-based mammography screening below age 50: balancing radiation-induced vs prevented breast deaths. The data have been underlined by study results of several service screening studies. Rosenblath R Screening mammography for women in their 40s: A retrospective study of the potential impact of U. 0. In our main analysis.6-1. Br J Cancer 2011. Drotman M. 72-99) and 82% (43-99). respectively. A sensitivity analysis. Draisma G.9%. 2012): “The sensitivity of mammography for invasive and in-situ breast cancers was 90% (95% CI. because the follow-up time is to short for this young age group.4-3. AJR 2013.Preventive Task Force’s 2009 Breast Cancer Screening Recommendations. Babagbemi K.S. and 0.2) for preclinical invasive breast cancer.“ References: 1. Reichmann M.3 (0.201:1401-1406 De Gelder R.04)). yielded a range of 0.5% to 2.05-0. Results also suggest annual screening is most suitable for women aged 40-49 in the United Kingdom due to short cancer sojourn times.” The authors conclude: “The extent of overdiagnosis due to screening in women aged 40-49 was small. 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.4) and 0. The screen-detectable mean sojourn time of preclinical non-progressive and progressive in-situ cancers was 1.

3. Duffy SW. single-arm. Warren Burhenne L Breast cancer screening with imaging: Recommendations from the Society of Breast Imaging and the ACR on the use of mammography. Berg W. Feig S. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years follow-up: a randomised controlled trial. 7. Radiology 2012. Sem Breast Disease 2004. Monticciolo D. Brenner J. Evans P. D’Orsi C. Bobrow L.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. Atwood MK. Kaplan HG Impact of mammography detection on the course of breast cancer in women aged 40-49 years. 8. 14:1-1. Effect of mammographic screening from age 40 years on breast cancer mortality a 10 years follow-up: a randomised controlled trial. J Am Coll Radiol 2010. Moss S. Monsees B. J Med Screen 2010. 368: 2053 – 2060 Moss SM. Sickles E. 17: 37-43 Lee CH. Trial Management Group. 7. breast ultrasound and other technologies for the detection of clinically occult cancer. Breast Cancer Res 2012. Modelling the overdiagnosis of breast cancer due to mammography screening in women aged 40-49 in the United Kingdom. Johns L. Kopans D. Cancer 2011. 117:714-722 Johns LE. 18-27 Malmgren JA. http://breast-cancerresearch. 10. Cuckle H. Garcia-Closas M. 6. Parikh J. Bassett L.11:1127-1134 Feig SA: Screening strategy for breast cancer. 6: 161-172 Hellquist BN. Mendelson E. Waller M. Dershaw D. The Lancet 2006. 4. Hendrick E. 9. Moss SM Randomized controlled trial of mammographic screening from age 40 (“Age Trial”): patterns of screening attendance. Lancet Oncol 2010. 5. Gunsoy N. . breast MRI.262(3):787 Moss SM et al. 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. Evans A. FH01 study.

otherwise occult. breast cancers. 21: 325-336 Berg W A. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0. Combined Screening With Ultrasound and Mammography vs Mammography Alone in Women et Elevated Risk of Breast Cancer. Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography. Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small. Niehoff A. et al.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR). 299 (18): 2151-216 . Dunser M. or about one third of the PPV of biopsies due to mammography. 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. inability to detect most DCIS cases.9 mm. Cormack J B. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate. Koekkoek-Doll P. Blume J D. operator dependency and lack of quality assurance. 90% with negative lymph node status. high false-positive rate. Biopsy rates were in the range 2. low ppv for biopsy.. References: 1.4-13. JAMA 2008.7%.7% for those biopsied due to positive ultrasound. six cohort studies of intermediate level of evidence (3b) were found. The arguments against ultrasound use as stand alone screening modality are reproducibility. Buchberger W. Semin Ultrasound CT MR 2000. 2.3%-4. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4.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. Only two of the studies included adequate follow-up of subjects with negative or benign findings. with PPV of 8. Obrist P. mean tumor size for those identified was 9.

566 patient evaluations. Chae EY. breast MRI. Duffy SW. 6. Heil J.E. Angnelli O. Franz D.82(8):e332-6. 4. Ciatto S. Golatta M. Schweitzer-Martin M. doi: 10. Junkermann H. and associated cost. 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. mammography and pathology results. Remida G. Bergonzini R.2013. Bellarosa S.M. Rom J. 12. Ghirardi. J.. Radiol Med (Torino) 2006. Mendelson E. Domschke C. 9. Radiology 2002. 8. Bani C. Harcos A. Ghirardi M. 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. Eur J Radiol. Arch Gynecol Obstet 2014 Oct 14. Rauch G. Sardo P. Corsetti V. Houssami N. Angelini O.44:539-44 Corsetti V.1016/j. 5. Kim HH.15(21):9101-5.3. 225: 165-175 .pub2. Cochrane Database Syst Rev. Rauch G. Ciatto S. Galligioni. Evaluation of an automated breast 3D-ultrasound system (ABUS) by comparing it with handheld ultrasound (HHUS) and mammography.ejrad. Ferrari A. Junkermann H. Comparison of the performance of screening mammography. Lichy J.CD009632. Sickles E.held ultrasound in the detection of breast cancer: an analysis of 5.4:CD009632. Scharf A. 7. 13.Radiol Clin North Am 2002. Heil J. Choi WJ. 111: 440-448 Corsetti V. Schott S. Epub 2013 Mar 27. J Am Coll Radiol 2010.03. Harcos A. Cancer 2011. Sohn C.1002/14651858.825 patient evaluations. physical examination and breast US and evaluation of factors that influence them: an analysis of 27. 40 (3): 431-41 Hellquist BN. Sohn C. Eur J Cancer 2008. Breast screening with ultrasound in women with mammography-negative dense breasts:evidence on incremental cancer detection and false positives. 10. bellarosa S.005. Bani C. 18-27 Golatta M. Cha JH. Ferrari A. Gordon PB. 7. Shin HJ. Comparison of automated breast volume scanning and hand. Role of ultrasonography in detecting mammographically occult breast carcinoma in women with dense breasts. Baggs C. 11. Hong MJ.Newhouse J. Kim H. Asian Pac J Cancer Prev. 2013 Apr 30. Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS).47(7):1021-1026 E. doi: 10. 2014. D’Orsi C. Ultrasound for breast cancer screening and staging. 117:714-722 Kolb T. breast ultrasound and other technologies for the detection of clinically occult cancer. Warren Burhenne L Breast cancer screening with imaging: Recommendations from the Society of Breast Imaging and the ACR on the use of mammography. Schuetz F. Scharf A. Houssami N. 2013 Aug. Eur J Cancer 2011 May.

Skaane P. Stoeblen F.Newhouse J. 17.577 diagnostic procedures. Kohler G. 26: 3943-3955 Schaefer KW. Heyer H. Warm M. Diagnostic performance and interobserver concordance in lesion detection with the automated breast volume scanner (ABVS). [Epub ahead of print] . Schulz K. Breast Cancer Res 2008. Kopans D. 18. Schimming A. Anticancer Res 2006. Acta Radiol 2014 Mar 28. Dershaw D. Thomas A. BMC Cancer 2009. Farrokh A. Radiology 2002. Kaminski-Hartenthaler A. 225: 165-175 Lee CH. Lichy J. Eben EB. 2013 Nov 12. Berg W. Hillemanns P. Non-palpable breast lesions in asymptomatic women: diagnostic value of initial ultrasonography and comparison with mammography.10:(DOI:101. Monsees B. BMC Med Imaging. Eur Radiol 2010. Klug U. 20:1085-1092 Wojcinski S. Duda V. Katalinic A. Jonat W. Hahn M. 21. Madjar H. Martin L. 19. Diagnostic performance and interobserver concordance in lesion detection with the automated breast volume scanner (ABVS).analysis of 102. Paepke S. doi: 10.Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study. Berzaczy D. Degenhardt F.13(1):36 Wojcinski S. Soergel P.. Gartlehner G. Kohlmann T. Soergel P. Kolb T. Nothacker M. 2013 Nov 12. BMC Med Imaging. Weinbrenner S. Van Noord MG.1186/bcr1831). Albert U: Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense tissue: A systematic review. Bassett L. Helbich TH. Feig S. Gyapong S. pii: 0284185114528835. 20. Monticciolo D. Chapman A. Boyd N: Potentials mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Schreer I Influence of additional ultrasound on cancer detection in a cohort study for quality assurance in breast diagnosis. 15. Comparison of the performance of screening mammography. Degenhardt F. Sandhaug M. 9: 335-344 Ohlinger R. Warm H. Evans P. Hillemanns P. Thaler K. Frese H. Schwesinger G.14. physical examination and breast US and evaluation of factors that influence them: an analysis of 27. Hendrick Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. Wodny M. Gyapong S. J. 16.825 patient evaluations. Heller M. Degenhardt F. Waldmann A.1186/1471-2342-13-36. Gullien R. Schulz-Wendtland R. Wefelnberg C. Grunwald S. Farrokh A. Brenner J.13:36.

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

Stalsberg H. Wu C. AJR 2005. Pan L. Randomized trial of breast-self-examination in Shanghai: Final results. Cancer Screening in the United States. Hu Y. Buist D D. 8. CA Cancer J Clin 2008. 7. 58: 161-179 Thomas D. Ray R. Allison C. Lin M. Cokkinides V. Seger D. Evans I. Brawley O W.6. Oestreicher N. 94 (19): 14445-1457 . 2008: A Review of Current American Cancer Society Guidelines and Cancer Screening Issues. Gao D. Self S. Porter P. J Nat Cancer Inst 2002. Chen F. Contriaty Z. Lehmann C. 184: 428-432 Schmith R A. The incremental contribution of clinical breast examination to invasive cancer detection in a mammography screening program. White W. Zhao G. Wang W.

Breast Cancer Res Treat 2007. 14: 1725-1731 . Risso GG. References: 1. Brancato B. Koretz M. Makarov V. Arch Gynecol Obstet 2006. Ciatto S. 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. Linz H.274 (2): 63-73 Fischer U. Cella C. Shcharynsky S. 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. Strano S. 33: 47-52 Fahrbach K. Baum F. Digital breast tomosynthesis allows an increased breast cancer detection rate and its use is recommended for screening centers in population-based trials. 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). 101(3): 291-7 Crystal P.Assessment of Breast Symptoms or Lesions (8/15) Further information: If clinical examination. Bianchi S. 3. von Heyden D et al The influence of preoperative MRI of the breasts on recurrence rate in patients with breast cancer. Ross SD. In case of suspicious microcalcifications extensively distributed in mammography several percutaneous biopsies should be performed before deciding upon mastectomy. Sledge I. Houssami N. Accuracy and underestimation of malignancy of breast core needle biopsy: the Florence experience of over 4000 consecutive biopsies. 2. MRI has a high sensitivity but a low specificity to allow definitive diagnosis. Zachariae O. Clin Ultrasound 2005. A comparison of the accuracy of two minimally invasive breast biopsy methods: a systematic literature review and meta-analysis. Catarzi S. mammography and ultrasound are not conclusive. 4. Minimally invasive biopsy allows definitive diagnosis in most cases at reduced expenditure. Eur Radiol 2004. morphological diagnosis based on biopsy material is warranted. Bonardi R. Ambrogetti D.

23:76-80 2. Gilbert FJ. Durand MA. Strudley C. Skaane P. Kasumi F. Gullien R et al Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population –based screening program. Bartel C. Eur Surg Oncol 2004. Eur Radiol 2012. Greer LN. Eur J Radiol 2007. Miller DP.-Köbrunner SH. Rosasco R. Morrish O. Pellegrini M.311(24):2499-2507 5. F Bernardi D. Breast Cancer 2007. Bandos AI. Raspe H. Gatsonis C. Monetti F. Fanto C. Diagnostic ultrasonography and mammography for invasive and non-invasive breast cancer in women aged 30 to 39 years. 356: 1295-1303 Perlet C. Rafferty EA. Greenberg JS. Macaskill P. Ciatto S. Cink TM. Cavagnetto F. Friedewald SM. Plecha DM.a multicentre . Hayes MK. 10. The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme . N Engl J Med 2007. Rose SL. Cancer 2006. 62 (2): 273-282 Tomosynthese 1. 9. Cooke J. Rescinito G. Heywang. Purushothaman H. Dobson HM. Heinig A. Montemezzi S.5. et al MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. Calabrese M One-to-one comparison between digital spot compression view and digital breast tomosynthesis. vacuum-assisted breast biopsy: results from a European multicenter study of 538 lesions. Magnetic resonanceguided. Sittek H.Carlson KL. Kuhl CK. Houssami N Incremental effect from integrating 3D-mammography (tomosynthesis) with 2Dmammography: Increased breast cancer detection evident for screening centres in a population-based trial. Conant EF Breast cancer screening using tomosynthesis in combination with digital mammography. 106: 982-990 Ijima K. Akiyama F. Willsher P. Young KC. Taourel P. Katalinic A. Duncan KA. Sakamoto G. Anderson I. Astengo D. 14 (2): 229-33 Schelfout K. JAMA 2014.267(1) 47-56 3. 6. Michell MJ. Tuttobene P. Barke DO. Copit DS. Caumo. 96:157-161 Lehman CD. The Breast 2014. Bricolo P. 30: 501-507 Van Goethem M. Kersschot E et al MR imaging of breast lesions and effect on treatment. Taglliafico A. Makita M. Gillan MG. Miyagi Y. 8. Schreer I: Beyond mammography screening: quality assurance in breast cancer diagnosis. Casselman J. Tada K. Schelfout K. Brunelli S. Tucker L. 7. Valentini M. Br J Cancer 2007. Radiology 2013. Duffy SW. Lim YY. Van Goethem M. Astley SM. Nishimura S.22:539-544 4. Kersschot E et al MR mammography is useful in the preoperative locoregional staging of breast carcinoma with extensive intraductal component.

Cosgrove DO. Junkermann H. Thomas A. Int J Womens Health 2013 Sep 30. Juhan V. doi: 10. Bandos AI. Hofwind S. retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone. Whelehan P. Henry JP. Ying L. Li DW. Schott S.2013. Rathfon GY. 3. Gullien R Two-view breast tomosynthesis screening with synthetically reconstructed projection images. Golatta M.8(10):e76322. Radiology 2014:271(3)655-663 Zuley ML. What are the characteristics of breast cancers misclassified as benign by quantitative ultrasound shear wave elastography? Eur Radiol. Cavanaugh BC. Degenhardt F. Locatelli M. Vinnicombe SJ.82(11):e676-9. Ekseth U.Characterization of focal breast lesions by means of elastography.5:61 . Tourasse C. doi: 10. Gur D Digital breast tomosynthesis versus supplemental diagnostic mammographic views for evaluation of non-calcified breast lesions Radiology 2013. Berg WA. 2013 Oct 18. Xie Y. Ohlinger R. Song YJ. Mendelson EB. Röfo 2013 Sep. Stavros AT. Performance of shear wave elastography for differentiation of benign and malignant solid breast masses.19(4):1-136.ejrad. Wojcinski S. PLoS One. Ganott MA. Heil J. 2013 Dec 11. Health Technol Assess. Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses. Bandos AI. Brandhorst K. Fang YX. Sadigh G. McLean D. Hillemanns P. Sohn C. Li G. Jordan LB. Jebsen IN.1016/j. Tardivon A. Eur J Radiol 2013 Nov. Doré CJ. Gao J. Catullo VJ. 7.6.266(1):89 Elastography 1. Radiology 2012 Feb.3310/hta19040. Skaane P.185(9):816-23. CohenBacrie C.262(2):435-49. 5. Svensson WE. Schweitzer-Martin M. Purdie CA. Hooley RJ. Rauch G. Sack I. 2. Hubbard S. Eben EB. Krager M. Acoustic radiation force impulse imaging with Virtual Touch™ tissue quantification: mean shear wave velocity of malignant and benign breast masses. Sumkin JH. 2015 Jan. Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ). Deng ZJ. 4. Schäfer FK. Lu AH. Comparison with digital breast tomosynthesis with full-field digital mammographic images. Haakenaasen U. BaluMaestro C. Evans AJ. Kelly AE. Yin TS. Fischer T. Gay J. Harcos A. Tang KF. Izadi M. [Epub ahead of print] 6. BE1 Investigators.029.06. Thomson K.

2013. Schulz-Wendtland R. Heil J. 2.13(1):36 . Junkermann H. Degenhardt F. Skaane P. Epub 2013 Mar 27. Gyapong S.15(21):9101-5.566 patient evaluations. Rauch G. Arch Gynecol Obstet 2014 Oct 14. Hillemanns P.82(8):e332-6. Scharf A. Kim HH. Rauch G. [Epub ahead of print] 5.1016/j. Hong MJ. Schuetz F. Sohn C. Scharf A. Heil J. Choi WJ. Shin HJ. mammography and pathology results. Harcos A. Baggs C.ejrad. Golatta M. 4. Gullien R. Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS). Golatta M. Farrokh A. Wojcinski S. BMC Med Imaging 2013 Nov 12. Cha JH. Sohn C. Evaluation of an automated breast 3D-ultrasound system by comparing it with hand-held ultrasound (HHUS) and mammography. Domschke C. doi: 10.005. Chae EY. pii: 0284185114528835. Eur J Radiol 2013 Aug. 3. Kim H. Franz D.03. Junkermann H. Asian Pac J Cancer Prev 2014. Comparison of automated breast volume scanning and hand. Schweitzer-Martin M.held ultrasound in the detection of breast cancer: an analysis of 5.Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study. Acta Radiol 2014 Mar 28. Soergel P. Sandhaug M.Automated Breast Ultrasound (ABUS) 1. Diagnostic performance and interobserver concordance in lesion detection with the automated breast volume scanner (ABVS). Schott S. Harcos A. Rom J. Eben EB. Stoeblen F.

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

) Houssami N. BMC Cancer 2008. Turnbull LW. Ann Surg Oncol 2014. Dixon M. Vapiwala N. 59:290-302 Houssami N. Tuttle TM. Purdie CA. Houssami N. Turner R. 119: 415-422 . The Breast Journal 2004. Breast Cancer Res Treat 2008. Lord. RM. Thomson K. Breast Cancer Res Treat 2010. 6. JCO 2009. 10 (Suppl. 2013 Dec 4. McCready DR. 18: 259-276 Mann RM. 8. Sever AR. Jordan LB. Macaskill P. Buckens CFM. Verkooijen HM Value of preoperative ultrasound guided lymphnode biopsy for preventing completion axillary lymphnode dissection in breast cancer: a systematic review and meta-analysis. Renne G.21:51-59 Evans A. 12. 3. Veldhuis WB. 8: 275 Brennan ME. Mali WPTM. 10. Hoogeveen Y L. Solin L J An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. Whelehan P. 4. 5. Macaskill P. Blickman J G. Bozzini A. Ciatto S. Irwig L. 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. van Dahlen T. Magn Reson Imaging Clin N Am 2010. et al.CA Cancer J Clin 2009. Thompson A. 107 (1): 1-14 Mann RM The effectiveness of MRI imaging in the assessment of invasive lobular carcinoma of the breast. [Epub ahead of print] Harms SE.2. JCO 2008. Macaskill P. Michie CO. 7. Loo CE. J Clin Oncol 2014. Warren. 27(33):5640-5649 Diepstraten SC. van den Bosch MAAJ. 11. Sensitivity of imaging for multifocal-multicentric breast carcinoma. Dixon M. MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. Meneghetti L. Report of the Working Croups an Breast MRI. 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. 26(19):3248-3258 Houssami N. Lord S.Does shear wave ultrasound independently predict axillary lymph node metastasis in women with invasive breast cancer? Breast Cancer Res Treat. Rauchhaus P. 9. Warren. Wobbes T et al The impact of preoperative MRI on the re-excision rate in invasive lobular carcinoma of the breast. R. Boetes C. Vinnicombe S. SJ.32(5):392-401 Mann R M. 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.

3. Vapiwala N. 14(1):1 -182 Van Goethem M. McCready DR. Manca A. 19: 3-6 Sardanelli F. Biltjes J. Hanby A. 368: 2053 – 2060 Peters NHGM. Borisch B et al Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. WalkerS on behalf of the COMICE Trial. Eur J Surg Oncol 2006. Olivier C. Boetes C. J Clin Oncol 2014. 32 (9): 901-910 Moss SM et al.MRI: Preoperative Staging (10/15) No further information References: 1. Harvey I. Macaskill P. van Esser S.32(5):392-401 Sardanelli F Overview of the role of preoperative breast MRI in the absence of evidence on patient outcomes. Brown J. Porizel P. Turner R. Eur J Cancer 2010. Solin L J An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. Eur J Cancer 2011. 46: 1296-1316 Turnbull LW.47(6):879-886 . 6. The Lancet 2006. van den Bosch MAAJ et al Preoperative MRI and surgical management in patients with nonpalpable breast cancer: The MONET-Randomised Controlled Trial. 2. Brown SR. 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. Magnetic resonance imaging in breast cancer. Sculpher M. Schelfout K. Breast 2010. Effect of mammographic screening from age 40 years on breast cancer mortality a 10 years follow-up: a randomised controlled trial. Tuttle TM. Houssami N. Turnbull LW. Walker LG. 4. Napp V. Tjalma W. 5. Verslegers J. Drew P.

2:621. Morrow M. doi: 10. Verkooijen HM.257(2):249-55.1097/SLA. ultrasound and magnetic resonance imaging findings correlated with proportion of the lobular component. Pijnappel RM.MRI Preoperative Staging in Lobular Invasive Breast Cancer (11/15) No further information References: 1. van den Bosch MA. 2013 Nov 20. . doi: 10. Menezes GL. Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes. El Sharouni MA.0b013e31827a8d17. 2013 Feb. Turner R. Invasive ductolobular carcinoma of the breast: spectrum of mammographic. Postma EL. Springerplus.1186/2193-1801-2-621. Houssami N. Ann Surg. van Diest PJ. 2.

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

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

Kok T. 9. Schild HH Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial.57(2):75-89 . Bergers E. Weigel S. Helbich TH Magnetic resonance imaging of the breast improves detection of invasive cancer. Invest Radiol 2011. Breast Cancer Res Treat 2010. Wagner T. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: A national cohort study. Int J Cancer 2014. 7. Warner E. Boetes C Assessment of falsenegative cases of breast MR imaging in women with a familiar or genetic disposition. Ponhold L. Honning MJ et al. Heindel W.13(20)6144 Saadatmad S. Clin Cancer Res 2007. Flöry D. 11.6. Kroiss R. 119: 399-407 Riedl CC. Leutner C. 10. Loo CE. Reiser M. 135: 2940-2949 Sardanelli F. Schrading S. Podo F. Rijnsburger AJ. König R. Klijn JGM.28:1450-1457 Obdeijn IMA. and Canadian studies combined. Heijnsdijk EAM. ultrasonography and contrast-enhanced magnetic resonance (The High Breast Cancer Risk Italian 1 study. 8. Fuchsjäger M. Rieber-Brambs A. MARIBS. preinvasive cancer and premalignant lesions during surveillance of women at high risk for breast cancer. Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carries and effects of MRI Screening-MRISC. 21: 1458-1468 Kuhl C. Wasser MNJ.Tombach B. Gilbert FJ et al. Bieling H. Arand B. Weber M. Vos JR. J Clin Oncol 2010. Final results. Cancer Epidemiol Biomarkers Prev 2012. Santoro F et al Multicenter surveillance of women at high genetic breast cancer risk using mammography. Nordhoff D.

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

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

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

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

in der DGGG e.V.V.de www.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 . V.ago-online.  Guidelines Breast Version 2015.ago-online. sowie in der DKG e.1   www.General Principles for Histopathologic Examination of Breast Cancer Specimens © AGO e.

ago-online. V.72 h Use of neutral buffered formalin 5 D ++ 5 D ++ 5 D ++ 5 D ++ 5 D ++ .Preanalytics: Fixation © AGO e.72 h for core biopsies Optimal fixation time for resection specimens: 12 . Guidelines Breast Version 2015. sowie in der DKG e.V.1    www. Oxford / AGO LoE / GR in der DGGG e.V.ago-online.de  Minimize time to fixation (cold ischemia time) Minimal fixation time of 6 hours for optimal antigen preservation Optimal fixation time 6 .de  www.

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

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

Workup: Core Needle Biopsies (US-guided or stereotactic) © AGO e.ago-online. V. calcifications).V. Oxford / AGO LoE / GR in der DGGG e. 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. sowie in der DKG e.de .V.1  Routine workup in step sections (14G: 3 sections / 11G.de www. 8G: 6–8 sections) 5 D ++  Correlation with imaging (density.ago-online. Guidelines Breast Version 2015.

photodocumentation or diagram 5 D + www.V. 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.ago-online. Oxford / AGO LoE / GR in der DGGG e. Guidelines Breast Version 2015.de www. sowie in der DKG e. at least 1 tissue block every 1 cm 5 D ++  Inking of resection margins.Workup: Breast-Conserving Specimens © AGO e. Sampling of resection margins in all dimensions 5 D ++  Documentation after slicing using specimen radiography.de .

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

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

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

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.V. in der DGGG e.1  Histologic tumor typing according to WHOClassification. mixed type  Pure types: > 90% special tumor type Examples: tubular or cribriform Ca.Reporting: Histologic Tumor Type © AGO e.ago-online. V. sowie in der DKG e. Guidelines Breast Version 2015.de www.ago-online.de Oxford LoE / GR AGO 3b ++ C . www.V. (4th ed..

de www. V. Guidelines Breast Version 2015.ago-online. may be used 5 D ++  Grading of DCIS according to WHOClassification. pure nuclear grading or additional criteria. 2012) 5 D ++  Reporting of tumor grading in numeric form (e.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.V.de AGO . such as Ki-67 proliferation fraction.V.ago-online. (4th ed.g.Reporting: Grade of Malignancy © AGO Oxford LoE / GR e. sowie in der DKG e.. G3) 5 D ++ www. in der DGGG e.

de www.V.ago-online. in der DGGG e.V.1 www. Guidelines Breast Version 2015.ago-online.Reporting: Tumor Size and Total Extent of Tumor © AGO Oxford LoE / GR e. V.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 ++ . sowie in der DKG e.

V.) pT 1 . V. in der DGGG e. 5 D AGO ++ . Criteria for pT4a/b/c/d must me met.Reporting: pTNM © AGO Oxford LoE / GR e.3: Invasive tumor size (largest focus in case of multiplicity) pT4: Invasion of dermis alone does not qualify as pT4.de pT4d: Negative skin biopsy does not rule out pT4d (inflammatory carcinoma).de www. sowie in der DKG e. pM: pM1 indicates any non-regional disease.V. Guidelines Breast Version 2015.1  Use of current UICC classifikation (7th ed. Use of MX is not recommended. www.ago-online. except 2nd primary contralaterally.ago-online.

V.1    www.V.g. tumor in multiple specimens) . Guidelines Breast Version 2015.de www. in der DGGG e.V. sowie in der DKG e.Reporting: Margins of Resection and R-Classification © AGO Oxford LoE / GR e.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.ago-online.

ago-online.ago-online.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. sowie in der DKG e.V.1 www. V. Guidelines Breast Version 2015.de www.Reporting: Lymphovascular invasion © AGO Oxford LoE / GR e. prognostic significance not established 5 + D ++ . in der DGGG e.

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

de www.1  Identification of tumor bed. 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.de  . in der DGGG e. Guidelines Breast Version 2015. 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. and absence of angioinvasion or LN metastases.Reporting: Evaluation after Neoadjuvant Chemotherapy © AGO Oxford / AGO LoE / GR e.ago-online.V.V. sowie in der DKG e.ago-online. V.

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

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

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 + +/- .V. V.1 www.V. Oxford / LoE / GR in der DGGG e.de www.ago-online. Guidelines Breast Version 2015. sowie in der DKG e.Additional special studies: Molecular analysis of ER/PgR status © AGO e.ago-online.

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

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

ago-online.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 - +/- . sowie in der DKG e.ago-online.1 www.V.Additional Special Studies: Molecular Analysis of HER2 Status © AGO e.V. V. Oxford / LoE / GR in der DGGG e.de www. Guidelines Breast Version 2015.

de AGO . Guidelines Breast Version 2015.V. V. sowie in der DKG e. in der DGGG e.Special studies: Evaluation of Ki-67 Score © AGO Oxford / LoE / GR e.de www.ago-online.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.

recurrence score etc.  Guidelines Breast Version 2015. ratio <2)) None of the available markers (Ki-67.V. sowie in der DKG e. RNA measurements are not suited for the definition of intrinsic types for purposes of therapy .) can reliably discriminate between luminal A and luminal B type Although derived from RNA expression studies. luminal A/B-Typ. 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.V. HER2+ for HER2-type.1   www. in der DGGG e.de  www.ago-online. 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.Intrinsic Breast Cancer Types (Molecular and Immunohistochemical Definitions) © AGO e.ago-online.de  Currently there is no generally accepted and proven translation of molecularly defined types (basal. grading. V.

ago-online. in der DGGG e. Guidelines Breast Version 2015.V. grading) .1 www. tumor type.Quality Assurance: Immunohistochemistry © AGO e.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. sowie in der DKG e.g.ago-online.

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

Quality Assurance: Reporting © AGO e.V.de www.1 www.de  Responsibility of one or two pathologists with special expertise in breast pathology  Regular interdisciplinary conferences with radiologic-pathologic correlation  Participation in quality circles . V.ago-online. in der DGGG e.ago-online. Guidelines Breast Version 2015.V. sowie in der DKG e.

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

org/download/pdf/s3_ll_mammaca_11_02_2008. 9. In: Manual der gynäkologischen Onkologie. Törnberg S. 2006 Royal College of Pathologists (UK) (2005). de Baca ME. Hum Pathol (2006) vol. Smith BL. 7. 985-8 . Reinthaller.nhs. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008. http://www.uk/breastscreen/publications/nhsbsp58.ago-manual.at/inhalt/i-mammakarzinom/15pathologie/ Schweizerische Gesellschaft für Pathologie (2002). Kleer C. Hayes DF. http://www.133(10):1515-38.senologie.sgpath. von Karsa L.ch Perry N. Winer E. Broders M. Deutsche Krebsgesellschaft und beteiligte medizinisch-wissenschaftliche Fachgesellschaften (2008).cancerscreening. Weaver DL. 2009 Oct. Hefler (Hrsg. Recommendations for the reporting of breast carcinoma.2. Arch Pathol Lab Med. Leitlinien zur Sicherung und Förderung der Qualitätskontrolle. http://www. Mammakarzinom Pathologie. de Wolf C. Office for Official Publications of the European Communities. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Luxembourg. NHSBSP guidelines for pathology reporting in breast disease.) http://www. 5. Recommendations for quality assurance and improvement in surgical and autopsy pathology. O'Malley FP. 6. Bose S. Lax.senologie. Reiner-Concin. 4. L. 3.org/download/pdf/s3_brustkrebsfrueherkennung_2008.html Association of Directors of Anatomic and Surgical Pathology. College of American Pathologists. Puthaar E (eds) European guidelines for quality assurance in breast cancer screening and diagnosis. 37 (8) pp. S. Page DL. Mod Pathol. Fitzgibbons PL. 1996 Jan. Interdisziplinäre Leitlinie Diagnose und Therapie des Mammakarzinoms der Frau.pdf Association of Directors of Anatomic and Surgical Pathology (1996). 8. Chen YY. Connolly JL. Tan LK.pdf Lester SC. Arbeitsgemeinschaft für gynäkologische Onkologie (AGO) der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) A. Holland R. Members of the Cancer Committee.9(1):77-81. http://www.

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

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

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

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

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de from clinical trials needed for optimal biomarker validation has not yet been established * * Simon. e. in sowie sowie inder derDKG DKGe. Paik.ago-online.V. inder derDGGG DGGGe. J Natl Cancer Inst 101: 1446-1452.de This sample collection may not represent the reported outcome of the clinical trial.V. e.1 2015.V. An optimal percentage of sample needed www. www. Hayes. V.Critical Issues Regarding LoEs for Biomarkers ©©AGO AGO e. The prospectively-planned retrospective validation of a biomarker (CTS level 1) may be biased by an insufficient number of clinical trial samples used for the biomarker analysis.1 Version It needs to be emphasized that the levels of evidence obtained by Oxford-criteria and CTS-criteria cannot be directly compared.V. e. 2009 .ago-online. in Guidelines Breast Breast Guidelines Version2015. V.

in der DGGG e. sowie in der DKG e.1 Factor LoEOx2001 GR AGO  ER / PgR 2a B +  HER2 (IHC.ago-online. V.V.de § Validated clinical data only available for this assay . during or after treatment 2b B +  Mitotic activity Index (MAI) 1a A + www. Guidelines Breast Version 2015. FISH) 2b B +  ER / PgR / HER2 as surrogate markers for molecular subtypes 2b B +  uPA / PAI (Femtelle® ELISA)§ in N0 1a A +  Proliferation markers  Ki-67 before.Prognostic Factors II in Early Breast Cancer © AGO e.V.

ago-online. 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. 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-/+.de Registration www.de $ 21 gene Recurrence score (Oncotype DX®) $ Genomic Health 21-gene recurrence score prognostic N-/+.Commercially Available Molecular Tests © AGO 70 gene signature (MammaPrint®) $ e. V.V. ER+ HER2endocrine treated Yes CE-Mark FDA 510(k) Clearance . Guidelines Breast Version 2015.1 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-/+.V. sowie in der DKG e. <61 Jahre Clinical Validation yes www.

V.ago-online.ago-online.V.de Prospective evidence MINDACT (pending) (completed) (n0. ongoing) www. HER2 positive patients may have been included - . completed) - RxPONDER (n1.de $ Validated clinical data only available for this assay * Trial performed bevore HER2 testing.Commercially Available Molecular Tests © AGO 70 gene signature (MammaPrint®) $ e.1 21 gene 8 gene signature PAM 50 Recurrence score (Endopredict®) $ (Prosigna®) $ (Oncotype DX®) $ Prognosis after 5 yrs not separately shown yes (late recurrences) Predictive impact (chemotherapy poorly validated yes * benefit) Prospectiveretrospective evidence (% of recruited patients) Multicenter validation yes yes not shown not shown NSABP B-14 (14%) NSABP B-20 (28%) ABCSG 6 (19%) ECOG 9127 SWOG 8814 (40%) ABCSG 8 (36%) ATAC (30%) MA.5 (66%) ABCSG 8 (44%) ATAC (16%) TAILORX www. Guidelines Breast Version 2015.V. in der DGGG e. sowie in der DKG e.12 (59%) MA.

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Tamoxifen www.de  Menopausal status 1c A ++  ER/PgR/HER2 as single markers 1c A -  Lobular subtype 2b B +  Ki-67 high (published cutoffs > 11 % and >14 %) 2b B +/-  Obesity (BMI >30 kg/m²) 2b B +/- .V.ago-online. sowie in der DKG e.V.1  AGO  ER/PgR status 1a A ++  IHC staining intensity (ER/PgR) 1a A + 2b D - 1c A ++ Tamoxifen CYP2D6 polymorphism Ovarian ablation   GR Endocrine therapy   LoEOx2001 Menopausal status Aromatase inhibitors vs. V. Factor  Guidelines Breast Version 2015.Predictive Factors – Endocrine Therapy © AGO e. in der DGGG e.

V. sowie in der DKG e.de $ Validated clinical data only available for this assay . V.V.ago-online. Factor LoEOx2001 (§ LoEOx2009) GR (§ CTS) AGO 1a A ++ uPA/PAI1 (Femtelle®) ELISA $ 1a A + 21 gene recurrence score (Oncotype DX®) $ I§ B§ +/- Guidelines Breast Version 2015.Predictive Factors – HER2 Targeted Therapy / Adjuvant Chemotherapy © AGO e. in der DGGG e.1 Anti-HER2-Therapy  HER2  Adjuvant Chemotherapy    www.

Cell Search®)   Prognosis at baseline I Ba +  Early Response assessment (3w) I B + I Aa -* Therapy decision solely based on dynamics of CTC numbers over time or CTC phenotype  www. in der DGGG e.ago-online.de * Study participation recommended .1 Factor LoE2009 CTS AGO Circulating tumor cells (CTC in blood. V.V. sowie in der DKG e.Prognostic factors – Metastatic breast cancer © AGO e.V. Guidelines Breast Version 2015.

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

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

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

.. P. J.. Taylor. However. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100. Y... McGale. D. 432–444. et al. S. Swain. R.C.. Gray.000 women in 123 randomised trials.. C... Because of this. Wang. K. Bergh. Lancet 379. References: 1. H. Cutter. M. A.C. doi:10.Low Absolute Risk Implies Low Absolute Benefit (4/20) Further information: Adjuvant chemotherapy reduces breast cancer mortality by one third. Albain. M. ..... Especially in ER positive tumors one has to weigh the benefit against potentially chemotherapy-induced side effects like chronic heart failure and leucemia / MDS. the benefit is closely related to the absolute risk of this individual patient. proper risk assessment is mandatory. & Piccart. R. Godwin. Darby. J. Davies. 2012. Peto.1016/S0140-6736(11)61625-5. S.. Clarke. Di Leo. C. Pan.

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

Simon RM. McShane LM.evidence if validated with consistent results.6858. Iain Chalmers. Sauerbrei W. J. 3. quiz S33. Cancer Inst. 101 (21): 1446–1452. Febbo PG. Bast RC. 23 (36): 9067–9072. 6. (5. Oncol.1200/JCO. Desch CE.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. J. (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Compr Canc Netw 9 Suppl 5: S1-32. Cancer Inst. Jeremy Howick. Available: doi:10. Oxford Centre for Evidence-Based Medicine. Marzo AM de. Oncol. 2. (2005) Reporting recommendations for tumor marker prognostic studies.01. Clin. Available: doi:10. 2009 are used as applicable. McShane LM. Natl. Ivan Moschetti. Gion M et al. Hayes DF. J. Kemeny NE et al. Paik and Hayes. and Hazel Thornton. 5. Carl Heneghan. J.0454. References: 1. Hammond ME et al. Bob Phillips.1200/JCO. Taube SE. 4. Aldape KD. 88 (20): 1456–1466. Fritsche H. Hayes DF (2012) Publication of tumor marker research results: the necessity for complete and transparent reporting.1093/jnci/djp335. Altman DG. Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence (Background Document).2012. Trish Greenhalgh. (2011) NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. 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. Alessandro Liberati. Available: doi:10. Paul Glasziou.42. Ladanyi M. 30 (34): 4223–4232. Clin. . Natl. Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. Paik S.2004.

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

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

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

D. B. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies Ann Oncol.. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011.20:1319-39. (2011) NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. 4.ca/cgi/content/full/158/3/DC1) NCCN 2008: http://www. Ann. doi: 10. 3. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. 25(10): 1901–1914. & Senn. Published online Apr 27. Chan et al.-J. Hammond ME et al.S. 2011..medscape. A.Prognostic Factors I in Early Breast Cancer (9/20) No further information References: 1. Wood. Oct 2014. Ann Oncol. 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. 22.cmaj. Statement: Obesity 1. Ladanyi M. . 2006: http://www. S. Marzo AM de. quiz S33.C. 2. H. Thürlimann. J Clin Oncol. 2008.. J Natl Compr Canc Netw 9 Suppl 5: S1-32. Canadian Medical Association (CMA. 7. Gelber.com/files/editorial/articles/548868/breast. Oncol. W. 5. Goldhirsch et al. 2007 Nov 25 (33): 5287-5312 Goldhirsch. 6.. R. A. 1736–1747 Febbo PG. Coates. M.pdf ASCO 2007: Harris L et al. D. Aldape KD. : Personalizing the treatment of women with early breast cancer: highlights of the St.1093/annonc/mdu042 PMCID: PMC4176449. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. 2014.

Gong J. Yuan P.4:7480. Sci Rep. Liu L. Liu C. Sun Y. Xia X. Chen W.1038/srep07480. Chen X. Body mass index and risk of breast cancer: a nonlinear dose-response meta-analysis of prospective studies. Rui R. 2014 Dec 15. Li J.2. . doi: 10.

C. Amendoeira. V. Allred. Coleman.L. McShane.A. Love.1200/JCO. Perez. Paik. A.. N. Bussolati.. doi:10. 118–145.. M. Bianchi.. Schwartz.. J.C. S. M.L. J. Hanna. M. Wolff.C. J.. Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and .. K. 2007. Clin..H..25. Goldstein. Mangu..D. W... Cote.. S.2775. 3.. et al.. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.... I. 28. C. et al. Dowsett. Hammond. Connolly. Fitzgibbons.2006.. Boecker. Hagerty. & Rhodes..G. E. Dervan. Fitzgibbons. Miguel. P.Reproducibility (10/20) Further information: Conventional pathology and immunohistochemistry is for methodological reasons subject to high inter-observer varaibility/variable reproducibility. R.. G. Hagerty. Pegram.. Allred. C.. D. Lester. Faverly. Press. 1999.. S. Francis. A. de. M.J.. Apostolikas.L. Oncol.H..P. L. S.P..F. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.F.09. Sloane. D.E. M. K.. Thus the clinician should be aware of potential problems and pitfalls when decision for adjuvant treatment is taken together with the patient. K..N. Drijkoningen. Hayes. Hammond. W. A. R. D. doi:10.E.2009. Bellocq.. M. Eusebi.L.B. J..M. Langer. D.. MIRROR trialists report upgrading of N0 status by central pathological review in an comparable amount.. C. & Miller. G. Hicks..1200/JCO..S... P. Clin..E. 2010. D. Elston. 2. M. Hayes. McShane. P. Oncol. A. & Gad. J. R. D. 2784–2795. ASCO-CAP guidelines estimate discordance between central and local pathology in about one fifth of cases for ER and PgR and HER2 status. Badve. 25. L.6529. P... N.W.. et al. Dowsett.M. References: 1.

