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breast, skin, and soft tissue

BREAST CANCER
Lindi VanderWalde, MD, Alyssa D. Throckmorton, MD, FACS, and Stephen B. Edge, MD, FACS

Breast cancer is the most common malignancy in women in negatives. It also suffers from a high false positive rate—results
the Western world. Its prevalence and public health impact that lead to further evaluation, often including needle or
are increasing in developing countries, and breast cancer surgical biopsy, that ultimately prove benign.
leads to the death of hundreds of thousands of women world- The age at which to start screening and the type of screening
wide annually. In the United States, surgeons are involved in are in part based on the individual’s level of risk. The key risk
the treatment of most women with breast cancer and are the factor for women is increasing age. Although breast cancer
entry point for most women with breast cancer into the oncol- can occur in some younger women, risk increases after age 40,
ogy care delivery system. Surgical care must be coordinated peaks in the late 50s, and remains at that level throughout the
with other components of comprehensive breast cancer treat- remainder of life. This lower risk at a younger age is coupled
ment. Therefore, surgeons must have a thorough understand- with somewhat reduced sensitivity of mammography in
ing of the principles and current practices of overall breast younger women, making the test of extremely low or no value
cancer medicine. This includes screening and evaluation of for women without defined high risk factors who are under
benign disorders and suspicious findings, the use of imaging age 40.
and other diagnostic modalities, cancer risk modeling and The American Cancer Society (ACS) and the United States
genetics, pathology, radiation therapy, systemic therapy, con- Preventive Services Task Force (USPSTF) provide the two pri-
cepts of treatment of metastatic cancer, surveillance follow-up, mary guidelines for breast cancer screening. These are based
and the emotional and social impact of a breast cancer primarily on randomized and population studies of the impact
diagnosis.
of breast cancer screening on breast cancer mortality and the
This review provides an overview of most topics related to
potential harms of screening stemming from the low specific-
breast cancer. It is extensively referenced with key past and very
ity (high false positive rate) that leads to many women requir-
recent literature through 2015 to give the reader a place to read
ing a biopsy that proves benign.
in more depth about most topics. It targets surgeons not primar-
Until recently, most guidelines called for mammography
ily specializing in breast disease, trainees, and students.
annually beginning at age 40. However, based on review of
The review addresses treatment of malignancies of the ductal
the available data by independent panels, both organizations
and lobular epithelial components of the breast—what are com-
recently changed recommendations for the 90% or more of
monly referred to as “breast cancer.” Malignancies of the non­
epithelial components of the breast, including mesenchymal women who are not among high–breast cancer risk groups.
origin (phyllodes tumors and a variety of soft tissue sarcomas) Both groups recommend starting mammography at a higher
and lymphoma,1,2 are much less common and are not included age and reducing the overall frequency of mammography.
in this review. The USPSTF guidelines recommend screening for women
without high-risk characteristics every 2 years beginning at
age 50 and that women age 40 to 49 make individual choices.3–5
Breast Evaluation The ACS guidelines revised in 2015 call for average-risk
and Management of women (who constitute about 90% of the population) to have
Findings Suspicious mammography annually from age 45 through age 54 and
for Cancer every other year thereafter.6
screening There is no upper age limit for screening mammography.
All women should Competing comorbidities and estimated life expectancy, but
undergo periodic screen- not necessarily the age of the woman, should be the main con-
ing for the presence of siderations in the decision regarding screening mammography
breast cancer. This should in older women. The ACS quantifies this by recommending
involve self- and profes- mammography every other year for older women with a
sional physical examina- projected life expectancy of at least 10 years.
tion and breast imaging. These changes have raised controversy, with some experts
Screening the general still recommending annual mammography beginning at age
population is proven to 40. The ACS guidelines acknowledge this and advise practi-
reduce the risk of breast tioners to discuss this with their patients, recommending that
cancer death. As is true women who want earlier mammography have this covered by
with all other health insurance. Surgeons should be aware of ongoing controversies
screening, this comes at about the value of screening based on the variability in its
some cost beyond the impact on mortality, the high rate of false positive examina-
financial cost. This tions, and the thesis that some lesions identified as “cancer”
includes incorrect negative results of tests—screening is only may not have lethal potential but instead represent overdiag-
moderately sensitive for detecting cancer—known as false nosis and lead to overtreatment.7–9

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© 2016 Decker Intellectual Properties Inc DOI 10.2310/7800.2035

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Approach to the Patient with Breast Cancer

Assessment and Management


of Breast Findings

Screening Mass/skin change/


(No signs/symptoms) bloody discharge

History; physical examination;


diagnostic imaging
Average risk: High risk/
screening inherited susceptibility:
mammography screening
at age 40 + mammography
at < age 40;
consider screening
magnetic resonance imaging
Suspicious Negative
finding imaging

Suspicious:
complete diagnostic imaging

Biopsy or close
follow-up

BI-RADS 1 or 2: BI-RADS 4 or 5
continue screening BI-RADS 3
6-month
follow-up
imaging

Biopsy
Needle biopsy preferred
Image guided if not palpable

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Needle biopsy finding

Ductal carcinoma in situ (DCIS)


Atypical hyperplasia or
lobulat carcinoma in situ

History and physical examination


treatment options:
surgical wide excision
Surgical excision with/without radiation
or
mastectomy
Choice based on:
Not cancer: extent/size of involvement
consider antiestrogen
Cancer: see DCIS or invasive cancer

Wide excision: breast conserving therapy If mastectomy:


Assess margin and final pathology consider sentinel node biopsy;
consider reconstruction

DCIS and margin negative


consider radiation DCIS and margin positive: Invasive cancer:
re-excision to negative margin; go to appropriate
then consider radiation algorithm
or consider mastectomy ± reconstruction
If wide excision/
breast conserving therapy
consider antiestrogen drug

Invasive cancer

History and physical examination; identify clinical stage


Obtain biomarkers (ER, PR, HER-2)

Clinical stage I or II Clinical stage III Clinical stage IV

Perform staging studies:


Treatment options: if metastases, treat as stage IV
breast conserving therapy (BCT) or
mastectomy
Or neoadjuvant systemic therapy
Staging studies negative:
followed by surgery ± radiation
neoadjuvant systemic therapy
(chemotherapy or endocrine)
based on biomarker status

ER/PR(+) HER-2(−) ER/PR(−) HER-2(+/−)


Surgery first or Size > 2 cm: Operable: Inoperable:
neoadjuvant therapy neoadjuvant therapy preferred mastectomy or BCT change systemic
if large Size < 2 cm: surgery first based on response therapy and/or
then radiation radiation

BCT: wide excision to Mastectomy with sentinel node biopsy Initiate systemic
negative margin and ± reconstruction; treatment
sentinel node biopsy (SNB); axillary node dissection with (+) based on biomarkers
breast radiation sentinel node biopsy Radiation for palliation
(may omit radiation age radiation with 4+ positive nodes Bone metastases
70+, ≤ 2 cm, ER+) (Consider with 1− 3 nodes)
Breast surgery for
0, 1, or 2 (+) nodes: no axillary palliation if needed
lymph node dissection Systemic therapy choice based on:
3 or more (+) nodes: AND biomarkers; stage; age/comorbidity