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Ki 67 data from GEPARTRIO have been updated by Denkert et al. M. J. C. . Correlations to survival parameter may differ according to individual parameters and are precised in the first slides. C. Müller. Schrader. Törne. Tumorassociated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. Engels.23. I. Kronenwett. M.. J. The FDA Metaanalysis confirms preexisting data from neo ALLTO. Weichert.. S.7370... References: TIL 1.. K. 2010. R. (SABCS 2012) and confirmed a strong correlation if cut-off values of ≤15 and > 35 are presumed to define low and high risk populations..M. B. Komor. doi:10... Denkert.. Solbach. C. W. It helps to define those subgroups of patients who benefit from NACT in terms of downstaging/pCR. M. Neosphere and GEPAR-trials demonstrating lower pCR rates in tumors coexpressing HR and HER2 compared to HER2+/HR-... Darb-Esfahani. Hanusch. von. et al. S. For the genomic signatures there are new data from the I-Spy trial confirming the predictive value of PAM50 and Mammaprint for pCR after neoadjuvant chemotherapy and – for the first time – correlation with 3 yr dfs. 105–113. Noske. 28. & Dietel.trialists and remains widely unchanged.. Loibl.Neoadjuvant Systemic Chemotherapy – Response Prediction I (16/20) Further information: This slide is based on the evidence mainly from analyses done by GEPAR. C. Oncol.. A. Roller. Clin. Budczies.1200/JCO.2009.

Kronenwett. Weichert.. B. M.. Budczies. Engels. Oncol. Müller.Neoadjuvant Systemic Chemotherapy – Response Prediction II (17/20) Further information: This slide is based on the evidence mainly from analyses done by GEPAR. R. Clin. & Dietel.trialists and remains widely unchanged.. It helps to define those subgroups of patients who benefit from NACT in terms of downstaging/pCR. Solbach.. Darb-Esfahani.. S.1200/JCO. Loibl.. J.. W. Komor.. C. 28.23. Neosphere and GEPAR-trials demonstrating lower pCR rates in tumors coexpressing HR and HER2 compared to HER2+/HR-. Denkert. S. Noske.M.7370. The FDA Metaanalysis confirms preexisting data from neo ALLTO. C. Schrader.. For the genomic signatures there are new data from the I-Spy trial confirming the predictive value of PAM50 and Mammaprint for pCR after neoadjuvant chemotherapy and – for the first time – correlation with 3 yr dfs.. et al. C. References: TIL 2. M. doi:10.. K. Ki 67 data from GEPARTRIO have been updated by Denkert et al. Törne. 2010. I. (SABCS 2012) and confirmed a strong correlation if cut-off values of ≤15 and > 35 are presumed to define low and high risk populations. Roller. 105–113.2009. M. Correlations to survival parameter may differ according to individual parameters and are precised in the first slides.. Hanusch. . A. von. Tumorassociated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.. J. C.

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. quantitative ER and PR expression as single markers do not identify patients with better outcome after AI. nodal status.(Dowsett M) Cyp2D6 polymorphism detection is not recommended in daily routine as the metaanalysis done by Goertz is not conclusive. 0. HER2 overexpression. who compared AI + Goserelin vs Tam in premenopuasal women report a nearly 50% increase in the risk of didease recurrence (HR 1. ABCSG12 trialists. .95 for ductal luminal A.64 for ductal luminal B. whereas little effect can be attributed to tumor size. 0. In postmenopausal women ATAC trialist report a nonsignificantly better relative benefit of AI vs Tam in thin women vs overweight women (BMI > 35).49) and a three-fold risk of death for overweight patients (BMI > 25) receiving AI+ Gos in comparison to TAM. Same is true for PG receptor levels. when compared to TAM. According to the ASCO /CAP guidelines the panel recommended endocrine therapy in patients whose breast tumors show at least 1% ER positive cells. The HR were 0. HER2-).49 for lobular luminal a and 0.HER2 overexpressing tumors present primarily with more aggressive biology.Predictive Factors – Endocrine Therapy (18/20) Further information: EBCTCG analysis provides ample evidence that hormone receptor status is predictive for endocrine response. age and grading.33 for lobular luminal B.

Woodruff T.: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. Copland S. Early Breast Cancer Trialists' Collaborative Group (EBCTCG).References: 1. 7. Paik S. 2009. Ingle J. 2. 1999. Blackwell K. Breast Cancer Res Treat. Pan HC. 2009. Relevance of breast cancer hormone . Anders C. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. Gu L.96(5):1336-43. Use of archived specimens in evaluation of prognostic and predictive biomarkers. Clark GM. Clarke M. 4. 8. Anderson RA. Antenos M. 113:137-44 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Thürliman B et al: Is chemotherapy necessary for premenopausal women with lower-risk node-positive. Natl. Lancet 365 (9472): 1687-717. Godwin J. Peto R. Prognostic and predictive factors. J. Cancer Inst. 2006. Cameron DA. Unruhe S.: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Harvey JM. Davies C. Behera M. Shaw H. Cutter D. 2005 Colleoni M et al. Osborne CK. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. 3. Snyder S. Osborne CK (Hrsg). J Clin Oncol 17 (5): 1474-81. Welch R. 9. Dowsett M. 5. Marcom PK. Peterson B. Cancer Invest. Harris JR. 6.26(3):28695 6. 2nd edition: Seiten 489-514.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. Philadelphia 2000. Simon RM. J Clin Oncol 24 (9): 1332-41. 101(21): 1446 – 1452 Clark GM et al. Lyons P. et al. J Clin Endocrinol Metab. Lippincott-Raven Publishers. Taylor C. Hayes DF. Darby S. endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. McGale P. Wang YC. Kimmick G. Morrow M. 2008 Apr-May. In: Diseases of the breast. 2011 May. Gray R. Lippmann ME.

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Most data are derived from trials evaluating chemotherapy + endocrine therapy versus endocrine therapy alone in HR+ patients (Viale IBCSG VIII + IX. Neither HER2 or HER3 (mRNA). tumor diameter . 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 . HR status and grading.18 in the low risk group resulting in a net 10 yrs dfs benefit of 12 % for the high risk group. 0. intermediate risk and low risk patients.56 in the high risk group. The last EBCTCG metaanalysis involving over 100 000 chemotherapy patients from 123 randomized trials demonstrated proportional risk reduction little affected by age.01) compared to 0. In SWOG 8814 evaluating N+ patients the HRs for 5 yr overall survival were 0.61 and 1. In the high risk group the univariate HR was 0.6) in the low risk group. . 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. Albain SWOG 8814 and Paik NSABP B-20) .31 for high risk. Data for Mammaprint (Knauer et al) refer to 541 patients from pooled study series from patiens who received endocrine therapy +/. The evidence for HER2 overexpression is much less well evaluated. During SABCS 2012 Baselga presented biomarker analyses evaluating patients with higher benefit from addition of pertuzumab from the CLEOPATRA trial. 0. nodal status.21 (p < 0. nor EGFR (mRNA) were predictive.84 in the intermediate and 1. with an net chemotherapy benefit of 28 % 10 year distant free survival benefit in the high risk group. In N0 patients from B-20 the RR was 0.Predictive Factors – HER2 Targeted Therapy / Adjuvant Chemotherapy (19/20) Further information: Her2 overexpression (ICH.chemotherapy. 58 (p= 0. FISH) is highly predictive for anti HER2 therapy.26. The prospecitvely randomized chemo N0 trial demonstrated that high levels of upA/PAI-1 are associated to increased CMF chemotherapy benefit. For other genomic signatures there are no data. 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.

The HR for her2 amplification and non amplification were 0.Baseline Ki-67 is as Viale et al demonstrated from retrospective analyses of two IBCSG trials no independent predictor of chemotherapy outcome. BCIRG 01. but not in the GEICAM trial. not HER2 amplification. when compared to CMF. HER2 overexpression was highly predictive for anthracyline outcome . TOP2A coamplification. BCIRG 001 and PACS 001.89 and 0. is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy.71 respectively. 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. Those for Topo normal versus Topo altered were 0. Endopredict and Oncotype DX did not predict taxane response in the GEICAM trial and in NSABP B28 respecively. No references .88 vs 0. Retrospective subgroup analyses of patients from large taxane trials (GEICAM.64 respectively. In a subgroup of the patients analysed by Gennari Di Leo published a metaanalysis comparing the impact of Her2 status and TOP2A (FISH). Identification of low proliferating tumors by central ki-67 evaluation was predictive for taxane outcome in EC-Doc. but these third generation trials do not have endocrine only arms. PACS 01.

Alvarez.08.M. de.C.. 2.. J.. de. G.. M... Reuben. J. 351. & Hayes. U. M. Doyle. Valero. 2011. H. J. Reuben. R. A number of trials showed that CTC can be used for treatment monitoring or direct treatment target. Med. Stopeck.C.V. Budd. L.N.N.F.F.. Handy.J. G.J. Hayes... Hortobagyi... Matera.M. and survival in metastatic breast cancer.W. Circulating tumor cells..V.C. 13.M. G. & Cristofanilli..1056/NEJMoa040766.. Stopeck. M.. doi:10. Doyle. N..M. Mego. D. L. A. doi:10. Fritsche... 781–791. R67.. M. Allard.M.J. Placido. A.. Laurentiis. J. M. Cristofanilli.T. Oncol.. CTC detection helps to identify patients with increased risk for relapse. G. 2005. 23. Hess. B.. Jackson. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. de. References: CTC 1. Breast Cancer Res.M. & Terstappen.. G.T. M. Giuliano. Clin. Ellis. Terstappen... N. doi:10. M. Allard. J. S. W. Miller. J. G.A. Ueno.. A. Giordano. 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. . Miller. M. V.1200/JCO. K.2005. M.140.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.M.R. J. Budd. 1420–1430. Engl. W.H. disease progression. Giorgi. 2004.W.1186/bcr2907. Matera. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer... M. Ellis. D. Hortobagyi. Reuben. Cristofanilli.T.J... 3. S.

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

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

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

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

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

sowie in der DKG e.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% ? .1 B3-Lesions:        www.V.V.Major B3-Lesions and Prospektive Prediktive Value (PPV) for Malignancy in Resection © AGO e. in der DGGG e.ago-online. Guidelines Breast Version 2015.V.

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

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

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

21 RR = 4. Guidelines Breast Version 2015.1  Number of Foci: 1 2 >3 RR = 2.10 RR = 2.V.de *AC Degnim et al.67 www.V. sowie in der DKG e.33 RR = 5.21  Type ductal lobular both RR = 3. Stratification of breast cancer risk* in der DGGG e.76 RR = 5.10  Age < 45 45 – 55 > 55 RR = 6.V.Risk of Breast Cancer after Atypical Hyperplasie (ADH.67 RR = 7.97  Microcalcifications: present not present RR = 3. 25: 2671-2677 . ALH) © AGO e.26 RR = 7. J Clin Oncol 2007.ago-online.83 RR = 3.

lobular carcinoma in situ.de  Includes: Atypical lobular hyperplasia. LCIS/CLIS  LIN1 .and contralateral enhanced breast cancer risk: 7 x at 10 years . in der DGGG e.1 www.V. Guidelines Breast Version 2015.Lobular Intraepithelial Neoplasia (LIN) © AGO e.V. sowie in der DKG e.3 classification is not sufficiently validated prognostically  Pleomorphic LIN and LIN with are classified as → B5a  Indicator/Precursor lesion: Ipsi.V.ago-online.

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

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

florid LIN.de  LIN in core.ago-online. 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. sowie in der DKG e.V.1 www. florid LIN.V.Strategy after Diagnosis of LIN © AGO Oxford / AGO LoE / GR e. with pleomorphic LIN. Guidelines Breast Version 2015. or LIN with necrosis b) Imaging abnormality is not removed  Complete resection 2b C ++ 3a C ++ 5 D ++ .V./ vacuum-assisted biopsy:  Open excisional biopsy.

sowie in der DKG e.de  Synonyms: Columnar cell hyperplasia with atypia.Flat Epithelial Atypia (FEA) © AGO e. Guidelines Breast Version 2015. columnar cell metaplasia with atypia. in der DGGG 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.1 www.V.ago-online.V.V. Therefore. . correlation with imaging is mandatory. ductal intraepithelial neoplasia grade 1A (DIN 1A)  Differential diagnosis:  ADH is discriminated by architectural features (micropapillary.

1 www. unless calcifications have not been completely removed * Terminal ductal-lobular unit 3b C + C + C ++ .Strategy after Diagnosis of FEA © AGO e. Oxford / AGO LoE / GR in der DGGG e.V.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. Guidelines Breast Version 2015. sowie in der DKG e.V.de  FEA in core biopsy/vacuum-assisted biopsy:  Open excisional biopsy 3b  Open excisional biopsy may be omitted.ago-online.

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

1 www.de  Papilloma without atypia in core needle or vacuum biopsies: → no further therapy. 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 ++ . in der DGGG e.ago-online.V. Oxford / AGO LoE / GR Guidelines Breast Version 2015. sowie in der DKG e.Strategy after Diagnosis of Central Papilloma © AGO e.V.V.

1 www.ago-online.Radially Sclerosing Lesion © AGO e. Guidelines Breast Version 2015.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.V.de  Benign pseudoinfiltrative lesion with central fibroelastic core and radical configuration.radial scar .V. in der DGGG e. sowie in der DKG e.V.3% (79/948)* * Bianchi S et al. Breast.  Includes: . . (2012) 21: 159–64.

ago-online.Strategy after Diagnosis of Radial Scar. 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 ++ . Complex Sclerosing Lesion (CSL) © AGO e.V.V. Guidelines Breast Version 2015.1 www.V.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. sowie in der DKG e.

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

Anastrozole) for postmenopausal women 1b A +/- Medical prevention should only be offered after individual and comprehensive counseling. Guidelines Breast Version 2015. the net benefit strongly depends on risk status. age and preexisting risk factors for side effects.V.V. sowie in der DKG e.Medical Prevention for Women at Increased Risk (including Women with LIN and ADH) © AGO Oxford / AGO LoE / GR e.66% in 5 years) . *Risk situation as defined in NSABP P1-trial (1.1    www.V. in der DGGG e.ago-online.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.

18 5.58 0.51-0.70 5.68 5. update 2005 © AGO e. in der DGGG e.63 0.97 2.28-0.88 0.48 1.55 3.24 2.66%): •LIN.42 4.47 3.25 0.77 11.15 3.34-0.98 6.57 0.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen) NSABP-P1 Study.52 0. grade Fraktures Endometriumcancer 11.83 > 3 relatives 1.V.49 0.grade 6.ago-online.43 0.59 3.46-0.27 3.16-1.92 1.46-0.87-6.70 0.10-0.03 5 www.87 10.27-1.V.67 0.34 0.54 0.28 0.69 2. sowie in der DKG e.02 0.72 0.24 0.48 0.41 6.V.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 1.01 0.de Should only be offered to women with enhanced breast cancer risk (Gail 1.29 5.64 0.50-0.78 0.91 3.54 0.43-1. Guidelines Breast Version 2015. ADH • Family history of breast cancer Should not be offered to women: • With moderate risk > 50year of age Lebensjahr •With enhanced risk for thrombembolism .93 11.

58-0.77 0.84 0.93 1.ago-online.73 0.70-0. sowie in der DKG e. JCO 2009. 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.36 1.08 0.84 58 17 5 AR*:Absolute risik per 1000 women.91 0.V. Guidelines Breast Version 2015.10 25 64 39 16 0. in der DGGG e.27-2.V.94 1.21-2. Visvanathan K et al.1 www.74 1.V.58-0. .99 1.27:3235-3258.06-1.87-0.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen. NNT/NNH** = number needed to treat or number needed to harm: shown are statistically signifikant associations for a follow-up-period of 96 month.82 15 12 14 9 68 81 73 115 0.72 1.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.

74 Should only be offered to women with enhanced breast cancer risk : (Gail 1. in der DGGG e.03 0.58-1.V.81-1.02 1.99 1.28 0.76-1.41 3.98 0.1 All women ± LIN + LIN ± ADH + ADH www.21 Raloxifen Rate / 1000 WE 4.81 RR 95% CI 1.61 4.03 5.30 3.ago-online.66%) or postmeopausal Should not be offered to women: • With moderate risk > 50year of age • With enhanced risk for thrombembolism .63 0.V.de Tamoxifen : Rate / 1000 WE 4.33 0.28 0. Guidelines Breast Version 2015.82-1.12 0. STAR trial 2006 e.76 9.06 5.72-1.83 4. sowie in der DKG e.V.Medical Prevention after Diagnosis of B3 Lesion (Raloxifen) © AGO NSABP-P2 Study.89 9.

383: 1041–48 Goss PE et al.364(25):2381-91 .52 (0. or LCIS Anastrozole:154 (8. Lancet 2014.78)  MAP.82)  No HR=0. Placebo: 188 (8.1 Inclusion criteria: Results for prior ALH. 2011 Jun 23.ago-online.61 (0.3: www.7%)  Yes (7y-BC-risk 12.V.20–1. or LCIS: Exemestane: 185 (8.64) Cuzick J et al.1%): HR 0. Placebo: 190 (9.84)  No (7y-BC-risk 4. N Engl J Med.2:  Prior ADH.3%)  Yes: HR=0.V.0%).31 (0. Guidelines Breast Version 2015.1%). in der DGGG e.26 (0.9%): HR 0. sowie in der DKG e.V.de  Prior ADH. ALH.31–0.11–0.12–0.Prevention for Lesions with Uncertain Biological Behaviour (Aromatase Inhibitors) © AGO e. LCIS (HR AI vs Plac):  IBIS. ALH. ADH.

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]) .

I. 2010 ASCO 2012: done National Institute of health (NIH): done San Antonio Breast Cancer Conference (SABCC 2013): done .2014 NCCN Breast Cancer Risk Reduction I 2013 NCCN Breast Cancer Screening and Diagnosis 2. Therapie und Nachsorge des Mammakarzinoms. Aktualisierung 2012 NCCN Breast cancer V.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.

Stacey D et al. JCO 2009. Breast cancer risk reduction V. Aktualisierung 2012 AWMF-Register-Nummer: 032 – 045OL Lebeau A. Therapie und Nachsorge des Mammakarzinoms. J Cancer Res Clin Oncol 2009. Schlake W.V.). Altland H. Leitlinienprogramm Onkologie der AWMF. NCCN. USA: NCCN. Mammakarzinom: aktuelle Empfehlungen fur Pathologen auf Basis der S3-Leitlinie.2014.34(4):293-302 Visvanathan K. NCCN. 1 ed. raloxifen and aromatase inhibition for breast cancer risk reduction.(4):1-35. Langversion 3.2. The Cochrane Library 2009. 2014 ed. Ali W. 2014. Decision aids for people facing health treatment or screening decisions (Review). Chlebowski R. Interdisziplinäre S3-Leitlinie für die Diagnostik. 27:3235-3258 Weir R. Muenchen: Zuckschwerdt Verlag. Day P.0. Breast cancer V. Kreipe H.2013. American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. Breast cancer screening and diagnosis V. National Comprehensive Cancer Network. Kreienberg R. USA: NCCN.V.I. USA: NCCN. . 2013 ed. National Comprehensive Cancer Network. 2007. 135:339-354 Albert US. Bennett C. (Hrsg. 2008 update of the guideline early detection of breast cancer in Germany. Pathologe. 2008. 2013 ed. Christchurch: New Zealand Health Technology Assessment (NZHTA). Risk factors for breast cancer in women:a systematic review of the literature.Aktualisierung 2008. 2013. Hurley P et al. 2013. O'Connor A. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 1. Deutschen Krebsgesellschaft e. NCCN. 2013.National and international guidelines Albert US. (Hrsg). National Comprehensive Cancer Network. und Deutschen Krebshilfe e.I. Dietel M. Duda V et al.2013.

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

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

5. Kreipe H-H.7:100. Ergebnisse der Referenzpathologie im MammographieScreening. Loening T. Hauptmann S.29(S2):178–80. Reliability and validity of needle biopsy evaluation of breast-abnormalities using the B-categorization--design and objectives of the Diagnosis Optimisation Study (DIOS). Lebeau A. Lantzsch T. 6. Taege C. Bianchi S. Boecker W. Höfler H. Pathologe. Heinig A. Decker T. Vezzosi V. Pickartz H. Ciatto S. . Br J Cancer. Bilous M.4. 2007 Jun 14. Thomssen C. Trocchi P. BMC Cancer. SchmidtPokrzywniak A. Stang A. Holzhausen HJ.96(8):1253–7. Kluttig A. Houssami N. Schmidt D. Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). 2007 Apr 22. 2008 Oct 9. Buchmann J.

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

J Clin Pathol 2009. 2013 Jul. Histopathology. Gromet M. Doualliez V. Becker AK.1038/modpathol. 2013 Sep. Stefano DD. Venkataraman S. Rocourt N. Piubello Q. Loreto CD. Carrillo G. Quero C. 96:1253-1257 . Webster F. Hayes MM. Br J Cancer 2007. Buckley ES. Annals of Surgical Oncology 2007. Palli D.63(1):83-95.372(1):78-89.94(9):861-9. Santen RJ. Giardina C. Bachelle F. Hassell PR. Bendinelli B. Farshid G. Arch Pathol Lab Med. Bersiga A. Pouliquen G. Degnim AC. 5. Taieb S. White RL.2. 2015 Jan 1. 10.20(6):606-14. Sarantou T. 2014 Feb. Atypical hyperplasia of the breast--risk assessment and management options. Chaveron C. Mod Pathol. Antonacci CM. Hiller JE.40(2):168-75. Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies. 2013 Jul. N Engl J Med. 9. Chauvet MP. Gordon PB. doi: 10. 8. 4. 11. 2013 Mar. Roder DM. 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.2014. Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. Calhoun BC. Dante S. Pure flat epithelial atypia: is there a place for routine surgery? Diagn Interv Imaging. Flippo T. 14(2):704-711 Hartmann LC. 6.159. [Epub ahead of print] Ceugnart L. Renne G. Houssami N et al: Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). D'Alfonso TM. 3. Castellano I. Cattani MG. 2014 Nov-Dec. Does isolated flat epithelial atypia on vacuum-assisted breast core biopsy require surgical excision? Breast J. Ghosh K. 62:1136-1140.do we have the answer yet? Eur J Surg Oncol. Schnitt SJ. Livasy CA. Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated? AJR Am J Roentgenol. Robin YM. Shin SJ. Dupont WD. Mehta TS. 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. 12. Wilson CM. Dialani V. 7. Laurino L. A systematic review of surgical biopsy for LCIS found at core needle biopsy . Frieling G. Chiu YL. Hayes B et al: Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience.200(3):682-8. Bianchi S. Jarraya H. Sobel A.137(7):927-35. 2014 Nov 21. Wang K. VANCB Study Group. van Niekerk D. Harrison DA.

Shen Y. Mayo Clin Proc. Shimo A. 2014 Oct. 29(Suppl):178-180 Maeda I. Maxwell AJ. 14. Jorns J. Dong W. Nishikawa T. Lee MC. 25. 21. Dempsey P. Glazebrook KN. Cancer Med. 2014 Apr 24. Miglioretti DL. Kawamoto H. Mac Bride MB. Lobular neoplasia: morphology and management.13. 2014 Jun. 24. Kanemaki Y. Breast. Khakpour N. J Clin Pathol. atypical. Tsugawa K. Hieken TJ. [Epub ahead of print] Menes TS. Breast. Takagi M. Hayami R. Yabuki Y. Kojima Y. Surg Oncol Clin N Am. Positive predictive value for malignancy of pure flat epithelial atypia diagnosis by percutaneous needle biopsy of the breast: management of FEA in ultrasonography. Sandhu NP. 18.breast. Acs G. 23. 2014 Oct. 2014 Apr. Garewal S. Jaffer S. Tozaki M. Prowler VL. Der Pathologe 2008. Rosenberg R. 2010 Nov-Dec.207(1):24-31. doi: 10. Lobular neoplasia. Diagnosis and management of benign.23(3):487-503. Dilaveri CA. Waugh P. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium. Bevers TB. Ghosh K. 19. 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. King TA.2014. and indeterminate breast lesions detected on core needle biopsy. Kerlikowske K.89(4):536-47 Parkin CK. Reis-Filho JS. [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. Kreipe H et al: Ergebnisse der Referenzpathologie im Mammographie-Screening.1016/j.23(4):352-6. Okanami Y. Middleton LP. 16. Joh JE. Surgical excision of pure flat epithelial atypia identified on core needle breast biopsy. Sabel MS. 22. Breast J. 2014 Jul. Wahner-Roedler DL. Arch Pathol Lab Med. 2010 Nov. Laronga C. Visscher DW. 17.16(6):573-80 . Sneige N. 2014 Aug.23(5):651-5. Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast. Oana Y.06.016. 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. Kiluk JV. Koizumi H. Breast Cancer.3(3):492-9 Neal L.138(10):1344-9. Tsuchiya K. Balch S. 20. Int J Cancer. Pang JC.63(11):987-93. 2014 Jan. Coyne R. Am J Surg. Outcomes of patients with lobular in situ neoplasia of the breast: the role of vacuum-assisted biopsy. 2010 Dec 2. 15.

2007.20(4):394-401. 2010 Sep 28. Ann Surg Oncol. Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia. Christchurch: New Zealand Health Technology Assessment (NZHTA). . Huynh KT. Giuliano A. Breast J. Rageth CJ. Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision? Ann Surg Oncol. Chung A. 28. 29. Papillary lesions of the breast: outcomes of 156 patients managed without excisional biopsy. 2014 Jul-Aug. Wyss P. Varga Z. Shamonki J.20(13):4137-44 Weir R et al: Risk factors for breast cancer in women:a systematic review of the literature. Sim MS.26. Rössle M. Kinnaird M. 27. 2013 Dec.

Breast Cancer res Treat 2007.999). Liberman L. Murray M.8-5233. 3. Catarzi S. diagnostic odds ratio. Experience of 47 cases diagnosed at vaccumassisted biopsy. Marjan D.95). Morris E. 2.987). 93. Bertelle L. positive likelihood ratio (PLR). 41.7 (95% CI. 683.972-0. 4.999 (95% CI. Brem RF. 0. 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. Holland A.098-0.177-0.03-0.2% (95% CI. After a review and quality assessment of 21 studies. specificity. Sanna P: Atypical ductal hyperplasia of the breast: the controversional management of a borderline lesion.55-211.128). Behrndt VS. 0. diagnostic accuracy of VAB were evaluated. 0. 15:196-202. 172:1405-1407 Ciatto S. Bonari R. underestimate rate of ADH and DCIS were 20. AJR 2007. Wynn R: Underestimation of atypical ductal hyperplasia at MRI-guided 9-Gauge vacuum-assisted breast biopsy. References: 1.05 (95% CI. Brancato B. AJR 1999. negative likelihood ratio. 101:291-307 Bedei L. Algorithm for quality assurance of minimal invasive guided biopsies.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. 0.84 (95% CI. Breast 2006. The summary estimates for VAB in diagnosis of breast carcinoma were as follows: sensitivity. 0. 0. Houssami N. Dershew D. Ambrogetti D. Falcini F. VAB is a highly sensitive and specific biopsy method for evaluating mammographically detected breast in women.9% (95% CI. 1891. Risso G: Accuracy and underestimation of malignancy of breast core needle biopsy: the florence experience of over 4000 consecutive biopsies. Bianchi S.09). 0.245) and 11. respectively. 188:684-690. 0.997-0.981 (95% confidence interval [CI]. Sanow L. .4).

Coyne R. 8.269(2):340-7. Menes T. Paranas N.372(1):78-89. 9. 6. Arora S. Middleton LP. Rao S. Sandhu NP. Sneige N. Hieken TJ. Breast Cancer Res and Treat 2008. Cohen MA. Ghosh K. Degnim AC. Diagnosis and management of benign. Dilaveri CA. Wahner-Roedler DL. 7. 15(3):843-847 Neal L. Bevers TB. Atkins KA.5. Nonni A. 109:397-402. Nicholson B. 2014 Jun. Zagrafos G. Glazebrook KN. Folou M. Radiology. Zagouri F. 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. and indeterminate breast lesions detected on core needle biopsy. 2014 Apr. 2013 Nov. Santen RJ. Atypical ductal hyperplasia at margin of breast biopsy Is Re-excision indicated? Ann Surg Oncol 2007. Dempsey P. Visscher DW. Sergentanis T. Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation. Shen Y. Foliadis C. Nagi C. Dupont WD. 2015 Jan 1. Jaffer S. Panopoulou E. Bramis J: Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: ablind study. Ghosh K. 10. Mayo Clin Proc. Cancer Med. Koulocheri D. Dong W. Atypical hyperplasia of the breast--risk assessment and management options. Mac Bride MB.3(3):492-9 . atypical.89(4):536-47 Hartmann LC. Moung C. N Engl J Med. Bleiweiss I.

25(19):2671-2677 Ellis IO: Impact of a national external quality assessment scheme for breast pathology in the UK. 2009 Feb.4). 4. Böcker W. Weigel S.35 (95%CI 6. Roterberg K. References: 1. JCO 2007. 3. Less than 45 years at diagnosis of ADH RR 6.5/10000 mammograms 1999 to 2.Atypical Ductal Hyperplasia (ADH) (7/25) Further information: ADH and breast cancer are asoziated with postmenopausal hormone treatment.1007/s00292-008-1101-4.13-16.4/10000 mammograms in 2005 Statement: indicator-/ precursor-lesion: Women have an enhanced breast cancer risk after ADH: one lesion RR 3. three lesions RR10.59:138-45. Menes T: Rates of atypical ductal hyperplasia have declined with less use of postmenopausal hormone treatment: Findings from the Breast Cancer Surveillance Consortium. Decker T. Stratification of breast cancer risk in women with atypia: A Mayo Cohort Study.24-12. Atypical ductal hyperplasia and atypical epithelial proliferation of ductal type].4). Hungermann D.94). . Cancer Epidemiol Biomarkers Prev 2009. Pathologe.18:2822-2828 Degnim A:.00-4.78 (95%CI 3. doi: 10.88 (95%CI 3. 2006.30(1):42-8.J Clin Pathol. According to the data of the Breast Cancer Surveillance Consortium (USA) rates of ADH decreased from 5. 2.

Degnim AC. ADH in core. and necrosis (P = . 2010). Allison KH 2010). Santen RJ. ADH without these features. Atypical hyperplasia of the breast--risk assessment and management options. 2015 Jan 1. An open excisional is recommended with exception of very small lesions (≤ 2 TDLU) and minimal atypia and complete removed imaging abnormality. Atkins KA. is associated with a minimal risk (<3%) of carcinoma and may undergo mammographic follow-up only (Nguyen CV 2010. Therefore. 14(2):704-711 Hartmann LC. Cohen MA. ADH lesions with significant cytologic atypia and/or necrosis are most likely to be associated with carcinoma and should be excised.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. Rao S. 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./ vacuum-assisted biopsy (LoE 3a) ADH at margins in resection specimen (LoE 3a) References: 1. 2013 Nov. >2) involved (P = . Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation.0306). 2. Annals of Surgical Oncology 2007. Nicholson B.0001).372(1):78-89. regardless of extent of involvement. Even in the case of complete removal of microcalcifications there is a risk of 5 % of underestimation of malignancy (Penco 2010). presence of significant cytologic atypia suspicious for intermediate or high-grade carcinoma (P < . Dupont WD. 3. Radiology. Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. Ghosh K. . and with complete removal of the targeted calcifications. N Engl J Med.269(2):340-7.0006).

8. . Mayo Clin Proc. 2010 Sep 28. Rosenberg R. J Clin Pathol 2009. Dilaveri CA. Balch S.207(1):24-31. 6. Mac Bride MB. Hieken TJ. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium. Sandhu NP. 9. Ghosh K. Am J Surg. and indeterminate breast lesions detected on core needle biopsy.4. atypical. 5. Houssami N et al: Borderline breast core needle histology: predictive values for malignancy in lesions of uncertain malignant potential (B3). [Epub ahead of print] Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia. 96:1253-1257 Menes TS. 7. Jaffer S. 2010 Dec 2. Ann Surg Oncol. Glazebrook KN. Visscher DW. Diagnosis and management of benign. 62:1136-1140.89(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. Kerlikowske K. Br J Cancer 2007. Miglioretti DL. 2014 Jan. 2014 Apr. Int J Cancer. Hayes B et al: Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience. Wahner-Roedler DL. Neal L.

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

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

Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur J Cancer 2006. Pinder S: Lobular in situ neoplasia and columnar cell lesions:diagnosis in breast core biopsies and implications for management. Pathology 2007. 39:208-216. 23:5534-5541 . and End Results Data. Epidemiology. 3. 4. 42:2205-2211 Arpino G:: Lobular neoplasia on core-needle biopsy: clinical significance. 101:242-250 Statement: Indicator-/ precusor lesion 1.2. Lakhani I: The management of lobular carcinoma in situ (LCIS). Chuba PJ: Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance. Journal of Clinical Oncology 2005. Cancer 2004.

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

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

the nature of these lesions as non-obligate precursors. An excisional biopsy was recommended in fully developed LCIS because of an upgrade rate of greater than of 25% [1] or 16% [2].Strategy after Diagnosis of LIN (13/25) Further information: In contrast to atypical ductal hyperplasia. Not surprisingly these small studies have led to widely discrepant results and conflicting interpretations of published data. However. This argument has to be taken seriously. and therefore there is some disagreement if excision should be recommended as a rule or not. Cohen MA./ vacuum-assisted biopsy (LoE 2b) 1. Atkins KA. Nicholson B. and at least all cases with LCIS and a mass lesion should be followed up by a surgical biopsy. Atypical lobular hyperplasia and lobular carcinoma in situ at core breast biopsy: use of careful radiologic-pathologic correlation to recommend excision or observation. 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. it is unlikely that an excisional biopsy could yield anything more significant [3]. References: LIN in core. 2013 Nov. because of the reported upgrade rates in fully developed LCIS. but results were inconclusive with lesions of lesser extent. . 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. especially if multiple lobules are involved. and risk of missing a radiologically occult invasive cancer.269(2):340-7. 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. Rao S. an open biopsy in classical LCIS should be considered as an option also [2]. namely atypical lobular hyperplasia.

Chiu YL.do we have the answer yet? Eur J Surg Oncol. Dong W. Pang JC. Jorns J. Rosenberg R. Farshid G.40(2):168-75. Giardina C. 2013 Jul. Outcomes of patients with lobular in situ neoplasia of the breast: the role of vacuum-assisted biopsy. Loreto CD.63(1):83-95. Bersiga A. 6. D'Alfonso TM. Shin SJ. 11. Dante S. Waugh P. Balch S. 9. Arch Pathol Lab Med.016. Bevers TB. Dempsey P. Hiller JE. Kerlikowske K. [Epub ahead of print] . 4. and indeterminate breast lesions detected on core needle biopsy. Lobular neoplasia. Surg Oncol Clin N Am. 2010 Nov. 2014 Jan. Jaffer S. Wahner-Roedler DL. J Clin Pathol. 2014 Feb.89(4):536-47 Parkin CK. Int J Cancer. Dilaveri CA. doi: 10.138(10):1344-9. Middleton LP. Arch Pathol Lab Med. 12. Carrillo G. Breast. 2014 Oct. atypical. Castellano I.137(7):927-35.06. 7. Roder DM. 8.3(3):492-9 Neal L. 2014 Oct. Wang K. Sandhu NP.207(1):24-31. Webster F. Visscher DW. Lobular neoplasia: morphology and management. Shen Y. 2013 Jul. Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast. Sabel MS. Ghosh K. 5. Sneige N. Renne G. Upgrade of high-risk breast lesions detected on mammography in the Breast Cancer Surveillance Consortium. Garewal S.63(11):987-93. Antonacci CM. Cattani MG. Hieken TJ. Diagnosis and management of benign. Piubello Q. Cancer Med.2. 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.1016/j. 2014 Apr. 2014 Jun. Laurino L. Stefano DD. 3. Miglioretti DL. 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. Glazebrook KN. VANCB Study Group.23(5):651-5. A systematic review of surgical biopsy for LCIS found at core needle biopsy . Menes TS. 2014 Jul. Buckley ES. 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. Reis-Filho JS.breast. Am J Surg.2014.23(3):487-503. 2010 Dec 2. Mac Bride MB. Histopathology. Mayo Clin Proc. Bendinelli B. King TA. Palli D. 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. Bianchi S. Quero C. 10. Maxwell AJ. Coyne R.

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

molecular-genetic findings. Marker Lesion FEA is highly associated with microcalcification (77%). A finding of FEA on benign breast biopsy may indicate the presence of ADH. 2.63(11):987-93. differential diagnoses. DCIS and tubulär carcinoma. A 2. Flat ductal intraepithelial neoplasia of the breast: A review of diagnostic criteria.005) was observed.to 3-fold increase in the occurrence of ADH in the presence of FEA versus in their absence (P < . 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. References: 1.Flat Epithelial Atypia (FEA) (14/25) Further information: FEA represents one of the earliest morphologically recognizable neoplastic alterations of the breast. The mammographic features are amorphous and pleomorphic microcalcification. Purdie CA et al: Management of in situ lobular neoplasia detected on needle core biopsy of breast. 30:36-41. a more advanced lesion is found at excision: ADH. Statement: Marker Lesion (LoE 3b) . J Clin Pathol. and clinical relevance . 3. Böcker W: Flache epitheliale Atypie. Pathologe 2009. In about one-third to one-quarter of cases of FEA seen at core biopsy. FEA might be associated with noninvasive cancer but not with invasive cancer. 2010 Nov. 133(6):879-892. a more worrisome lesion (Boulos FI). Moinfar F.It is time to appreciate the Azzopardi concept! Arch Pathol Lab Med 2009.

Hum Pathol 2009. 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. Kunju L: Significance of flat epithelial atypia on mammotome core needle biopsy:should it be excised? Hum Pathol 2006. 2. 3. Pandey S: Columnar Cell Lesions of the Breast: Mammographic Findings with Histopathologic Correlation. Epub ahead of print. 20:1149-1155 Boulos F: Histologic Associations and long-term cancer risk in columnar cell lesions of the breast. 4. 113:2415-2421 . 5. Modern Pathology 2007. Radiographics 2007.1. Cancer 2008. 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.

Sarantou T.2014. 4. . Venkataraman S. Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies. 2. In cases of FEA combined with an ADH further surgery depends on the ADH lesion (Ingegnoli A. Robin YM. 2014 Nov-Dec. Wilson CM. [Epub ahead of print] Ceugnart L. J Clin Pathol 2009. 62:1136-1140. Jarraya H. Doualliez V. Statement: FEA in core (LoE 3a) Statement: FEA at margins in resection specimens (LoE 3b) References: 1. 2010). Dillon MF: Predictive Value of Breast Lesions of "Uncertain Malignant Potential" and "Suspicious for Malignancy" Determined by Needle Core Biopsy. Flat ductal intraepithelial neoplasia 1A diagnosed at stereotactic core needle biopsy: is excisional biopsy indicated? AJR Am J Roentgenol. Annals of Surgical Oncology 2007. Harrison DA. van Niekerk D. Mod Pathol. Gromet M. 2010). Dialani V. 2013 Mar. Hayes MM.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.94(9):861-9. Chaveron C. Schnitt SJ.200(3):682-8. 6. 2013 Sep.20(6):606-14.1038/modpathol. Calhoun BC. doi: 10. Livasy CA. Pure flat epithelial atypia: is there a place for routine surgery? Diagn Interv Imaging. Flippo T. 2014 Nov 21. Taieb S. 3. Chauvet MP.159. Pouliquen G. Sobel A. Mehta TS. Becker AK. 5. Frieling G. 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. Rocourt N. Gordon PB. Hassell PR. Does isolated flat epithelial atypia on vacuum-assisted breast core biopsy require surgical excision? Breast J. Bachelle F. White RL.

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

Intraductal papillomas and ductal adenomas may show regressive changes. World Health Organization. and both locations can be either solitary or multiple. 2010 May 1. editors.23 Suppl 2:S36–45.Papilloma (16/25) Further information: Benign intraductal papillomas occur either as a central papilloma originating from the ducts in the subareolar region. 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]. These changes may cause diagnostic difficulties in core needle biopsy [2]. and are usually of low grade. Both central and peripheral papillomas are characterized by fibrovascular cores with epithelial and myoepithelial cell layers. such as sclerosis or infarction. References: 1. 2012. . the distinction of ADH and DCIS within a papilloma rests with quantitative criteria [1]. World Health Organization. An intermediate or high grade DCIS within a papilloma can be diagnosed regardless of the extent of atypia. Mod Pathol. As with atypical intraductal proliferative lesions. 2. Ellis IO. Lakhani SR. Atypical epithelial proliferations (ADH and DCIS) may occur in papillomas. Breast core needle biopsy: issues and controversies. while larger atypical epithelial proliferations within a papilloma fulfill the criteria of an intraductal papilloma with low grade [3]. Tan PH. Schnitt SJ. An intraductal papilloma with ADH is diagnosed when the atypical epithelial proliferation is < 3 mm. also also epithelial or myoepithelial hyperplasia or squamous or apocrine metaplasia. Who Classification of Tumours of the Breast. This definition replaces alternative terminologies that were focused on the proportion of atypical cells (30% or 90%) within a papilloma. Bilous M. because was historically used both for usual type ductal hyperplasia and for papillomas. or peripherally.

Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma. 1996 Jul 14. Dupont WD.3.78(2):258–66. . Page DL. Jensen RA. Cancer. Salhany KE.

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

Varga Z. Ann Surg Oncol. 2012 Aug 10. . 2014 Jul-Aug. Breast J. 8. Cheng W. Papillary lesions of the breast: outcomes of 156 patients managed without excisional biopsy. Wyss P.20(4):394-401.7.20(1):94–101. Wen X. Nonmalignant Breast Papillary Lesions at Core-Needle Biopsy: A Meta-analysis of Underestimation and Influencing Factors. Rössle M. Rageth CJ.