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Screening for breast cancer for those at increased risk for and evaluation for symptoms related to metastatic disease
breast cancer may need to start at a younger age, be more should be performed on women with suspicious clinical or
frequent, and include techniques other than mammography. imaging findings [see Table 1]. The patient may notice subtle
In total, this only applies to 10% or less of the population. Risk findings such as pain, early retraction of the nipple, skin ery-
factors include a strong family history of breast cancer and/or thema or dimpling, or periodic nipple discharge. A previous
known family mutations in breast cancer–related genes, a his- history of imaging findings and biopsies is important. The
tory of radiation to the chest (most commonly mantle radia- physician should query for the presence of masses or lumps
tion for Hodgkin disease as a young adult), and specific in the breast, any apparent swelling, edema or thickening in
histologic findings on a previous breast biopsy. Women with the breast tissue or skin, and the presence or absence of dis-
a lifetime risk of breast cancer greater than 20% should con- charge from the nipple (character, color, consistency, fre-
sider mammography at a younger age as well as annual quency and mode of expression—spontaneous or elicited).
screening magnetic resonance imaging (MRI). MRI detects The patient should be queried regarding any changes in the
some cancers that are not evident on mammography, particu- appearance of the nipple and the areola as well as the presence
larly in those under age 40. For most situations, mammogra- of swelling, scaling, eczematous changes, or peeling of the
phy is still indicated, and MRI and ultrasonography are only skin.
adjuncts to mammography. However, an emerging literature The physician should also document factors related to
suggests that when breast imaging screening is done for high- breast cancer risk: age at onset of menarche and menopause,
risk women under age 30, there are few or no breast cancers age at first-term pregnancy, hormone use, and a detailed fam-
detected by mammography that are not detected by MRI, and ily history of cancer. This history should include the type and
there are theoretical concerns that repeated radiation exposure age at onset of cancer of all types (not just restricted to breast
could be harmful in this age group.10,11 and ovarian cancer) in all maternal and paternal first-degree
Breast density on a mammogram is another risk factor for and second-degree relatives. Finally, a thorough history of
breast cancer. There are limited data that additional imaging medication use should be recorded. In addition to common
with ultrasonography or MRI is of value. This remains an area prescription medications, the patient should be queried
of substantial debate.12,13 However, recent legislative mandates regarding the use of exogenous hormone therapy as well as
in many US states require notification of women with mam- supplements, other alternative medicine, and illicit drugs
mographically dense breasts of this fact, the potential increased because of their potential effects on hormone metabolism and
risk associated with dense breasts, and that additional screen- bleeding. Note that these findings are important to document
ing imaging may be warranted, such as automated breast for long-term risk evaluation and management but do not sig-
ultrasonography or tomosynthesis. nificantly impact the path for evaluation of a new breast find-
There are tools (models) to estimate the future risk of breast ing that must be managed on its own merit.
cancer and guidelines as to who should begin early screen- Some women have a family history suggesting a syndrome
ing.14,15 The most widely used is the Gail model, which assesses of inherited susceptibility to breast and ovarian cancer or to
risk for women with moderately increased risk based on age, other inherited cancer syndromes. For these women, genetic
age at menarche, number of children, previous breast biop- testing may be an option. If a geneticist or certified genetic
sies, and first-degree relatives with breast cancer (see http:// counselor is available, this is best managed by referral for for-
www.cancer.gov/bcrisktool/ for a Gail model breast cancer mal genetic counseling and consideration of testing. Current
risk calculator). However, the Gail model does not consider indications for genetic counseling for breast and ovarian cancer
paternal family history, maternal family history other than
first-degree relatives, or the age of cancer in family members
or other cancer types, making it less applicable to younger Table 1  Components of the Breast History
women with a more extensive family history. Other risk History of current problem
assessment tools include models such as the Tyrer-Cuzick   Symptoms of presenting problem (presence of mass, pain, imag-
model and Pedigree Assessment Tool.16 ing finding)
  Other breast symptoms
  Mass, pain, skin changes, swelling
Management of Clinical or Screening-Detected Findings   Nipple discharge
  Character (clear, green, red, dark)
Women with a finding of concern on screening studies or   Frequency, duration
on self- or professional examination should undergo a thor-   Laterality (unilateral, bilateral)
ough evaluation. This includes a history and physical exam-   Symptoms of systemic problems
ination, diagnostic breast imaging if not previously done, and   New bony pain, constitutional symptom
Past and family history
possibly biopsy.   Past history of breast issues, including results of previous biopsies
  Family history
history and physical examination
  Breast, ovarian, and other cancers in siblings, parents, parents’
History siblings, grandparents
  Breast cancer risk factor information
Most women with breast cancer are asymptomatic at the   Age at menarche, menopause (natural or surgical)
time of cancer diagnosis. The absence of findings on the history   Age at first-term pregnancy
and physical examination should not alter the need for further   Use, type, and duration of exogenous hormones
evaluation or biopsy of nonpalpable findings on imaging stud-   Results of previous biopsies
ies. However, a complete history of breast-related symptoms   Results of genetic testing in self or family (if any)

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risk include a personal history of breast cancer under the age imaging
of 50, triple-negative breast cancer under age 60, ovarian can- Mammography
cer at any age, male breast cancer, bilateral breast cancer, mul-
tiple first- or second-degree relatives with breast or ovarian The mainstay of breast imaging is mammography. The
cancer, or a known mutation in a breast cancer–related gene majority of breast cancers are detected by screening mammog-
or other syndrome in the family. raphy. With rare exceptions in very young women, evaluation
of a breast lesion is not complete without mammography.
Physical Examination Other imaging tools may add information, increase the sensi-
tivity of breast imaging, and enhance the accuracy and speci-
Examination of the breast and chest wall begins with maneu-
ficity of breast imaging but do not replace mammography.
vers to accentuate skin puckering or retraction, including
A standard screening mammogram includes two views of
extending the arms over the head and/or flexing the pectoral
each breast: the craniocaudad view and the mediolateral
muscles with the hands on the patient’s hips. Examination of oblique view (oblique to ensure inclusion of the axillary tail of
the axilla is best performed in the sitting position. The key to the breast on the image). Concerning findings on a mammo-
successful examination of the axilla is relaxation of the muscles gram include masses, asymmetry of the glandular tissue, dis-
of the shoulder girdle. This is best accomplished with the exam- tortion in the architecture of the breast tissue, and the presence
iner supporting the full weight of the arm abducted from the of calcifications grouped (“clustered”) in an area of breast tis-
body at about an angle of 60° while palpating the axilla with the sue. When an abnormality is identified, the patient should
other hand. Care should be taken to examine the axilla fully have an extended mammographic examination known as a
underneath the pectoral muscles and along the chest wall diagnostic mammogram. Other images to supplement the
toward the latissimus muscle. It is important to examine both standard projections are obtained and may include accentu-
axillae. The supraclavicular region should be carefully exam- ated positions to change the perspective on a suspected lesion,
ined for the presence of enlarged lymph nodes as well. localized “spot” compression, and magnified images. Any
The most common technique for examining the breast for finding should be compared with previous mammograms to
mass lesions involves accentuating the skin of the breast by determine if it is new.
placing the patient’s hand behind her head in the supine posi- The results of all mammograms in the United States must,
tion. The surgeon should develop a standard manner of exam- by Medicare regulations, be classified by a numerical score
ining the breast so that she or he consistently examines the called the Breast Imaging Reporting and Data System
(BI-RADS) [see Table 2].17 A score of 5 denotes an obvious can-
entirety of both breasts. It is generally best to begin the exam-
cer, 4 a suspicious lesion requiring biopsy, 3 a lesion that is
ination with the breast opposite the breast of concern so that
“probably benign” and warrants close follow-up, 2 an obvious
this examination is not forgotten. Most examiners use a pro-
stable benign finding, and 1 a normal study. A score of 0 means
cess of pushing the breast tissue back against the underlying
that additional imaging is required before a score of 1 to 5 is
rib cage starting at the areola and working out in a circular assigned, and a score of 6 is used for a diagnostic mammogram
motion extending through the entire breast, recognizing that with a known biopsy-proven cancer. The scoring system and
the breast tissue extends into the axilla. The character, size, criteria are used to classify the findings of other breast imag-
and location of any masses identified should be noted. The ing.18 This score and/or the specific language related to that
location should be noted using the face of a clock and distance score are included on every mammogram report. A BI-RADS
from the nipple. For example, the location of a mass in the score of 4 and 5 denotes a lesion that is of sufficient concern to
upper outer quadrant of the left breast might be designated as require biopsy.17 Mammography has a relatively low specific-
at the 2 o’clock position, 6 cm from the nipple. The density and ity, with about 60 to 70% of all lesions classified as BI-RADS 4
glandularity of the breast should also be recorded. It is import- or 5 proving to be benign. New technologies may improve the
ant to compare areas of dense glandular tissue with the con- sensitivity and specificity of mammography. Most notable is
tralateral side to identify subtle differences in the size and breast tomosynthesis, which provides a quasi-three-­dimensional
density of breast tissue. Although the primary examination is reconstruction of the breast.19
performed in the supine position, frequently, patients will A key point is that suspicious physical findings (e.g., lump
self-identify a lesion in a position other than the supine posi- or discharge) should be evaluated and biopsied even if breast
tion. The patient should be queried as to whether the lesion is imaging is normal. Mammography only detects 80 to 90% of
breast cancers and is less sensitive in women with dense glan-
palpable and should be examined in the position where she
dular tissue and for lobular cancer.
noticed the lesion.
The skin of the nipple and areola should also be carefully Ultrasonography
examined, and after warning the patient, the nipple may be
Ultrasonography is an adjunctive imaging tool to define the
compressed to elicit a discharge. In cases where the woman characteristics of a lesion identified by other imaging modali-
reports a discharge, sometimes only she can elicit this, and she ties. Ultrasonography itself has not been shown to be a useful
should be encouraged to do so. The character and color of the stand-alone screening tool. Ultrasonography primarily defines
discharge, the specific quadrant of origin, and the number of whether a lesion is cystic or solid. Malignant lesions are solid
ducts with a discharge should be noted. Cytologic examina- and tend to have irregular borders and inhomogeneous acous-
tion of the nipple discharge for “atypical” cells is not useful tic shadowing [see Figure 1a]. When a sonogram shows a
and may be misleading. It should not be considered a neces- sharply defined lesion that transmits the sound completely
sary step for women with a nipple discharge. (fluid), the unequivocal characteristics of a simple cyst, no