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.

follow-up and medical intervention) providing comprehensive disclosure of risks and benefits in absolute terms. 4. 2010 . 6. Christchurch: New Zealand Health Technology Assessment (NZHTA). and End Results Data.Aktualisierung 2008. [Epub ahead of print] Weir R: Risk factors for breast cancer in women:a systematic review of the literature.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. Risk communication should provide women with information of risk reduction strategies (e. 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. helping women to make an informed decision to her personal needs and values. Chuba PJ: Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance.g. Epidemiology. USA. 5. Muenchen: Zuckschwerdt Verlag. JCO 2007. (Hrsg). Youk J: Sonographically guided 14-gauge core needle biopsy of breast mass: A review of 2. 2010 Sep 28. 2007. 3.1. AJR 2007. References: 1. Whiffen A: Predictors of Breast Cancer Development in Women with Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia. 190:202-207 Albert U. 1 ed. 7. Ann Surg Oncol. 2008. ed 2010. National Comprehensive Cancer Network: Breast cancer screening and diagnosis V. 2. NCCN. NCCN. Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 1. 25(19):2671-2677. Journal of Clinical Oncology 2005. 23(24):5534-5541 Degnim A: Stratification of breast cancer risk in women with atypia: A Mayo Cohort Study.420 cases with longterm follow-up.

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

96 months follow-up of the randomized IBIS-I trial. The Cochrane Library 2009.(4):1-354 Bozovic-Spasojevic I1. 2. Visvanathan K:. Studies on medical prevention for women at increased risk that included women with LIN and ADH are in bold.38(5):329-39. 3.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. J Natl Cancer Inst 2007. Cancer Treat Rev. raloxifen and aromatase inhibition for breast cancer risk reduction. Tamoxifen für Frauen > 35 Jahre –Reduktion von DCIS und invasivem Karzinom NSABP. JCO 2009. References: 1. Cardoso F.P1: (LoE 1a A AGO +) . Chemoprevention for breast cancer. 4. American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. Azambuja E.g. 99:272-282 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). McCaskill-Stevens W. helping women to make an informed decision to her personal needs and values. 2012 Aug. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . Dinh P.

Sarto GE. Tu D. Chlebowski RT. Fabian CJ.3 (Mammary Prevention 3): a randomized. Alés-Martínez JE. Lickley L. Richardson H. J Clin Oncol. Fabian CJ. Ruiz A. 2014 May 10. Goss PE. Royal Marsden Italian Trial Aromataseinhibitor (Exemestan. Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer .3 Study Investigators. Martin LW. Ellard SL. Robbins J. Pruthi S. Cheung AM. Anastrozol) für postmenopausale Frauen (LoE 1b A AGO +/-) MAP. Spadafora S. Chlebowski RT. Fischer B: Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 2007. Hiltz A. Winquist E. Maunsell E. 2011 Jun 23. Exemestane for breast-cancer prevention in postmenopausal women. Johnston D. Johnson KC. 99:272-282. placebo-controlled trial evaluating exemestane for prevention of breast cancer.96 months follow-up of the randomized IBIS-I trial. Wactawski-Wende J. Ingle JN. Dubé P.3 1. Sarto GE. Ingle JN. Tu D.1. Pujol P. Farmer P. McTiernan A. Cooke AL. J Natl Cancer Inst 2005. Goss PE. Brundage M. Maunsell E. Hendrix S. Alés-Martínez JE. Rowland KM. Quality of life in MAP. Wactawski-Wende J. 2. Gelmon KA. Gelmon KA. Richardson H.1 1. 97:1652-1662 IBIS. . Pujol P. Pater JL. Thayer DW.364(25):2381-91. Cheung AM. NCIC CTG MAP. N Engl J Med. Garber JE.32(14):1427-36.

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

3. raloxifen and aromatase inhibition for breast cancer risk reduction. J Natl Cancer Inst 2005. Visvanathan K: American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen) (22/25) No further information References: 1. JCO 2009. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . JAMA 2006. 97:1652-1662 . 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. 295(23):2727-2741. Fischer B: Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 2007. 4.96 months follow-up of the randomized INIS-I trial. 2.

follow-up and medical intervention) providing comprehensive disclosure of risks and benefits in absolut terms (numbers needed to treat and numbers needed to harm). 99:272-282 O'Connor A: Decision aids for people facing health treatment or screening decisions (Review).(4):1-354 .96 months follow-up of the randomized INIS-I trial. Visvanathan K:. 3. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer . J Natl Cancer Inst 2007. 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. JCO 2009. Side Effects) (23/25) Further information: Risk communication should provide women with information of risk reduction strategies (e. The Cochrane Library 2009. 2. References: 1. helping women to make an informed decision to her personal needs and values.g.Medical Prevention after Diagnosis of B3 Lesion (Tamoxifen.

J Natl Cancer Inst 2005. J Natl Cancer Inst 2007. raloxifen and aromatase inhibition for breast cancer risk reduction. 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. 97:1652-1662 . 295(23):2727-2741. JCO 2009. Visvanathan K: American Society of Clinical Oncology Clincal Practice Guideline: Update on the use of pharmacologic interventions including tamoxifen. 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. 2.96 months follow-up of the randomized INIS-I trial.Medical Prevention after Diagnosis of B3 Lesion (Raloxifen) (24/25) No further information References: 1. 4. 3. 27:3235-3258 Cuzick J: Long-term results of tamoxifen prophylaxis for breast cancer .

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

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

de .V.V. 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.ago-online.1 www.Ductal Carcinoma in Situ DCIS © AGO e.

Pretherapeutic Assessment of Suspicious Lesions (BIRADS IV) © AGO Oxford / AGO LoE / GR e.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 .V.ago-online.V. in der DGGG e. Guidelines Breast Version 2015. sowie in der DKG e.

V. sowie in der DKG e. Oxford / AGO LoE / GR in der DGGG e.V.ago-online. MRI etc.V.Surgical Treatment for Histologically Proven DCIS I © AGO 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.) without preoperative needle biopsy should be avoided . suspicious US.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. Guidelines Breast Version 2015.

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

/ Locoregional Recurrence © AGO Oxford / AGO LoE / GR e.V. sowie in der DKG e.V.DCIS – Prognostic Factors for the Incidence of Local. Ki-67+ Palpable + ER-.ago-online. p16+.V. Guidelines Breast Version 2015. in der DGGG e. negative) ER/PgR (positive vs.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 ++ - . Ki-67+ HER2/neu (positive vs. HER2+. negative) DCIS-Score DCIS with microinvasion – treatment in analogy to invasive breast cancer Intrinsic subtypes (luminal A.1 www. HER2+.) Van Nuys Prognostic Index Palpable DCIS Palpable + COX-2+. B.

Omitting radiotherapy implies elevated risk for local recurrence without effect for overall survival even in the subset of “good risk” patients.V. in der DGGG e.ago-online.5 cm. Guidelines Breast Version 2015 . sowie in der DKG e. mammographically detected * Analysis in ongoing trials .DCIS Radiotherapy © AGO Oxford / AGO LoE / GR e. low and intermediate nuclear grade. There remains a lack of level-1 evidence supporting the omission of adjuvant radiotherapy in selected low-risk cases: < 2.V.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.de Side effects and disadvantages of radiotherapy must be balanced against risk reduction.

1 Goodwin A. Post-operative radiotherapy for ductal carcinoma in situ of the breast.ago-online.V.V. in der DGGG e.de . sowie in der DKG e. www. Cochrane Database Syst Rev.V. 2013 Nov 21.CD000563. Ghersi D. Wilcken N.Cochrane Analysis Radiation after Surgery (all/with Radiation after Breast Conserving Surgery) © AGO e.pub7. doi: 10.1002/14651858. Guidelines Breast Version 2015 .11:CD000563. Parker S.

V.1  Tamoxifen (only ER+)  www.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 . sowie in der DKG e. in der DGGG e.V. Guidelines Breast Version 2015 .DCIS Postoperative Systemic Treatment © AGO Oxford / AGO LoE / GR e.ago-online.V.

Guidelines Breast Version 2015 .23(5):546-51.V.Cochrane Analysis Tamoxifen after DCIS (all/with Radiation) © AGO e.V. Staley H. doi: 10. Postoperative Tamoxifen for www.breast.de ductal carcinoma in situ: Cochrane systematic review and meta-analysis. in der DGGG e.1016/j. doi: 10. . Breast.015.ago-online. Epub 2014 Jul 9.1 Staley H. Postoperative tamoxifen for ductal carcinoma in situ.CD007847.pub2. sowie in der DKG e. 2012 Oct 17. Bruce J. 2014 Oct.V. McCallum I.1002/14651858. McCallum I.06. Bruce J.2014.10:CD007847. Cochrane Database Syst Rev.

V.Local Recurrence of DCIS after Tumorectomy w/o Irradiation © AGO e. sowie in der DKG e.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.de No radiation after first tumorectomy  Treatment like primary disease Prognosis for invasive recurrences seems to be better than for primary invasive breast cancer.V. Oxford / AGO LOE / GR in der DGGG e.V. .ago-online. About 50% of recurrences are invasive. Guidelines Breast Version 2015 .

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Palpabel + COX-2+p16+Ki-67+
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HER2-Überexpression
ER/PgR (positiv vs. negativ)
DCIS-Score
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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)
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© AGO

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

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

1 www. sowie in der DKG e.ago-online.g. Oxford / AGO LoE / GR in der DGGG e. Guidelines Breast Version 2015.V. V.de  During pregnancy and / or breast feeding (no blue dye)  After previous tumor excision  Previous major breast surgery (e. reduction mammoplasty. 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 .V.Sentinel Lymph Node Excision (SNE): Indications II © AGO e.

Sentinel Lymph Node Excision (SNE): Marking © AGO e.V. V.1 www. sowie in der DKG e.V.ago-online. Oxford / AGO LoE / GR Guidelines Breast Version 2015. in der DGGG 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 .

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. Oxford / AGO LoE / GR Guidelines Breast Version 2015.V. sowie in der DKG e.de margins 3b C + Surgery after neoadjuvant chemotherapy go to chapter „Neoadjuvant chemotherapy“ . V.Procedure after Neoadjuvant Therapy © AGO e.ago-online. in der DGGG e.

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

Update Januar 2015 Screened data bases: Pubmed 1998 . Winer EP. 2013 Sep. EBCC 2014 Screened consensus conference: . Rezai M. ASCO 2014. SABCS 2014. Panel members. Cochrane library: .. Piccart-Gebhart M.2015. Thürlimann B. Ann Oncol.Breast Cancer Surgery Oncologic Aspects (2 and 3/15) Further information and references: Thill M. Gelber RD. doi: 10.http://onlinelibrary. Senn HJ.Goldhirsch A.24(9):2206-23.1093/annonc/mdt303.com/cochranelibrary/search 1 . ESMO 2014..wiley. 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. Coates AS. Epub 2013 Aug 4.

2011 Jan. 3. AJR Am J Roentgenol.47(7):1021-6 Krekel NM et al: Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. BMC Surg. Valente SA et al. 4.17(2):581-8. Ann Oncol. et al: European guidelines for quality assurance in breast cancer screening and diagnosis. 2011 May. Perry N. Broeders M. et al: Guidelines from the European Society of Breast Imaging for diagnostic interventional breast procedures. and Magnetic Resonance Imaging.: Accuracy of Predicting Axillary Lymph Node Positivity by Physical Examination. Holland R. Eur J Cancer. Tardivon A. Corsetti V et al. Hendriks JH. Statement: Mammography / Ultrasound 1.19(4):614-22.Pretherapeutic assessment (4/15) No further information References: Statement: Palpation 1. 5. 2007 Feb. Mammography.196(1):225-6.11:8 2 . 2011 Mar 16. de Wolf C. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial). Eur Radiol. 2008 Apr. Ultrasonography. Helbich T. GCP Statement: General 1. Microcalcifications associated with ductal carcinoma in situ: mammographic-pathologic correlation (1994) Semin Diagn Pathol 11:181-92 Wallis M. Fourth edition--summary document. 2.

Dogan BE.43(13):1905-17 Wallis M.17(2):581-8. Al-Azawi D.19(4):614-22. Tardivon A.AJR Am J Roentgenol. 2007 Sep. Rauch GM. Statement minimalinvasive biopsy 1.: Multidisciplinary considerations in the management of high-risk breast lesions. 5.255(1):38-43. Linebarger JH. Hill AD: Ultrasound-Guided Core Biopsy: An Effective Method of Detecting Axillary Nodal Metastases. Houssami N.. Andersen JJ.: Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. 2012 Jan. Hill DA. Sprague BL. Yang WT. Venta L. Hart SA. Ann Surg. J Am Coll Surg. 2011 Aug. Helbich T. Duke D. Abraham LA. Ann Surg. Prospective comparison of stereotactic core biopsy and surgical excision as diagnostic procedures for breast cancer patients (2003) Ann Surg 235:537-541 Cheng MS. 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.214(1):12-7. Fox J. Ciatto S. Fourth edition--summary document. Stinson T. Krishnamurthy S. Houssami N. Bevers T. 2012 Jan. Core needle biopsy rate for new cancer diagnosis in an interdisciplinary breast center: evaluation of quality of care 20072008.Ann Oncol. 2012 Feb.198(2):292-9. et al. 10. Lei W. Landercasper J. Eur J Cancer. Kuerer H. 4. 9.198(2):W132-40. et al: Guidelines from the European Society of Breast Imaging for diagnostic interventional breast procedures. AJR Am J Roentgenol. Miglioretti DL. Bennett C. 2007 Feb. 3 . 2. Broeders M. Collins LC. Power C. Accuracy of screening mammography in women with a history of lobular carcinoma in situ or atypical hyperplasia of the breast. 7.254(2):243-51 Solon JG.145(3):765-73. Onega T. Eur Radiol. Hudak JM. Ellis RL. 3. De Maiffe BM. Liu P. Morrow M. Craft P. 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. 2012 Feb. 8. Gundrum JD. 2008 Apr. Breast Cancer Res Treat. Marcou KA. 6. Smith TB.: Outcome Analysis of 9-Gauge MRI-Guided Vacuum-Assisted Core Needle Breast Biopsies. Yang WT. de Wolf C. et al: European guidelines for quality assurance in breast cancer screening and diagnosis. Perry N.6. 2014 Jun.

Schnall MD. Thomas KM. Zaghiyan K. 2009 Dec 20. Am Surg. Evans DG. Warren RM. Houssami N. 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. 6. .11(6):R80. 59:290-302 Thompson DJ. Khazen M.30:21-30. 2009 Aug. 2009 Oct 21. 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. Kwan-Lim G. Eeles RA. Karlan SR. Irwig L. 2. 8. Bozzini A. Breast Cancer Res. Phillips EH. R. 3. Sonography and MRI for Detection and Characterization of Invasive Lobular Carcinoma of the Breast. 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. Gayther SA. Weinstein SP. Ramus SJ. et al: MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study.Statement MRI 1. Reiner CS Mammography. 2007 Aug 11. Boggis CR. 7. 2009 Nov 11. Radiology. Rosen M. 27(33):5640-5649 Houssami N. Kwan-Lim G. 2009 Oct. 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. Bryant E. Bieling HB. Lennard F. Dixon M. Warren RM. Reed S. The UK study of MRI screening for breast cancer in women at high risk (MARIBS).252(2):35868. Conant EF.75(10):937-40.CA Cancer J Clin 2009. 4. Warsi I. [Epub ahead of print] Dang CM.370(9586):485-92 Houssami N. 8: 275 Gilbert FJ. Localio AR. Renne G. J Clin Oncol. Multimodality screening of high-risk women: a prospective cohort study. Macaskill P. 5. The Lancet. Lord S. Easton DF. Warren. BMC Cancer 2008. Increased use of MRI for breast cancer surveillance and staging is not associated with increased rate of mastectomy. 9. 4 . Schrading S. Brennan ME. J Clin Oncol. Leach MO. Meneghetti L. JCO 2009.26(19):3248-58. Garzoli E.27(36):6124-8. Leach MO. Kuhl CK. Eeles RA. Sensitivity of imaging for multifocal-multicentric breast carcinoma. Evans DG. Ciatto S. Thompson DJ. et al. 10. Michael M. 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. 2008 Jul 1. Breast Dis.

77(10):1368-71. Lee SK. Epub 2011 Apr 16. 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. Shin JH. 15. 2014. Vapiwala N. Harvey I. Manca A. Kim S. Kim JH. Lee JE. Reeder-Hayes KE. 2011 Oct. Brown J. Meyer AM. Brown S. Olivier C. Pinder S. Preoperative breast MRI and surgical outcomes in elderly women with invasive ductal and lobular carcinoma: a population-based study.11. Douek M Multiple foci of invasive breast cancer: can breast MRI influence surgical management? Breast Cancer Res Treat. Romero LM: Does preoperative magnetic resonance imaging beneficially alter surgical management of invasive lobular carcinoma? Am Surg. Nam SJ. Lau B. Hanby A.119(1):163-7.128(1):1-5. Kim SW. Han BK. 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. 13. 14. Lim HI. 2010 Jan. Breast Cancer Res Treat. Kim JS. Turnbull L. Choi JH.143(1):203-12 5 . Napp V. J Clin Oncol. Turnbull LW. Macaskill P. Johnson L.14(1):1-182. 2010 Jan. Kim WW. Choe JH. on behalf of the COMICE Trial Group. Biddle AK. Wheeler SB. Turner R. 12. McCready DR. 2011 Jul. Kang SS. Walker L.32(5):392-401 Fortune-Greeley AK. 17. Cho EY. Sculpher M. Solin . Yang JH. Carpenter WR. 2014 Jan. Muss HB. 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). Ko EY. Health Technol Assess. Walker S. Drew P. Houssami N. Tuttle TM.

Seitz E. Ye S. 2003 Schneider C. Comparison of 18 FDG PET-CT and bone scintigraphy for detection of bone metastases in breast cancer patients. Moadel RM. Rong J. Yun M. Breast Cancer Res Treat 82:29-37. Rutgers.Pre-operative staging (5/15) No further information References: Statement: history and physical examination 1. Surg Oncol. 4. Wang S. 18FDG PET-CT for diagnosis of distant metastases in breast cancer patients. Steiner RA et al: Frequency and distribution pattern of distant metastases in breast cancer patients at the time of primary presentation Arch Gynecol Obstet. 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. 2003 Nov.90(2):105–12.22(2):86-91 Hong S. Breast Cancer Res Treat 2005. Ding Q. 2013 Jun. Zheng Z. 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. 6 .269(1):9-12. EJ et al: Quality control in the locoregional treatment of breast cancer (2001) EJC 37: 447-453 Gerber B.33(2):97-101. 6. 3. Isasi CR. 2. Blaufox MD. Fehr MK.22(2):139-43. 7. Wang S. Clin Nucl Med. 2008 Feb. A meta-analysis. Surg Oncol. 5. A meta-analysis. 2013 Jun. Li J. GCP Statement: high metastatic potential / symptoms 1. A meta-analysis of FDGPET for the evaluation of breast cancer recurrence and metastases. Cardarelli R. Shie P.

Scherr P. Froehlich JM. Willemse EM. Meili A.8. Doert A. Schmid DT. Gutzeit A. Comparison of diffusion-weighted whole body MRI and skeletal scintigraphy for the detection of bone metastases in patients with prostate or breast carcinoma. Eckhardt BP.39(4):333-43. Graf N. 7 . Binkert CA. 2010 Apr. Skeletal Radiol. von Weymarn CA.

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

Fleckner S. Ann Surg Oncol 1999. 32:937-940. 6:676-681. Castiglione G et al. 190:918-922. Polo K. 5. Plast Reconstr Surg 2006. Orecchia R et al. 117:1381-1386. Petit JY. 5.: Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. Ann Surg 2009 Mar. 2009. 17:97-105. Pusic AL et al. Simmons RM. Ann Surg Oncol 2002 Jun. 117:1381-1386 Benediktsson KP. 8. 34:143-148. Rivadeneira D. Nipple-sparing mastectomy for breast cancer and risk reduction: oncologic or technical problem? J Am Coll Surg 2006. Jacobs VR. 7. 2. Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications Ann Surg. Nipple-sparing mastectomy in association with intra operative radiotherapy (ELIOT): A new type of mastectomy for breast cancer treatment. 6:331-335. Howard MA. Local and distant recurrence rates in skin-sparing mastectomies compared with non-skin-sparing mastectomies. Perbeck L. Simmons RM. Nipple sparing subcutaneous mastectomy: sixty-six months follow-up. Skin-sparing mastectomy with immediate breast reconstruction: a critical analysis of local recurrence. Eur J Surg Oncol 2008. 4. Niemeyer M. Devalia H. Pinotti JA. 3. Fish SK.249(3):461-8 Statement: Nipple sparing mastectomy 1. Sacchini V. Dooley WC. Fish SK et al. 6. 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. 9 . 10. Am J Surg 2005. Paepke S. Surg Oncol 2007. 203:704-714. Veronesi U. Breast cancer local recurrence after mastectomy and TRAM flap reconstruction: incidence and treatment options. Polo K. Pusic AL et al. Anderson A et al. Plast Reconstr Surg 2006. 11. 9. Schlossberg L. Schmid R.9(5):462-6 Greenway RM.250(2):288-92 Gerber et al. Caruso F. 96:47-51. Eur J Surg Oncol 2006. Breast Cancer Res Treat 2006. Skin-sparing mastectomy and immediate breast reconstruction: a prospective cohort study for the treatment of advanced stages of breast carcinoma. Barros AC et al. Oncological safety and patient satisfaction with skin-sparing mastectomy and immediate breast reconstruction. Kiechle M. Schmalfeldt B. Foster et al. Breast cancer local recurrence after mastectomy and TRAM flap reconstruction: incidence and treatment options. Cancer 2000. Patani N. Fifteen-year series of skin-sparing mastectomy for stage 0 to 2 breast cancer. Howard MA. Paepke D. Ferrara M. Gayle L et al.4.

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

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

2014 Oct.. 2006 Sep. Irwig L. 2007 Apr.32(14):1502-6. Ann Surg Oncol. Pockaj BA.. Radiography of the surgical specimen in early stage breast lesions: diagnostic reliability in the analysis of the resection margins. 12 . Morrow M. 2014 Mar. Am J Surg. Ciccarelli G. 2002 Nov. 1. 5. 7. Newman LA. Clin Radiol.46(18):3219-32. Solin LJ. Menna S. Giuliano AE. Sahin et al: Role for Intraoperative Margin Assessment in Patients Undergoing Breast-Conserving Ann Surg Oncol.21(10):3192-7. Eur J Cancer. 4.12(1):28-36 Statement: tumor free margins . El-Eid S. Overmoyer B Breast conservation surgery achieving>or=2 mm tumor-free margins results in decreased local-regional recurrence rate.14(4):1458-71. 2. 2006 Jan-Feb. Ann Surg Oncol. Somerfield MR. Radiol Med (Torino). Breast J.184(5):383-93. Latson L. Hunt. 2010 Dec. 2006 Dec. 2007 Apr. J Clin Oncol.1. Mason G.21(3):717-30 Buchholz TA.61(9):789-96. Balleyguier C. 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. Macaskill P.201:194–198. 6. Cabioglu N. Harness JK. Cendán JC et al. Rouzier R. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Singletary: Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Dixon JM. Tan KY et al. Hammond ME.. Macaskill P. Marinovich ML. 2014 May 10. Downs-Kelly E. Specimen radiography as predictor of resection margin status in non-palpable breast lesions. Marinovich ML. Lyman GH. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Breast specimen ultrasound and mammography in the prediction of tumour-free margins. Di Virgilio MR. Brennan ME. Griggs JJ. Metaanalysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breastconserving therapy. Mazouni C.76(12):1064-7. Kunos C. J Am Coll Surg 2005. 3. Accuracy of Intraoperative Frozen-Section Analysis of Breast Cancer Lumpectomy-Bed Margins. Houssami N. ANZ J Surg. 2. Houssami N.112(3):366-76. 4. 3.

Ehdaivand S. re-excision . JAMA Surg. Stempel M. Lin NU. Leong T. ANZ J Surg. J Surg Oncol.Statement: tumor free margins in intrinsic subtypes 1. 2014 Mar. Mirocha J. Winer EP.30(2):146-51. Statement: stereotactic excision alone . Hughes ME. Moy B.. 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. Moore SE: Margins and outcome of screen-detected breast cancer with extensive in situ component.. Ann Surg Oncol. Jackman RJ. Effect of margin width on local recurrence in triple-negative breast cancer patients treated with breast conserving therapy. Eaton A. Freedman G. Ottesen RA. Price LL. Windle I: Predictors of surgical margin status in breast-conserving surgery within a breast screening program. 2007 Apr.. 2008 Sep. 2002 Aug. node-negative breast cancer: a multi-institutional study. Sioshansi S.224(2):548-54 13 . Van de Vrande SL. Ann Surg Oncol. Cramer C. Morrow M. 1.. Wong MH. Orell E. 3. Edge SB. Patil S.76(7):591-5 Schouten van der Velden AP. Statement: . Breast-conserving therapy for triple-negative breast cancer.. Liou DZ. 2006 Jul.118(16):3893-8 Gangi A.21(4):1209-14. Kurniawan ED. Gonzalez-Angulo AM. Weeks JC. Ho A. 2. Rugo HS. Outcomes by tumor subtype and treatment pattern in women with small. 2007 Dec 1. 1. Wazer DE. Chung A.149(3):252-8 Vaz-Luis I. 2014 Jul 10. 4. 2.32(20):2142-50. Cawson JN..15(9):2542-9. Mamet R. Ikeda DM: Atypical ductal hyperplasia: can some lesions be defined as probably benign after stereotactic 11-gauge vacuum-assisted biopsy. 2012 Aug 15. J Clin Oncol. Cancer. Pilewski M. Burstein HJ. Am J Clin Oncol.96(7):569-74 McIntosh A. Chen Y. Theriault RL. Lomme MM. eliminating the recommendation for surgical excision? Radiology. 3. 2014 Apr. Birdwell RL.Triple negative breast cancer is associated with an increased risk of residual invasive carcinoma after lumpectomy. Kitchen PR. 4. Giuliano AE. Eisenberg D: Recurrence rates and analysis of close or positive margins in patients treated without re-excision before radiation for breast cancer.

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142(3):579-90.. Viale G. 2013 Dec. 189. 2009 Feb. Sim AS. Musmeci S. Da Lima L. Multiple re-excisions versus mastectomy in patients with persistent residual disease following breast conservation surgery. 2000. Intra M.95(16):1182-3. Breast Cancer Res Treat. 179. Huston T. Schwentner L.113(3):577-83. Martins D. 2003 Aug 20. Veronesi U. Wischnewsky M. Janni W. 3. Inflammatory breast issue. Novopashenny I.Breast Conservation Surgery (8/15) No further information References: Statement: Multicentricity 1. Galimberti V. [Epub ahead of print] Statement: positive microscopic . et al. Sosnovskikh I.. Luini A. ANZ J Surg. Breast Cancer Res Treat. Amer J Surg 2005. Kreienberg R. 2. Tartter P. Wallner PE. Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue. 2. 2.12942. 1. Garcia-Etienne CA. 81-85 Cellini C. Gentilini O. Botteri E. 15 . Amer J Surg. Abrams JS. BRENDA Study Group. Conservative surgery in patients with multifocal/multicentric breast cancer. reexcision. Mazzarol G. doi: 10. Veronesi P. and is there a role for guideline-adherent adjuvant therapy? A retrospective multicenter cohort study of 8. Goldhirsch A. Ebner F. Rotmensz N.1111/ans. Comparing the outcome between multicentric and multifocal breast cancer: what is the impact on survival. 662-666 Statement: Inflammatory Carcinoma 1. 2014 Dec 5. and local recurrence of breast cancer. Wolters R. Caliskan M.: Lumpectomy margins. Sitoh NY. Wöckel A. Tan MP.935 patients. Coleman CN. J Natl Cancer Inst.

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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. Ashikaga T. Mamounas EP. de Lara CT. Klinkenbijl JH. van Tienhoven G. Kopkash K. Frazier TG. Snoj M. Pesek S. Podoloff DA.36(9): 2239-2251 Lyman GH. World J Surg 2012. Krag D. Wool N.8(10):881-8. Julian TB. 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. 6. Rutgers EJ. McCready DR. Lancet Oncol. Miller BJ. 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. American Society of Clinical Oncology Clinical 29 . Martel P. J Clin Oncol. 2007 Oct.144(4):606-9. Avigdor S. Ann Surg Oncol. Ali A. Jalovec LM. Vaini-Elies V. Temin S. Robidoux A. Surgery. Hurkmans C. Rodier JF. Newman LA. 2008 Oct. van de Velde CJ. Weaver DL. Ferron G. Harlow SP. Straver ME. Wilt M. Wolmark N. Mansel RE. Cataliotti L. Costantino JP. Krag LE. Velten M. Sentinel node identification rate and nodal involvement in the EORTC 10981-22023 AMAROS trial. Scarth HM. Duez N. Anderson SJ. Avril A. Krag DN. Houvenaeghel G. Meijnen P. Weaver DL. 3. Giuliano AE. Fogg L. Perkins CL. Burstein HJ. Mammolito DM. The false-negative rate of sentinel node biopsy in patients with breast cancer: a meta-analysis. 2. Ashikaga T. Classe JM. Hayman J. discussion 609-10. Brown AM.17(7):1854-61. Dravet F. Westenberg HA.25(24):3664Bines S. Turner RR. Fondrinier E. Lorimier G. Bosserman LD. 4. 5. Routiot T. van der Mijle H. Mignotte H. Benson AB 3rd. Edge SB.Sentinel Lymph node excision: Marking (13/15) No further information References: Statement radiotracer/blue dye: 1. Cody H 3rd. Noyes RD. 2010 Jul. Brémond A. 2007 Aug 20. Bogaerts J.

2014 May 1. Korant A. Wiese D. Loh SW. Eur J Surg Oncol. Blue dye is sufficient for sentinel lymph node biopsy in breast cancer. Tan EY. Klaase JM. Tavassoli A. Teo C. Varghese P. Bonatsos G. 2009 Aug. 4. 2011.101(4):383-9. Ko EY. 2012 Aug.104(1):37-40. Chen JC. Forghani MN. A prospective trial comparing 1% lymphazurin vs 1% methylene blue in sentinel lymph node mapping of gastrointestinal tumors. discussion 389. Fritz P. Purushotham AD. Birbas K. Seah DW. Shin JH.30(12):1711-21. Chan MY. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. 2. Bonatsos VG. Sirop S. 2011 Jul 1. Statement: ICG: 1. Yang JH. Br J Surg.16(8):2224-30. Sadeghi R.32(13):1365-83 Ang CH. Canizales A. Abdollahi A. J Ultrasound Med. A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer. Mostafa A. for identification of sentinel lymph nodes in patients with early stage breast cancer. Gattuso J.38(8):651-6. Tan MY. Practice. Abdel-Rahman AT. Cho EY. Soni M. 2014 Oct. Han BK. Rohbakhshfar O. Kang SS. 8. Chakravarty B. Nam SJ. Kaklamanos IG. Gayar A. 2014 Mar. Wishart GC. 2007 Mar.7. Benson JR. Horgan K. Saha S.33(2):147-52. Br J Surg. 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. Iddings D. 30 . 2015 Feb. Jones L. Eur J Surg Oncol. 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. Prospective comparison of peritumoral and subareolar injection of blue dye alone.19(10):918-22. Lee JE. Ann Surg Oncol. 5. Ahmed M.102(3):169-81. Methylene blue dye versus combined dye-radioactive tracer technique for sentinel lymph node localisation in early breast cancer. 3. Akberali S. Wells CA. Statement: methylene blue 1. Clin Oncol. Methylene blue dye-related changes in the breast after sentinel lymph node localization. Syrigos K. Carpenter R. Fattahi AS. J Surg Oncol. Douek M.

2015 Jan. Kothari A. Ten Haken B. and blue dye versus the radioisotope method in breast cancer: a randomized controlled trial. Tassinari D. Cortadellas T. Tong M. Diaz-Botero S. Pinder S. Panzini I. Accardi FG. Rubio IT. Eur J Surg Oncol. Cordoba O.21(4):1254-9. Statement: SPIO: 1. Guo W. Statement: Comparisons 1. Douek M. 2014 Jul. 2014 Sep. Lee ES. 2014 Apr. Grootendorst M. 2014 Apr. Fogacci T. Radioisotope. Polkowski W. Agbaje O. Park IH. Zechmeister K. SentiMAG Trialists Group.41(1):64-70. Ann Surg Oncol. Anninga B.2. Hauser N. Ro J. 2015 Jan. van Haasteren V. Esgueva A. Joo J. Jeong HJ. Eur J Surg Oncol. The superparamagnetic iron oxide is equivalent to the Tc99 radiotracer method for identifying the sentinel lymph node in breast cancer. 3. Monypenny I. Ko KL. Shin KH. Berclaz G. Purushotham AD.41(1):46-51 Thill M. Grosse B. Kwon Y. Flenghi L.J Breast Cancer. Gianni L. Lee S Comparison of sentinel lymph node biopsy guided by the multimodal method of indocyanine green fluorescence. Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG Multicentre Trial. Frisoni G.The use of indocyanine green to detect sentinel nodes in breast cancer: A prospective study. Statement: General 1. Drew P. Rodriguez R. Wyld L.23(2):175-9. Purushotham A.17(3):250-5. Kim SK. Hall-Craggs MA. The CentralEuropean SentiMag study: sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. Jung SY. Tamburini E. 31 . Nicoletti S.15(8):e351-62.21(4):1237-45. Kang HS. Lancet Oncol. 3. Kim SW. Pankhurst Q. Lee KS. Kang SH. Samorani D. Novel techniques for sentinel lymph node biopsy in breast cancer: a systematic review. Ann Surg Oncol. Gao W. Douek M. Use of Fluorescence Imaging in Combination with Patent Blue Dye versus Patent Blue Dye Alone in Sentinel Lymph Node Biopsy in Breast Cancer. 2014 Apr. Brown D. Ricci M. Breast. Kurylcio A. 2. Fabbri E. Welter R. Ahmed M. radioisotope. Espinosa-Bravo M. Klaase J. Garmo H.

doi: 10. Yamagami K. Yoshimura K.1245/s10434-013-2890-0. Kinoshita T.20(7):2213-8. Toi M. Shimizu A. 32 . Tagaya N.2. Niimi M. Sugie T. Sawada T.Comparison of the indocyanine green fluorescence and blue dye methods in detection of sentinel lymph nodes in early-stage breast cancer. Ikeda T. Ann Surg Oncol. Epub 2013 Feb 21. 2013 Jul. Suwa H.

Dowsett M. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. Mauri D. Surgical treatment of primary breast cancer in the neoadjuvant setting. Dontu G. Ferrozzi F. Tampellini M.A plea for the biopsy marker: how. Aglietta M. Italy (2010). David J. why and why not clipping after breast biopsy? Breast Cancer Res Treat. 2. Loibl S. Daidone M. Hunt KK. Ames FC. Desmedt C. Harris AL. Tortora G. Am J Surg. Gianni L. de Azambuja E. 2014 Jul. Pusztai L. Statement: operation and : tumor resection in new margins 1.132(3):881-93.Procedure after neoadjuvant treatment (14/15) No further information References Statement: clip marking 1. 2012 Apr. Kümmel S. Sotiriou C.Surgical conservation planning after neoadjuvant chemotherapy for stage II and operable stage III breast carcinoma. Miller WR. 2001 Dec. Sapino A. J Natl Cancer Inst Monogr. Dogliotti L. Buzdar AU. Petronini P. Ross MI. Holtschmidt J. Puztai L. Kuerer HM. Generali D. Br J Surg. Makris A. 2005 Feb 2. Singletary SE. Trop I. Uzan S. Untch M.2011(43):147-51. Hortobagyi GN. Bertolini F. Bottini A. Pavlidis N. 2. Buchholz TA. Thomassin-Naggara I. Kaufmann M. Tondini C. Di Cosimo S. Darai E. Olivetti L.182(6):601-8. Cremona.101(8):912-24 33 . Lalonde L. Berruti A. Fox SB. Van't Veer L. Valero V. Curigliano G. Danova M. Ioannidis JP. Damia G. 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.97(3):188-94. Mansel RE. Kennedy D. 2011. 3. Conte P. Thorne H. Bruzzi P. Fenaroli P. Tagliabue E.

2014 Oct 9. 1. 2010 Dec. 2007 Apr. Ann Surg Oncol. Macaskill P. Distant and Overall Survival of 6. 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. Accuracy of Intraoperative Frozen-Section Analysis of Breast Cancer Lumpectomy-Bed Margins. Pockaj BA. Sahin et al: Role for Intraoperative Margin Assessment in Patients Undergoing Breast-Conserving Ann Surg Oncol. Radiography of the surgical specimen in early stage breast lesions: diagnostic reliability in the analysis of the resection margins.201:194–198.21(10):3192-7. 6. Metaanalysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breastconserving therapy. 34 . Marinovich ML.. 7. Denkert C. [Epub ahead of print] Statement: tumor free margins .46(18):3219-32. Houssami N. Blohmer JU.21(3):717-30 Buchholz TA. Marinovich ML. Cendán JC et al. Irwig L. Harness JK. Ann Surg Oncol. Rezai M.14(4):1458-71. 3. Gerber B. 2007 Apr. Impact of Multifocal or Multicentric Disease on Surgery and Locoregional.32(14):1502-6. Downs-Kelly E. J Clin Oncol. Solin LJ. Kümmel S. Heil J. 5. Mason G. Somerfield MR. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis.134 Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. Loibl S. 2. Hammond ME. Houssami N. Morrow M. 4. Giuliano AE. 2014 Oct. 2014 May 10. Ciccarelli G. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Lederer B.112(3):366-76. Hunt. Menna S. Ann Surg Oncol. von Minckwitz G. Radiol Med (Torino). J Am Coll Surg 2005. Lyman GH.4.. Newman LA. Brennan ME.. Cabioglu N. Di Virgilio MR. 2014 Mar. Eur J Cancer. Macaskill P. Ataseven B. Griggs JJ. Dixon JM. Kühn T. El-Eid S.

Roncadin M.23(1):11-6. Balduzzi A. Piroth MD. Cancer Treat Rev. Adamowicz K. Optimal timing for adjuvant radiation therapy in breast cancer: a comprehensive review and perspectives. Goldhirsch A. Azria D. 2010. Belkacémi Y. International Breast Cancer Study Group. Colleoni M. Christensen VJ.a retrospective analysis. Int J Radiat Oncol Biol Phys. Jassem J. Gagel B. Pinkawa M.35(5):409-16 Harris EE. Solin LJ. Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy. Murray E. Gruber G. Statement: Tamoxifen concurrent with chemotherapy 1. Orecchia R. J Clin Oncol. 2. Price KN. Colleoni M. Goldhirsch A. 2009 Aug. 2009. Hwang WT. Crit Rev Oncol Hematol.71(2):102-16. 2011. Leonardi MC. Cole BF. Combining systemic therapies with radiation in breast cancer. 4. 2008 Apr 23. Fox K. Dellapasqua S.80(2):398-402. Asadpour B. Cardillo A. 2005 Jan 1. Castiglione-Gertsch M. Koukourakis MI.36(6):443-50. Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. Sequencing chemotherapy and radiotherapy in locoregional advanced breast cancer patients after mastectomy . Marczewska M. Stanzel S.8:114.Ajuvant therapy after primary surgery (15/15) No further information References: Statement: Timing of radiation and chemotherapy 1. 3. Tsoutsou PG. 2. Timing of adjuvant systemic therapy and radiotherapy after breast-conserving surgery and mastectomy. Karlsson P. Eble MJ. Cancer Treat Rev. Iorfida M. 35 . Chua BH. BMC Cancer.

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

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

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

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

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

Algorithm of Breast Reconstruction © AGO 1st choice: Implant-Reconstruction e.V. in der DGGG e.ago-online. Implant alone not suitable – hostile environment Guidelines Breast Version 2015.1 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. V.de . sowie in der DKG e.V.

Guidelines Breast Version 2015. RT.ago-online.1 www. age . sowie in der DKG e.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. in der DGGG e.Postmastectomy Reconstruction © AGO Oxford / AGO LoE / GR e. Diabetes. smoking status. V.V.V.

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

ago-online.V. V.de  . sowie in der DKG e. Guidelines Breast Version 2015.Timing of Postmastectomy Implant Reconstruction © AGO Oxford / AGO LoE / GR e.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.V. in der DGGG e. antibiotic therapy (at least 48 h) 3b C +  www.

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

ago-online.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. sowie in der DKG e.V. V.Lipotransfer © AGO e.de  . Guidelines Breast Version 2015. Oxford / AGO LoE / GR in der DGGG e.V.

sowie in der DKG e. more liponecrosis) 2a B +/- . more wound healing problems. Guidelines Breast Version 2015.Postmastectomy Pedicled Reconstruction © AGO Oxford / AGO LoE / GR 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. in der DGGG e.V.V.1 Reconstruction (BR) with autologous tissue TRAM. V.de  BR following RT 2a B +  BR prior to RT (more fibrosis.ago-online.

V.ago-online. Guidelines Breast Version 2015. in der DGGG e.V. DIEP are potentially muscle-sparing procedures. sowie in der DKG e./ IGAP-flap Free gracilis flap (TMG) 3a 3a 3a 4 B B 4 +/+ C +/- C +/- C +/- Advantage:  www.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 .1 Free tissue transfer      Free TRAM-flap DIEP-flap SIEA-flap SGAP.de Free TRAM. Disadvantages:       Time. The DIEP has a lower rate of abdominal hernias.Free Tissue Transfer © AGO Oxford / AGO LoE / GR e. V.

V.g.ago-online. Guidelines Breast Version 2015.1 www.Pedicled vs.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. Free Tissue Transfer © AGO Oxford / AGO LoE / GR e. impaired muscle function) has to be taken into consideration in all flap techniques  A ++ .V. in der DGGG e. sowie in der DKG e. V.

V. in der DGGG e. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Flap-implant combination LDF* + implant  IR following RT  IR prior to RT Advantages:  www.Flap-Implant Combination © AGO Oxford / AGO LoE / GR e. V.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 + + - .ago-online.

Guidelines Breast Version 2015. in der DGGG e.ago-online. sowie in der DKG e.Skin/Nipple Sparing Mastectomy (SSM/NSM) and Reconstruction © AGO Oxford / AGO LoE / GR e. inframammary fold  Lowest incidence of complications 2b B + . V.V.1  Skin sparing mastectomy (SSM/NSM)    Safe (same recurrence rate as MX) Higher QoL for patients NAC can be preserved under special conditions  www.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.V.

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.e. salpingoophorectomy (BSO) 2a A ++* 1b A ++  Further need for education of physicians regarding possibilities and advantages of RRBM *Counselling. sowie in der DKG e.ago-online. in der DGGG e.Bilateral Risk Reducing Mastectomy in Healthy Women (RRBM) © AGO Oxford / AGO LoE / GR e.V. risk prediction and follow-up in • * Study participation recommended specialised centres recommended . V.V.de  RRBM reduces breast cancer incidence 1b A ++  RRBM in deleterious BRCA1/2 mutation 2a B +*  RRBM in high risk (i. Guidelines Breast Version 2015.1 www.

V.Types of Risk Reducing Mastectomy © AGO Oxford / AGO LoE / GR e.V.1 Risk Reducing Mastectomy reduces breast cancer incidence.V. Guidelines Breast Version 2015. in der DGGG e. sowie in der DKG e.de  * Study participation recommended .ago-online. 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.

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

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

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

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

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

MD http://www. MD. Kristine Calhoun.uptodate.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.com/contents/oncoplastic-techniques-in-breastconservingsurgery?source=machineLearning&search=oncoplastic+surgery&selectedTitle=1%7E1&sectionRank=1&anchor=H14027 079#H14027079 .

Iera M. Fakhr I. 2014 Dec. Styblo TM. Spautz C. 2014 Dec 5. Partial breast reconstruction using various oncoplastic techniques for centrally located breast cancer. Long-Term Comparison of Aesthetical Outcomes After Oncoplastic Surgery and Lumpectomy in Breast Cancer Patients. Freitas AM. Pinell-White X. Ann Surg Oncol.72(2):145-9. Chung HY. Sitoh NY. 2014 Feb. 2014 Nov.12942. Carlson GW. Rietjens M. Yang JD. [Epub ahead of print] Tan MP. Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue. Aesthet Surg J. de Oliveira VM. Anselmi K. J Egypt Natl Canc Inst. 6. doi: 10. 7. Capp E. Park HY.41(5):520-8. Losken A. Park HC.Oncoplastic breast conserving surgery (4/21) Further information: AGO Voting for this new slide and content 45/0 References: 1. 2014 Dec 18. Edelweiss MI. 5. The oncoplastic reduction approach to breast conservation therapy: benefits for margin control. Losken A1.26(4):203-9. A meta-analysis comparing breast conservation therapy alone to the oncoplastic technique. Lee JW. doi: 10. 4. Arch Plast Surg.1111/ans. Styblo TM. Cho BC. Santos G.34(8):1185-91. . Kim MC. 3. Dugal CS. Kim HY. Zucca-Matthes G. ANZ J Surg. Urban C. Outcome of different oncoplastic surgical (OPs) techniques for centrally located breast cancer (CLBC). [Epub ahead of print] Moustafa A.0b013e3182605598. 2. Sim AS.1097/SAP. Arana GH. Carlson GW. de Lima RS. Ann Plast Surg. 2014 Sep. Kuroda F. Hart AM.

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

Nelson JA. Garwood E. Wang QY. Esserman LJ. and Superficial Inferior Epigastric Artery Flap: A Systematic Review and Meta-analysis. Zeijlmans van Emmichoven IA. Longo B. Ann Plast Surg. Meta-analysis of the safety and factors contributing to complications of MS-TRAM. Pagnoni M. de Bock GH. DIEP. Latissimus dorsi flap for total autologous immediate breast reconstruction without implants. 3. Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. 7. Alvarado M. and SIEA flaps forbreast reconstruction. Ewing C.38(4):681-91.48(2) Wang XL1. 2014 Oct. 4. Aesthetic Plast Surg. Tuggle CT 3rd. Serletti JM. 2015 Jan. 2. Werners LL. 2014 Apr. Basta MN. Serletti JM. 2014 Dec 19 Wang F. Dreise MM.063 cases from the 2005-2010 NSQIP datasets. Shubinets V. Which Breast Is the Best? Successful Autologous or Alloplastic Breast Reconstruction: Patient-Reported Quality-of-Life Outcomes. Hwang ES. A Systematic Meta-analysis of Prosthetic-Based Breast Reconstruction in Irradiated Fields With or Without Autologous Muscle Flap Coverage. Wu LC. Mun GH. 6. Plast Reconstr Surg. Eltahir Y. Ann Plast Surg. Fosnot J. Liu LB. Lee KT. Sorotos M.21(10):3223-30 Fischer JP. Falesiedi F. J Plast Surg Hand Surg. Ann Surg Oncol. Song FM. Sbitany H. 2014 Aug. Plast Reconstr Surg 2014 Dec. Foster RD.134(6):871e-9e . 2014 Santanelli di Pompeo F. Peled AW. Fischer JP1. 5. Werker PM. Effects of Obesity on Postoperative Complications After Breast Reconstruction Using Free Muscle-Sparing Transverse Rectus Abdominis Myocutaneous. Complications and morbidity following breast reconstruction--a review of 16.Postmastectomy Reconstruction (6/21) Further information: Voting for this new slide and content 45/0 References: 1. Deep Inferior Epigastric Perforator.135(1):43-50. Laporta R. Au A. Fiscalini AS.

2015 Jan 7 Garvey PB. Gray RJ. Chung KC. Plast Reconstr Surg. . 124(3):752-64.134(4):648e-55e Agarwal S. Gutowski K. Buchel EW. Selber JC. 2006 May Man LX. Postmastectomy Expander Implant Breast Reconstruction Guideline Work Group. Gray D. 2009 Sep.8. Ann Surg Oncol. Kidwell KM. Pockaj BA. Kozlow JH. Hernández JL. 2014 Oct. 11. Ahuja A. Alderman A. Farberg A. 10. Casey WJ 3rd. Plast Reconstr Surg. Samson TD.DIEP and pedicled TRAM flaps: a comparison of outcomes. Serletti JM. Plast Reconstr Surg. ASPS clinical practice guideline summary on breast reconstruction with expanders and implants. Momoh AO. 9. Abdominal wall following free TRAM or DIEP flap reconstruction: a meta-analysis and critical review. Immediate Reconstruction of the Radiated Breast: Recent Trends Contrary to Traditional Standards.

D'Souza N. Jacks LM. Mehrara BJ. Santoro TD. Forouhi P. et al. 2012 Feb. Martinelli G.126:1. Hofer SO. Rey P. Petit JY.22(1):64-9.10. Watson JP. 2011 Jul 6. 2013 Feb. Plast Reconstr Surg 2010. Bruce Mann G. Ann Surg Oncol. Immediate versus delayed reconstruction following surgery for breast cancer. Ann Plast Surg 2005. 4. 8. Cochrane Database Syst Rev.breast. Plast Reconstr Surg 2006.008. Langstein HN. A Comparison of Surgical Complications Between Immediate Breast Reconstruction and Mastectomy: The Impact on Delivery of Chemotherapy-An Analysis of 391 Procedures. De Boer RH. Fedorowicz Z. Rietjens M. Plast Reconstr Surg 2010. Albino FP. Ismail A. Earl H. Koltz PF. Zhong T. 2011 Jul 6. Irradiated autologous breast reconstructions: effects of patient factors and treatment variables. Darmanin G. 3. Ling MN. McCready DR.Timing of Reconstruction (7/21) Further information: No voting this year References: 1. Azzawi K.118:1100 . Immediate versus delayed reconstruction following surgery for breast cancer. Does immediate breast reconstruction compromise the delivery of adjuvant chemotherapy? Breast.2012. Youssef O. D'Souza N.19(2): Chang RJ.55:250-4.(7):CD008674. 2. Influence of neoadjuvant chemotherapy on outcomes of immediate breast reconstruction. Da Lio AL. doi: 10. Malata CM. 6. Epub 2012 Nov 22. Darmanin G.1016/j. Kirkpatrick K. Fedorowicz Z. 7. Immediate breast reconstruction and highdose chemotherapy. Shaw WW. De Lorenzi F. 5. Cochrane Database Syst Rev.(7):CD008674.126:12. Cook FE. Arcilla E. Complications after microvascular breast reconstruction: experience with 1195 flaps. Baxter N.

ejso. . 2013 May. Eur J Surg Oncol.02. Schaverien MV.39(5):430-6.2013. doi: 10. Epub 2013 Mar 5.9. Effect of neoadjuvant chemotherapy on outcomes of immediate free autologous breast reconstruction. Munnoch DA.1016/j.015.

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

A'hern R. doi: 10. Ward A. Djohan R. 2012 Jan. Delayed-immediate breast reconstruction. An analysis of long-term complications. Ross GM. 2011 Oct. infected implant-based breast reconstruction and strategies for salvage. Smartt JM Jr. Tendulkar R. Links Mirzabeigi MN. Tran T. 14. Couturaud B. Wishart GC.x.77(10):1349-52.01182. Plast Reconstr Surg. Malata CM. Berry MG. Brooks S. 2008 Oct 31. Gui GP. McCarthy CM. 118(4): 825-839. Dietz J. Hill M. and patients satisfaction. Am Surg. 9. A prospective analysis of early complications.The impact of radiation on surgical outcomes of immediate breast reconstruction. [ Whitfield GA. Plast Reconstr Surg. Radiother Oncol.113(6):1617-28. Alderman AK et al. Bennett SP. Fitoussi AD. Sonnad SS. 2012 Jan.129(1):1e-7e. Horan G. 2006. J Plast Reconstr Aesthet Surg. Miles D.6.121(2):381-8.1524-4741. Jandali S. Nutter B. 10. Management of exposed. Breast J. Behranwala KA. . Tran T. Epub 2011 Jun 25. Serletti JM. 7. 13. A single surgeon‘s 12-year experience with tissue expander/implant reconstruction: part I. Wilson CB. Risk factors for complications of radiation therapy on tissue expander breast reconstructions.18(1):28-34. 15. Extended trimethoprim/sulfamethoxazole prophylaxis for implant reconstruction in the previously irradiated chest wall. Epub 2011 Nov 20.204(1):7-12 Cordeiro PG. 8. J Plast Reconstr Aesthet Surg. Irwin MS.122(1):19-28.2011. Plast Reconstr Surg 2006 Sep 15.1111/j. Incidence of severe capsular contracture following implant-based immediate breast reconstruction with or without postoperative chest wall radiotherapy using 40 Gray in 15 fractions. 2008 Feb. The influence of radiotherapy on capsule formation and aesthetic outcome after immediate breast reconstruction using biodimensional anatomical expander implants. Lee M. Lum SS. Isik FF. Dua RS. Salmon RJ. Kronowitz SJ et al. Plast Reconstr Surg.59(10):1043-51. 12. Does patient satisfaction with breast reconstruction change over time? Two-year results of the Michigan Breast Reconstruction Outcomes Study. 2004. 16. Part II. Plast Reconstr Surg. True incidence of all complications following immediate and delayed breast reconstruction. J Am Coll Surg 2007 Jan.64(10):1270-7. aesthetic outcomes. 11. 2011 Oct. 2008 Jul. Lyons J.

Management of exposed. Couturaud B. Fitoussi AD. infected implant-based breast reconstruction and strategies for salvage. 2011 Oct. Bennett SP. Berry MG. Salmon RJ. Epub 2011 Jun 25. . J Plast Reconstr Aesthet Surg.17.64(10):1270-7.

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

1097/PRS. Wright CK. Ann Plast Surg. Roostaeian J. Covarelli P.bjps.08. 2013 Mar.2012.8.66(3):323-8. Castellani E. 2011 Jul. 2012 Dec.ejso. Clayton JL. blinded. 2013 Jan. 11. Noya G.10. doi: 10. The scarless latissimus dorsi flap for full muscle coverage in device-based immediate breast reconstruction: an autologous alternative to acellular dermal matrix. Mericli AF. Caracappa D. Gerber B. In Vivo. Sanguinetti A. . Dieterich H. Pusic AL. Drake DB. Mehrara BJ. 10.27(3):383-6. Epub 2012 Sep 13.130(5 Suppl 2):57S-66S. 2013 May-Jun. Epub 2012 Nov 13. 14. 16. Arcuri G.38(12):1225-30. Pataia E. Barberini F. 13. Current trends in breast reconstruction: survey of American. Society of Plastic Surgeons 2010.1097/SAP. et al. Charny MC. McCarthy CM. 2012 Nov.0b013e31825f05b4.026. Optimizing therapeutic timing in patients undergoing mastectomy through use of the Tiloop® synthetic mesh: single-step surgery. Ann Plast Surg 2011 Hanna KR.0b013e31822f6765.1016/j.2012. A short-term follow-up of implant based breast reconstruction using a titanium-coated polypropylene mesh (TiLoop(®) Bra). J Plast Reconstr Aesthet Surg. Dunavant C. Johnson RK.39(3):242-7. Barr L.70(1):10-5. DeGeorge BR Jr. Comparison study of two types of expander-based breast reconstruction: acellular dermal matrix-assisted versus total submuscular placement. doi: 10.002.ejso. Elliott LF et al.12. 128:403e–410e. Rulli A.2012. Plast Reconstr Surg. Dieterich M. Stubert J. 9. Comparison of implant-based immediate breast reconstruction with and without acellular dermal matrix. 2011. Reimer T. Epub 2012 Dec 21. Tebockhorst S. The use of acellular dermal matrices in two-stage expander/implant reconstruction: a multicenter.015. Halvorson EG. 128(1):71-9 Gurunluoglu R.1016/j. Plast Reconstr Surg. Plast Reconstr Surg. Gurunluoglu A. Vardanian AJ.1016/j. doi: 10. Disa JJ. 12. Riedel E. randomized controlled trial. Lee CN. Eur J Surg Oncol. 15. Nocera N. Eur J Surg Oncol. Lin KY. Salzberg CA. doi: 10. 2013 Mar. Gandhi A. Williams SA. Cost minimisation analysis of using acellular dermal matrix (Strattice™) for breast reconstruction compared with standard techniques. doi: 10. Immediate breast reconstruction using porcine acellular dermal matrix (Strattice™): long-term outcomes and complications.

3. . 2014 Mar.Megavolume autologous fat transfer: part I. Stringhini P.34:475–80. et al. CADTH Rapid Response Reports. 5. Plast Reconstr Surg. The oncologic outcome and immediate surgical complications of lipofilling in breast cancer patients: a multicenter study. Autologous Fat Grafting for Reconstructive Surgery: A Review of the Clinical and Cost-Effectiveness [Internet]. Ann Plast Surg 2010. Biggs TM. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. Rigotti G. Determining the oncological risk of autologous lipoaspirate grafting for post-mastectomy breast reconstruction.128:341–6. Cardoso E. 2013. Lohsiriwat V. 4. 2014 May.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. Petit JY. Petit JY. Plast Reconstr Surg 2011. Rietjens M. 2. et al. Khouri RK1.133(3):550-7. Evaluation of fat grafting safety in patients with intra epithelial neoplasia: A matched cohort study. Ann Oncol. Clough KB. Theory and principles. Rigotti G. Marchi A. et al. Milan-Paris-Lyon experience of 646 lipofilling procedures. Khouri RK Jr. Botteri E.24:1479–1484.

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

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

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

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

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

Yueh JH.Pedicled vs. 2014 Jun 6.2(5) .A comparative analysis of 2 national breast reconstruction surveys: concerns regarding autologous and microsurgical breast reconstruction. Lee BT. Colakoglu S. Tobias AM. Free Tissue Transfer (13/21) Further information: No voting this year Reference: 1. Momoh AO. Ann Plast Surg. Analysis of Complications and Patient Satisfaction in Pedicled Transverse Rectus Abdominis Myocutaneous and Deep Inferior Epigastric Perforator Flap Breast Reconstruction. Curtis MS. Plast Reconstr Surg Glob Open. de Blacam C. Bronsert M1. 2. 2011 Jun 8. Westvik TS. [Epub ahead of print] Gurunluoglu R1.

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

2014. 2014 Oct. Diminishing relative contraindications for immediate breast reconstruction: a multicenter study. Mehrara BJ Bilateral implant breast reconstruction: outcomes. doi: 10. predictors. Veronesi P. Fischer JP. Cordeiro PG1. 4. 3. McCarthy CM1. Axelrod DM.Skin/Nipple Sparing Mastectomy (SSM/NSM) and Reconstruction (15/21) Further information: No voting this year References: 1.238(1):120-7. Kuchenmeister I. J Plast Surg Hand Surg.39(4):320-8. 2014 Dec. Makovitzky J. The lateral inframammary fold incision for nipple-sparing mastectomy: outcomes from over 50 immediate implant-based breast reconstructions. Ann Plast Surg. Krause A. 2008 Mar 22. Wu LC. Garusi C. Eur J Surg Oncol. 5. Pusic AL1. Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. Petit JY.1016/j. Gerber B. Choi M. Wink JD1. Direct-to-implant breast reconstruction: an analysis of 1612 cases from the ACS-NSQIP surgical outcomes database. 6. Nipple-sparing mastectomy: risk of nippleareolar recurrences in a series of 579 cases.72(6):625-30 Albornoz CR1.ejso. Rotmensz N. Matros E2. 2003 Jul. Nelson JA. Serletti JM. Skin sparing mastectomy and immediate breast reconstruction: a review.015. McCarthy C. Guth AA. Breast J.12043. Manconi A. Rietjens M. Galimberti V.19(1):31-40. Muller H. Courtney CA.219(4):788-95. De Lorenzi F.2012. Friese K. Luini A.48(6):375-81. Rey P. Breast Cancer Res Treat. [Epub ahead of print] Blechman KM. J Am Coll Surg. 2. Bosco R. Orecchia R. and matched cohort analysis in 730 2-stage breast reconstructions over 10 years. Epub 2013 Jan 17. Epub 2012 Dec 17. Martella S. Agrawal A. 2013 Apr. 7. Kundt G. 2013 Jan-Feb. Disa JJ. Karp NS. Levovitz C. . Ann Surg.12. Antony AK1. Reimer T. Disa JJ1. Veronesi U. Sibbering DM. Mehrara BJ1. doi: 10.1111/tbj. Ivaldi GB. Botteri E. Shapiro RL.

8. 9. Fiscalini AS. Peled AW. Garwood E. Ewing C.21(10):3223-30. Foster RD. Sbitany H. . 2014 Oct. Ann Surg Oncol. Esserman LJ. Alvarado M. José Roberto Filassi. 5(3): 478–494. Aug 10. Eduardo Montag. Alexandre Mendonça Munhoz. Wang F1. 2014.Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. and Rolf Gemperli Immediate nipple-areolasparing mastectomy reconstruction: An update on oncological and reconstruction techniques World J Clin Oncol. Hwang ES.

doi: 10.2013. 2013 Sep. Tan M. Epub 2013 May 18. Julian-Reynier C. 2. Germany. Bartels CC. Bouhnik AD. . the Netherlands and the United Kingdom.025.1016/j. Evans DG. Ann Surg Oncol. Meijers-Heijboer HE. Tilanus-Linthorst MM.49(13):2798-805.14(12):3335-44. Nippert I. Brekelmans CT. van Geel AN. Harris H. Seynaeve C.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. Links Den Heijer M. Heemskerk-Gerritsen BA. Tibben A. Eur J Cancer. 2007 Dec. Schmidtke J. International variation in physicians' attitudes towards prophylactic mastectomy . Epub 2007 May 31. van Asperen CJ. Klijn JG.ejca.comparison between France. Menke-Pluymers MB. Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic.04.

Kanbour M. 1521e1527 Jonas A. 2. [Epub ahead of print] Jessica Gahm. Nelson. Per Hansson. 4. Jennifer McGrath . Polat AK. Journal of Plastic. Liza C. Joseph M. Aesthetic Plast Surg. Journal of Plastic. Aykan A. Alhan D. Ozturk E. 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. M. Decision Making and Factors Influencing Long-term Satisfaction With Prophylactic Mastectomy in Women With Breast Cancer.37(2):303-11. McGuire K. Yıldız R. Yvonne Brandberg. Isik S. 2013 May 2. Soran A.1007/s00266-012-0044-6. Ahrendt G. 1513e1520 . doi: 10. Fischer . 2013 Apr. Sahin I. Marie Wickman. John P. One-staged silicone implant breast reconstruction following bilateral nipple-sparing prophylactic mastectomy in patients at high-risk for breast cancer. Thomas C. Reconstructive & Aesthetic Surgery (2013) 66. Ibrahim A. Reconstructive & Aesthetic Surgery (2013) 66. Epub 2013 Jan 16. Bonaventura M. Wu. Balci FL. Serletti . Am J Clin Oncol. Breast sensibility after bilateral riskreducing mastectomy and immediate breast reconstruction: A prospective study. Delayed autologous breast reconstruction: Factors which influence patient decision making. 3. Christina Pasick . Johnson R.

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 .

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

in der DGGG e.V.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.Adjuvant Endocrine Therapy © AGO e.V.ago-online. sowie in der DKG e. V.de  Version 2015: Scharl / Stickeler .  Guidelines Breast Version 2015.

Assessment of Steroid Hormone Receptor Status © AGO e.de 0% pos. in der DGGG e. sowie in der DKG e. V.V.ago-online. cells: endocrine non-responsive 1 pos. cells: endocrine responsive Status unknown: endocrine responsive . Guidelines Breast Version 2015.1 Oxford LoE: 1 GR: A AGO: ++ Endocrine responsiveness: Immunohistochemistry (ER and / or PgR) www.V.

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

V. Oxford / AGO LoE / GR Guidelines Breast Version 2015.de . V. sowie in der DKG e. in der DGGG e.V.ago-online.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.Adjuvant Endocrine Therapy © AGO e.

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

N+ status at presentation)  Duration.General Principles in Adjuvant Endocrine Therapy AGO ++ © AGO 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.V.  Standard treatment duration 5 years  Treatment up to 10 years may be considered based on the individual risk of relapse (e. sowie in der DKG e.g. V.1 www. Guidelines Breast Version 2015.ago-online.de .V.

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

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

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

Burstein HJ. Godwin J. Ingle JN. et al.23:6931-40. et al.17: A randomized. Extended adjuvant treatment with anastrozole: results from the Austrian Breast an Colorectal Cancer Study Group Trial 6a (ABSCG 6a). 349: 1793-1802 Goss PE. Martino S. Wasan KM. 3.17L). Godwin J et al. Ingle JN.16:707-15. placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women.23(Suppl. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.97:1262-71. a randomised trial. 4.1. 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.17. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Goss PE et al. Goss PE. Goss PE. 2.365:1687-717. Tamoxifen 20 mg/d for 5-10 yrs. 4. Jakesz R. Ann Oncol 2005. J Clin Oncol 2005. Abs 527 Mamounas E et al. et al.Benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen intent to treat analysis of the NSABP-B33. 2. 5. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials. J Natl Cancer Inst 2005. J Clin Oncol 2005. et al. 100 (suppl1):abstract 49. Winer EP. et al. Lancet 2005. Breast Cancer Res and Treat 2006. Pritchard PH. Hudis C. Lancet. Whelan TJ.):10S. Assessment of quality of life in MA. 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. 378:771-84. et al. 2011 . 1. Samonigg H. Lancet. Davies C. published online 2012 Early Breast Cancer Trialists' Collaborative Group. a randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer N Engl J Med 2003. Hongchao P. 3. J Clin Oncol 2005. Greil R. 6. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA. 1a A ++ Voting: 100% acceptance Davies C.23:619-29. 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.

Giobbie-Hurder A. S1-1 Davies C.381:805-806 . Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. Mallon E et al. 6. a randomised trial. Godwin J et al. Hongchao P. 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. Lancet 2013. Metzger O.5.

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

Gonadotropin-releasing hormone analogue for premenopausal women with breast cancer.000 patients: patient's characteristics. Moore AP. [Epub ahead of print]. 5. Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer. Almog B. 2014 Jun.Fertility and cancer: psychological support in young women who contemplate emergency assisted reproductive technologies (ART) prior to chemo.306(16):1760.chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Fertility preservation counselling* Fertility preservation with assisted reproduction therapy 1.ctrv. doi: 10. 2010 Jul 16. 2011 Oct 26. author reply 1760-1. JAMA. Minton SE. Del Mastro L. 2011 Jul 20. Carter WB. Boni L. 6. .2013. efficacy and risks of applied preservation techniques. Wunder D.1016/j. de Ziegler D. J Clin Oncol. Michelotti A et al. Bellavia M. 2. Arch Gynecol Obstet. [Epub ahead of print] Loibl S. Shalom-Paz E. Shehata F et al. Munster PN.13075. Kupka MS et al. Jauckus J.12. Reprod Biomed Online. 3. Xu P. 2012 Jan 9. Cox CE. doi: 10. 2010 Oct.21(4):566-71.and/or radiation-therapy. Fertility preservation for breast-cancer patients using IVM followed by oocyte or embryo vitrification. 2010 Dec 1. Epub 2013 Dec 8. 4 C + Voting: 100% acceptance 4 C + Voting: 100% acceptance Lawrenz B.2010. Epub 2010 May 13. Besse D. Gross-King M. Cancer Treat Rev. Ismail-Khan R. 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. Swiss Med Wkly.306(3):269-76. spectrum. Fertility preservation in >1.140:w13075. JAMA.4414/smw.001. Gerber B.40(5):675-83. 4. Lacevic M.

Behera M. 2010 Jul. DeMichele A. Blackwell K. Copland S. 5. 2011 May. Stankiewicz C. Anders C. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer.116(3):592-9. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors.94(2):638-44. 2011 Apr. Cancer. Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. 6. Su HI. Snyder S.26(3):28695 Anderson RA. Partridge AH. Antenos M. 2008 Apr-May. Ginsburg E. Ruddy KJ. 2010 Feb 1. Matro J. 4. Freeman EW.95(5):1857-9. Chung K. Abusief M. Schapira L. 2. Shaw H. Lyons P. Fertil Steril. Green J. Woodruff T. Meyer M. . 96(5):1336-43. Cancer Invest.Testing ovarian reserve (12/20) No further information References: 1. Fertil Steril. Gracia CR. Obstetrics & Gynecology 2015 . Velders L. ACOG Committee Opinion No. Marcom PK. 618: Ovarian Reserve Testing. Gu L. J Clin Endocrinol Metab. Antral follicle count provides additive information to hormone measures for determining ovarian function in breast cancer survivors. 3.125 : 268–273 Su HI. Kimmick G. Unruhe S. Welch R. Gracia CR. Sammel MD. Sammel MD. Peterson B. Gelber S. DeMichele A. Cameron DA.

2013 Nov 20. Havrilesky LJ. Giersch JM et al. Moormann PG. Contraception.31(33):4188-98.Contraceptive Options for Premenopausal Women after Diagnosis of Breast Cancer (13/20) No further information References: 1. . Strom BL. Epub 2013 Oct 21. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer.2013. doi: 10. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Backman T.69(5):353-60. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. Obstet Gynecol.106(4):813-7.9021.48. 2. J Clin Oncol. 2004 May. 2005 Oct. 3.1200/JCO.

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 .

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

V.de . sowie in der DKG e.V.ago-online.V.1 www.  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.Adjuvant Cytotoxic and Targeted Therapy © AGO e. in der DGGG e.

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

Adjuvant Chemotherapy without Concurrent Trastuzumab: Overview © AGO Oxford / AGO LoE / GR e.ago-online.V. sowie in der DKG e. in der DGGG e. V.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.de  Dose-dense in case of high tumor burden .

ago-online. Guidelines Breast Version 2015. in der DGGG 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 +/- .V.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.V. V.Recommended Regimens for Adjuvant Chemotherapy © AGO e. sowie in der DKG e.

sowie in der DKG e. V.ago-online.V. in der DGGG e.1 www.V.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 .Dose-dense and/ or Dose-escalated Adjuvant Chemotherapy in Case of High Tumor Burden © AGO Oxford / AGO LoE / GR e. Guidelines Breast Version 2015.

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

Oxford / AGO LoE / GR in der DGGG e.V.V.de .Adjuvant Treatment with Trastuzumab I © AGO e.ago-online. Guidelines Breast Version 2015. V.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. sowie in der DKG e.

de  For 1 year For 2 years For 0.V.5 years * Loading dose .Adjuvant Treatment with Trastuzumab II © AGO Oxford / AGO LoE / GR e. V. sowie in der DKG e. in der DGGG e.ago-online.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. Guidelines Breast Version 2015.

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

de (delayed adjuvant treatment) 5 1b D B -  Lapatinib + Trastuzumab 1ba B -  Pertuzumab 5 D -  Bevacizumab 1b B -- a .ago-online.V.V. sowie in der DKG e.1  Lapatinib  www. Oxford / AGO LoE / GR in der DGGG e. Guidelines Breast Version 2015. V.Adjuvant Therapy with Other Targeted Agents © AGO e.

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

2014 Jul. 24:2206–2223. 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.Subtype-specific general systemic strategies (3/12) No further information: References: 1. . 2. Goldhirsch A. Ann Oncol 2013. Coates AS et al. Chemotherapy in early breast cancer: when. Winer EP. how and which one? Breast Care (Basel).9(3):154-60. Schmidt M.

Möbus V. Moore TD. Weiss E. Srkalovic G. Sandbach J. Augustin D. Kirby RL. Kiechle M. Asmar L. Wallwiener D. Thomssen C.25(8):1551-7. Kreienberg R. Ann Oncol. Clin Oncol. J Clin Oncol.Paclitaxel mono weekly (1b B +/-) . Chew HK. Vukelja SJ. Budd GT. Kuhn W. Hyman WJ. McIntyre KJ. Statement: If anthracyclines cannot be given . 2009 Mar 10. Hortobagyi GN. Kreipe HH. Burton GV. 2015 Jan 1. Rinn KJ. Hoffmann G. Lew DL. Cho JK. Gralow JR. Savin MA. Meyer WG. Pippen JE. Erber R. 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. Mohrmann S. Isaacs C. Barlow WE. Böhmer S. Lisboa B. Albain KS. Stewart JA. Jones S.Docetaxel plus cyclophosphamide (1b B +) Vote result of the AGO recommendation: 100% 1. Gluz O. Holmes FA. Mackey D. Muss H. Kates RE. Blum JL. Salim M. Jänicke F. Hobday TJ.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. Moore HC. Flaherty LE. SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer. McGregor BA. Huober J.27(8):1177-83. Nitz U. Scholz M. Hartmann A. 2. Sattler D. Livingston RB. Richards DA. Mennel RG.33(1):58-64. Bordelon JH. Riedel S. Boehm KA. 2014 Aug. Harbeck N. 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. O'Shaughnessy J. Statement: If anthracyclines cannot be given . Du Bois A.

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

Dose-dense chemotherapy versus conventional chemotherapy for early breast cancer: a systematic review with meta-analysis. J Clin Oncol. Lemos Duarte I. Kreienberg R. Schneeweiss A.2. Untch M.21(3):343-9. von Minckwitz G. and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. Moebus V. Jackisch C. Deeke Sasse A. Kuhn W. Konecny GE. Runnebaum IB. 2012 Jun. da Silveira Nogueira Lima JP. paclitaxel. . 3.28(17):2874-80. Passos Lima CS. Hinke A. Nitz U. Harbeck N. Huober J. 2010 Jun 10. Lueck HJ. Thomssen C. Breast. Kurbacher C. du Bois A. Intense dosedense sequential chemotherapy with epirubicin.

Levine EA. Provencher L. Statement: Anthracycline/ taxane based regimen AC  Pw A60Cq3w x 4  P80qw1 x 12 (1b A ++) Vote result of the AGO recommendation: 100% .48. Zhao F. 2014 Statement: Anthracycline/ taxane based regimen DAC D75A50C q3w x 6 (1b A ++) Vote result of the AGO recommendation: 100% 1. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable. Epub 2013 Aug 12. Budd GT. Ligibel J.1275. doi: 10. Zapas JL. Rastogi P. 2013 Sep 10. S3-03. abstr CRA1008) Sparano JA. Saphner T. 2013 (suppl. Wolff AC.1200/JCO. Azar CA. et al: S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. J Clin Oncol. node-positive breast cancer: the NSABP B-38 trial. Moore HCF. Tang G. Brufsky AM. Costantino JP. Northfelt DW.2012.31(26):3197-204. Wolmark N. Fehrenbacher L. Wood WC. Swain SM. Mamounas EP. Davidson NE. Atkins JN. J Clin Oncol 31:51s. SABCS. Polikoff JA. Donnellan PP. 2. Perez EA. Geyer CE Jr. Robidoux A. Paik S. Barlow WE. Biggs DD. Sledge GW. Martino S. 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.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.

Richards DA. Bordelon JH. Schneider CJ. 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. 23:3686-3696. Winer EP. Savin MA. D. Cirrincione CT. Greg Yothers. Vukelja SJ. Scot M. Jones S. J Clin Oncol.1. Bernard Fisher. 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. Sandbach J. Norton L. Hudis CA. Statement: Anthracycline-free regimen Pac mono 80 mg q1w x 4-6 (1b B +/-) Vote result of the AGO recommendation: 100% 1. Mennel RG. Blum JL. Atilla Soran. Kirby RL. Riedel S. Asmar L. Clin Oncol. 2009 Mar 10. Berry DA. Kimmick G.27(8):1177-83. Shapiro CL. O'Regan R. and Norman Wolmark. Martino S. Eleftherios P. Becker HP. Meyer WG. Perez EA. Shulman LN. Burstein HJ.32(22):2311-7. Lawrence Wickerham. Boehm KA. Muss H. Barry Lembersky. Mamounas. Muss H. 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). John Bryant. Pippen JE. Hyman WJ. McIntyre KJ. 2014 Aug 1. Louis Fehrenbacher. Holmes FA. O'Shaughnessy J.Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28 J Clin Oncol 2005. Statement: Anthracycline-free regimen CMF 600/40/600 mg q3w x 6 (1a A +/-) . Sedlacek. Mackey D.

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

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.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. J Natl Cancer Inst 2005.97:1724e33 Jones RL. Contu A. Walsh G. epirubicin. Venturini M. Caroti C.28:77e82. Dosedense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. Statement: Dose-dense regimen EC q3w / Pac q2w (1ba A +) EC q2w / Pac q1w (1b B +) Vote result of the AGO recommendation: 100% 1. Walley B. 3. et al. Aitini E. 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. Levine MN. Bramwell V. Chapman JA. Chua S. et al. Cyclophosphamide. Burnell M. Br J Cancer 2009. Gelmon K. Statement: Dose-dense regimen ACPac / AC-Pac q2w (1b A +) Vote result of the AGO recommendation: 100% . Ashley S. Agarwal R. Del Mastro L. O'Brien M. 2. J Clin Oncol 2010. Baldini E. et al.100:305e10.

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

Kokko R. doi: 10. Colantuoni G. Helle L. Pajunen M. Epub 2011 Nov 21.35. and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. Huovinen R. Joensuu H. Bighin C. Yin W. Di Blasio B. J Clin Oncol. Asola R.Fluorouracile added to EC/AC (1ba A . Nilsson G. Del Mastro L. Du Y. Pastorino S. Gamucci T. PLoS ONE 2012 7(3): e32474. all given every 3 weeks or 2 weeks. Bruzzi P. Turletti A. Tondini C. cyclophosphamide. Lindman H. 2012 Jan 1. Paija O. Aitini E. Poikonen P. Tanner M. Zhou Q.30(1):11-8. Villman K. Parisi AM. Lu J. Statement: 5. docetaxel.1200/JCO. Auvinen P.4639. De Laurentiis M. Statement: Platinum containing regimen in TNBC (5 D +/-) Vote result of the AGO recommendation: 100% No References available. De Placido S. in . Jukkola-Vuorinen A. Adjuvant capecitabine. Garrone O. Kataja V. Olmeo N.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.-) Vote result of the AGO recommendation: 100% 1. Epirubicin and cyclophosphamide (EC) followed by paclitaxel (T) versus fluorouracil. Montemurro F. Ahlgren J. Bono P. Yan L. Cognetti F. Kellokumpu-Lehtinen PL. Lambertini M.2011. Zhou L. Boni C. Shao Z. First efficacy results of capecitabine with anthracycline-and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis. Leinonen M. Valle E. Durando A. Barni S. epirubicin and cyclophosphamide (FEC) followed by T. Puglisi F. Shen Z. 2. Nyandoto P. Jiang Y.

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

Gelmon K. Jackisch C.382(9897):1021-8. 2013 Sep 21. Lichinitser M.353(16):1659-72. Smith I. 2. Heinzmann D. Untch M. Dowsett M. Procter M. Suto T. Baselga J. Köhne CH. Gelber RD. Dal Lago L. Baselga J. Goldhirsch A. de Azambuja E. 2007 Jan 6. Huang CS. Gelber RD. 3. Wilcken N. Ward C. Smith I. Goldhirsch A. Gianni L. McFadden E. [Epub ahead of print] Statements: >10 mm/> 5-10 mm/ <= 5mm . Andersson M. Baselga J. Barrios CH. Elliott R. Suter TM. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Procter M. Semiglazov V. 2014 Nov 17. Piccart-Gebhart MJ. Lancet. Vindevoghel A. Bergh J. Song S. Kaufmann M. Andersson M. Lopez RI. Otero-Reyes D. Piccart-Gebhart MJ. Harbeck N. Pivot X.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. Weber HA. Cameron D. Nitz U. Dowsett M. Coleman R. pii: mdu524. Bell R. N Engl J Med. Dowsett M. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Mallmann P. Procter M. Thomssen C. randomised controlled trial. Steger G. Hillenbach C. McFadden E. Dolci MS. Gelber RD. Lancet. Inbar M. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Kim SB. Gianni L. Brunt AM. Jackisch C. Láng I. Wardley A. Ann Oncol. Smith I. Weber HA. 2005 Oct 20. Iwata H. Goldhirsch A.369(9555):29-36. Suter TM. Mariani G. Herceptin Adjuvant (HERA) Trial Study Team. Bell R. Lum BL. 4. Rüschoff J. Guillaume S. Lohrisch C. Piccart-Gebhart MJ. Stroyakovskiy D. Feyereislova A. Herceptin Adjuvant (HERA) Trial Study Team. Untch M. Straehle C. Leyland-Jones B. Bell R. Leyland-Jones B. Greatorex V. HERA study team. Sánchez Rovira P. Jackisch C. Wist E. Untch M. Cameron D. Ismael G. Cameron D. Melichar B.

Meric-Bernstam F. Ravdin PM.1. Berry DA. Litton JK. Stranzl H. Broglio KR. Gonzalez-Angulo AM. Guray M. Valero V. Theriault R. Epub 2009 Nov 2. Cardoso F. node-negative tumors 1 cm or smaller. Larsimont D. . Buchholz TA. Peintinger F.27(34):5700-6. Feoli F. Sahin A. 2009 Dec 1. Rakkhit R. Hanrahan EO. Piccart-Gebhart M. Hortobagyi GN High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive. J Clin Oncol.

Kauffman. Kaleva-Kerola J. Martino S. 2007 Jan 6. HERA study team. 2005 Oct 20. Paik S. Klein PM. NCCTG/NSABP. Thomssen C. E. Untch M. Leyland-Jones B. 2005 Oct 20. Isola J. Alanko T. Mamounas EP. Jyrkkiö S. Dowsett M. Lichinitser M. Davidson NE. Jenkins RB. Rüschoff J. 5. Smith I. Jääskeläinen AS. Kutteh LA. Suman. Cameron D. Piccart-Gebhart MJ. Gelber RD. McFadden E. Fehrenbacher L. C. Nitz U. Wardley A. Láng I.354(8):809-20. Perez. Lingle WL. Yothers G.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. P. Asola R. Baselga J.369(9555):29-36. Dakhil SR. Lohrisch C. Kataja V. Suman VJ. J. Coleman R. Vogel VG. E. Wilcken N. 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. Hemminki A. FinHer Study Investigators. P. Mamounas. Mariani G. Kellokumpu-Lehtinen PL. Brown AM. Ingle JN. Dowsett M. Elomaa I. Davidson. Smith I. A. 4. Herceptin Adjuvant (HERA) Trial Study Team. Bryant J. Utriainen T. Lancet. Gelber RD. Pajunen M. Ingalsuo S. E. Johansson K. Wist E. Cameron D.353(16):1673-84. J. Joensuu H. Jeong. Ward C. Inbar M. Harbeck N. Pisansky TM. Barrios CH. Steger G. N Engl J Med. Romond EH. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. S. Sánchez Rovira P. Romond. Suto T. Swain SM. Geyer. 2006 Feb 23. Wolmark N. H. Rauhala M. N. Wolmark. Visscher DW. Straehle C. Geyer CE Jr. Procter M.Adjuvant treatment with Trastuzumab II (9/12) Further information and references: Statement: Start of treatment Vote result of the AGO recommendation: 100% 1. Turpeenniemi-Hujanen T. Bell R. Andersson M. 2. Bell R. Guillaume S. Tan-Chiu E. Kaufman PA. Tarkkanen M. Perez EA. Mallmann P. Leinonen M. Kokko R. N Engl J Med. Salminen T. 3. N. Jackisch C. Goldhirsch A. Huang CS. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. Gelmon K. Feyereislova A. Journal of . A. Flander M. Martino. Baselga J. Piccart-Gebhart MJ. V. Procter M. Kaufmann M. Helle L. Greatorex V. Dolci MS. Gianni L. Goldhirsch A. Lopez RI. Bergh J. E. Iwata H. Suter TM. Bono P.353(16):1659-72. E. Untch M. N Engl J Med.