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Table 2  BI-RADS Classification16


Category/Definition Optimal Management Probability of Cancer
0 Needs additional imaging Perform additional imaging Not applicable
1 Negative Routine screening Close to 0%
2 Benign Routine screening Close to 0%
3 “Probably benign” Short-term follow-up (usually in 6 months) ≤ 2%
4a, b, and c Suspicious Biopsy Low: 2–10% (a); intermediate: 10–50% (b);
moderate: 50–95% (c)
5 Highly suggestive of cancer Biopsy 95%+
6 Biopsy-proven cancer Imaging done for treatment planning Not applicable
BI-RADS = Breast Imaging Reporting and Data System.

further intervention is needed [see Figure 1b]. For breast lesions breast cancer risk of at least 20 to 25% as estimated using a risk
that have solid components or are completely solid tissue (not model that includes family history.23
fluid), ultrasound features alone are insufficient to define if MRI evaluation of the breast in a woman with a known
the lesion is malignant. Biopsy is usually warranted for a solid cancer has the dual purpose of screening the remainder of
lesion. The exception may be a small mass in a young woman breast tissue as well as providing additional information on
that has the clear characteristics of a fibroadenoma for which the extent of the known cancer.24 MRI detects mammographi-
short-term follow-up in 6 months with ultrasonography may cally occult breast cancer in the contralateral breast in as many
be sufficient [see Figure 1c]. For solid lesions seen on ultraso- as 3% of women.22 MRI may also assist in surgical planning. It
nography, fine-needle aspiration (FNA), core-needle biopsy, is critical to recognize that surgical planning for cancer treat-
or vacuum-assisted needle biopsy may be guided by the same ment cannot be based on the MRI finding alone. A second
ultrasonography. suspicious lesion seen on MRI generally requires biopsy con-
Many surgeons use breast ultrasonography in their office as firmation before it is used to justify more extensive surgery.
an adjunct to the physical examination and to perform biop- Retrospective studies show that the surgical treatment plan-
sies. This should be encouraged if the surgeon is qualified. ning is changed by MRI findings in as many as 20% of cases—
Surgeons who perform ultrasonography in the office need to most commonly alteration from planned breast conservation
to mastectomy.
be fully familiar with its value and limitations and should
MRI should not be used automatically as a routine for all
undergo appropriate training and certification of their skill.
cancers. It might seem intuitive that the added information is
Certification in the use of breast ultrasonography is available
helpful, but it may cause harm. Every study to date that has
through the American Society of Breast Surgeons and is man-
examined the question has failed to show any difference in
datory for surgeons performing ultrasonography as part of a
outcomes, including local recurrence and breast cancer sur-
National Accreditation Program for Breast Centers (NAPBC)
vival by virtue of having presurgical MRI.25,26 However, the
center accreditation20 and for reimbursement from at least one
use of MRI may paradoxically unnecessarily increase the use
insurance company. Surgeon-performed ultrasonography may of mastectomy.
or may not replace ultrasonography performed as part of the MRI may be useful in women with locally advanced breast
radiologist’s diagnostic breast imaging. cancer for whom neoadjuvant chemotherapy is being consid-
Magnetic Resonance Imaging ered to downsize the tumor to allow breast conservation. An
MRI-defined clinical response quantified as changes in enhance-
MRI may be used in breast cancer screening and evaluation ment and in reduction in tumor volume may be prognostic of
of breast cancers.21 With the exception of screening in very ultimate cancer outcome.
young women (under age 30), a key point is that MRI is an
adjunct to mammography and ultrasonography, not a replace- Other Imaging Modalities for the Breast and for Screening for
ment. Specifically, MRI does not identify calcifications, one of Metastatic Cancer
the key hallmarks of breast cancer on mammography. MRI Other breast imaging modalities include sestamibi imaging
visualization of breast cancers requires contrast enhancement and positron emission tomography (PET).27–29 Sestamibi
using intravenous gadolinium. MRI may detect cancers that imaging remains investigational. PET is of minimal value in
are occult on mammography but suffers from a substantial evaluating the primary tumor. Whole body imaging using
rate of false positive findings that leads to otherwise unneces- PET–­ computed tomography (CT), CT, or bone scanning is
sary biopsies and significant patient concern.22 necessary in those patients presenting with locally advanced
Indications for breast MRI continue to evolve. MRI screen- breast cancer because they have a substantial chance of having
ing at annual intervals is useful in women at defined marked distant metastases, which may change treatment plans. How-
increased risk for developing breast cancer, usually by virtue ever, imaging of the asymptomatic patient with clinical stage
of a family history of multiple affected close relatives or per- I and II breast cancer is not appropriate unless there are symp-
sonal history of atypia or lobular neoplasia on previous toms suggestive of metastatic disease.30 The likelihood of find-
biopsy. Consider MRI screening for women with a lifetime ing asymptomatic metastatic disease is very low, and the rate