Alanko T. Tabah-Fisch I. Buyse M. Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer. Bell R. Gianni L. Weber HA. Pajunen M. Gralow. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Lancet. Visscher. Clinical Oncology. Visco F. 2011 Slamon D. Riva A. and Robert B. 7. Beiyun Chen. Epub 2009 Nov 2. Perez. Jenkins. Jyrkkiö S. Herceptin Adjuvant (HERA) Trial Study Team. 2011 Oct 6. Davidson.1056/NEJMoa0910383. Edith A. 18S (June 20 Supplement). Lindsay MA. Otero-Reyes D. Chan A. doi: 10. with or without trastuzumab. Eiermann W. Baselga J. randomised controlled trial. Bono P. Kaufman. Ingalsuo S. Goldhirsch A. Glaspy J. Procter M. Epub 2013 Jul 18. Julie R. Andersson M. Daniel W. Robert N. Köhne CH. Turpeenniemi-Hujanen T. Leinonen H. Vera J. and cyclophosphamide with either docetaxel or vinorelbine. Press M. Breast Cancer International Research Group. Epub 2011 Jun 9. 8. Lu J. 10. Bendahmane B. No. Shen Z. Utriainen T. Helle L. 2013 Sep 21. Dowsett M. Kellokumpu-Lehtinen PL. Pienkowski T. Thomas M. Piccart-Gebhart MJ. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. James N.365(14):1273-83. Auvinen P. Huusko M. McFadden E. Jackisch C. Pisansky. as adjuvant treatments of breast cancer: final results of the FinHer Trial. Leinonen M. Pawlicki M.6. Vindevoghel A. PLoS One. Fluorouracil. Yin W. Dal Lago L. de Azambuja E. Salminen T. Shaker R.382(9897):1021-8. J Clin Oncol. Isola J. Kataja V. Dakhil. Sauter G. Kokko R. Statement: Duration Duration Trastuzumab 1 year Vote result of the AGO recommendation: 100% Duration Trastuzumab 2 year . Asola R. Shao Z. 2007 ASCO Annual Meeting Proceedings Part I. 2009 Dec 1. Valero V. Heinzmann D.1016/S01406736(13)61094-6. Jiang Y. von Minckwitz G. J Clin Oncol 29:4491-4497. N Engl J Med. Vol 25. Suman. Cameron D. Alvaro Moreno-Aspitia. Nancy E. 2011.27(34):5685-92.6(6):e21030. Adjuvant trastuzumab in HER2positive breast cancer. Smith I. doi: 10. epirubicin. Liu MC. Gelber RD. Leyland-Jones B. 2007: 512 Joensuu H. Bee V. Untch M. Suter TM. Peter A. Song S. 9. Möykkynen K. JoAnne Zujewski. Ingle. Mackey J. Brunt AM. Crown J. Martin M. Pinter T.

Romieu G.14(8):741-8. Untch M. Serin D. Smith I. Brunt AM. Otero-Reyes D. de Azambuja E. Lancet. Pierga JY. 3. Abadie-Lacourtoisie S. Heinzmann D. Kerbrat P. PHARE trial investigators. Fumoleau P.382(9897):1021-8. Goldhirsch A. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Köhne CH. Bell R. Rios M. 2013 Sep 21.5 years Vote result of the AGO recommendation: 1 +/ 23 +/-/ 6 -/ 1 -1. Piccart-Gebhart MJ. randomised controlled trial. Lancet Oncol. Cany L. Herceptin Adjuvant (HERA) Trial Study Team. Khayat D. Jouannaud C. Suter TM. Pivot X. Kramar A. Weber HA. 2013 Jul. 2.Vote result of the AGO recommendation: 100% Duration Trastuzumab 0. Dal Lago L. Lortholary A. Procter M. Jacquin JP. McFadden E. Gelber RD. Jackisch C. Catala S. Espié M. Leyland-Jones B. Cameron D. Song S. Gianni L. Baselga J. Pauporté I. Bachelot T. Debled M. . 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Andersson M. Vindevoghel A. Dowsett M. Tubiana-Mathieu N.

Clinical cardiac tolerability of trastuzumab. 2. J Clin Oncol. 2008 Feb. Mackey JR. J Clin Oncol. Spence A. Rodeheffer R. Suman VJ. Martino S. Provencher L. Sawyer MB. Bighin C. 4. Dent S. Ageev FT. Klijn JG. Knap M. Davidson NE. Rodeheffer RJ. PiccartGebhart MJ. Bergh J. 5.22(2):322-9.15(1):24-35. van Veldhuisen DJ. Procter M. Perez EA. Muscholl M. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Delgado D. Ingle JN. Muehlbauer S. . J Clin Oncol. Winer EP. 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. Groetz J. Dakhil SR. Gelber RD. Carlomagno C. Hudis CA. Verma S. 2007 Sep 1. Epub 2008 Feb 4. Kaufman PA. Hitre E. Passalacqua R. Perren T. Iwata H. Suter TM. 3. Jaffe AS. 2008 Mar 10. Gnant M. Gralow JR. Côté MA.25(25):3859-65. Gersh BJ. Paterson A. Gelmon KA. Epub 2007 Jul 23. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. 2004 Jan 15. Perez EA. Sledge GW. Curr Oncol. Clemons M.Adjuvant trastuzumab – Cardia mMnitoring for CHF (10/12) Further information and references: Statement: Cardiac Monitoring Vote result of the AGO recommendation: 100% 1.26(8):1231-8.

Peter A. Winer EP. Wolff AC. Ellis M. Moy B. Lancet. Burstein HJ. Visscher. Leyland-Jones B. Gelber RD. Albain
KS. Herceptin Adjuvant (HERA) Trial Study Team. Tolaney SM. Heinzmann D. Shapira I. Wolff AC. J Clin Oncol 29:4491-4497. Carey LA. Thomas M. Carey LA. Nancy E. Guo H. Ingle. JoAnne Zujewski.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. Dal Lago L. McFadden E. Daniel W.
Partridge AH. Winer EP. Pisansky. randomised controlled trial. Barry WT. Alvaro Moreno-Aspitia. 2013 Sep 21. Moy B. Yardley DA. Dang CT. Ellis M. Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer. Edith A. James N. Song S. Albain KS. Andersson M. Cameron D. Adjuvant paclitaxel and trastuzumab for node-negative. SABCS 2013. 2015 Jan 8. and Robert B. Marcom PK. Overmoyer BA. Rugo HS. Weber HA. Jackisch C. Hudis CA. N Engl J Med. Dang CT. Vindevoghel A. de Azambuja E. Rugo HS. Burstein HJ. Yardley DA. Marcom PK. Dowsett M. S1-04 Tolaney SM. Jenkins. Smith I. Otero-Reyes D. 2. . Krop IE. Dakhil. Piccart-Gebhart MJ. Barry WT. Statement: P q1w12 without A in pT < 3 cm pN0 Vote result of the AGO recommendation: 100% 1.382(9897):1021-8. Perez. Köhne CH. HER2-positive breast cancer. HER2-positive
breast cancer (BC). Shaker R. Hudis CA. Bell R. A phase II study of adjuvant paclitaxel (T) and
trastuzumab (H) (APT trial) for node-negative.372(2):13441. Gralow. Davidson. Brunt AM. Krop IE. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label. Shapira I. Untch M. Suter TM. Beiyun Chen. Kaufman. Gianni L. Julie R. Guo H. 2. Overmoyer BA. Procter M. Suman. Baselga J. Vera J. Partridge AH. 2011 Goldhirsch A.

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

No. Vol 24. 18S (June 20 Supplement).N9831. 2006 ASCO Annual Meeting Proceedings Part I. 2006: 523 . Journal of Clinical Oncology.

O'Shaughnessy J. Baselga J. Lindquist D. RC0639: phase II study of paclitaxel. Boyle F. Jenkins RB. Dueck A. Breast Cancer Res Treat. Patel T. Pritchard K. Viale G. and lapatinib as adjuvant therapy for early stage HER2-positive breast cancer. Perez EA. Lancet Oncol. Piccart-Gebhart M. Colon-Otero G. Santillana S. Williams LS. First results from the phase III ALTTO trial (BIG 02-06. Boyle F. Moy B. their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Xu B. trastuzumab alone (T). de Azambuja E. Gelber RD. Dakhil S. 2014 Statement: with Lapatinib + Trastuzumab Vote result of the AGO recommendation: 100% 1. Rodeheffer R. de Azambuja E. Kaufmann M.138(2):427-35. Boyle F. Northfelt D. Holmes AP. Goldhirsch A. 2013 Apr. Piccart-Gebhart M. First results from the phase III ALTTO trial (BIG 02-06. Gomez H. Gomez H. Gradishar W. McCullough AE. Smith IE. ASCO. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised. their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Ghanem-Cañete I. Martin M. Zujewski JA. Palmieri FM. Jackisch C. Perez EA. Aktan G. Buzdar AU. Santillana S. Smith I. Smith I. Wolff A. 3. 2. Dueck AC. Dueck A. Goldhirsch A. TEACH investigators. 2013 Jan. Viale G. Chavarri-Guerra Y.Adjuvant Therapy with Other Agents (12/12) Further information and references: Statement: with Lapatinib Vote result of the AGO recommendation: 100% 1. NCCTG 063D) comparing one year of antiHER2 therapy with lapatinib alone (L). Pritchard K. Zujewski JA. Lang I. Untch M. Rappold E. trastuzumab alone (T). Kahanic S. Perez EA. Piccart-Gebhart M. Gelber RD. Tenner KS. phase 3 trial. Finkelstein DM. trastuzumab. NCCTG 063D) comparing one year of antiHER2 therapy with lapatinib alone (L). Johnson D. Pritchard KI. Holmes AP. Wolff A. controlled. Lang I. Fumoleau P. Xu B. ASCO. 2014 . Franco S. Moreno-Aspitia A1.14(1):88-96. Untch M. Jackisch C. Goss PE1. Baselga J. Ejlertsen B.

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

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

de . V. in der DGGG e. sowie in der DKG e.V.V.  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 2015.1 www.ago-online.Neoadjuvant Systemic Therapy © AGO e.

Guidelines Breast Version 2015. regimen Dose dense & escalated in case of high tumor burden •  ++ HR+/HER2.de Trastuzumab plus • Sequential A/T-based regimen with concurrent T + H • Anthracycline-free.V.1  In case of indication for chemotherapy.Subtype-specific General Systemic Strategies © AGO e. carboplatin-cont.ago-online. 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. V.V.and “high risk”   ++ HR+/HER2.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 ++ + . sowie in der DKG e.  in der DGGG e.

V. V.1 Oxford / AGO LoE / GR Survival is similar after neoadjuvant (preoperative.V.Neoadjuvant Systemic Chemotherapy Clinical Benefit © AGO e.ago-online. sowie in der DKG e. 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. in der DGGG e.de  * Study participation recommended .

V.1 www. sowie in der DKG e. Guidelines Breast Version 2015.ago-online.Neoadjuvant Systemic Chemotherapy Indications © AGO Oxford / AGO LoE / GR e. in der DGGG 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 +  . V.V.

N0 o.V.de .1  Young age B 1a A +  cT1 / cT2 tumors o. V.V. in der DGGG e.ago-online. sowie in der DKG e.Neoadjuvant Systemic Chemotherapy Response Prediction I © AGO e. Factor CTS LoEOx2001 GR AGO Guidelines Breast Version 2015. 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.

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

Guidelines Breast Version 2015.1 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. in der DGGG e. sowie in der DKG e.ago-online.g.de  In case of family history of BC/OC or BRCA alteration *Study participation recommended .V.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. E -P-CMF.

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

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

1     www.ago-online.V. sowie in der DKG e.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 . Guidelines Breast Version 2015.V. V.Neoadjuvant Targeted Therapy in HER2 Positive Tumors © AGO Oxford / AGO LoE / GR e. in der DGGG e.

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

V.1 In case of early response following 6 to 12 weeks of neoadjuvant chemotherapy: Complete all chemotherapy before surgery i.e. ≥ 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. Oxford / AGO LoE / GR in der DGGG e.de  + .V.ago-online. V.Neoadjuvant Systemic Therapy Procedures in Case of Early Response © AGO e. sowie in der DKG e.

Guidelines Breast Version 2015.V.V.de In case of no change:  Completion of NST.1 www.ago-online.Neoadjuvant Systemic Therapy Procedures in Case of No Early Response © AGO Oxford / AGO LoE / GR e. sowie in der DKG e. V. in der DGGG e. 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 .

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 + . Guidelines Breast Version 2015.1 www. V.Local/Regional Procedure after Neoadjuvant Therapy © AGO e. Oxford / AGO LoE / GR in der DGGG e. sowie in der DKG e.ago-online.V.V.

ago-online.V. sowie in der DKG e.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.Surgical Procedure of the Axilla Before or After NACT © AGO Oxford / AGO LoE / GR e.V. in der DGGG e. Guidelines Breast Version 2015. 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) .

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

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

ago-online. sowie in der DKG e.Adjuvant Systemic Therapy after Neoadjuvant Systemic Treatment © AGO e. Guidelines Breast Version 2015.V. Oxford / AGO LoE / GR in der DGGG e. V.V.de 3  Experimental therapies in clinical trials 5  Further chemotherapy C D + .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.

V. T status 1b B + Guidelines Breast Version 2015.de Who are inoperable Optimal duration of neoadjuvant endocrine therapy is unknown No long term results for neoadjuvant endocrine therapy (vs.Neoadjuvant Endocrine Therapy in Patients with Endocrine-responsive Breast Cancer © AGO e.1  Premenopausal patients  www.  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. V.V. in der DGGG e.ago-online. sowie in der DKG e. adjuvant endocrine therapy) . N status. level of Ki-67.

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 .

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

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

and 5-fluorouracil (CMF) in stage III breast cancer: GOCS experience. 2. et al. J Clin Oncol 2007: 25. et al. 4414 Mittendorf EA. 3883 Abdel-Fatah TM. J Clin Oncol 2011: 29. et al. 1956 Von Minckwitz G. 2014 [Epub ahead of print] .Breast Cancer Res Treat 2014: 143. 6. 313 Berruti A. Nottingham Clinico-Pathological Response Index (NPRI) after Neoadjuvant Chemotherapy (Neo-ACT) Accurately Predicts Clinical Outcome in Locally Advanced Breast Cancer. methotrexate. and cyclophosphamide (FAC) compared with cyclophosphamide. et al. et al. 4.1. doxorubicin. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. 3. Sixteen years follow-up results of a randomized phase II trial of neoadjuvant fluorouracil. 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. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2014: 32. 5. Symmans WF. 1796 Leone JP. Clin Cancer Res. J Clin Oncol 2012: 30. et al.

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

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9. GBG 44): a randomised phase 3 trial. et al. 1139 Bonnefoi H. randomised phase 3 trial. phase 3 trial and their association with pathological complete response. Lancet Oncol 2013: 14. Neoadjuvant treatment with docetaxel plus lapatinib. randomised phase 3 trial.144 Robidoux A. Robidoux A. J Natl Cancer Inst 2014. open-label. 4. Lancet Oncol 2013: 14. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised. trastuzumab. 135 . et al. 5. Untch M et al. 1183-1192 Alba E. Ann Oncol 2014 [Epub ahead of print] Nagayama A. or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. et al. Lancet Oncol 2012: 13. et al. De Azambuja E. Lancet Oncol 2014: 15. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. 106(9): [EpuB ahead of print] Lapatinib + Trastuzumab in combination with chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 1183-1192 De Azambuja E. et al. or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. 1137 Lapatinib in combination with chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 2. multicentre. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label. Ann Oncol 2014 [Epub ahead of print] . 1137 Bonnefoi H. phase 3 trial and their association with pathological complete response. open-label. Lancet Oncol 2014: 15. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised. multicentre. Br J Cancer 2014: 110. 3. Neoadjuvant treatment with docetaxel plus lapatinib. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label. trastuzumab. 3. Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto. et al. 2. et al.

open-label. Lancet Oncol 2012: 13. 869 Anti-HER2 agent in combination with endocrine treatment Abstimmungsergebnis der AGO-Empfehlungen: 3+. 2. multicentre. 16+/-. randomised trial. Gianni L. 2012: 13. J Clin Oncol 2013: 31. 106(9): [EpuB ahead of print] Pertuzumab + Trastuzumab in combination with chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. phase 2 trial. Nagayama A. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracyclinecontaining and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). 3. clinical stage I-III breast cancer (HannaH study): a phase 3. et al. J Natl Cancer Inst 2014. J Natl Cancer Inst 2014. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. 2. 106(9): [EpuB ahead of print] Two anti-HER2 agents without chemotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. et al. 25-32 Rimawi M. 25-32 Schneeweiss A. or early HER2-positive breast cancer (NeoSphere): a randomised multicentre. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive. Annals Oncol 2013: 24.4. 2012: 13. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. Lancet Oncol. phase 2 trial. 3. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced. 6- . et al. Lancet Oncol. et al. et al. or early HER2-positive breast cancer (NeoSphere): a randomised multicentre. 2278-84 Nagayama A. inflammatory. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. open-label. Gianni L. et al. 1726 Ismael G. inflammatory. open-label.

2. placebo-controlled. 1050 . human epidermal growth factor receptor 2negative. Double-blind. operable breast cancer. SABCS 2014 (S6-02) Guarneri V. phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive. et al. J Clin Oncol 2014: 32.1. multicenter. et al. randomized. Rimawi MF.

2. results from the geparquinto study (GBG 44). et al. N Engl J Med 2012: 366. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. et al. Annals Oncol 2013: 24. 299 Bear HD. Von Minckwitz G. Ann Oncol 2014: 25. 3. N Engl J Med 2012: 366. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers. et al. 13+/-. et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. et al. et al. 91. Von Minckwitz G. 13 . 3. et al. 2363 Bevacizumab in combination with chemotherapy in TNBC Abstimmungsergebnis der AGO-Empfehlungen: 2+/-.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. 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). N Engl J Med 2012: 366. et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. 299 Bear HD. 310 Von Minckwitz G. 2363 Sikov WM. 171. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. N Engl J Med 2012: 366. 2. J Clin Oncol 2015: 33. 5. 4. 310 Gerber B. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. 2978 Von Minckwitz G. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.

Von Minckwitz G. 2. 3506 Von Minckwitz G. J Clin Oncol. Von Minckwitz G. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. et al. 4. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. 3. J Natl Cancer Inst 2008: 100. 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.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. ≥ 18 weeks of treatment Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 542 Von Minckwitz G. open phase IIb study. and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized. J Natl Cancer Inst 2008: 100. et al. Ann Surg Oncol 2012: 19. et al. Response-guided neoadjuvant chemotherapy for breast cancer. 552 Kaufmann M. et al. et al. J Clin Oncol 2001: 19. controlled. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 2013: 31. Dose-dense doxorubicin. docetaxel. 3623-30 .e.

Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.Neoadjuvant Systemic Therapy Procedures in Case of No Early Response (14/20) Further information and references: In case of no change: Completion of NST. 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. J Clin Oncol 2006: 24. et al. 1508 Smith IC. 2. J Natl Cancer Inst 2008: 100. et al. followed by surgery Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Bear HD. Ann Surg Oncol 2012: 19. et al. J Clin Oncol 2002: 20. 2. et al. J Clin Oncol 2003: 21. 1456 Von Minckwitz G. Kaufmann M. 2019 DAC x 2  NX x 4 Abstimmungsergebnis der AGO-Empfehlungen: 45/0 . 4165 Bear HD. et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 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. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. 3. 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.

Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. et al. 1508 Additional adjuvant chemotherapy with non-cross-resistant regimen Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. 1956. J Clin Oncol. Von Minckwitz G. 2011 . Ann Surg Oncol 2012: 19. J Clin Oncol 29. Kaufmann M. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 2013: 31. Mittendorf EA. et al.1. 3623-30 In case of progressive disease: Stop of NST and immediate surgery or radiotherapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. Response-guided neoadjuvant chemotherapy for breast cancer.

3. et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 1927 Kaufmann M. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. 1184 Kaufmann M. Ann Surg Oncol 2012: 19. Ann Oncol 2007: 18. 1184 Kaufmann M. 2. 1508 Surgery Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. et al. 2. Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. et al. Ann Surg Oncol 2012: 19.Surgical Procedures (15/20 and 16/20) Further information and references: Mark previous tumor region Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. et al. et al. Kaufmann M. Cancer 2010: 116. 3. 1927 . et al. Cancer 2010: 116. Kaufmann M. Ann Oncol 2007: 18. 1508 Microscopically clear margins Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1.Local/Regional Procedure after Neoadjuvant Systemic Therapy . Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. Ann Oncol 2007: 18. Kaufmann M. et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. 1927 Kaufmann M.

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

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

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

et al. Ring A. Ring A. 2. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 2003: 21. 4540 Radiotherapy after surgery 2–3 weeks after surgery BCS Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol 2003: 21. 4540 Daveau C. et al.Neoadjuvant Systemic .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. 1452-145 . 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.

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 .

4. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. et al. 3. 1527 Smith I. anastrozole. Neoadjuvant endocrine treatment in primary breast cancer .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. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. et al. 5108 Semiglazov VF. or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. Cancer 2007: 110. et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole. J Clin Oncol 2005: 23. Eiermann W. Ann Oncol 2001: 12. Cancer 2007: 110. Semiglazov VF. 5. et al. Breast 2009: 18. 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. tamoxifen. 339 Ellis MJ. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. J Clin Oncol 2011: 29. 2342 Aromatase inhibitors (for > 3 months) Abstimmungsergebnis der AGO-Empfehlungen: 45/0 . Tamoxifen. 244 Optimizes the option for breast conserving therapy Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. Randomized phase II neoadjuvant comparison between letrozole. or both in combination: the Immediate Preoperative Anastrozole. et al. et al. 2. 244 Mathew J.review of literature.

1527 Smith I. Tamoxifen. anastrozole. et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole. et al. 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. 339 Ellis MJ. et al. Neoadjuvant endocrine treatment in primary breast cancer . 2. Mathew J.review of literature. et al. 5108 Mathew J.1. Breast 2009: 18. Randomized phase II neoadjuvant comparison between letrozole.review of literature. tamoxifen. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Neoadjuvant endocrine treatment in primary breast cancer . 3. 4. Breast 2009: 18. et al. or both in combination: the Immediate Preoperative Anastrozole. or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. Eiermann W. J Clin Oncol 2011: 29. 339 . J Clin Oncol 2005: 23. Ann Oncol 2001: 12. 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.

Efficacy of six month neoadjuvant endocrine therapy in postmenopausal. 2190 Prognostic factors during/after NST: quantitative ER-expression. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. 3. docetaxel. controlled. level of Ki-67. et al. T status Abstimmungsergebnis der AGO-Empfehlungen: 45/0 1. hormone receptorpositive breast cancer patients--a phase II trial. 1380 . and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized. 3506 Fontein DB. Von Minckwitz G. J Clin Oncol 2001: 15. Ellis MJ. J Natl Cancer Inst 2008: 100. et al. Eur J Cancer 2014: 50. et al.2. Dose-dense doxorubicin. N status. open phase IIb study.

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

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

ago-online. Guidelines Breast Version 2015.V. in der DGGG e. the corresponding DEGRO view is written in blue colour .V.de  If agreement had not been reached in any statement.V. sowie in der DKG e.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.Preliminary Note © AGO e.

V.Whole Breast Irradiation – © AGO LoE 1b B e.de (lymph node areas) Study participation recommended . 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. sowie in der DKG e.Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer): . conventionally fractionated RT (25-28 fractions) www.V. Guidelines Breast Version 2015. in der DGGG e.ago-online.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.ago-online. Guidelines Breast Version 2015. 14: 1086–94)  Elderly patients should be advised about the following :  In older patients with pT1-2 (=<3 cm) pN0 hormone receptorpositive breast cancer.94). which contributed to the significantly higher rates of diseasefree survival and overall survival in the 40 Gy group compared with the 50 Gy group. telangiectasia. p=0. Lancet Oncol 2013.8. 95% CI 0.59–0. sowie in der DKG e. .“  In 1 of 5 trials: “There were significantly fewer distant relapses up to 10 years in the 40 Gy group (HR 0.74. in der DGGG e. A benefit with regard to metastasis-free survival and overall survival has not been found yet.Additional Information with Regard to Effects of Breast Radiotherapy (BCT) © AGO e.042) (START B: Haviland JS et al.1 www. breast irradiation for breast conserving therapy is able to reduce the risk of a local recurrence by about 8% over 10 years.“ (HROS=0.V.de  Hypofractionation:  „Some normal tissue effects were less common after the 15 fraction regimen than the control schedule (breast shrinkage. and breast oedema).

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

I.98%) 98% (96% .V.72%) HR=0. 0.71%) 67% (62% .17 to 1. P < . 31:2382-2387 . since 8/1996 only pT1cN0 ER/PR+ or unknown allowed © AGO e. Tamoxifen + RT Time:1994-1999.63 to 2.s.18.48. sowie in der DKG e.) Tamoxifen Tamoxifen plus Radiotherapy Hazard Ratio Local recurrence 90% (85%-93%) 98% (96%-99%) HR=0.42.001) Mastectomyfree 96% (93% . n.V. in der DGGG e.97%) 95% (92% .V.99%) HR=0. n.18 (95% CI.77 to 1.BCS >=70y <4 cm cN0: Tamoxifen vs.95 (95% CI. n. 0.ago-online.1 www. Guidelines Breast Version 2015.) Distant metastasis-free 95% (91% .07 to 0.) Hughes KE et al J Clin Oncol 2013. 0.50 (95% CI.s) Overall survival 66% (61% .97%) HR=1.20 (95% CI.32. 0.de @10 yrs (95% C.s.

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

p=0.7% (7.4% (14.0001 ≤40 years (=11.45–0.04).7) HR=0.5–17. Cumulative Risk of Ipsilateral Breast Tumour Recurrence www.5) 19.007 51–60 years (=2.5% (9.V.I.ago-online.7–24.) Overall Survival (=-1.66 (0.92).V.0% (9.05 (0.0–14.3–14.1% (57. p=0.0% (25.4) 12.Boost vs no Boost: EORTC 22881-10882 Trial © AGO e.7% (5.42–1. Lancet Oncol 2015.019 (Median F/U 17.96%) 10. in der DGGG e.3) 13. p<0.1%) HR=0.34–0.3% (6.003 41–50 years (=5. to: Bartelink et al.8) 36.9–33.56 (0.19) n. sowie in der DKG e. Guidelines Breast Version 2015.4% (14.de All patients 12.8) HR=0.V.52–0.I.1 @20 yrs (95% C.2 y) acc.4) 16.98).8–16.) 59.2) HR=0.020 >60 years (=3.69 (0.4% (14.6–64.46–1. p=0.0) 61.7% (56.65 (0. 16: 47–56 .8–14.9%) 13.0) HR=0.4%) Boost (n=2.3–63. p=0.81).657) Hazard Ratio (95% C.1–18.66 (0.8–46.6%) 24.4–18.3) HR 1.s.661) No boost (n=2.2% (9.0%) 9.04).92–1.

in der DGGG e.de      > 3 tumor infiltrated lymph nodes (Lnn. 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. go to Further information.V. **Study participation recommended . low risk* AGO1 1–3 tumor infiltrated Lnn.) 1–3 tumor infiltrated Lnn.1 www.Postmastectomy Radiotherapy (PMRT)** to the Chest Wall © AGO Oxford / AGO LoE / GR e.ago-online. sowie in der DKG e.V. (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+. high risk AGO1 1–3 tumor infiltrated Lnn.V. Guidelines Breast Version 2015.

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

sowie in der DKG e.V. RT of chest wall indicated and ACOSOG Z011-criteria fulfilled  No axillary treatment www.de  Mastectomy.V. SLN:  BCT and ACOSOG Z011-criteria fulfilled 1b B  No axillary treatment 1b B  BCT and ACOSOG Z011-criteria not met 1b B  Mastectomy. RT of chest wall indicated and ACOSOG Z011-criteria not met or Mastectomy.ago-online.V. in der DGGG e. Guidelines Breast Version 2015.1 Axillary dissection or RT of the axilla.Axillary Intervention in Patients with Positive Sentinel Lymph Nodes © AGO Oxford / AGO LoE / GR e. If 1-2 pos. SLN  Axillary dissection 1b B  Radiotherapy of the axilla 1b B ++ + *Study participation recommended . if >=3 pos. RT of chest wall not planned 5 5 D D +/-* +/++* +/-* +/- 1b D ++ Axillary dissection or RT of the axilla.

go to Further information .  pN0 high risk w. if radiotherapy of the internal mammaria lnn. adj. tumors (HR+.de Supra-/infraclavicular lymphatic regions   pN2a  Level III involved  pN1a high risk* AGO1  pN1a low risk* AGO1  pN1a (every risk) DEGRO1  pN0 high risk. who had systemic chemoth.V./med. chain is indicated (see below)  After NACT/NAT (indications as for PMRT) AGO1  After NACT/NAT if cN+ (indications acc. 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.V.Radiotherapy (RT) of Other Locoregional Lymph Node Areas © AGO e.V. PMRT) DEGRO1 Internal mammaria lymph node region (IMC)  pN1-pN2 and HR pos. in der DGGG e.CT)  IMC-RT. Guidelines Breast Version 2015.ago-online. sowie in der DKG e. centr.1 www.

84 . ECCO Amsterdam 2013 .91 (0.1 Adjuvant treatment n* Hazard ratio (95%CI) No adjuvant reported 625 0.Multivariate Analysis of Overall Survival: Effect of Radiotherapy of the Internal Mammaria Lymph Nodes © AGO (median follow-up 10.72 (0. in der DGGG e.ago-online.88 (0.V.01) www.76 – 1.1. sowie in der DKG e.55 – 0.9 yrs) e.06) Both (endocrine th.32) Endocrine therapy 1185 0.V.82 (0.05 (0.V.59 . and chemotherapy) 1200 0.de * missing data on 40 patients Poortmans et al. Guidelines Breast Version 2015.63 .94) Total 4004 0.1.1.39) Chemotherapy 954 1.

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

Whelan T. Ewertz M. Arriagada R. Ewertz M. Correa C. Lancet. Whelan T. EBCTCG (Early Breast Cancer Trialists' Collaborative Group).801 women in 17 randomised trials. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Godwin J. Gray R. .378(9804):1707-16. 1. 2011 Nov 12. Cutter D. Taylor C.383(9935):212735. McGale P. Cutter D. Wang Y. Peto R. Pierce L. Clarke M. Darby S. Lancet. Gray R. Peto R.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. Duane F. Taylor C. Wang Y. 2014 Jun 21. Mannu G. Davies C. Correa C. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: metaanalysis of individual patient data for 10. Wang Z. Darby S. McGale P. 1.

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

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

2013 Oct. Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO). Sautter-Bihl ML. 1. Fastner G. Strahlenther Onkol. Harms W. Sedlmayer F. Souchon R. Fietkau R.DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer. Dunst J. Haase W. . Sauer R.189(10):825-33. Budach W. Feyer P. Wenz F.

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

Arthur DW. Levine MN. Chan EK1. Wai ES4. White JR. 2014 Mar 15. 6. 2013 Jan. Gohla G. Accelerated fractionation with a concurrent boost for early stage breast cancer.5. Woods R2. Bane AL1. Whelan TJ. 2014 May. 2014 MarApr. Int J Radiat Oncol Biol Phys. Vicini FA. Freedman GM. 8. Shah C. Arthur DW. Babiera GV. Woodward WA. Bloom ES. Cuttino LW. Julian TB. Parpia S. Pond GR. Nichol A4. Khan AJ.20(2):131-46. Freedman GM. Speers C5. . Vicini FA. McBride ML2. Radiother Oncol. Shortened radiation therapy schedules for early-stage breast cancer: a review of hypofractionated whole-breast irradiation and accelerated partial breast irradiation. Allen Li X. Pritchard KI. Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy. Ann Oncol. Fyles AW.88(4):786-92. Shaitelman SF1. Pignol JP. Breast J. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: long-term hospital-related morbidity from cardiac causes. 7. Wilkinson JB.25(5):992-8. Chambers S.106(1):15-20. Virani S3. Tyldesley S6.

59– 0. Haviland JS1. Magee BJ.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. 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. Dobbs HJ. metastasis-free survival and overall survival has been observed. Lancet Oncol 2013.“ In 1 of 5 trails: “There were significantly fewer distant relapses up to 10 years in the 40 Gy group (HR 0. Lawton PA. Bliss JM. Venables K. Hopwood P. Sydenham MA. Yarnold JR. 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. HR-positive breast cancer after BCS and endocrine therapy is small (2-8 % after ten yrs) and decreases with increasing age. Simmons S. START Trialists' Group. Lancet Oncol. Barrett-Lee PJ. Dewar JA. telangiectasia. Barrett J. References: 1. Agrawal RK.“ (HROS=0.74. No advantage with regard to secondary mastectomy. 14: 1086–94 Elderly patients should be counseled about: Absolute benefit of WBRT in older women with pT1-2 (up to 3 cm) pN0. p=0.8.042) START B: Haviland JS et al.94).14(11):108694. and breast oedema). Mills J. 95% CI 0. 2013 Oct. . Owen JR.

Schnaper LA. Hudis CA. 2013 Jul 1. Lancet Oncol. J Clin Oncol. McCormick B. Winer EP. Hughes KS. Cameron DA. Wood WC. Kunkler IH. Bellon JR. Jack WJ. 2015 Jan 27. Berry DA. Schnaper LA. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.31(19):2382-7. Smith BL. Can older women with early breast cancer avoid radiation? The Lancet Oncology. Cirrincione CT. Muss HB. Dixon JM. 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. Williams LJ.2. Hughes KS. 3. on behalf of the PRIME II investigators. 4. Available online 28 January 2015 .

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.6 yrs. Dixon JM.. Berry DA. Cameron DA. 2. 2013 Jul 1. Williams LJ. on behalf of the PRIME II investigators. References: 1. Muss HB. 2013: N=636 eligible: WE+Tam RT vs WE + Tam med F/U 12. not specific breast cancer treatments. Winer EP. Available online 28 January 2015 . Schnaper LA. Hughes KS. Smith BL. Bellon JR. not the length of life. J Clin Oncol. 2015 Jan 27. Jack WJ. Can older women with early breast cancer avoid radiation? The Lancet Oncology. Hughes KS.31(19):2382-7. comorbid conditions.Radiotherapy in Elderly Patient Life Expectancy less than 10 Years (6/15) Further information: Hughes KS et al. Lancet Oncol. Schnaper LA. Kunkler IH. 3. dictate survival. McCormick B. and the biology of the tumor dictates the rate of IBTR. We would suggest that in this older population. Hudis CA. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Cirrincione CT.

.6 yrs. 2013: N=636 eligible: WE+Tam RT vs WE + Tam med F/U 12. Schnaper LA. 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. Hughes KS. Cirrincione CT. not the length of life. J Clin Oncol. Hudis CA.31(19):2382-7. Muss HB. the biology of the tumor dictates the rate of IBTR. Tamoxifen + RT (7/15) Further information: Hughes KS et al. Bellon JR. Wood WC. Reference: 1.BCS >=70y <4 cm cN0: Tamoxifen vs. comorbid conditions. McCormick B. dictate survival. not specific breast cancer treatments. Berry DA. 2013 Jul 1. Smith BL. Winer EP. We would suggest that in this older population.

04.94. Dubois JB.Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) – Partial Breast Irradiation (8/15) Further information: The primary objective of this trial was Overall Survival. p=0-09). References to the statements: Radiotherapy (RT) after Breast Conserving Surgery (Invasive Cancer) . Bartelink et al. Weltens C. Struikmans H. 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.I.81-1. http://dx. Bartelink H. Kirova Y. Collette L. Morgan D. 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. According to the publication. Schinagl D.doi. Mirimanoff RO. Van Limbergen E. Collette S. Horiot JC. ipsilateral second cancer or death due to breast cancer. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. the endpoint “Time to First Recurrence” is the time from randomization to first relapse defined as a loco-regional or distant relapse. Oei B. Lancet Oncol 2014. A reproducible benefit was observed with regard to Time to Ipsilateral Breast Tumour Recurrence as shown above. Jager J. Rodenhuis C. published online Dec 9. Supplementary appendix. Maingon P. Reference: 1. Poortmans P. no survival benefit) (LoE 1a A AGO+) 1. Whole-breast irradiation with or without a boost for patients . Miralbell R. Remouchamps V.org/10. Fourquet A. Bongartz R. 0.1016/S1470-2045(14)71156-8. Elkhuizen P.Partial Breast Irradiation Boost-RT (improves local control. 95%-C.

Radiother Oncol. Boost-RT in pts <40 years (LoE 1b A AGO++) Boost-RT in pts 40-60 years (LoE 1b B AGO+) 1. Orecchia R. Fussl C. Peintinger F. Ziegler I. 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. Radiotherapy and Oncology 82 (2007) 265–271 Intraoperative irradiation (IORT/IOERT) As boost-irradiation followed by WBI (LoE 2a B AGO+) 1. Valentini V. Deutschmann H. Sedlmayer F. Merz F. Horiot JC. Stierle C. Fastner G. 2015 Jan. Zehentmayr F. if G3 or >T1 (LoE 2b B AGO+/-) Antonini et al. Morgan D. Struikmans H. Oei B. Sedlmayer F. Fastner G. Greil R. 2013 Aug. 2. Boost-RT in pts >60 years.treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. Ciabattoni A. Menzel C. Jager J. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Lancet Oncol. Maingon P. Fourquet A. Van Limbergen E.16(1):47-56. Rodenhuis C. Miralbell R. Reitsamer R. . Lemanski C. Farmini A.108(2):279-86. Bongartz R. Reitsamer R. Reinartz G. Mirri A. Fischer T.16(1):47-56. 2015 Mar 1. Hager E. Elkhuizen P. Deutschmann H. Remouchamps V. Collette S. Mirimanoff RO. Weltens C. 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. Int J Cancer. Poortmans P.136(5):1193-201. Kopp P. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis. Kirova Y. Bartelink H. 2015 Jan. Collette L. Dubois JB. Fischer T. Schinagl D.

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

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.

148(2):345-53. 7. Halyard MY. et al. Gligorov J. Gligorov. et al.19:1110-6. Concurrent trastuzumab — internal mammary irradiation for HER2 positive breast cancer: “It hurts to be on the cutting edge”. J Clin Oncol 2009. no concurrent trastuzumab in parasternal RT) 1. Caussa L. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. 2. Nat Clin Pract Oncol 2008. Radiation recall reaction induced by adjuvant trastuzumab (Herceptin).5:645-54. Beuzeboc P. 4. Radiother Oncol 2010. Fourquet A. Jacob J. et al. Case Report Med 2009.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. Chung C. Gobillion A. Pierga JY. Facts and controversies in the use of trastuzumab in the adjuvant setting. Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. Ozsahin M. Dueck AC. Dendale R. 5. Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study. Belin L. 2014 Nov. Campana F.27:2638-44.94:119-20 (Letter to the editor). Breast Cancer Res Treat. Belkacémi Y. Vincent-Salomon A. Piccart-Gebhart MJ. Ann Oncol 2008.2009:307894. Cardoso F. 3. Granger B. Stuart D. Keves M.13:276-80. Cancer Radiother 2009. . Dinh P. Kirova YM. [Monocentric evaluation of the skin and cardiac toxicities of the concomitant administration of trastuzumab and radiotherapy]. Kirova YM. Pisansky TM. Belkacemi and J. de Azambuja E. 6.

Toillon RA. Oncologist 2010. Colleoni M. 2009 Jan. 4. 2.80:398-402. Sauerbrei W. Castadot P. Rolles M. Radiotherapy for invasive breast cancer: Guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de Vence. 4.34:245-8 Ishitobi M. Trombetta MG. Belkacémi Y. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Lancet Oncol. Fourquet A. Anticancer Res 2011. Acute cardiotoxicity with concurrent trastuzumab and radiotherapy including internal mammary chain nodes: A retrospective single-institution study. et al.90:122-126 Tamoxifen concurrent with radiotherapy (LoE 2b B AGO +) 1. Tsoutsou PG. Crit Rev Oncol Hematol 2011. AI (letrozole. antihormonal therapy.. Chargari C1. Shaffer R. anastrozole) concurrent with radiotherapy (LoE 2b B AGO +) 1. Chargari C1. Optimal sequence of implied modalities in the adjuvant setting of breast cancer treatment: an update on issues to consider. et al.79:91-102 Valakh V. Gligorov J. et al.31:367-371. Tyldesley S. et al. Lancet Oncol 2010. Toillon RA. Recht A. Castadot P. . Braun M. Int J Radiat Oncol Biol Phys 2011. International Breast Cancer Study Group. Magné N. Cole BF. Eur J Cancer 2010.10(1):53-60.10(1):53-60. 2009 Jan. Influence of concurrent anastrozole on acute and late side effects of whole breast radiotherapy. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Lancet Oncol. 3. 2.46:95-101. Radiother Oncol 2009. German Breast Cancer Study Group (GBSG). Werts ED.. et al. Cutuli B.11:215-216.8. and personalised medicine. Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy. Am J Clin Oncol 2011.. Macdermed D. Radiotherapy. 3. 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. Komoike Y. Nakahara S. et al. 5. on behalf of the Association of Radiotherapy and Oncology in the Mediterranean area (AROME).15:1169-78 Winzer KJ. Risk of ipsilateral breast tumor recurrence in patients treated with tamoxifen or anastrozole following breast-conserving surgery with or without radiotherapy. et al. Magné N. Karlsson P. Belkacemi Y. Macdermed D.

Cottu P. et al. Bontemps P. 2015 Feb 3:20140800. Bourgier C. Romieu G. Belin L.5. Fourquet A. Sozzi WJ. Levy C. Denis F. Reynaud-Bougnoux A. Baumann P. Br J Radiol. Missohou F. Peignaux K. Lancet Oncol 2010. Belkacemi Y. Crit Rev Oncol Hematol 2012. Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. . Azria D.84 Suppl 1:e35-41 Other compounds (bevacizumab) 1. De La Lande B. 6. Campana F. Late toxicities and outcomes after one year of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple negative non-metastatic breast cancer. Dendale R. Lemanski C. Bollet M. Azria D.11:258-265. Kirova YM. Betz M. Identifying patients at risk for late radiation-induced toxicity. Pernin V. Ozsahin M. Gobillion A.

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

ago-online.de .  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.Therapy Side Effects © AGO e. sowie in der DKG e.V. in der DGGG e.1 www.V.V.

ago-online.de Long-Term Toxicity No general assessment scale 1 WHO 2 Handbook for reporting results of cancer treatment.0 .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. N0 48 (1979) (WHO offset Publications. NHI.V. According to WHO1 or NCI-CTC2 Guidelines Breast Version 2015.gov/ftp1/CTCAE/About.nci. Common Toxicity Criteria.V.Bethesda. sowie in der DKG e.nih. CTCAE v4.V.html .Toxicity Assessment © AGO Acute Toxicity e. (2010) http://evs. in der DGGG e. Geneva) NCI. USA.

Guidelines Breast Version 2015.1 www.ago-online. 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 + ++ +++ + + + .de Nausea/ Vomit.Cytotoxic Anti-Cancer Drugs Acute Toxicity I © AGO Haematol. Toxicity e. sowie in der DKG e. in der DGGG e.V.V.V.

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

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

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.Feasibility of Treatment Combinations Considering Toxicities © AGO Oxford / AGO LoE / GR e. sowie in der DKG e.ago-online.V.de .V. Guidelines Breast Version 2015.V. in der DGGG e.

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

V.4% in patients treated with anthracyclinecontaining chemotherapy 2b Tamoxifen approximately doubles the risk for developing endometrial cancer 2b .15 years 2a Anthracycline-containing regimens increase the risk of MDS and leukaemia to 0. chemotherapy induced secondary malignancies are rare events Oxford LoE 2a Alkylating agents increase the risk of leukaemia dosedependently to a total of 0.V.2–0. sowie in der DKG e.5-1% 2b Radiotherapy increases the risk of leukaemia by 0.2–1.de  With regard to solid tumours.2–0. in der DGGG e.Secondary Malignancies I © AGO e.V. Guidelines Breast Version 2015.ago-online.4 % within 10 .7 % within 8 to 10 years 2a PARP-inhibitors are associated with an increased risk of AML and MDS to 0.1      www.

sowie in der DKG e.V.de Enhanced risk especially among ever smokers 2b . in der DGGG e.V.V.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.ago-online.  Guidelines Breast Version 2015.Secondary Malignancies II (after Radiotherapy) © AGO Oxford LoE e.

ago-online. sowie in der DKG e. but delays conception to a less fertile period www. CIA) .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.V. in der DGGG e.Chemotherapy Related Amenorrhea (CRA) © AGO Oxford LoE 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.V. Guidelines Breast Version 2015.V.

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

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 ++ .1   www. sowie in der DKG e.V. in der DGGG e. Guidelines Breast Version 2015.V.(Therapy Associated) Sleeping disturbance © AGO Oxford / AGO LoE / GR e.ago-online.

ago-online.  Guidelines Breast Version 2015.(Therapy Associated) Depression © AGO Oxford / AGO LoE / GR e. in der DGGG e.V.1 www.de Depression is an often reported adverse event in breast cancer patients (20–30%) 2a B  Psychological interventions are effective to improve mood. sowie in der DKG e. 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  + .V.V.

V. in der DGGG e. sowie in der DKG e.V.ago-online.(Therapy Associated) Cognitive Impairment © AGO Oxford / AGO LoE / GR e.1 www. Guidelines Breast Version 2015.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 .

in der DGGG e.ago-online.V.Side-effects and Toxicity of Endocrine Agents © AGO Visual Disturbances e.V. sowie in der DKG e. Guidelines Breast Version 2015.1 www.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.

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

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

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

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

hyperglycemia. infections. skin rash.ago-online.V. skin rash.Small Molecules © AGO e. LEE011)  myelosuppression. fatigue Oxford / AGO LoE / GR 1b A 2b B 3 C 3 C Everolimus  Pneumonitis.V.V.1 Lapatinib  Diarrhea.de Fatique. in der DGGG e. stomatitis.neutropenia . myelosuppression cdk4/6 inhibitors (palbociclip. Guidelines Breast Version 2015. Thrombocytopenia PARP-inhibitors (olaparib)  www. sowie in der DKG e.

Therapy Side Effects (2/22) Further information: Screened data bases: Pubmed 2007 .asco. 2012): http://www. 2012) http://www.gov ASCO (American Association of Clinical Oncology. SABCS 2010 – 2013. Practice Guidelines.org CMA (Canadian Medical Association . ASCO 2010 – 2013. Cochrane data base (2013) Screened guidelines: NCI (National Cancer Institute .org No references . 2012): http://www.2013.cancer.nccn.cmaj. 2012): http://www.ca NCCN (National Comprehensive Cancer Network .

Bethesda. Common Terminology Criteria for Adverse Events v4. 2. Toxicities are graded according to WHO or NCI standards. This implies that toxicities concerning liver. menopausal symptoms or impairment of cognitive function are systematically underreported by these tools. N0 48 (1979) (WHO offset Publications. USA.nci.0 (CTCAE. WHO Handbook for reporting results of cancer treatment. Most trials end five or ten years after the last patient in.nih. such that late and very late effects are rarely documented.html . Geneva) NCI. published 2010). kidney heart or skin are well documented and graded. depression.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. http://evs. Acute Toxicity according to WHO1 or NCI-CTC2: References: 1.gov/ftp1/CTCAE/About. Other toxicities like fatigue.

Petrelli F et al: Mortality. N Engl J Med 344:1997-2008. de Azambuja E. 4. 5. 2.: Long-term toxic effects of adjuvant chemotherapy in breast cancer. 2001 Azim HA Jr. 3. Lancet. 2011. 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. J Clin Oncol. Shapiro CL. 2012 Sep. 2012 Oct 10.377:914-23 Kaufmann PA. Colozza M.30(29):3578-87 Cortes J. Bines J. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. leukemic risk. Awada A. O'Shaughnessy J. Piccart MJ.22(9):1939-47. 6. Breast Cancer Res Treat. Twelves C et al. and cardiovascular toxicity of adjuvant anthracycline and taxane chemotherapy in breast cancer: a meta-analysis.Cytotoxic Anti-Cancer Drugs – Acute Toxicity I (4/22) No further information References: 1. Recht A: Side effects of adjuvant treatment of breast cancer. 2011 Sep. Ann Oncol. Loesch D et al. abstract S6-6 .135(2):335-46 Jim HS et al: Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy.

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 .

CMF: 3% vs.01).1 % of patients from the FE100C arm.term toxicity cardiotoxicity and secondary acute leukemia/MDS are clinically relevant. 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. 5%. FAC: The Southwest Oncology Group evaluated long term cardiotoxcity from patients randomized to protocol S8897. . 0%.68) or at 10 to 13 years (CAF vs. In this trial patients were randomized to CAF or to CMF.3 % and in 4. Similar data were presented recently by Perez et al. CMF: 8% vs. There was no significant difference in the proportion of women with an LVEF less than 50 % at 5 to 8 years (CAF vs. but not in the 10 to 13 year sample.16). in N9831 trial.5 % of patients from the FE50C arm and 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. 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 %. Cardiotoxicity: Early cardiotoxicity of anthracyclines has been well established in clinical trials. decrease > 15%: 2. As patients with breast cancer are getting older and as survival rates improve long term cardiotoxicity is of growing interest.4%. Delayed (> 1 month after the end of chemotherapy) symptomatic cardiotoxicity was reported in 1.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 %. In terms of long. A was given on day 1 and 8. p=0. p=0. 180 patients from an potential sample of 1176 patients entered. In 2992 patients completed AC 5% had LVEF decrease disallowing trastuzumab (decrease below normal: 2. Limited data are available on long-term cardiac safety of A based regimens.6%).

Similarly as in the previous study anthracycline–treated women were younger. For women aged 71 to 80 adjuvant chemotherapy was not associated with chronic heart failure.004). because these patients are per se younger. After ten years the increased risk of chronic heart failure was amplified rather than attenuated. The first one by Doyler et al.4% vs. Pinder et al reported data from a total of 43. 2.21% in controls (p=0. analyzed data from 31478 patients. A containing regimens outside clinical trials in the elderly There are 2 important studies from the SEER database in older women. 1.027). Preexisting heart disease was beside of afro-american race the most important risk factor for cardiac failure after A-exposure. where trials in which total doses of anthracycline was reduced by substitution of taxane. 5575 of them received A-based chemotherapy (18%).44). p=0. The adjusted hazard ratio was 1.48 (95% CI.25 to 1.35 (95% CI. and 1.7 % when comparing anthracycline treated patients to the other or no adjuvant chemotherapy groups.9 % and 9.36% decrease in LVEf after 7 years vs. In this age group at five years of follow-up the observed absolute differences were of 1 % and 4.g.26 to 1. The hazard ratios for cardiomyopathy.10 to 2. had subsequently less . E+ therapy was associated with 1. 1. the PACS 01 trial reported significantly lower incidence of cardiac toxicity in the 3xFEC-3xDoc arm than in the 6xFEC arm (0.(antihormontherapy or nil) regimens in 3577 breast cancer patients.6 % respectively in rates of chronic heart failure between anthracycline based chemotherapy and other adjuvant chemotherapy or no chemotherapy.38 (95% CI. 1. in which lower doses af anthracyclines are used. In these analysis age > 65 years old and body mass index > 27 were significant predictors of cardiac toxicity. with less comorbities and a higher risk of recurrence. This study highlights bias of all studies. and heart disease for patients > 65 years treated with doxorubicin compared with patients who received no chemotherapy were 2. E.3%.The second analysis from the FASG trials compared E+ and E.93). only 0.26 for women aged 66 to 70 treated with a compared other chemotherapy. Taxanes and cardiac safety Data on cardiac safety in anthracycline-taxane sequential trials are in favour of taxane-based combinations. investigating cardiac affects of A-chemotherapy.338 women from the SEER’S database. These data have been confirmed in the Cochrane analysis. 1. with less comorbidity and had more advanced diseases than women who received non anthracycline based regimens. cardiac failure. with absolute differences of 5.52). respectively The relative risk remained elevated 5 years after diagnosis.

which is reversible after cessation of trastuzumab. 2010.135(2):335-46 . Breast Cancer Res Treat. Cochrane Database Syst Rev. obesity. There are only limited data on cardiac safety of A-free regimens in adjuvant setting in breast cancer.37 (95%CI: 0. 17. van Dalen EC Different anthracycline derivates for reducing cardiotoxicity in cancer patients.3%). 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. dose. Review. “Anthracycline. Update in: Cochrane Database Syst Rev. and cardiovascular toxicity of adjuvant anthracycline and taxane chemotherapy in breast cancer: a meta-analysis.or trastuzumab-associated cardiotoxicity may occur earlier/more frequently…” 1.)” “Liposome encapsulated anthracyclines (doxorubicin) induce less cardiotoxicity” 1. 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.cardiac events.14-0. although the negative synergistic cardiac effect of Herceptin should be considered separately of anthracycline cardiac side effects. leukemic risk. than standard A-based regimens (OR=0.95)).(3):CD005006. Jones et al. References: Statements “Equivalent cardiotoxicity of doxorubicin and epirubicin at recommended dose levels (450–500 and 900–1000 mg/m² cum. Petrelli F: Mortality. resp. 32% of HER2+ EBC patients treated with trastuzumab are 'over-60'. Trastuzumab and cardiac safety Most studies have excluded elderly patients (> 60 or 65 years) or patients with other risk factors (cardiovascular diseases.(5):CD005006. In clinical practice. 2012 Sep. hypertension) from studies including trastuzumab. Also with regard to other risk factors there is an increased risk of trastuzumab related cardiotoxicity during treatment. These patients have an increased cardiovascular risk profile and develop trastuzumab related cardiotoxicity commonly. 2010 Mar 17.

Review. 25:3808-3815 Fumuleau P: Long term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group Results. Sánchez-Ollé G. Ann Oncol. Carreras MJ. Tabernero J. Dtsch Arztebl Int 108:365-371. 2011 Sep. de Azambuja E.” 1. Cortés J. Ann Oncol. 2011 Aug 9.22(9):1939-47. Pulignano G. Doyler JJ: Chemotherapy and cardiotoxicity in older breast cancer patients: a population based study. 2012 Dec. Faggiano P. 3. 34:8597-8605. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Di Cosimo S. N Engl J Med.23(12):3058-63. Vidal M. J Clin Oncol. Gerber B: Adjuvant therapy for women over age 65 with breast cancer. Tuccia F. 4. De Mattos-Arruda L. Further references: 1. Baselga J. Bovelli D. 2. Gómez P. Souchon R. Cioffi G. “Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Annals of Oncology 2006. Tarantini L.365(14):1273-83 . Muñoz-Couselo E. Simoncini E. Azim HA Jr. ICARO (Italian CARdio-Oncologic) Network. Lestuzzi C. J Clin Oncol 2007. 17:85-92. 2. Serrano C. 2006. Pinder MA: Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. Piccart MJ. Nat Rev Cardiol. Ann Oncol. Ceccherini R. 2010 Oct. Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis. Ewer SM. Bines J. Saura C. 2011 Oct 6.: Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Adjuvant trastuzumab in HER2-positive breast cancer. Slamon D: Breast Cancer International Research Group. 3. 2011 “Monitoring of cardiac function before / during / after treatment: Echocardiography (LVEF or SF in %)” Ewer MS. Bellet M.2. Colozza M. Pérez J. Sautter-Bihl ML. Gori S. Long-term toxic effects of adjuvant chemotherapy in breast cancer.7(10):564-75.

Bernard-Marty C. Hershman: Anthracycline cardiotoxicity after breast cancer treatment.22:257-67. Oncology (Williston Park). Breast. 10. Brain EG. 6. Erdkamp F. . 2010 Nov. 2009 Mar.22(5):1011-8. 2007 Oct 17. Leonard RC: Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet). Verma S: Is cardiotoxicity being adequately assessed in current trials of cytotoxic and targeted agents in breast cancer? Ann Oncol. Ann Oncol.23(3):227-34. Aapro M. Epub 2010 Nov 22. 2011 May. Ferguson T: Taxanes for adjuvant treatment of early breast cancer.5. 2009 Aug. 7.. 9.(4):CD004421. Cochrane Database Syst Rev. Ann Oncol.21(11):2153-60. 2011. Krzemieniecki K. Costa RB: Efficacy and cardiac safety of adjuvant trastuzumab-based chemotherapy regimens for HER2-positive early breast cancer.18(4):218-24. Batist G. Lluch A: Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper. Leonard R. 8.

At a median follow-up of 3.9% with or without RT. p = 0. However other reports did not confirm such an connection. 2009). 2009 Viani GA. References: Statements “Trastuzumab simultaneous to radiotherapy” 1.442. 2. The cumulative incidence of CEs with AC-T-H was 2. Adjuvant trastuzumab in the treatment of Her2 positive early breast cancer: a metaanalysis of published randomized trials. Radiotherapy (RT) was administered either without or with concurrent trastuzumab (H). concurrent adjuvant RT and H for early-stage BC was not associated with increased acute AEs (Halyard al.7% with or without RT. the cumulative incidence was 1. BMC Cancer 2007. 1503 patients were irradiated.J Clin Oncol 27: 2638-2644. RT with H did not increase relative frequency of cardiac events (CEs) regardless of treatment side. 95% CI 1.326. respectively. Stefano EJ. Afonso SL. Therefore the results of the ongoing CONSeT-trials has to be awaited. Reported data regarding the influence of tamoxifen given simultaneously to radiotherapy are diverging. Thus. Halyard MY.01) and might increase the risk of late lung sequelae (OR = 2. De Fendi LI. Soares FV.120-5.7 years.7% v 5.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 3.025). 0 to 6. Dueck AC: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. With AC-TH-H.5 years).7 years (range. Simultaneusly given tamoxifen to radiotherapy might increase the risk of Grade 1 lung fibrosis (p = 0. 7:153-164 . Pisansky TM.

Fasching PA. Slamon D. Tesch H. Blohmer JU. Glaspy J. 2006.365(14):1273-83 “Anthracycline simultaneous to radiotherapy” 1. von Minckwitz G. Thomssen C. Eiermann W. Breteau N. Huober J. Int J Radiation Oncology Biol. Untch M. Kaufmann M. Press M. Riva A. Calais G. 2010 Apr 20. 2010 Mar 20. Fourquet A. Harbeck N. Pawlicki M. J Clin Oncol. von Minckwitz G. Thomssen C. Serin D. Untch M. Jackisch C. du Bois A. Breast Cancer International Research Group. Crown J. Lück HJ. “Trastuzumab simultaneous to doxorubicin” 1. Dan Costa S. Lindsay MA. Eidtmann H. Kühn T.28(9):1473-80. 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. 2011 Oct 6. Meerpohl HG. Tjulandin S. Pienkowski T. Toledano A. Lichinitser M. Visco F. Rezai M. Azria D. J Clin Oncol. Robert N. Gerber B. Bendahmane B. Liu MC. Phys. Coumbos A. Kreienberg R. Jackisch C. Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conserving surgery enhances late toxicities: long-term results of the ARCOSEIN multicenter randomized study. Muscholl M. Jonat W. Martin M. Bee V. du Bois A. Garaud P. Manikhas AG. 65: 324-332. Hanusch C. Müller V. 2. .28(12):2024-31. Loibl S. Hilfrich J. Cyclophosphamide. Sauter G. Chan A. Valero V. Le Floch O. Mehta K. N Engl J Med. Body G. Catalani O. Tabah-Fisch I. Lehle M.: Adjuvant trastuzumab in HER2positive breast cancer. Pauschinger M. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. Bosset JF.“Trastuzumab simultaneous to epirubicin” 1. Bauerfeind I. Mackey J. Buyse M. and Epirubicin (HERCULES) trial. Pinter T.

Telli ML. 7:153-164 . Further references: 1. Simeonova A. Kaminsky A. 2011 Jun. On the interaction of adjuvant radiotherapy and tamoxifen treatment for breast cancer.34(3):245-8. BMC Cancer 2007. Guardino AE. Feyer P. 2. 25: 3525-3533 Viani GA. Labban G. 2007 Oct. Souchon R. Kahán Z. Siebenlist K. Strahlenther Onkol. Thurzó L. Hoeller U. Kraus-Tiefenbacher U. Hunt SA.The CONSET trial is launched. 3. Acta Oncol.80(4):1109-16. Cserháti A.“Tamoxifen simultaneous to radiotherapy” 1. Radiat Oncol. Werts ED. Am J Clin Oncol. 2012 Dec 18. Concurrent versus sequential radiotherapy and tamoxifen in breast cancer . Welzel G. Gupta D. Adjuvant trastuzumab in the treatment of Her2 positive early breast cancer: a metaanalysis of published randomized trials. Sperk E. Mai S. 3.50(1):154-5. Boda K. Trastuzumab-Related Cardiotoxicity: Calling Into Question the Concept of Reversibility. 2011 Jul 15. Wenz F. Carlson RW. Afonso SL. 2007. Khalid MK. Soares FV. 2. Organgruppe "Mammakarzinom" der DEGRO. Trombetta MG. Sfintizky A. Factors of influence on acute skin toxicity of breast cancer patients treated with standard external beam radiotherapy (EBRT) after breast conserving surgery (BCS). Influence of concurrent anastrozole on acute and late side effects of whole breast radiotherapy. 2011 Jan. Borgmann K.183(10):535-44. Munshi A. [Epub ahead of print] Varga Z. 4.: Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients. De Fendi LI. Valakh V.7(1):217. Int J Radiat Oncol Biol Phys. Stefano EJ. Kelemen G. Parda D. Journal of Clin Oncol.

and there is no evidence that the toxicity is dose related. Ludke A. Jassal DS.4%).16(3):70-4. LVEF dysfunction of grade 3 or higher was reported in 2. Left ventricular ejection fraction (LVEF) should be measured at baseline and at regular intervals. 2002 Zeglinski M. Signs and symptoms are similar to those observed in patients who develop anthracyclineinduced cardiomyopathy and include tachycardia. . 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. 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. nonspecific. Trastuzumab-induced cardiac dysfunction: A 'dual-hit'. which may ultimately progress to congestive heart failure (Keefe. in neither trial cardiotoxicity was increased through the addition of pertuzumab to trastuzumab both in the absence or presence of taxane containing chemotherapy. LVEF dysfunction (any grade) was more frequently seen in the placebo group than in the pertuzumab group (8. Cancer 95:1592-1600. and medically manageable. particularly anthracyclines. 2011 Fall. References: 1.3% vs 4. Trastuzumab-associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab. severe and life-threatening damages are rare and the majority of reported cardiac effects are mild to moderate. However. 2002). Singal PK. and exertional dyspnea. There are also data for trastuzumab and pertuzumab from phase 2 trials and randomized phase 3 trials. palpitations. 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.2% of the patients in the placebo and pertuzumab arms respectively. 2.8% and 1. Keefe DL: Trastuzumab-associated cardiotoxicity.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. Exp Clin Cardiol.

Smith IE. 366:109-119 . N Engl J Med 2012.5(6):324-35. Nat Clin Pract Oncol. Baselga J. 2008 Jun.3. Popat S. Kim S-B et al. Pertuzumab plus Trastuzumab plus Docetaxel for metastatic breast cancer. Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects. 4. Cortes J.

uterine cancer. 95%CI 7. acute myeloid leukemia and homonal therapy with uterine cancer (HR 1.46 to 8.7 to 4. acute myeloid leukemia. ovary.2 Patients 50 years and older.60) and chemotherapy with decreased risk for all secondary non-breast cancers. kidney.6 times more likely to develop AML than the total femal Australien population.78.7.4%.98.5). colon.77 to 4. 95%CI1. with highest age-specific relative risk for AML in the 30. non Hodgkin’s lymphoma.to 49-age group.1.7).04).27).2 For women > 65 years receiving polychemotherapy (CAF.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. 95%CI 1. Compared with the general female dutch population.8.1 to 34. rectum. The occurance of a second non-breast cancer was associated with a decrease in overall survival (HR 3. radiotherapy was associated with increased lung cancer risk (HR 2.2 than RR 2. to have discontinued treatment for toxicity or to die of acute myeloid leucemia/MDS was significantly elevated.6). ACP) the risk to develop grade 4 hematologic toxicity. uterus.7 to 17. melanoma. chemotherapy with increased risk of melanoma. 95%CI 1.1-3 Patients younger than 50 years.1 Mitoxoantrone-based chemotherapy was associated with a higher leukemic risk than with anthrazyclines (RR 16.1-5 .000 women-years (13.1 to 5. bladder. Epirubicin and doxorubicin had a similar risk.3 Granulacyte colony-stimulating factor (G-CSF) increased the risk of developing AML/MDS.43.15 to 4.1 Standard incidence ratios were elevated for cancers of esophagus.20). soft tissue sarcomas.31. 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. 95%CI 5. stomach. 95%CI 3.2 Risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) Women with a prior breast cancer were ~2.6 (95%CI 9. lung. radiotherapy was associated with increased risk of soft tissue sarcoma (HR 3.40 to 2.1.

Details to chemotherapy regimes: French FEC The French Adjuvant Study Group reviewed their 16-year experience with their FEC regimen of 5-Fluorouracil. and 1. 0. 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 34.7 % (95 % confidence interval [CI]. About two-third of the patient population received epirubicin-based adjuvant chemotherapy while slightly lower than one-third received CMF-like regimens.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years. As for leukemia. g.3 % (95 % CI. Canadian CEF comprises epirubicin doses of 120 mg/m2.3 % for those patients treated with adjuvant epirubicin and <0.1 % for those treated with other adjuvant therapies (CMF-like. 75. The leukemia risks associated with epirubicin-containing regimens (CEF or EC) and other regimens as doxorubicin and cyclophosphamide (AC or CMF) were registered. two who had received AC. 0 % to 4. 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.v.3 %) among the 678 who received CMF. The incidence of secondary leukemia was very low: 0. and one following CMF. . antihormonal therapy). epirubicin (50. A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia. the conditional probability of sAL was 1. two acute lymphoblastic leukemia): Seven among women treated with CEF.9%.7 %) among the 231 treated with AC.5 to 3. q3w. 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. Using competing risk statistics. 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. Of note. Cumulative epirubicin doses mostly were below 600 mg/m2. 0. which were followed for a median of 104 months. 100 mg/m2) and cyclophosphamide i. data of 3653 women are available. 0 % to 1.4 % (95 % CI. e.

006). P = . Occurrence of AML/MDS was summarized by incidence per 1. A was given at 60 mg/m2 q 21 days x 4. 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.21 % (95 % CI. Materials and Methods:Six complete NSABP trials have investigated AC regimens (B-15. References for statements 1-4: 1. Rates were compared across regimens. 1200 mg/m2 q 21 days x 4. but data are inconsistent (see slide 10/20). Results:The incidence of AML/MDS was sharply elevated in the more intense regimens.01 % (95 % confidence interval [CI].62 %). Breast radiotherapy appeared to be associated with an increased risk of AML/MDS. cumulative dose and by the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. although the incidence of AML/MDS was small relative to that of breast cancer relapse.38. and 2400 mg/m2 q 21 days x 4. Visser O. B-16. and by treatment with or without breast radiotherapy. 0.(2008) Risk of primary nonbreast cancers after breast cancer treatment: a dutch population-based study.000 patient-years at risk and by cumulative incidence.63 % to 1. and B25). In all regimens. In patients receiving two or four cycles of C at 2400 mg/m2 with granulocyte colony-stimulating factor (G-CSF) support. . 0. B-23. cumulative incidence of AML/MDS at 5 years was 1. compared with 0. Louweman M et al.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). Patients who received breast radiotherapy experienced more secondary AML/MDS than those who did not (RR = 2.11 % to 0. J Clin Oncol 26: 1239-46. by age. 2400 mg/m2 q 21 days x 2.41 %) for patients treated with standard AC. B-18. C was given as follows: 600 mg/m2 q 21 days x 4 ("standard AC"). and the data indicated that G-CSF may also be independently correlated with increased risk. Schaapveld M. Six distinct AC regimens have been tested and are distinguished by differences in cyclophosphamide intensity. G-CSF support and to a smaller extent which were characterized by increased rates of subsequent AML/MDS. 1200 mg2 q 21 days x 2. B-22.

3. Taylor C. and granulocyte colonystimulating factor: risik factors for leukemia and myelodsplastic syndrome after breast cancer. 2011 Aug 27.378(9793):771-84. Berry D. 82. Beadle G. Baade P. Peto R. McGale P. Wang YC. Engholm G. Clin Breast Cancer 4: 273-9. Darby S. Ann Oncol 47: 755-64. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Andersson M. 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. Le Deley M. Davies C. Suzan F. J Clin Oncol 25: 3699-704. Fritschi L(2009) Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers. Ann Oncol 20: 103-9. Gray R. Gambotti L et al.(2007) Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stmulating factors during breast cancer adjuvant chemotherapy. 89 programmes during 1977-2001. 4. 6. Cirrincone C et al. De Rycke Y. J Clin Oncol 25: 292300. 5. Hershman D. 8. Pan HC. J Natl Cancer Inst 99: 196-205 Reference for Statement Tamoxifen and endometrial cancer 1. 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.(2007) Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B experience. Lancet. Neugut A. B J Cancer 98: 870-4. Jacobson J et al. Kirova Y. Godwin J. Jensen M. .2. 7.(2008) Second malignancies after breast cancer: the impact of different treatment modalities. Ingle J. Cutter D. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). radiotherapy. mitroxntrone. Clarke M. Dowsett M. Muss H. Catali B et al.(2007) Anthracyclines.

patients younger than 50 years. oesophagus. bone and soft tissue sarcoma) with no evidence of elevated risk for sites receiving medium (05. 95%CI 1. lung.43.46 to 8. Lancet 366: 2087-3106.31.60) and patients older than 50 years were more likely to develop soft tissue sarcoma (HR 3. 3. Senkus-Konefka E. risks were higher for sites that should have received higher doses and also higher for young age at exposure. . J Clin Oncol 26: 1239-46.9 Gy) or low doses (< 0.-0.1 According to the cohort data of the SEER registries 1973 to 2000 risk for second cancers was dose dependend. Overall risks were generally lower for patients treated in recent years (1993 +).5 Gy). 95%CI 1. J Clin Oncol 18: 229-35.33 to 1.9. 95%CI 7. radiotherapy was associated with an increased lung cancer risk (HR 2. Louweman M et al.(2008) Risk of primary non-breast cancers after breast cancer treatment: a dutch population-based study. Gilbert E et al.9-45. The RR were 1.(2010) Second solid cancers after radiotherapy for breast cancer in SEER cancer registries. Results of a Dutch population-based study. Radiotherapy treatment assuming standard protocol with 50Gy tumour dose and beem energy 6 MV photons.45 (95%CI 1.58) for high dose second cancer sites (1 +Gy.4) according the results of the nested breast cancer cohort study population of the Connecticut Tumor Registry.5 Data are inconsistent for an elevated risk of AML/MDS after radiation exposure. Schaapveld M.6-8 The risk of lung cancer was elevated for ever-smokers who receive PMRT (HR18.6-8 References: 1. 4.15 to 4. 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.04). pleuro. Visser O. 2. But the pattern of risks observed were consistend with the general literature on radiation carcinogenesis.Secondary Malignancies II (11/22) Further information: Radiotherapy increased the risk of sarcoma and lung cancer. Berrington de Gonzalez A. Jassem J(2011) Complications of Breast cancer Radiotherapy. B J Cancer 102: 220-6. Curtis R.

Le Deley M. B J Cancer 98: 870-4. 6. De Rycke Y. radiotherapy. Suzan F. 7. Kaufman E. 8. Hershman D. Kirova Y.(2007) Anthracyclines. Catali B et al. Clin Breast Cancer 4: 273-9 . J Clin Oncol 25: 292300. Neugut A(2008) Effect of breast cancer radiotherapy and cigarette smoking on risk of secundary lung cancer. Jacobson J.5. Desai M.(2008) Second malignancies after breast cancer: the impact of different treatment modalities. and granulocyte colonystimulating factor: risik factors for leukemia and myelodsplastic syndrome after breast cancer. J Clin Oncol 26: 392-8. 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. mitroxantrone. Gambotti L et al.

doxorubicin-docetaxel in women with operable. CIA) Preservation of ovarian function is an important issue in the population of breast cancer patients especially in the patient younger than 40.g. von Minckwitz G.(2010) Longer therapy. GnRH analogues nor cryopreservation of ovarian tissue are convincing.1 After modern taxananthracyclin containing chemotherapy the risk of CRA is markedly lower compared to older chemotherapy regimens. The effects are more pronounced the older the patient and the longer the chemotherapy. iatrogenic amenorrhoe. N Engl J Med 362: 2053-65. 3. Druz M. Data from the NSABBP B-30 trial (sequential versus concurrent ACT. and survival in early breast cancer. Gimenes D. Geyer CJ et al. Especially in younger patients the restitution of menses after 2 years is greater than 90 %.4 The dose of drug delivered was not a key factor explaining the differnces.4 References: 1. New Engl J Med 353: 2268-70 . in particular when the tumor was ER-positive. Fertil Steril 94: 138-43.not a matter of dose. 4. The treatment compromising most oftenly fertility is chemotherapy. node-positive. 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.Chemotherapy Related Amenorrhea (CRA) (12/22) Further information: Synonyma: Chemotherapy / Treatment induced Amenorrhea (TIA.3. Jeong J. Wolmark N (2010) Amenorrhoe from the breast cancer therapy . J Clin Oncol 29:2334-2341. Jeong J. Gerber B. Up to now neither data for ovarian protection with e. 2011 Swain S.2 However one third of the patients probably will be infertile after chemotherapy. Swain S. 2. Fanelli M(2010) Fertility preservation in women with breast cancer undergoing adjuvant chemotherapy: a systematic review. early stage breast cancer) amenorrhoe in premenopausal women was associated with improved dissease-free and overall survival regardless of treatment.

. Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. et al:. Land SR.29(9):1110-6.5. 2011 Mar 20. Ganz PA. J Clin Oncol. Geyer CE Jr.

2010).(Therapy Related) Fatigue (13/22) Further information: Fatigue is a commen side effect during and after antineoplastic therapy. 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. In terms of pharmacological treatments for fatigue in a palliative setting. Especially in breast cancer incidence of moderate to severe fatigue ranges between 30 and as high as 60% (Lawrence 2004. including direct effects of cancer. which are used broadly in daily praxis. 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. Blaney 2012). 2010). 2006). Anemia might contribute to a subset of cancer patients presenting with fatigue (Cella et al. comorbid physical symptoms. has not yet been evaluated. 2006). Contrary to what was expected. It was shown in a meta-analysis by the Cochrane Collaboration that psychosocial interventions specifically addressing fatigue proved efficient (Goedendorp et al. 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. psychosocial factors. Behavioral and psychological interventions (Stanton et al. 2011) have demonstrated efficacy in reducing fatigue among breast cancer patients and survivors. adverse effects of cancer treatment. These authors concluded that improvements in fatigue were ambiguous and that strategies for behaviour change should underpin these interventions (Markes et al. This symptom is typically underreported and under-treated and might adversely affect quality of life (Bower. Several factors are thought to contribute to cancer-related fatigue. 2010). . 2009) and the same authors reported a randomized controlled trial showing that cognitive behavioural therapy was effective in reducing cancer-related fatigue. 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. 2006). 2005) as well as physical exercise (McNeely et al. 2004). 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. However. physical activity did not mediate the effect of cognitive behavioural therapy on fatigue in this study (Goedendorp et al. 2008). However the effectiveness of glucocorticoides. Bower et al.

assessment. et al: Outcomes from the Moving Beyond Cancer psychoeducational. Kwan L. J Clin Oncol 23:6009-6018.References: Fatigue is frequently present… 1. 2004 Psycho-social interventions… 1. 5. Cancer 106:751-758. 2013 Jan. 4.1002/14651858. Miller K.11:CD006145. 2006 Lawrence DP. Blaney JM. Breast Cancer Res Treat 112: 5-13. 2. Cochrane Database of Systematic Reviews 2009.1002/14651858.Stone: How common is fatigue in disease-free breast cancer survivors? A systematic review of the literature. facilitators and preferences in the context of fatigue. Ganz PA. Psychosocial interventions for reducing fatigue during cancer treatment in adults.Cochrane Database Syst Rev. Arevalo JM. Verhagen CAHHVM. Brain Behav Immun. No. Desmond KA. DOI: 10.pub3. Bower JE. Epub 2011 Oct 6.22(1):186-94. doi: 10. Goedendorp MM. randomized. Ganz PA. Lowe-Strong A. Rankin-Watt J. quality of life and physical activity participation: a questionnaire-survey. Art. controlled trial with breast cancer patients. 2011 Jan. Campbell A. 6. et al: Evidence report on the occurrence.CD006145. J Natl Cancer Inst Monogr 32:40-50. Cole SW : Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Minton . Gracey JH. 26:768-777.CD006953. . 1. Psychooncology. 2008 Bower JE. 2012 Nov 14. 2.2072.. 3. et al: Fatigue in long-term breast carcinoma survivors: A longitudinal investigation.pub2 Stanton AL. Issue 1. and treatment of fatigue in cancer patients.1002/pon. Gielissen MFM. 2005 Physical exercise….: Exercise for the management of cancer-related fatigue in adults. Kupelnick B. Bleijenberg G.Cancer survivors' exercise barriers.: CD006953. Ganz PA. Byron-Daniel J. J Clin Oncol. Irwin MR. Cramp F..25(1):147-50. 2008 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. doi: 10.

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and depressive symptoms predicted baseline levels of subjective sleep disturbance. 2010). 2006). 2009). 2005). and depressive symptoms predicted the trajectory of subjective sleep disturbance (Dhruva et al 2012). fatigue and depression may stem from distinct TNF-a mediated inflammatory processes. Indeed. a randomized controlled trial of behavioural therapy for women with insomnia caused or exacerbated by breast cancer found significant improvement in subjective sleep complaints. . 2001. evening fatigue. Ancoli-Israel et al. References: Sleep disturbances are a common problem…. Liu et al 2012). 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. Berger et al. 2009). as well as improvements in mood and quality of life (Savard et al.htm . supporting their use among breast cancer patients (Berger et al. it was shown that 43% of the patients met the criteria for insomnia syndrome. 2011. Savard et al. 2008.R24#R24New data suggest that sleep disturbances. although no trials have evaluated the efficacy of these medications in cancer populations. including insomnia secondary to medical conditions. Comorbidity.(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. 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. E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. 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. Those with insomnia complaints had significantly more depression and fatigue than good sleepers (Palesh et al. behavioral symptoms in breast cancer survivors 2008. especially found in chemotherapy treated patients (Bower et al. Insomnia was approximately three times higher than the proportions reported in the general population.

Marler MR. 2005 Smith MT. 2. 2006 Behavioral therapies have demonstrated efficacy…. et al: Prevalence. Support Care Cancer 14:201-209. Wara W. 2009 Savard J. Farr LA. and after radiation therapy. demographics. depression. Bower JE. Simard S. Perlis ML. Dhruva A. Berger AM. Swift PS. Lee K. 2002 .. 3. Paul SM.20(2):245-52. Kuhn BR.26(5):706-13 McChargue DE. 26:768-777. Ancoli-Israel S.44(2):215-28. J Clin Oncol 23:6083-6096. Fiorentino L.: A longitudinal study of measures of objective and subjective sleep disturbance in patients with breast cancer before. Miaskowski C. 2012 Jul. Natarajan L. 3. Support Care Cancer. Matthews EE. Park A.2011 Palesh OG. Rissling M. Roscoe JA. Visovsky CG. 5. Parker BA. sleep. Predictors of adherence to a behavioral therapy sleep intervention during breast cancer chemotherapy. 1. Sankaranarayanan J. et al: Fatigue. Irwin MR et al: Inflammation and behavioural symptoms after breast cancer treatment: do fatigue. J Clin Oncol 27: 6033-6040. Liu L. et al: Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. 7. during. 2012 Feb. Cooper BA. 4. Highland KB. part I: Sleep and psychological effects. 2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. Liu L. et al: Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer. J Clin Oncol. and sleep disturbances share a common underlying mechanism? J Clin Oncol 29:35173522. Ivers H. 2. Dunn LB. Mills PJ. Ganz PA. 2008 Ancoli-Israel S. and circadian rhythms prior to chemotherapy for breast cancer. Dimsdale JE. and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. 6. 2012 Aug. West C.: Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy.1. J Clin Oncol 28:292-298. J Pain Symptom Manage. et al: One-year outcomes of a behavioral therapy intervention trial on sleep quality and cancer-related fatigue. Aouizerat BE. Am J Psychiatry 159:5-11. Berger AM. Sadler GR. Brain Behav Immun. Mustian KM.

Hoyt MA. Hart SL.pone. Antidepressents have also shown to improve depression. et al: The efficacy of exercise in reducing depressive symptoms among cancer survivors: a meta-analysis. mortality in depressed cancer patients (Gallo et al. Stanton AL.0030955. 2012 Jul 3. Cuijpers P. Diefenbach M. Psychological distress and depressive symptoms are typically highest in the first 6 months after cancer diagnosis and then decline over time. even among those who were not depressed at study entry. References: Statements 1-4 1. in particular paroxetine has been shown to be effective in reducing depressive symptoms in breast cancer patients. J Natl Cancer Inst. The occurrence of depression in breast cancer patients is more strongly influenced by psychosocial and physical factors. Spring B. rather than severity of the disease or treatment regimen (Bardwell et al. doi: 10. 2. Kilbourn KM.1371/journal. Mohr DC. Craft LL. even though the occurrence of a major depressive disorder might be lower. PLoS One. 2007).(Therapy Associated) Depression (15/22) Further information: Depression is an often reported adverse event in breast cancer patients. In terms of treatment psychological interventions seem to be most effective distressed patients even though these interventions do not prolong survival. Depressed mood is correlated with fatigue and sleep disturbance in the context of breast cancer. Pescatello LS. Depression negatively affects quality of life and there is also evidence of increased morbidity and. Steel JL. Berendsen M. 2010). 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. .104(13):990-1004. Brown JC. 2012.7(1):e30955. The majority of studies find that 20-30% of breast cancer patients experience elevated depressive episodes (Bower. possibly.1093/jnci/djs256. Huedo-Medina TB. 2008). doi: 10. Meta-analysis of efficacy of interventions for elevated depressive symptoms in adults diagnosed with cancer. 2006). Anderson DR.

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. J Clin Oncol 28: 991-998. doi: 10.1136/bmj. J Clin Oncol 24:2420-2427. Morales KH.3. BMJ. Natarajan L. Dimsdale JE.c4737. Ann Intern Med 146:689-698. 2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. Ameral VE. Zheng Y. 2011 Mar. doi: 10. and Depression Among Breast Cancer Survivors. 5. 26:768-777. Tea Consumption. 8. Eyding D. J Clin Oncol. Lelgemann M. 6.26(2):69-74. Int Clin Psychopharmacol. 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. Chen X. Grouven U. 2008 Gallo JJ. 7. et al: The effect of a primary care practice-based depression intervention on mortality in older adults: A randomized trial. 2010 Oct 12. 2007 Bardwell WA.341:c4737. Iovieno N. 4.1097/YIC. et al: Objective cancer-related variables are not associated with depressive symptoms in women treated for early-stage breast cancer.0b013e328340775e. Tedeschini E. Lu W. 2006 . et al: Exercise. Bogner HR.

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. Among breast cancer survivors who remain disease-free for more than a decade. and estrogen or testosterone reduction. inflammation and cytokine dysregulation. often referred to as chemobrain. 2010). although a subset of patients continued to show deficits for up to 10 years after treatment (Fan 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. among breast cancer patients during and after chemotherapy have been reported in 16 to 75% (Bower et al. 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.E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. 2008. the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes. are there several candidate mechanisms for chemotherapyinduced cognitive changes. Considering adjuvant endocrine treatment.htm R122#R122 Interestingly. The biologic base for these changes is unclear. Vardy et al. Patients rated their own cognitive functions as improved after 6 months. 2010). 2007Stewart et al. quality of life. including direct neurotoxic effects. Other potential treatment approaches include methylphenidate. and standard neuropsychological test performance after treatment and at the 2-month and 6-month follow-ups (Ferguson et al. whereas exemestane use was not associated with statistically significant lower cognitive functioning in postmenopausal patients with breast cancer (Schilder et al. 2007). Cognitive behavioral therapy might lead to significant improvements in self-reported cognitive function. tamoxifen use was associated with statistically significant lower functioning in verbal memory and executive functioning. DNA damage and telomere length. These results again do not support that adjuvant chemotherapy is associated with cognitive side effects in breast cancer patients.(Therapy Associated) Cognitive Impairment (16/22) Further information Reports of cognitive deficits. 2006). neuropsychological tests did not reveal any differences in cognitive function between breast cancer patients after chemotherapy and healthy controls (Debess et al. 2005). However. 2007). In a current study examining 120 breast cancer patients treated with CMF. 2011). behavioral symptoms in breast cancer survivors 2008. 2007). In patients after treatment completion there is improvement in cognitive function over time. as well as genetic polymorphisms (Ahles et al. which has been used to improve cognitive .

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. Breast Cancer Res Treat 121:91-100. . Bielajew C.30(29):3578-87. Faul LA.2011. 2006 3. Beex LV. Lee YH. Engebjerg MC.:Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. 8. J Clin Oncol 28:1294-300. Small BJ. J Clin Oncol 2011 Dec 19. behavioral symptoms in breast cancer survivors 2008. Castellon SA. doi: 10. cerebellar. Collins B. 2007 Ahles TA.1200/JCO.htm . J Clin Oncol 25:2455-2463. 4. 7. Seynaeve C. Nat Rev Cancer 7:192201. 2012 Oct 10. 26:768-777.R110#R110 References: Therapy-related cognitive deficits (chemobrain)… 1.5640. Ewertz M: Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study. 2007 Stewart A.function in patients with advanced cancer. Phillips KM. 2008 Vardy J. 2. Clin Neuropsychol 20:76-89.R130#R130 E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. Deprez S. Dy CJ. Hussin MG. et al: Altered frontocortical. 9. Tannock IF: Evaluation of cognitive function associated with chemotherapy: A review of published studies and recommendations for future research. E:\Dokumente und Einstellungen\ute\Lokale Einstellungen\Temp\Literatur Nebenwirkungen\Bower. Chait S. (Epub ahead of print) Debess J. behavioral symptoms in breast cancer survivors 2008. 2010 Bower JE: Behavioral symptoms in patients with breast cancer and survivors. 2007 Silverman DH. 6.39. Smeets A et al: Longitudinal assessment of chemotherapy induced structural chan ges in cerebral white matter and its correlation with impaired cognitive function. et al: A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. 5. Popa MA. J Clin Oncol. 2010 Schilder CM. Rourke S. Riis JØ. and basal ganglia activity in adjuvanttreated breast cancer survivors 5-10 years after chemotherapy. Saykin AJ: Candidate mechanisms for chemotherapy-induced cognitive changes. Jim HS. Breast Cancer Res Treat 103:303-311. Amant F. Jacobsen PB. J Clin Oncol.htm .

2012 Dec 4.1016. findings.19.: Mindfulness-based stress reduction for breast cancer-a systematic review and meta-analysis.19(5):e343-52.: Chemotherapy and cognitive deficits: mechanisms. Saykin AJ. menopausal symptoms. Lertora JJ. Dobos G. 2. Psychooncology 16:772-777. Curtis R. Fan HG. et al: Cognitive-behavioral management of chemotherapy-related cognitive change.1111/bjhp. Palliat Support Care. Rozans M.5(3):273-80. Ahles TA. J Clin Oncol 20:335-339. Dreisbach A. 3. Roth AJ. 2005 Cognitive-behavioral therapy…. Curr Oncol. 2007 Sep.and 2-year follow-up of a prospective controlled study. 2. 2007 Methylphenidate might improve cognitive function…. doi: 10. and cognitive function in women after adjuvant chemotherapy for breast cancer: 1. 2012 Oct. doi: 10. J Clin Oncol 23:8025-8032. Yi QL. [Epub ahead of print] Cramer H. Lauche R. Groarke A.10. Ferguson RJ. 2002 . et al: Palliative uses of methylphenidate in patients with cancer: A review. et al: Fatigue. 1. Houede-Tchen N. Kerin M.12009. 1.3747/co. Nelson CJ. Nandy N.: Cognitive-behavioural stress management enhances adjustment in women with breast cancer. and potential interventions. Br J Health Psychol. Paul A.

105:75-89 Mouridsen H. Perez EA. 25. References: 1. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG1-98 trial. J Natl Cancer Inst 2011 . Amir E. Verma S. 2.47). Gligorov J. et al: Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer.5%. Ribi K et al. 2008 Jan 15. as well as the occurence of bone fractures (OR=1.Side-effects and Toxicity of Endocrine Agents I (17/22) Further information: In a metaanalysis on 19. 4. while the OR for endometrial carcinoma (OR=0. 5. Cardiovascular safety profiles of aromatase inhibitors. 3. Breast Cahcer Res Treat 126 :221-226. Rabaglio M et al. Breast Cancer Res Treat 2007. JCO 2007. Bria E. (Cuppone F et al 2008) In an actual systematic review and metaanalysis of 30.26) for aromatase inhibitors was confirmed. .112(2):260-7. 103 :1299-1309.34 translating into a minimal risk of 0. 106:1-9 Nabholtz JM.023 patients in 7 trials comparing aromatase inhibitors with tamoxifen. Verma S. 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. Coates AS. Breast Cancer Res Treat 2007. 7. Niraula S et al. 29:785-801. Cancer. 2006. Safety of aromatase inhibitors in the adjuvant setting. Keshavia A. 57155722 Gandhi S. 2011 Cuppone F. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients : asystemtatic review and méta-analysis. Aldridge J.: Aromatase inhibitors and cardiac toxicity: getting to the heart of the matter. 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. 6. Drug Safety.818 pts.55) was significantly lower in comparison to tamoxifen (Amir et al. 2011). Phillips KA. Seruga B.34) and venous thrombosis (OR=0. the increased risk for developing cardiovascular disease (OR=1.

2006. 33(6):688-95. Morris GJ. Pandya N. . Semin Oncol. Toxicity of aromatase inhibitors.8.

Wolmark N. 2010).1002/14651858. randomised trial.2:CD003474. Epub 2012 Jun 14.0%.19(5):259-68. denosumab.4%. Falkson CI. Gralow JR. Cochrane Database Syst Rev.3747/co. Wong MH. 2012 Jul. Osteonecrosis of the jaw occurred infrequently (2. Lembersky BC. Mamounas EP. Dakhil S. Pavlakis N. Perez EA.39) (Stopeck et al. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid. Lancet Oncol. zoledronic acid. Pritchard KI. the routine use of bisphosphonates as adjuvant treatment for patients with early breast cancer is not recommended (Paterson et al 2012. doi: 10. Baez-Diaz L. with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. 2011). placebo-controlled. Anderson SJ. 1.13(7):734-42.67% (RR= 1. 2012 Feb 15.: Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art. doi: 10. P = . 2012 Oct. Robidoux A.: Bisphosphonates and other bone agents for breast cancer. that bisphosphonates might have anticancer benefits for older postmenopausal women. Weir LM. Costantino JP. Stockler MR. In terms of toxicity rates of adverse events (AEs) and serious AEs were similar between groups.1011.61) (Van den Wyngaert et al. Curr Oncol. King KM. Geyer CE Jr. Zheng P. Lad T. Swain SM. Paterson AH. Bisphosphonates. Wong et al 2012). . Clemons M.: Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre. Denosumab) (18/22) Further information: A recently published randomized study compared denosumab.pub3. doi: 10. 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.Side-Effects and Toxicity – of Bone Modyfing Agents (BMA. Gelmon KA.CD003474.1016/S1470-2045(12)70226-7.19. Brufsky AM. Fehrenbacher L. hypocalcemia occurred more frequently with denosumab. 2. a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand. Paterson AH. Although there amounting data. 3. References: 1.

1093/jnci/djq516 Vahtsevanos K. et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Bergner R. 2007 Pavlakis N. Grötz KA. Lipton A. J Support Oncol. 2010 doi: 10. 5. Diel IJ. Huizing MT et al. 2. Bisphosphonates for breast cancer. 2010 Pazianas M: Osteonecrosis of the Jaw and the Role of Macrophages. 2009 Acute phase rea Gastrointestinal side effects… 1. Schmidt R. 19:2035-40. J Clin Oncol 28: 5132-5139. 7. et al.4. Verrou E. Wouterds K. Kyrgidis A. J Clin Oncol 27: 5356-5362. 5:475-482. RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem? Support Cancer Care. Stockler R. Stopeck AT. J Natl Cancer Inst. Cochrane Database Syst Rev 2005 Jul 20:CD003474 . Body JJ. double-blind study. Adverse effects of bisphosphonates: current issues. Van den Wyngaert T. 2011. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized. 6.

95% CI.9% in patients with multiple myeloma.56) were associated with increased risk for ONJ development.621 patients who received 29. 95% CI. 3. patients should have a comprehensive dental examination. 18. and each zoledronate dose (aOR = 2. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication. and 4. Sivakumar T.5%.74 to 137.4103/0973-029X. Multivariate analysis demonstrated that use of dentures (aOR = 2. Verrou E. et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Patients with breast cancer demonstrated a reduced risk for ONJ development. J Clin Oncol 27: 5356-5362. doi: 10. Nair BJ. which turned out to be non-significant after adjustment for other variables. Smoking. and prostate cancer. 95% CI. Joseph AP: Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: A systematic review. 95% CI. References: 1.43).6%.94% to 18. 2009 . Vahtsevanos K. 5.1%.98893.Recommendations for Precautions to Prevent ONJ (19/22) Further information: The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0. In conclusion.15 to 3. 2012 May. Kyrgidis A.02 to 60. having ever received zoledronate (aOR = 28. history of dental extraction (aOR = 32.02. 2.02. periodontitis.03 to 3.97.31). Before initiation of a bisphosphonate.16(2):210-4. given monthly reported an crude ONJ incidence of 8. and root canal treatment did not increase risk for ONJ in patients receiving BP. 1. 1. A study with 1. Varun B.09. randomized controlled trials are needed to validate these results. however. validated dental extractions and use of dentures are risk factors for ONJ development. respectively. J Oral Maxillofac Pathol.96).006 intravenous doses of BP. breast cancer.

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% v 0. a low ejection fraction at the start of paclitaxel treatment. of these 59 patients. though it was higher in the trastuzumab group than in the observation group (severe CHF.1% of trastuzumab-treated patients with symptomatic heart failure events after cessation of trastuzumab. In the NSABP B-31. TIC occurred more frequent in patients with troponin elevation (TNI+.1%). The incidence of cardiac end points remains low even after longer-term follow-up and the majority of cardiac events resolved (Procter et al. 2010).Key-Toxicities Antibodies/Antibody-drug-conjugates – Small Molecules (21/22) and (22/22) Further information: In the HERA trial. 0. The majority of these patients recover with appropriate treatment (Russell et al. P < . 2010). and trastuzumab treatment. 59 of 73 patients with a cardiac end point reached acute recovery. Independent predictors for cardiac events were age older than 50 years. 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. Complete or partial recovery was observed in 86. All of these events in the combination-therapy group were considered to be related to treatment. 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. 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.6 years. and all women had an LVEF value that was at or above the lower limit of the normal range on subsequent assessment.0% incidence of symptomatic heart failure events compared with 0.0%. confirmed significant LVEF decreases.45% in the chemotherapy-alone arm.8% v 0.001).and NCCTG 9831-trial trastuzumab-treated patients had a 2. . 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point. Troponin increase identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy. At a median follow-up of 3. the incidence of cardiac end points remained low. 62% v 5%.6%) In the trastuzumab group. TNI was measured before and after each trastuzumab cycle. Thus. 3.

1. J Clin Oncol 28: 3416-3421. Alba E. Eiermann W. Lawrence J.07).68). Blackwell KL. Expert. Most adverse events were grade 1. N Engl J Med 365:1273-1283. 5. 4. 2. 2010 Russell SD.25) and hemorrhagic events (OR=4. the hand–foot syndrome. Garcia-Saenz JA. 3. Suter TM. and rash that was distinct from the hand–foot syndrome. and dizziness was reported in the monotherapy group.76). Abraham J: Biological mechanisms of bevacizumab-associated adverse events. Esteva FJ. Sengupta P. Oncologist 2009. J Clin Oncol 28: 3422-3428. vascular or fatal events and febrile neutropenia. 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. Khandheria B. Diarrhea. or 3. and rash occurred more often in the group of women who received combination therapy. 2. fatigue. de Azambuja. One case each of grade 4 fatigue.The most common adverse events were diarrhea. 2010 Higa GM. headache. Slamon D.14:1–11 . Robert N et al: Adjuvant trastuzumab in Her2-positive breast cancer. left ventricular dysfunction (OR=2. Zamorano J: Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations. respectively References Cardiotoxicity…. dyspepsia. Rev Anticancer Ther 2009. 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. vomiting. 2011 Procter M. hypertension (OR=12. Grade 4 diarrhea occurred in two women in the combination-therapy group (1%). while no increased incidence was found for gastrointestinal perforation. nausea. Perez-Isla L.9:999–1007 Martin M. et al: Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. Marquez A.

Langer B. 2011 Blowers E. Thomssen C. 58 Miller K. Untch M. Hall K: Managing adverse events in the use of bevacizumab and chemotherapy. Reichardt P. 4. Ebert A. 2011 (Epub ahead of print) Hamilton EP. Oncology 80:314-325. 2010 Bevacizumab …. Ramirez-Merino N et al: Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a metanalysis. Blackwell KL: Safety of Bevacizumab in patients with metastatic breast cancer. Eidtmann H. Emons G. 1. Wang M. 2. 2011 Von Minckwitz G. Loibl S et al:Integrating bevacizumab. and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer. Biodrugs. Lacouture ME. Cardinale D. 2. Muscholl M. 2007 Lapatinib… 1. 2011 . N Engl J Med 357: 2666-2676. Harbeck N.Safety results of the GeparQuinto trial. Curr Opin Oncol 23:343-351. Boura P et al: Bevacizumab-induced hypertension. et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. Colombo A. Anadkat MJ: Prphylaxs and treatment of dermatologic adverse events from epidermal growth factor receptor inhibitors. J Clin Oncol 28: 3910-3916. 2011 Syrigos KN. 3. Torrisi R. Eur J Cancer 2004. et al: Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. du Bois A. 40:988–97 Troponin I…. Br J Nurs 2009.6. Heilman V. Wu PA. 6. Balagula Y. everolimus. Gralow J. Calvo V. Hoffken K. Annals of Oncology Oct. Cortes J. 25:159-169. Blohmer JU. Ann Oncol 22:301-306. Meerpohl HG. Kuhn W. Luck HJ: Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. Jackisch C. Wallwiener D. Pauschinger M.18:351– 6. 5. Eidtmann H. Wiese W. Karapanagiotu E.

Fang L. Wu S. Oncologist 15:944-953. Baselga J. 2012 Nov 8. 4. Miles D. Guardino E. Trastuzumab emtansine for HER2-positive advanced breast cancer. 2006 Pertuzumab 1. Welslau M.135(2):347-54. 2. 366:109-119 T-DM1 1. Breast Cancer Res Treat. Krop IE. Cortes J. 5. Forster J. 2012 Sep. et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2012. Amonkar MM. Oncologist 15:924-934. Sherill B. Everolimus: 1. Dang CT. Verma S.367(19):1783-91. Lu MW.366: 520-529 . Kim S-B et al. 2010 Cameron D. 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.: Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis. Casey M. Olsen S. N Engl J Med. Baselga J. Everolimus in postmenopausal hormone receptor positive advanced breast cancer. N Engl J Med 355:2733-2743. Olica C et al: Lapatinib plus capecitabine in women with Her2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. 2010 Geyer CE. Oh DY. Pegram M. Blackwell K. Gianni L. N Engl J Med 2012. Pertuzumab plus Trastuzumab plus Docetaxel for metastatic breast cancer. EMILIA Study Group. Lindquist D. Baselga J. Drucker AM. Rugo H et al. Diéras V. Campone M. Lacouture ME.3.

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

V. sowie in der DKG 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.1 www. Guidelines Breast Version 2015. in der DGGG e.ago-online.Supportive Care © AGO e.V.

6. in der DGGG e.7.Guideline Spectrum © AGO e.de“ In preparation: multidisciplinary guidelines of the AWMF: „Supportive Therapie bei onkologischen Patientinnen .2012.2015 . announced 1. sowie in der DKG e. planned release: 30.V.V.ago-online. Rehabilitation und Sozialmedizin der DKG: http://www. V.de In the German environment.onkosupport. Guidelines Breast Version 2015. but underline that the listings of relevant guidelines do not claim to be complete. The listing is clearly biased towards German and English language Special emphasis is put on aspects concerning breast cancer patients www. special interest is earnt by the publications of the „Arbeitsgem.interdisziplinäre Querschnittsleitlinie“. Supportive Maßnahmen in der Onkologie.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.

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 + -+ + . sowie in der DKG e.V. Guidelines Breast Version 2015. V.V.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. in der DGGG e.1 www.ago-online.Erythropoiesis-stimulating agents (ESAs) © AGO Oxford / AGO LoE / GR e.

Practical Use of ESAs © AGO Oxford / AGO LoE / GR e. or 40.c. or 120. in der DGGG e.1  Epoetin α and Darbepoetin are equieffective 1b A ++ 1a A ++ 1b B +  Darbepoetin: 2. Guidelines Breast Version 2015.c.c.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 .000 IU q2w s. www.V.V.c.000 IU q3w s. weekly 1b A ++  Darbepoetin: 500 µg s.c.c. V. sowie in der DKG e.o.ago-online.  Epoetin α: 80.25 µg/kg s. 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.000 IU 1 x /week s. q3w 1b A ++  In case of FID give IV iron supplementation 1a B +  p.

V. Guidelines Breast Version 2015. sowie in der DKG e.de  Rodgers GM.1 www.and chemotherapy-induced anemia. 28: 4996–10 .org  Rizzo JD et al: ASCO/ASH/Clinical Practice Guideline update on the use of epoetin and darbepoetin in adult patients with cancer. in der DGGG e.ago-online. Available from: URL: http://www. J Clin Oncol 2010.V.nccn.2015. NCCN Clinical Practice Guidelines in Oncology 2.Relevant Guidelines © AGO e.V. Gilreath JA et al: Cancer.

V. according to NCCN Guidelines) with www.de * High risk definition: estimated duration of neutropenia < 100/µl > 7d . V..Prophylaxis of Infections NB Rarely Applicable to Patients with Solid Tumors (e.g.ago-online. sowie in der DKG e. BC) ASCO Practice Guideline „Antimicrobial Prophylaxis.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. Guidelines Breast Version 2015. in der DGGG e..“ 2013 © AGO Oxford / AGO LoE / GR e.

V.ago-online.V. FN risk ≥20% FN risk 10-20% FN risk <10% Guidelines Breast Version 2015. V.EORTC and ASCO G-CSF Guideline-Based FN Risk Assessment Step 1: Assess frequency of FN associated with the planned chemotherapy regimen © AGO e.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. 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 . in der DGGG e.1 Step 2: Assess factors that may increase the risk of FN: www. sowie in der DKG e.

sowie in der DKG e.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.ago-online.1 www. J Clin Oncol 31: 794-810. Guidelines Breast Version 2015.V. V. 2013 . in der DGGG e.V.Relevant Guidelines © AGO e.

Local therapy with crystal violet solution 0. 5%) mouth rinsing. fluconazole  Local antiviral treatment Aminoquinuride / tetracaine-HCl . etheric oils. polyvidon-iodine. hexetidine.V. sowie in der DKG e. extracts of camomile.pdf © AGO e.V. nystatine.Mucositis Mucositis http://www. Dexpanthenole (Panthenol®-Solution. mometasonfuroate + propylene glycol  Mucosa protecting measures (during / after application of chemotherapy): Sucking ice cubes (especially from pineapple juice) during 5fluorouracile. in der DGGG e.or HD-melphalane. H.5% or tinctura myrrhei. Aciclovir®  Local anaesthesia: Benzocaine PO . Guidelines Breast Version 2015. 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!).1 www. V.  Local antimycotic treatment: Amphotericine B.ago-online.mascc.org/assets/documents/MukositisGuidelinesMASCC2006(dtV).de  Desinfecting / antiphlogistic measures: Mouth rinsing with infusions of camomile or salvia.

V.V.de  Start related to chemotherapy and duration .Granulocyte Colony-stimulating Factors © AGO Oxford / AGO LoE / GR e.g. sowie in der DKG e. DAC. dose-dense CT) www. in der DGGG e.ago-online. Guidelines Breast Version 2015.1  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.

J Clin Oncol 24:3187-3205. V.Relevant Guidelines © AGO e.ago-online.V. 2006 Crawford et al: Hematopoietic growth factors.1 www. in der DGGG e. 2010 . 2013 Smith et al: 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors. Ann Oncol 21 (suppl 5): v248v251. sowie in der DKG e.de Crawford et al: Myeloid Growth Factors. Guidelines Breast Version 2015. J Natl Compr Canc Netw:1266-1290.V.

Guidelines Breast Version 2015.V. Link et al: erstellt 04/07) Definition (oral temperature of >38.f.1 www. in der DGGG e.dgho-infektionen.V.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) . (DGHO) www.Management of Febrile Neutropenia c. sowie in der DKG e. Recommendations by Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. V.de (H.ago-online.5°C or two consecutive readings of >38°C © AGO e.V.

V.de regularly issues such recommendations in German.V.ago-online. V.de Recommendations need to be regularly updated according to the changes in microbial sensitivity and resistance towards antiinfective treatments.V. Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. sowie in der DKG e. (DGHO) www.dgho-infektionen. in der DGGG e. Guidelines Breast Version 2015. .1 www.Calculated Antibiotic Therapy in FN © AGO e.

in der DGGG e.de .onkosupport.pdf Oxford / AGO LoE / GR  Treatment of anthracycline extravasation 2b B ++ 5 D ++  In cardiac risk patients  Consider alternative regimens (anthracycline-free. liposomal) www.V. Guidelines Breast Version 2015.1 http://www. sowie in der DKG e. V.ago-online.Dexrazoxane © AGO e.de/e974/e2538/e3782/e3494/ ASORS_AV_Paravasate-Guidelines_04-2010.V.

1000 mg). alternatively: 24 h continuous ice cooling 2. 2000 mg). 2000 mg). for at least 3 days. V. Local application (with swab) of dimethylsulfoxid 99% (DMSO) every 3-4 hours for at least 3 days (better 14 days). IV 1–2 hrs Day 2: 1000 mg/m² (max. in der DGGG e. .V.V. following measures are recommended 1. Local cooling: ice packs for 15 min every 6 hrs. The interval may be extended to 6 hours from day 4 onward.ago-online. Guidelines Breast Version 2015.1 www. IV 1–2 hrs Otherwise or if treatment with dexrazoxane is not indicated. allow it to dry on air. IV 1–2 hrs Day 3: 500 mg/m² (max.de Day 1: 1000 mg/m² (max.Paravasation Dexrazoxane © AGO e. sowie in der DKG e.

in der DGGG e.V.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 + .mascc.Antiemetic Therapy http://www. Oxford / AGO LoE / GR Guidelines Breast Version 2015.V.org/antiemetic-guidelines www. V.1 www.ago-online.de © AGO e.onkosupport. sowie in der DKG e.

o.de Phenothiazine/ bis zu 300 mg i. Keine Kombination mit Astemizol. Diarrhoe.v. transiente Leberwerterhöhung mäßig Dexamethason 8-20 mg i. Depressionen. psychotische Reaktionen. Tropisetron Granisetron Palonosetron Guidelines Breast Version 2015. Flushsymptomatik Transaminasenanstieg Darmatonie in hoher Dosierung sehr hoch Aprepitant 125 mg d1. 0.v.v.V. Wirkstoffgruppe Substanz Dosierung Nebenwirkungen Potenzial Serotoninantagonisten Ondansetron 8 mg i. 6 Tbl.. 2 x 4-8 mg p. Terfenadin. Cisaprid Metoclopramid bis zu 120 mg/24h als Dauerinfusion od.o. 1-3 x/d Blutzuckerentgleisung.1 NK 1-Antagonisten Dopaminantagonisten/ substituierte Benzamide Alizaprid www.transdermal 5 mg i..v. sehr hoch Fosaprepitant 150 mg d1 i.) NEPA (Netupitant and Palonosetron) Angstreaktion. 1-3 mg i. od. Flush. Senkung der Krampfschwelle.o.v. 25 mg i. 5 mg p. Blutdruckanstieg fixe Kombinationsp artner (oral) NE 300 mg PA 0. Cytochrom-P-450Aktivierung mit Dosisreduktion von Dexamethason (2 x 8 mg). Kopfschmerzen. Diarrhoe Haloperidol 1-3 mg 4 x/d Sedation.ago-online./24 h ( 6 Amp.v.V. 1-3 x/d mäßig Prednisolon 100-250 mg i.v.v.Supportive Therapy Antiemetics © AGO e. V. als Tropfen Dyskinesien hoch in der DGGG e. 80 mg d 2-3 p. oder p. sowie in der DKG e.o.5 mg Butyrophenone Corticosteroide (Antidot:Biperiden) sehr hoch .

pregabaline. WHO Step 1 Diclofenac resinate.dgs-praxisleitlinien. in der DGGG e. The dose of opioids should be titrated step by step according to the analgetic effect. fentanyle (transdermal). V. Guidelines Breast Version 2015. as back-up levomethadone. carbamazepine.de) © AGO e. sowie in der DKG e.1 Non-opioids. buprenorphine (sublingual or transdermal). WHO Step 3 www.V. Additional drugs – „adjuvants“ Gabapentine. amitriptyline. paracetamole Mild opioids. bisphosphonats . WHO Step 2 Tramadol (preferentially „retard“-formulations) or tilidine / naloxone (also as „retard“-formulations) Strong opioids. ibuprofene and / or metamizole.Analgesia (Deutsche Gesellschaft für Schmerztherapie Praxisleitlinie Tumorschmerz 2014 www.de Morphine.ago-online. hydromorphone. oxycodone.V.

V. Guidelines Breast Version 2015.ago-online. Al-Mgsilicate hydrate Analgetics. in der DGGG e. sowie in der DKG e.1 www. V.V. tinctura opii. opioids  Loperamide. codeine. caoline / pectine.de Adsorbent agents  Carbo medicinalis.Diarrhea Diarrhea © AGO e. morphine IV. butylscopolamine Colitis pseudomembranosa  Metronidazols or (if not effective) vancomycine .

1  Psylium. sodium amidotrizoate  Sorbite Motility stimulating laxatives www. V.V. Bisacodyl. sowie in der DKG e. paraffin) Opioid-receptor-antagonists (in opioid-related constipation)  Methylnaltrexone .V.g. Ricinus.Constipation Constipation Important Side Effect of Opioid Treatment Swelling agents © AGO e. sodium-picosulfate Emollients (Internal lubricants e.de  Sennae.ago-online. in der DGGG e. AGO +)  Oral radio-opaque material: ultima ratio e.g. Guidelines Breast Version 2015. flaxseed (shredded) Osmotic laxatives  Macrogol > Lactulose (Cochrane review LoE 1a.

1 www. including effective control of pain and other symptoms.”3 1 Smith et al.Palliative Care © AGO e. in der DGGG e.ago-online. J Clin Oncol 30 880-887. 2012 3Cardoso et al.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. Guidelines Breast Version 2015. should be a priority.”2  “Expert palliative care. Breast 21:242-252. sowie in der DKG e.V. 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. V.V. 2012 et al. J Natl Compr Canc Netw 10:1284-1309.

Supportive Care (2/ 22) No further information No references .

In the German environment. Rehabilitation und Sozialmedizin der DKG: http://www.2012. special interest is earnt by the publications of Arbeitsgem.7.6. planned release: 30. The listing is clearly biased towards German and English language. announced 1.de In preparation: multidisciplinary guideline of the AWMF: „Supportive Therapie bei onkologischen PatientInnen interdisziplinäre Querschnittsleitlinie“.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. Supportive Maßnahmen in der Onkologie . Special emphasis is put on aspects concerning breast cancer patients.2015 No references . but underline that the listings of relevant guidelines do not claim to be complete.onkosupport.

Whether and how ESAs affects tumour control remains uncertain. 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. extracting data from a total of 91 trials with 20. (b) treatment with ESAs should be stopped when chemotherapy ends. updated in November 2007..Erythropoesis-Stimulating Agents (ESAs) (4/22) Further information: Prior to 2007. and (b) describe patterns of ESA treatment subsequent to the first ESA administration at Hb above 12 gm per dL. 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 the FDA mandated further label changes on July 30. 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. More data are needed for the effect of these drugs on quality of life and tumour progression. 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. . In March 2007. and treatment was to be withheld if Hb exceeded 13 gm per dL. 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. lymphoid. 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). cervical. In 2012 a Cochrane review was published by Tonia et al. 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. concluding that ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths.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. although many patients did not reach that level. the FDA changed the labeling of the ESAs to add boxed warnings. In January 2008. head and neck. 2008. There is suggestive evidence that ESAs may improve QoL. and non-small cell lung malignancies. that ESA therapy should not be initiated in patients receiving chemotherapy at Hb levels of 10 gm per dL or higher.

2009 Sep.accessdata. Urban N. Rovati B. Bohlius J.31P2:2416-2432. Maintaining normal hemoglobin . McBride R. Am J Health Syst Pharm.gov/drugsatfda_docs/label/2010/103234s5199lbl. :Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: A descriptive study of a large outpatient oncology practice database. 2009 Dec 2.PMID: 19535656 [PubMed .CD003407. Aravind S. Neugut AI. Hyde C. Tonia T. Voznyi E. Martin A. Issue 12. http://www. 2009 Jul 1. Valliant-Saunders K. Roth A. No. Dodwell D.:Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Pawlicki M. Henke M. Kaiser JF. Epub 2009 Nov 10.66(13):1180-5. 2000-2007.PMID: 19903808 [PubMed . Grasso D.: CD003407. Erythropoi. DeSantis ER. Vercammen E. Weingart O. DeSantis ER.indexed for MEDLINE] Manzoni M. 2009. Am J Health Syst Pharm. Danova M. Blau CA. Cochrane Database of Systematic Reviews 2012. :Use of erythropoietin-stimulating agents in breast cancer patients: a risk review. 7. J Natl Cancer Inst. 2.Clin Exp Med.101(23):1633-41.fda. Manikhas G. Valuckas K. Stem Cells. Malin J. Mettler A. Pienkowski T. Schwarzer G.pdf PREPARE-Studie. Mattern D. Tjulandin S. Further references: Statement: An increased mortality and tumor progression by the use of ESF can not be safely ruled out 1.pub5. Buono DL. 3. Semiglazov V.Use of erythropoietin-stimulating agents in breast cancer patients: a risk review. Tsai WY.:Chemotherapyinduced anemia in breast cancer patients treated with pegfilgrastim-supported dose-dense regimens. Baselga J. DOI: 10. Review.1002/14651858. Liu X. Biakhov M. 6. Nalysnyk L. 2. 2009 Oct 10. 5. Bencardino K.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116830. Ranganathan G. Art. 4.References: 1.htm Leyland-Jones B.as supplied by publisher] Miller CP. Lowe KA. Delfanti S. [Epub ahead of print]PMID: 19821012 [PubMed . Tinelli C.27(9):2353-61.fda. Mariucci S. Makhson A. Wu Y.etin or darbepoetin for patients with cancer. Engert A. Crouch Z. Crouch Z. http://www. 2009 Jul 1. 3. Seidenfeld J. Robert N.66(13):1180-5. Clin Ther.:Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer.indexed for MEDLINE] Hershman DL.

NCCN Clinical Practice Guidelines in Oncology 2011 Available from: URL: http://www. Oncologist 2008. Somerfield MR.org 4. 2005 Sep 1. Rizzo JD. J Clin Oncol 2010. 5. 13 (suppl 3): 33–6. J Oncol Pract. 3. Hurley P. Rizzo JD et al: ASCO/ASH/clinical practise guideline/epoetin and darbepoetin/adult patients with cancer.000132.6(6):317-20.2010. doi: 10.23(25):5960-72 Relevant Guidelines: 1. Seidenfeld J. Temin S. 2010 Nov. Aktualisierung 2012 in Vorbereitung Rodgers GM: Cancer. . 28: 4996–10 Aapro MS.and chemotherapy-induced anemia. Link H: Update 09/2007/EORTC guidelines/anemia management/erythro-poiesisstimulating agents.levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. 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. J Clin Oncol. Brouwers M.nccn. 2.1200/JOP.

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. 28: 4996–10 . Rizzo JD et al: ASCO/ASH/clinical practise guideline/epoetin and darbepoetin/adult patients with cancer. J Clin Oncol 2010. References: 1.

Relevant guidelines (6/22) No further information 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. 28: 4996–10 . Rodgers GM und Gilieath JA: Cancer.and chemotherapy-induced anemia. J Clin Oncol 2010. NCCN Clinical Practice Guidelines in Oncology 2013 Available from: URL: http://www.nccn. 2.

Recent evidence has demonstrated non-significant but consistent. leading to an overall reduction in total infections. unless other factors increase risks for complications or mortality to similar levels. 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. neutropenic diet.Prophylaxis of Infection (7/22) Further information: According to relevant guidelines. (ASCO absolute neutrophil count < 100/µl > 7days) N.: Standard chemotherapy protocols such as used in breast cancer patients do not regularly justify antibiotic prophylaxis. Interventions such as footwear exchange. respiratory or surgical masks. protected environments. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. An oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis. Lau J. The guideline encourages the use of myeloid growth factor prophylaxis to render antimicrobial prophylaxis unnecessary. the consensus was that this evidence was not strong enough to recommend prophylaxis. that chemotherapy for solid tumors rarely leads to the mentioned conditions.21. or nutritional supplements are not recommended because evidence is lacking of clinical benefits to patients from their use . 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). 0. The authors clearly state.37). 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. fluoroquinolone prophylaxis significantly reduced the incidence of Gram-negative infections by about 80% compared with those without prophylaxis (relative risk=0.12-0. Engels EA. Barza M.B.16:1179-1187: In a meta-analysis that evaluated 18 trials (N=1408) in which fluoroquinolones were compared to either placebo or TMP/SMX. 95% CI. However. improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. J Clin Oncol 1998.

Ritchie DS. Bucaneve G. Bow.353:977-987. Wei A. Use of antibacterial prophylaxis for patients with neutropenia.org/cgi/doi/10. Cain MJ.1200/JCO. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis.2012. Lau J. 2. Prophylactic antimicrobial agents and the importance of fitness. Lingaratnam S. J Clin Oncol 1998.8661 published ahead of Print on January 14.. N Engl JMed 2005. Baden LR. Nicole M. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. Intern Med J. Mileshkin L. Hawley. et. 3.45.353:988-998. Flowers.16:1179-1187 Slavin MA. Thursky KA. Micozzi A. Relevant Guidelines Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. 4. and Scott D. Engels EA. Douglas K. Cullen M. Amelia A.45. Christopher R.I.“ 2013 The latest version is at http://jco. Ramsey ASCO Practice Guideline „Antimicrobial Prophylaxis. Barza M. Billingham SN. et. Clare Karten.8661 .1200/JCO.353:1052-1054. Booth DL. Kieren A. al. Australian Consensus Guidelines 2011 Steering Committee. 2011 Jan. Charise Gleason.2012. Marr. Rolston. 5. Langston. Jerome Seidenfeld. Australian Consensus Guidelines 2011 Steering Committee. Eric J.41(1b):102-9. N Engl J Med2005. al.References: 1. Kuderer. Gaunt C.ascopubs. Menichetti F. 2013 as 10. N Engl J Med 2005. Kenneth V.. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas.

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.Relevant guidelines (9/22) No further information References 1. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. 2013 .

“ References: Relevant Guidelines http://www. Diagnostik. Die Pathogenese der Mukositis ist nicht vollständig geklärt.pdf .Mucositis (10/22) Further information: „Mukositis kann als schwere und dosislimitierende Nebenwirkung bei Chemotherapie und Strahlentherapie von Malignomen auftreten. 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. Außerdem stellt die Mukositis bei neutropenischen Patienten einen zusätzlichen Risikofaktor für eine Sepsis dar. Therapie und Prophylaxe werden bisher nicht standardisiert durchgeführt und sind hauptsächlich auf die Symptomkontrolle ausgerichtet.org/assets/documents/MukositisGuidelinesMASCC2006(dtV). sondern sie beeinträchtigt auch erheblich die Lebensqualität der Patienten.mascc.

a Cochrane review sought to assess the effect of prophylactic colony-stimulating factors (CSFs) in reducing the incidence and duration of FN. is the most serious manifestation of neutropenia usually requiring hospitalization and intravenous antibiotics. A recent study demonstrated in high risk breast cancer that 6 mg lipegfilgrastim. was as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. There is evidence. of a decrease of all-cause mortality during chemotherapy and a reduced need for hospital care. In 2012. severe neutropenia accompanied by fever. CSFs have shown evidence of benefit in the prevention of FN. though less reliable. so called „febrile neutropenia (FN)“. No reliable evidence was found for a reduction of infection-related mortality. . In clinical practice. and all-cause and infection-related mortality during chemotherapy in patients with breast cancer. Furthermore. a novel glyco-pegylated granulocytecolony stimulating factor. The authors concluded that „In patients with breast cancer receiving chemotherapy. 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. pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis. a higher dose intensity of chemotherapy with CSFs or diminished rates of severe neutropenia and infections. Without stringent management FN is associated with significant morbidity and mortality.“ In a comparative effectiveness study. 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. neutropenic events are the main limiting factors towards achieving this aim.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.

4. BMC Cancer. multicenter. Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized. doi: 10. Pisconti S. 8.References: 1. Silvestris N. Grasso D. Colucci G. Epub 2012 Mar 23. Azzariti A.2011. Danesi R. Roberts RD. Milazzo S. 2008 Jan.16 Suppl 2:S111-7. Issue 10.69(5):2133-40. doi: 10. 2009 Oct 10. Chia V. Del Re M. Deeter R. 5. Ashley S. Tinelli C. Curry JM. Nuovo GJ. Delfanti S.13(1):386. Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines. Buchner A.1186/1471-2407-13-11. Badre S. Impact of neutropenia on delivering planned chemotherapy for solid tumours. Becker L. Dhadda A. Khan M. Sundar S. active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy. Cochrane Database of Systematic Reviews 2012. 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). Sutherland S. Eur J Cancer Care (Engl). Arnedos M. Danova M.17(1):19-25. Cinieri S. DOI: 10. Horneber M.13:11. Bencardino K. Li X. 6. Gladkov OA.:Chemotherapyinduced anemia in breast cancer patients treated with pegfilgrastim-supported dose-dense regimens. Lombardi L. Bias P. [Epub ahead of print] Naeim A. 2013 Aug 14.: CD007913. Kuppusamy P. 2.112(1):1-4.as supplied by publisher] Khan S. [Epub ahead of print]PMID: 19821012 [PubMed . Cancer Res. 2013 Jan 8. Guarini A. Bondarenko I. Liu JP. Mariucci S.652089.Expert Opin Ther Targets. 3. Marsh CB. Maiello E. Delcuratolo S. Smith I. 2009 Mar 1.pub2. .1002/14651858. 2008 Nov. Breast Cancer Res Treat.1517/14728222. Brunetti AE. Renner P. 2012 Apr. Epub 2007 Dec 1. Routine prophylactic granulocyte colony stimulating factor (GCSF) is not necessary with accelerated (dose dense) paclitaxel for early breast cancer.Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages.CD007913. Fyfe D. Elaesser R. Zwahlen M. BMC Cancer. Art. Eubank TD. De Vita F. No. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. Henk HJ. 7. Manzoni M. Birkmann J. Rovati B.Clin Exp Med. Epub 2009 Feb 17.

Eur J Cancer. Stimulation der Granulopoese mit G-CSF Kurzgefasste interdisziplinäre Leitlinie 2008 der Deutschen Krebsgesellschaft.157:145-65. Charles L. Christopher E. European Organisation for Research and Treatment of Cancer. Aapro MS. Jeffrey Crawford. Cameron DA. George Somlo. Donnelly JP. Winn. Wade. Kearney N. Rodger J. Lyman GH. Howard Ozer. Cross. Antoinette J.org/professionals/physician_gls/pdf/myeloid_growth. Lodovico Balducci.de/download/ll_o_04.nccn. Somerfield. http://www. James C. Bohlius J. Wade. Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. 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. Lyman.Relevant Guidelines: ASCO: Thomas J. George Demetri. Pettengell R. Gary H. http://www. ASORS erstellt wurde. Mark R. James Khatcheressian. Smith (Chair). Scott B. James L. Lee Schwartzberg. Pizzo. and Antonio C. Armitage.pdf . 2011 Jan. Kleiner JM.pdf Lyman GH. 2011. Scott J. Cantor.krebsgesellschaft. Charles A. Schiffer. Wozniak.2012 Panel Members Myeloid Growth Factors.47(1):832. die unter der Veranwortung der ASO bzw. Weber DC. Zielinski C. 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. James O. Tjan-Heijnen VC. Walewski J. Desch. Bennett. Dal Lago L. Cancer Treat Res. Philip A.

J Clin Oncol 24:3187-3205. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors. Myeloid Growth Factors. 2010 . Crawford et al. 2013 Smith et al. 3. 2006 Crawford et al. Hematopoietic growth factors. J Natl Compr Canc Netw:1266-1290.Relevant guidelines (12/22) No further information References: 1. Ann Oncol 21 (suppl 5): v248-v251. 2.

2011 Oct 20. Clark JA. Gill FA.analysis of randomized controlled trials. 5.Management of Febrile Neutropenia (13/22) Further information: The most important treatment aspect is to initiate calculated antibiotic treatment as soon as possible.J Clin Oncol No place like home? Outpatient management of patients with febrile neutropenia and low risk. Loggers ET. 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.29(30):3952-4. Yeap BY. Fraser A. Feasibility of outpatient management of fever in cancer patients with low-risk neutropenia: results of a prospective randomized trial. Khan WA. Witebsky FG. Karim M.“ References: 1. Robichaud KJ. Malik IA. but reduces the amount of time spent in hospital and the neutrophil recovery period.72:101-111. 4. et al. Talcott JA.98:224-231. It was not clear whether CSF has an effect on infection-related mortality. but no later than 2 hours after onset of fever. J Antimicrob Chemother 2006. Yahav D.. that „ the use of CSF in patients with febrile neutropenia due to cancer chemotherapy does not affect overall mortality.29(30):397783 Freifeld AG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. 2. Lu C. 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. Paul M. Leibovici L. Siegel RD. After inclusion of 13 studies the authors concluded. Am J Med 1982. according to updated guidelines.57:176-189 Pizzo PA. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta. Sepkowitz KA. Godley PA. Am J Med 1995. . 3. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011 Oct 20.

Relevant Guidelines: ASCO: Thomas J. George Demetri. Lyman G.V. Armitage. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Antoinette J. Pizzo. de Naurois J. Schiffer.org/professionals/physician_gls/pdf/myeloid_growth. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Charles L. Wozniak. Charles A. James L. Cantor. and Antonio C. Ann Oncol 2010. DOI: 10.21(Suppl 5):v252-6 Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. Novitzky-Basso I. Mark R. Gary H. http://www. et al. Wade. Art. Link et al: erstellt 04/07) .CD003039. Jeffrey Crawford.nccn.6. 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. Scott J. No. Djulbegovic B. 7. Issue 4. Gill MJ. Howard Ozer. Somerfield. Lyman. .de (H. George Somlo. James C. Rodger J. Philip A. Lee Schwartzberg. et al. Smith (Chair). Clark LGO. (DGHO) www. Wade. Cochrane Database of Systematic Reviews 2000. Scott B. Castro AA. James O. Desch. Ann Oncol 2010. Novitzky-Basso I. Colony stimulating factors for chemotherapy induced febrile neutropenia. Christopher E.pdf de Naurois J.: CD003039. Bennett. Cross.2012 Panel Members Myeloid Growth Factors. James Khatcheressian.21(Suppl 5):v252-6 Clark OAC. Lodovico Balducci. Winn.dgho-infektionen.1002/14651858. Gill MJ.

Calculated Antibiotic Therapy in FN (14/22) Further information: The most important treatment aspect is to initiate calculated antibiotic treatment as soon as possible.V. (DGHO) www.dgho-infektionen. according to updated guidelines.de (H. Link et al: erstellt 04/07) . References: Relevant practice guidelines: Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e. but no later than 2 hours after onset of fever. Recommendations need to be regularly updated according to the changes in microbial sensitivity and resistance towards antiinfective treatments.

Importantly. Cardiac monitoring should continue in patients receiving doxorubicin.29. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. A Cochrane review investigated Cardioprotective interventions for cancer patients receiving anthracyclines and concluded: …“The nine included studies of dexrazoxane enrolled 1403 patients. for patients who have received more than 300 mg/m(2) doxorubicin who may benefit from continued doxorubicin-containing therapy. both in the metastatic as well as in the adjuvant breast cancer setting.20 to 0.“ References: 1. Consider use with metastatic BC and other malignancies. Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting. Although infrequent.41). A great number of studies review and discusses the relationship of cardiotoxicity and anthracycline use. The meta-analysis of dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (Relative Risk (RR) 0. and explores available treatment options for the anthracycline-treated patients based on evidence from recent Phase III trials. the monoclonal antibody trastuzumab. or metastatic setting with initial doxorubicin-based chemotherapy. No evidence was found for a difference in response rate or survival between the dexrazoxane and control group. cumulative dose-dependent cardiotoxicity is nevertheless a significant side effect of this therapy resulting in reduced cardiac reserve or even frank cardiac failure. Although used in several types of malignancy. particularly in the breast cancer setting. 95% CI 0. anthracyclines are most commonly used in breast cancer treatment.Dexrazoxane (15/22) Further information: Anthracyclines are among the most active chemotherapeutic agents in cancer treatment. . recent advances have also seen the increasing use of another cardiotoxic agent. Only for one adverse effect (abnormal white blood cell count at nadir) a difference in favour of the control group was identified.

27(1):127-45. 2008 Apr 16. Schuchter LM. Expert Rev Cardiovasc Ther. Justice R. Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity. Wasserman TH. Epub 2008 Nov 17. Gradishar WJ. Optimal treatment strategies in postmenopausal women with hormone-receptor-positive and HER2-negative metastatic breast cancer. Kewalramani T. Langer SW. 2008. Eidtmann H. Mouridsen HT. Ceste M. Miglietta L.2. Kane RC. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.(2):CD003917. Cohen GI. Milanese S. Giaretto L. Green DM. Epub 2008 Dec 20. Knoblauch P. 6. Dickinson HO. Jones RL. de Wit M. Ann Oncol. J Clin Oncol. Emami B. 8. Thigpen JT. 2009 Jan 1.112 Suppl 1:53-66. 5. Jensen PB. 2008 Apr. Cochrane Database Syst Rev. Dagher R. Manfredi R. Lanfranco C. Testore F. Ferro S. 2007 Mar. Giaccone G. Trotti A 3rd. McGuinn WD Jr. Cardioprotective effect of dexrazoxane in patients with breast cancer treated with anthracyclines in adjuvant setting: a 10-year single institution experience.8(4):257-63 van Dalen EC. Gligorov J. von Hoff D. de Conciliis E. Hensley ML. Caron HN. Lotz JP.6(10):1311-7. Oncologist. 2008 Dec. Mitchell RB. Epub 2006 Dec . Rosti G. 2008 Nov. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. Hagerty KL. 4. Bosso G. Pazdur R. Buter J. Dahlstrøm K.18(3):546-50.13(4):445-50. Parello G. 7. Meropol NJ. Ferrero G. Breast Cancer Res Treat. Simoni C. Am J Cardiovasc Drugs. 3. Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Rasmussen A.

Karin Jordan download: http://www. Prophylaxe und Therapie [ PDF-Datei ] Arbeitsversion der ASORS Paravasate-Guidelines (Stand April 2010) Maike de Wit. Petra Ortner.Empfehlungen zu Diagnose.de/e974/e2538/e3782/e3494/ASORS_AV_Paravasate-Guidelines_04-2010.6:50-55. Diagnostik und Therapie der zytostatikaassoziierten Paravasation .Paravasation Dexrazoxane (16/22) Further information: Although indicated and approved for cardioprotection. Markus Ruhnke. The agent is administered systemically. Michael Untch. Regine Mayer-Steinacker. Hans-Peter Lipp.pdf Witte J.onkosupport. Jalid Sehouli. Carsten Bokemeyer.Was tun wenn‘s brennt? Im Focus Onkologie 2010. de Wit M. Prävention. References: Relevant practice guideline Zytostatika-induzierte Paravasate . . dexrazoxane has been suggested as being helpful in the case of anthracyclin paravasation.

but are less effective in the prevention of nausea. With the introduction of cisplatin.mascc. 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. the corresponding figures are 76% and 33%. A systematic Review summarizes recommendations from the evidence-based guidelines developed by the Multinational Association of Supportive Care in Cancer (MASCC). therefore.Antiemetic Therapy (17/22) Further information: Nausea and vomiting are two of the most severe problems for patients treated with chemotherapy. A large number of trials have fine-tuned antiemetic therapy and made evidence-based recommendations possible for the majority of patients receiving chemotherapy. research was stimulated and has now resulted in the development of two new classes of antiemetics. such as olanzapine. In a subsequent trial. There is. www.org . The combination of ondansetron. dexamethasone was not superior to aprepitant but instead had similar efficacy and toxicity in preventing delayed emesis. the serotonin and neurokinin antagonists. 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. nausea and vomiting induced by chemotherapy was an almost neglected research area. the cytotoxin with the highest emetic potential. References: 1. a particular interest in initiating trials to investigate agents with potential anti-nausea effect. New antiemetics have been highly successful in the prophylaxis of emesis. and are always accessible on the MASCC website. are updated every 6 months (as new data arise). Until the late 1970s. In women receiving cyclophosphamide/anthracycline-based chemotherapy for breast cancer. To encourage implementation. Guidelines such as the MASCC antiemetic guidelines are only useful if they are continuously updated and implemented in the daily clinic. the MASCC guidelines have been translated into several languages. In patients with breast cancer treated with anthracycline plus cyclophosphamide chemotherapy and receiving the same antiemetic prophylaxis for acute emesis.

Ann Oncol.21(22):4112-9. Rodrigues-Pereira J. Eldridge K. 6. Hipple A. Aprepitant Protocol 052 Study Group. Carides AD. Caldwell KC. Grunberg SM. Evans JK. Tjulandin SA. Hesketh AM. Bertoli LF. .:Oral ondansetron for the control of cisplatin-induced delayed emesis: a large. Ann Oncol 17: 4112–4119 Hesketh PJ. 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. Siebel M. de Wit R. Beck TM. and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Mantovani G. 2006 Sep. Lawson F. randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Results from a randomized. Epub 2003 Oct 14 Poli-Bigelli S. Bushey J. A phase III. Suarez T. Massa E. 8. Horgan KJ. Julie Ma G. placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. randomized. Gralla RJ. Greenberg B. Aprepitant as salvage antiemetic therapy in breast cancer patients receiving doxorubicin and cyclophosphamide. Evans JK. (2006) Comparison of an aprepitant regimen with a multiple-day ondansetron regimen.2. Hayden M. 3. Whaley W. Effectiveness of a singleday three-drug regimen of dexamethasone. Dugan M. 5.97(12):3090-8. Roila F. Reines S. Dessì M. 9. Grunberg SM. Tchekmedyian NS. Lepori S. Younger J. Wood M. Aprepitant Protocol 054 Study Group. 2008 Nov 27. Anderson N. Warr DG. [Epub ahead of print Grunberg SM. Support Care Cancer. Cancer. Navari RM. for antiemetic efficacy in high-dose cisplatin treatment. :Systematic review of the clinical effect of glycocorticoids on nonhematolic malignancy BMC Cancer (2008). Lordick F. Weisberg T. [Epub ahead of print] Aapro MS. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Astara G.8:84 Hesketh PJ. 7. Madajewicz S. doubleblind. Elmer ME. Nowd P. [Epub ahead of print] Schmoll HJ et al. Chawla SP. Arnaoutakis K. placebo-controlled trial in Latin America. both with dexamethasone. Sanz-Altamira P. Epub 2006 Jun 9. J Clin Oncol. double-blind. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational. 2008 Dec 6. Macciocchi A. et al. Yunus F. Madeddu C. Muss H. Crit Rev Oncol Hematol. 4. Burdette-Radoux S. Garewal H. 2003 Nov 15. palonosetron. 2008 Aug 23. Morrica B. Ianus J. Carides AD. Beck K. Chang AY. Support Care Cancer. Loi C. 2003 Jun 15. Trainor B. double-blind. Olivares G.17(9):1441-9. Manikhas GM. Krentzin M. Horgan KJ. Keith B.

Noonan K. Nabati L. doi: 10. 12. ASORS erstellt wurde.4547. 1996 Nov. Stelts S. Espersen B.org/antiemetic-guidelines Antiemetische Prophylaxe gemäß MASCC. Tonato M. Hardwick JS. Saito M.krebsgesellschaft. Armstrong DK. 13. 2011 Mar. Michaud LB. J Clin Oncol. 2012 Apr. Corticosteroids in the treatment of chemotherapy-induced nausea and vomiting. Ann Oncol.51. Morrow G. Carides A. J Natl Compr Canc Netw. J Clin Oncol. Bria E. Goedhals L. McRae J. Siler D. multicenter. double-blind study protocol--EASE. Hesketh P. Bierman PJ. J Natl Compr Canc Netw. Antiemesis. Beckford E.2013. DeVandry S. Herrstedt J. Ballatori E. 11. Grunberg S. 2011 Apr 10. Herrstedt J.10(4):493-9. Paska W. Rittenberg C. Maru A.13(9):2408-16. National Comprehensive Cancer Network. Ettinger DS. Support Care Cancer. Consensus recommendations for the prevention of vomiting and nausea following highemetic-risk chemotherapy. Ellis G. Depierre A. double-blind. double-blind study comparing placebo. J Clin Oncol. Bradbury B. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized.1200/JCO. 14. die unter der Veranwortung der ASO bzw. Rugo HS. 2012 Apr. Roila F. Seitz JF. Dinis J. Stucky-Marshall L. Kloth DD. doi: 10. .de) ] Kurzgefasste interdisziplinäre Leitlinie 2008 der Deutschen Krebsgesellschaft. Barbour SY. Epub 2011 Mar 7. Einhorn LH. Aprepitant versus dexamethasone for preventing chemotherapy-induced delayed emesis in patients with breast cancer: a randomized double-blind study. Lim D. Wilkinson JR A multicentre.1200/JCO. Urba SG. Stewart DJ.2010. Ruggeri B. Kirkegaard S. randomized comparative trial of ondansetron versus placebo.mascc.10. 15. Epub 2013 Dec 9.19 Suppl 1:S25-32. Barbour S. McQuade B. 2014 Jan 10. Olver I.31. Grunberg S. Todaro B. Chua D. Taylor A. Kris MG. Tonato M. Ballatori E. Boice JA.und ASCO-Guidelines [ PDF-Datei (auf www. Del Favero A.7(9):945-52 Kris MG.7859. Sorscher SM.29(11):1495501. Ondansetron Delayed Emesis Study Group. Berger MJ. ondansetron and ondansetron plus dexamethasone for the control of cisplatininduced delayed emesis. 1995 Sep.10(4):456-85. Relevant Guidelines http://www.32(2):101-6. Roila F.

. Hesketh PJ. 2011 Nov. Temin S.7(6):395-8. Kris MG. Antiemetics: american society of clinical oncology clinical practice guideline update. Prestrud AA. J Oncol Pract.Basch E. Lyman GH.

Supportive Therapie: Antiemetics (18/22) No further information No references .

dgss.org Schmerztherapie bei Tumorerkrankungen http://www. www.de/download/ll_n_02.krebsgesellschaft.pdf .Analgesia (19/22) No further information References: Relevant guidelines Deutsche Gesellschaft zum Studium des Schmerzes.

B. Benson 3rd.Diarrhea (20/22) No further information References: Relevant Guidelines 1.M. Catalano. J.. frequency and guideline-based management Ther Adv Med Oncol.. Kornblau. C. Alexander Stein. S. R. .. Wieland Voigt.A. J. Engelking. 2010 January.B... Martenson Jr. (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. Ajani. et al. 2. J Clin Oncol 22: 2918–2926.A. Karin Jordan Chemotherapy-induced diarrhea: pathophysiology. 2(1): 51–63. A.

A Cochrane meta-analysis investigated differential efficacy of different agents.“ References: 1. Katri Elina Clemens. The authors concluded. the safety of this product is not fully evaluated. is now licensed for the treatment of opioidinduced constipation in palliative care when response to usual laxative therapy is insufficient. However. 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. an opioid-receptor antagonist. . Eberhard Klaschik Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide Ther Clin Risk Manag. 2010. rigorous. 6: 77–82. Sufficient fluid uptake should be encountered by treating health care providers. Opioid therapy usually results in constipation and regular digestion should always be aimed at. this is seen in both adults and children. form of stool. relief of abdominal pain and the need for additional products.“ More recently. Particularly around the time in autumn and winter. On subgroup analysis. Large. the authors concluded. that „The findings of our work indicate that Polyethylene glycol is better than lactulose in outcomes of stool frequency per week. the use of parenteral methylnaltrexone for the management of constipation in palliative care patients was evaluated. except for relief of abdominal pain. Subcutaneous methylnaltrexone. when indoor heating begins and air humidity is consequentially reduced. Polyethylene Glycol should be used in preference to Lactulose in the treatment of Chronic Constipation. independent trials are needed.Constipation (21/22) Further information: Constipation is not infrequently encountered during chemotherapy.

Zuurmond WW. 4.22(7):796-807. Larkin PJ. Centeno C. Ellershaw JE. Sykes NP. Cochrane Database of Systematic Reviews 2010. Nabal M. Lee-Robichaud H. Noguera A. Palliat Med. Thomas K. European Consensus Group on Constipation in Palliative Care. 2008 Oct. 3. Drake R.2. Issue 7. Ripamonti C. Morgan J. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Zucco F. Elsner F. Jones L. . Nelson RL. Issue 1. Eugene B. Tookman A. The management of constipation in palliative care: clinical practice recommendations. Cochrane Database of Systematic Reviews 2011. Gootjes JR. Candy B. Goodman ML. Lactulose versus Polyethylene Glycol for Chronic Constipation.

Cardoso et al. is important in the treatment of metastatic breast cancer patients. Breast 21:242-252. 2012 . including effective control of pain and other symptoms. It is evident that the access to palliative care. Levy et al. 2012 3. J Natl Compr Canc Netw 10:1284-1309. Smith et al. 2012 2.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. References: 1. This should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden. J Clin Oncol 30 880-887.

Diagnosis And Treatment Of Patients With Primary And Metastatic Breast Cancer © AGO e. in der DGGG e.V. V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Breast Cancer: Specific Situations .

sowie in der DKG e.V.ago-online.V.1 www. 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 . in der DGGG e.Breast Cancer: Specific Situations © AGO e. Guidelines Breast Version 2015.

Guidelines Breast Version 2015. V.Breast Cancer: Specific Situations © AGO e. sowie in der DKG 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.V.ago-online. in der DGGG e.de .V.

de  Aggressive biological behavior 2a B  Benefit from chemotherapy 1b A ++  Benefit from endocrine therapy 1b A ++  Endocrine therapy (TAM). Guidelines Breast Version 2015.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 ++ . V.V. sowie in der DKG e.V.ago-online. in der DGGG e.1 www.

V.Breast Cancer During Pregnancy* or Breast Feeding © AGO Oxford / AGO LoE / GR e. in der DGGG e. sowie in der DKG e.1  Breast imaging & biopsy like in non-pregnant 4 C ++  Staging: ultrasound. Guidelines Breast Version 2015. 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). 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.de  * Participation in register study recommended . V.V.

V. in der DGGG e. EC  Taxanes  MTX (e. sowie in der DKG e.ago-online. LoE / GR Guidelines Breast Version 2015.1   www.Breast Cancer During Pregnancy* © AGO Oxford / AGO e. 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 .de   Radiation therapy during pregnancy (Neo-)adjuvant chemotherapy only after first trimester (indication as in non-pregnant)  Anthracyclines: AC. V.g.V.

breast feeding may be contraindicated depending on drug toxicities 5 C ++ C C ++ D ++ * Participation in register study recommended .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.V. V. in der DGGG e. 4 avoid delivery 3 weeks from prior chemotherapy If further systemic therapy is needed after delivery.ago-online.1    www. Guidelines Breast Version 2015. sowie in der DKG e.V.Breast Cancer During Pregnancy* © AGO Oxford / AGO LoE / GR e.

ago-online. V.V.1 LoE BC during pregnancy / lactation  Adequate treatment is essential 3a Pregnancy and lactation after BC www.Pregnancy Associated Breast Cancer*: Outcome © AGO e. in der DGGG e. Oxford Guidelines Breast Version 2015.de  Outcome not compromized 3a * Participation in register study recommended .V. sowie in der DKG e.

in der DGGG e. sowie in der DKG e.Geriatric Assessment © AGO e. social network. and psycho-social health Basic activities of daily living (dressing.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. that are measured).V. V.de  Physical. G8 . Guidelines Breast Version 2015.ago-online. bathing.V. mental. access to support services Assessment tools:     Charlson Comorbidity Index (widely used. etc. meal preparation. 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.) Living arrangements. medication management.

V.) 1a A ++  Chemotherapy (standard regimens) www.Treatment for Fit Elderly Patients (Life Expectancy > 5 yrs. in der DGGG e.ago-online. 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+. V. 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. sowie in der DKG e. hormone receptor positive and if endocrine therapy is planned (CAVE: increased risk local recurrence) .V. and Acceptable Comorbidities) © AGO Oxford / AGO LoE / GR e.

V. sowie in der DKG e. Rec pos) 2b B +  No radiotherapy ( ≥ 65 y. Rec pos) 1b  Hypofractionated radiotherapy 2b C +  No chemotherapy if >70 years and negative 2b C risk-benefit analysis +  www. V.1  Reduced standard treatment  Options extrapolated from trials in elderly: ++ No breast surgery (consider endocrine options) 2b C +  No axillary clearing (≥ 60 y. pT1. in der DGGG e.Treatment for Frail Patients (Life Expectancy <5 yrs. cN0.ago-online.de 2b C B ++ . Guidelines Breast Version 2015. Substantial Comorbidities) © AGO Oxford / AGO LoE / GR e. pN0.V.

Male Breast Cancer: Diagnostic Work-Up and Loco-Regional Therapy © AGO Oxford / AGO LoE / GR e. V.1    www.V. sowie in der DKG e.V. in der DGGG e.ago-online.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 . Guidelines Breast Version 2015.

GnRHa and AI (metastatic BC) 4 C +* . sowie in der DKG e.Fulvestrant (metastatic BC) 4 C +/- 4 C ++ www.de  Palliative chemotherapy as in women *Participation in register study recommended .Male Breast Cancer: Systemic Therapy © AGO Oxford / AGO LoE / GR e.1  Adjuvant chemotherapy as in women 2a B ++  HER2 targeted therapy 5 D +*  Endocrine therapy 4 D ++ .Aromatase inhibitors (metastatic BC) 4 C +/- . V.V.Aromatase inhibitors (adjuvant) 2b B -* . Guidelines Breast Version 2015. in der DGGG e.ago-online.Tamoxifen 2b B ++ .V.

Primary Inflammatory Breast Cancer (IBC. in der DGGG e.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 ++ .1    www. cT4d) © AGO e.V. detection rate < 75%) Preoperative chemotherapy  Regimens as in non-inflammatory BC  Anthracycline and taxane-based  In HER2 + disease.de    In case of invasive BC and clinical signs of inflammation (e. addition of trastuzumab  In HER2 + disease. V.  Guidelines Breast Version 2015.ago-online. addition of trastuzumab and pertuzumab  In Her2 . sowie in der DKG e.V. ≥ 1/3 of the breast affected) determine stage cT4d Staging Skin punch biopsy (at least 2.g.

sowie in der DKG e. 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 + .g.1 www.Axillary Metastasis in Carcinoma of Unknown Primary (CUP) © AGO Oxford / AGO LOE / GR e. CupPrint™) 2c B +/-  ER. ENT investigation) 3 B ++  PET / PET-CT 3b B +/-  Gene expression profiling (e.V. Guidelines Breast Version 2015. thyroid sonography. PgR.de  Mammography / Breast ultrasound 3 B ++  Breast MRI 3 B ++  Staging (CT thorax / abdomen.V. V. in der DGGG e.ago-online.

sowie in der DKG e.1 Histological verification  Mammography.de  .g. invasive breast cancer. Guidelines Breast Version 2015.V. 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.ago-online. in der DGGG e.Paget´s Disease of the Breast © AGO Oxford / AGO LOE / GR e.V. V. 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. DCIS)  Therapy according to standard of the underlying disease Surgery must achieve R0  Wide excision (like DCIS) + radiotherapy  www.

1      Complete (wide) local excision or MRM SNE / Axillary dissection in cN0 Staging Systemic adjuvant therapy (chemo. V.V.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. chemotherapy after R1 resection Distant metastases (very rare)  Treatment like soft tissue sarcomas . in der DGGG e.ago-online. endocrine) Adjuvant radiotherapy  www. Guidelines Breast Version 2015.Malignant and Borderline Phylloides Tumor © AGO Oxford / AGO LOE / GR e.

1 Treatment of Primary Disease:  Mammography. Sonography to determine extent of disease  Preoperative MRI to determine extent of disease  Diagnosis by core biopsy  Diagnosis by FNB  Staging  Prognostic factors: size. 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. 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. R1) .de Oxford / AGO LOE / GR Adjuvant chemotherapy (anthracycline-based). radiotherapy  www.V.ago-online. V. Guidelines Breast Version 2015. in der DGGG e. sowie in der DKG e.V.Sarcoma / Angiosarcoma of the Breast (Note: very aggressive!) © AGO e. size > 5 cm. radiotherapy in case of high risk (grade II-III. grade.

NCCN: http://www. EBCC (2005 – 2014). Meta-Analysis.nccn. No references . SABCS 2005 – 2014. Randomized Controlled Trial. Screened for: Clinical Trials. Cochrane data base (2012). ASCO 2005 – 2014.pdf This chapter of rare diseases cannot deliver references for every statements separately but is providing them where possible.org/professionals/physician_gls/PDF/breast. ECCO/ESMO (2005 – 2014). Reviews Screened guidelines: . Practice Guideline.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 .

Delaloge S. 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. Gentilini O. 2014 Jun. Azim HA Jr. Loibl S. Therefore chemotherapy is almost always indicated. Loibl S. Fourquet A. Abulkhair O. Panizza P. First international consensus guidelines for breast cancer in young women (BCY1). Gentilini OD. Meirow D. Aebi S. 2012 Dec. Freilich G. Treatment with tamoxifen of up to ten years is beneficial. Costa A.48(18):3355-77 . References: International Guidelines: There is now a bi-annual International Consensus Conference on Breast Cancer in Young women (BCY): 1.23(3):209-20. 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. Graziottin A. Radiotherapy seems to deliver additional benefit.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. Pagani O. Kaufmann B. Eur J Cancer. Cardoso F. Harbeck N. Kotti-Kitromilidou AM. Breast. the FERTIPROTECT Project is a platform to gain information how and where to get information. 2.or endocrine therapy. Peccatori F. Delaloge S. Marotti L. Rodger A. Amant F. Peccatori F. Pagani O. Partridge AH. Cardoso F. Penault-Llorca F. Kelly CM. Harbeck N. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. European Society of Breast Cancer Specialists. Martincich L. In Germany.

Women age < or = 35 years with primary breast carcinoma: Disease features at presentation. 14: 594-599 (Review) Early Breast Cancer Trialists' Collaborative Group (EBCTCG).103: 2466-2472 Rapiti E. Foekens JA. J Clin Oncol 2008. 8(5): e105–e110. Breast 2005. 3.320(7233):474-8. 2. J Natl Compr Canc Netw. 2000 Feb 19. Hsu DS. Lancet 2005. Breast cancer in adolescents and young adults: a review with a focus on biology. Schechter NR. Eur J Cancer 2005. Gonzalez-Angulo AM et al. Oh JL. Ann H. Cancer 2005. J Clin Oncol 2008. BMJ.41(10):1446-52.65:1345-52. et al. 4. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. Factors influencing the effect of age on prognosis in breast cancer: population based study. Model Program to Improve Care for a Unique Cancer Population: Young Women With Breast Cancer J Oncol Pract. 2013. 2013.. Freedman RA et al. .11(9):1060-9. Partridge et al. 5. Special issues related to the adjuvant therapy in very young women. 3. Broadwater G. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. 6. Kroman N. Bonnen M. Breast. et al .26:3324-30. Survival of young and older breast cancer patients in Geneva from 1990 to 2001. J Natl Compr Canc Netw. Chemotherapy in young women 1. et al . 2013. 7.365: 1687–1717 M. 2012. 8. Anders CK. 2. De Laurentiis et al. Acharya CR.11(9):1060-9.Prognosis in young women 1. Zhang Y. Strom EA. 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. Tichy JR et al. et al.22 Suppl 2:S176-9. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.26 (1). Perkins GH.44–53. Aebi S. Outlaw ED. Management of breast cancer in very young women.

31(suppl): abstr 5 Benefit from trastuzumab 1. Partridge et al. M. N Engl J Med 2009. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. C. 2007.29 (17) 2334-2341 Adjuvant Breast Cancer Trials Collaborative Group. Jakesz R. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS. 2. Regan M.381. Endocrine therapy in young women 1. Huober J et al. Smith I. 2.H. 2007.124:133–140. Effect of Luteinizing Hormone-Releasing Hormone Agonist on ovarian function after adjuvant breast cancer chemotherapy: by the GBG 37 ZORO study. Cuzick J. Breast Cancer Res Treat. Lancet. 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 . Davies et al. Ambroisine L.369(9574):1711-23. Kaufmann M. 2010.Lancet.44. 3. 2. Sainsbury R.2692–2698 Benefit from temporary amenorrhoea after adjuvant chemotherapy (chemotherapy induced or GnRHa-related) 1. J.369(9555):29-36 A. Clin Oncol 2011.99:516–525 . 3. Lancet 2013.360 (7) 679–691 Gerber B et al. et al. 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. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Gnant et al.805–816 Gray RG. Davidson N.4. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6. HERA study team: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. 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.953 women with early breast cancer. a randomised trial. J Clin Oncol 2013.

Costantino. Kim SW. iatrogenic amenorrhea. Nam SJ. Gomez HL. Cancer Treat Rev 2013 in press Yang B et al.in particular BCT) 1. Lee H. et al. Lee JE. S. 6. Horiot JC. Francis PA. and CALGB (Alliance).4. Longer therapy.23(5):670-5. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage. Pajon. Guerriero G. de Bock GH et al. E. 2. 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. 2014 Oct. Minasian LM. Bratta M. abstr LBA505) Surgery in young women (Surgery like ≥ 35y .P. Martino S..H. Struikmans H. Kim M. . Meyskens FL. Boyle FM. 8. IBCSG. Albain KS. C. Rea S. Gelber RD. J. Int J Radiat Oncol Biol Phys. Eur J Cancer 2005. and survival in early breast cancer. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: Systematic review and meta-analysis of randomized trials. Jun SY. Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy. fibrosis and survival after breast conserving treatment: 10 year results of the EORTC trial 22881-10882. Recchia F. Ovarian function preservation with GnRH agonist in young breast cancer patients: does it impede the effect of adjuvant chemotherapy? Breast. Barlow WE. Lee SK. Kim J. hormone receptor-negative breast cancer: An international Intergroup trial of SWOG. Goldstein LJ. Br Cancer Res Treat 2006. 9. J Clin Oncol 32:5s. J. 5. Partridge AH.22(2):150-7. Impact of radiation dose on local control. Moore HCF. Hortobagyi GN. Necozione S. Garg AK et al. (362). 2015 Mar. Fehrenbacher et al. Fabian CJ. ECOG. Rosselli M. 7.100:S8-10].. – Radiation boost therapy can reduce in-breast recurrence [Bartelink H.R. Bae SY.M. 2007 Dec 1. 2014 (suppl. Unger JM. Dakhil SR.69(5):1478-83. Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy. N Engl J Med 2010 . LH-RH analogues in the treatment of young women with early breast cancer: Long-term follow-up of a phase II study. 25. Poortmans PM. Int J Oncol. Geyer Jr. Lee JH. Phillips KA. Hitre E. Swain. Vallejos C. L.E. Jeong. Long-term results of European Organisation for Research and Treatment of Cancer Studies.2053–2065 Del Mastro L et al. Kil WH.46(3):1354-60. Porter DJ.

Breast 2013 Jan 5. Mahmood U et al. 2. et al. Genetic and fertility counselling 1. Ginsburg E. Review. Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer. Partridge AH EP. 2013.and gravidity-matched controls. Cao JQ et al. J Clin Oncol. J.3.18:105–108 Lee MC etzt al.20(6):e593-e601. 3. 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. Jeruss JS. 5. Effect of Luteinizing Hormone-Releasing Hormone Agonist on ovarian function after adjuvant breast cancer chemotherapy: by the GBG 37 ZORO study. 7. Rosenberg R. 2011. Schapira L. Przypyszny M.17(3):162-72. Gerber B. Sampson E. Menopausal symptoms and fertility concerns in premenopausal breast cancer survivors: A comparison to age.2012. Meyer ME. Fertility and menopausal outcomes in young breast cancer survivors. Prospective study of fertility concerns and preservation strategies in young women with breast cancer. Int J Radiat Oncol Biol Phys. 2009 Dec.32(11):1151-6 . Ginsburg ES. 8. Menopause. Clin Breast Cancer 2008. (:65-69 Hulvat MC. Maintaining fertility in young women with breast cancer. pii: S0960-9776(12)00252-4.83(5):1387e93. Ruddy KJ. 4. 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). Curr Treat Options Oncol. Tamimi RM. Peppercorn J. 4.10(5-6):308-17. Winer. Gelber SI. Borges VF. Partridge AH.: Fertility and reproductive considerations in premenopausal patients with breast cancer. Comparison of recurrence and survival rates after breast-conserving therapy and mastectomy in young women with breast cancer. Cancer Control. 2010 Jul. 6. Curr Oncol. 2014 Apr 10. Gelber S. Come SE. 269-276 2011 Ruddy KJ et al.

As a consequence. Pregnant breast cancer patients have an average age of about 32-38 years. Given the increasing average age of pregnant women. short nursing periods. late menopause. there is no reason to replace an indicated mammography by an . 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. Moreover. This fact urgently needs to be acknowledged and accepted by physicians since the diagnosis of breast cancer is frequently being delayed in pregnancy. Thus. The same imaging techniques as in non-pregnant women are available. Moreover. 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.html The individual breast cancer risk is strongly influenced by endocrine factors. breast cancer incidence is also increasing with age. Moreover. the diagnosis is typically made at a later stage than outside of pregnancy. 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. Early menarche. 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. Breast ultrasound will not harm the fetus. the position in the MRI may not be acceptable for most pregnant women. MRI does not have the danger of radiation but experiences with pregnant breast tissue is limited and interpretation may be difficult. the co-incidence of a breast cancer diagnosis with the patient also being pregnant or nursing is becoming more frequent. low number of children. since the danger of too much radiation for the fetus can be overcome by appropriate protective measures.de/studien/adjuvant/brustkrebs-in-der-schwangerschaft. and increasing age at first birth are significant risk factors. The average time interval between first symptoms and a definite diagnosis is about 5-15 months. mammography can also be used if needed. Pregnancy or nursing period are no reason for delaying appropriate diagnostic work-up of a suspicious lesion. Thus.

there is an increased risk for growth retardation. There is growing evidence that the use of taxanes is safe. Indication for chemotherapy follows the guidelines for non-pregnant patients. The same is probably true for vinorelbine. chemotherapy can only be applied after the 12th week of pregnancy.e. i. Thus. FEC. In addition. Among the most frequently used chemotherapeutics in breast cancer. 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. Dose-dense chemotherapy does not appear to increase the risk of fetal or maternal complications. As in non-pregnant patients. 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. Undertreatment should be avoided. no major complications have been reported. EC and Epi weekly are safe combinations. In general. However. should take the delivery date into account. after organogenesis. In conclusion. For anthracyclines. pregnancy is not a reason for withholding an indicated chemotherapy – the timing however. but is not recommended at the moment. this can be done by minimal invasive techniques such as core or vacuum biopsies under local anesthesia. chemotherapy does not cause an increased rate of malformations. since adjuvant chemotherapy may be indicated in most cases anyway. radiation therapy is of course possible and thus breast conserving therapy is a valid option in breast cancer during pregnancy. there is no evidence for major complications. Physiological changes in pregnant or nursing breasts cause an increased false-positive rate in imaging procedures. one has to consider the individual teratogenic potential of the different chemotherapeutics and plan the delivery date accordingly. after delivery. Thus. Yet. antimetabolites such as methotrexate (or 5-fluorouracil) should not be used due to their teratogenic potential. thus increasing again the danger of a delay in diagnosis. in pregnant or nursing women. An open biopsy is only indicated in situations where minimal invasive procedures may not allow a definite diagnosis. Treatment with trastuzumab in HER2-positive tumours in pregnant women cannot be recommended.MRI in pregnant patients. and intrauterine fetal death. Yet. premature labour. every suspicious palpable tumor definitely needs to be submitted to a histological diagnosis. 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. premature delivery. After diagnosis. 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. Which is possible cytotoxic agent in pregnant metastatic breast cancer patients. After the first trimester. .So far.

Untch M. 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. There is neither evidence of direct damage to the fetus due to breast cancer nor of metastases into the fetus. 2013. Neven P. Giermek J.g. termination may be considered if therapy options for the mother are severely compromised by the pregnancy. References: 1. fetal underdevelopment. Termination of pregnancy does not improve the prognosis of the breast cancer and thus is not considered a therapeutic option. treatment and follow-up. Moreover. Yet. Yet. so that bisphosphonates are contraindicated in pregnancy. hypocalcaemia and skeletal retardation. Wildiers H.24 Suppl 6:vi160-70 Outcome information (GBG registry): 1. Moreover. Diagnosis of a malignancy during pregnancy causes extreme burden and conflicts for the pregnant women and their families touching on emotional. social and ethical aspects next to medical issues. Rack B. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis. . since maternal side effects (e. Ring AE. von Minckwitz G. Amant F. Nekljudova V. fatigue. depending on gestational age. Ann Oncol. nursing is not recommended during chemotherapy due to excretion of many chemotherapeutics into the milk. Van Calsteren K. the placental excretion function disappears after delivery and the newborn may not be able to metabolize potential chemotherapy remainders. Fehm T. Most pregnant cancer patients want to “live long enough to see their child grow up”. religious. Harbeck N. nursing should be stopped before surgery on order to reduce volume of the breast and its blood flow. Prognosis is not improved by cessation of nursing. However. Schlehe B. rare placental metastases have been described. Cancer. embryolethality. Bontenbal M. Linn SC. Müller V. Witteveen PO. Thus. Han SN.Results of studies of bisphosphonates in pregnant animals have shown maternal toxicity. hematotoxicity) may increase the maternal risk for delivery-associated complications. Westenend PJ. The delivery should not be planned for the immediate three weeks following a chemotherapy cycle. Peccatori FA et al.

. Eur J Cancer 2010. Nekljudova V.31(20):2532-9. Bontenbal M. Amant F. Loibl S. Imaging and management of breast masses during pregnancy and lactation. Schwedler K. Müller V. Heyns L. 491-497 Nicklas AH et al. evidence-based review and recommendations. chest X-ray if indicated 7. Wang PI. 2.2010. Van Calster B.. 20: 442-444 . von Minckwitz G. et al. Rack B. et al. 3. Fehm T. Amant F. Westenend PJ. Van Calster B. Han SN. Halaska MJ. Annane K et al. Thomssen C. 27: 623-632 Hogge JP et al. doi:10. Fetal Diagn Ther 2005. Loibl S.13(9):887-96. Bock K.1016/j.. treatment and follow-up. Breast J 1999. 6. Statement: Surgery like in non-pregnant patients 8. Arch Gynecol Obstet 2005 Ahn BY et al.010. Gziri MM. Breast cancer in pregnancy: Recommendations of an international consensus meeting. 2013. Imaging strategies in the pregnant cancer patient. Lenhard M. et al. Lancet Oncol. Van Calsteren K. Giermek J. Semin Oncol 2000.09. Peccatori FA et al. Rationale for a diagnostic chain in gestational breast tumor diagnosis. Kaufmann M. 5.24 Suppl 6:vi160-70 Statement: Staging: ultrasound. 4. Deckers S.2. Van Calsteren K. Infiltrative breast cancer during pregnancy and conservative surgery.ejca.198:785-792. Cancer.46:3158-3168. Schlehe B. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis. Statement: Breast imaging & biopsy like in non-pregnant 1. Ring A. J Ultrasound Med 2003. AJR Am J Roentgenol 2012. Linn SC. 2013 Jul 10. Imaging of pregnant and lactating patients: part 2. 5: 272283. Pregnancy and lactation-associated breast cancer: mammographic and sonographic findings. J Clin Oncol.. Harbeck N. 2012 Sep. Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study. Ann Oncol. Treatment of breast cancer during pregnancy: an observational study.

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Lancet Oncol 2012. pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis. Neven P. 2013. Loibl S. Breast cancer in pregnancy. Loibl S. Management of breast cancer during pregnancy using a standardized protocol J Clin Oncol 1999.13:887-896. Van Calsteren K. Treatment of breast cancer during pregnancy: an observational study. 17: 855-861 . Berry DL et al. Statements: Delivery should be postponed until sufficient fetal maturation since termination of pregnancy does not improve maternal outcome 4. Treatment of breast cancer during pregnancy: an observational study. Lancet. Han SN. Cancer.Breast cancer during pregnancy (7/18) Further information: These statements are derived from common sense and literature cannot fully be assigned. treatment and follow-up. Avoid delivery  3 weeks from prior chemotherapy 5. Statements: Delivery mode like in non-pregnant. et al. Lancet Oncol 2012. Peccatori FA et al.379(9815):570-9. Amant F. References: In general 1. Ann Oncol. Han SN.13:887-896. et al. von Minckwitz G. 2012 Feb 11. von Minckwitz G. 2.24 Suppl 6:vi160-70. 3. Loibl S..

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