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Figure 1  Ultrasound images of representative breast lesions demonstrating key characteristics: (a) breast cancer showing irregular borders, inho-
mogeneous echogenicity (solid), and posterior acoustic shadowing; (b) simple cyst showing anechoic interior (fluid), sharp borders, and posterior
acoustic enhancement; (c) fibroadenoma showing homogeneous echogenicity (solid), sharp borders, and normal through transmission of sound, with
no posterior shadowing or enhancement. FN = from nipple.

of falsely positive studies with attendant invasive procedures subsequent cancer care. It may complicate the ability to do
is substantial. Avoiding overuse of staging studies in stage I breast-conserving surgery and eliminate the option for presur-
and II breast cancer is a national standard as codified in gical systemic drug therapy (neoadjuvant therapy). “Patient
guidelines and national quality measures, including the choice” is not a valid reason to justify surgical excisional biopsy
Choosing Wisely effort of the American Board of Internal in place of percutaneous biopsy. If the patient asks for surgical
Medicine Foundation.31 excision in place of needle biopsy, the surgeon should provide
careful counseling so that the woman understands that she
biopsy of suspicious may be harmed by unnecessary surgery.
findings Surgical biopsy without a previous percutaneous needle
A breast lesion suspi- biopsy should be performed only when needle biopsy cannot
cious for malignancy be performed for specific technical reasons. Technical reasons
requires tissue biopsy. that may preclude needle biopsy include the anatomic loca-
Percutaneous needle tion of the lesion close to the chest wall, in the far periphery
biopsy is preferred over of the breast, or very superficially in a small breast, which are
surgical excision. For the all locations that pose difficulty in positioning of the patient or
majority of cases where visualization with stereotactic biopsy equipment. Less than
the lesion proves benign 10% of nonpalpable lesions require surgical biopsy.
by needle biopsy, subse- The most widely used technique for percutaneous needle
quent surgery is com- biopsy is core-needle biopsy or vacuum-assisted needle biopsy
pletely unnecessary. In using a device with a rotating blade inside a needle. These
cases where the lesion is provide sufficient tissue for standard histology and for bio-
a cancer, initial surgical marker assessment. FNA provides cytology only; although
biopsy often leads to the used extensively in the past, FNA only allows cytologic eval-
need for a second reoper- uation. FNA is still widely used in the assessment of axillary
ation on the breast. Initial lymph nodes.
surgical biopsy ulti- Needle biopsy may be directed by surgeon palpation or
mately may compromise image guidance. Lesions that are clearly palpable may be

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accurately localized for biopsy by palpation without using woman with invasive cancer has the risk of harboring occult
imaging equipment. However, it is best to use image guidance microscopic metastatic disease that can ultimately lead to
if there is any question that the lesion is palpable or if the clinically apparent metastatic disease and death.
lesion is not palpable. Core biopsy of the breast can be guided
by different imaging modalities (ultrasonography, stereotac- staging of cancer
tic, or MRI), depending on the character of the lesion, how it Decisions about treatment require accurate information on
is best visualized, and the expertise and preference of the pro- the extent of the cancer, the presence of certain biologic
vider. In general, if the lesion is seen on ultrasonography, this markers and gene expression patterns, and other factors,
is the easiest way to localize the lesion for the patient and the
including age, performance status, and personal preference.
physician. If not, then mammographic localization is used.
One of the key factors impacting treatment is the stage of the
MRI localization for biopsy is tedious for the patient and the
cancer using systems that codify the anatomic extent of the
physician and costly. Its use is reserved for those cases of
lesions seen only on MRI. cancer at the time of diagnosis. The clinically used staging
In most cases, a benign finding on core- or vacuum-assisted system is the TNM system of the American Joint Committee
needle biopsy is definitive, and surgical excision is not neces- on Cancer (AJCC).36 This system categorizes the size and
sary. In a few cases, surgical excision is required for lesions extent of the primary tumor (T), the involvement of regional
defined as benign by needle biopsy. This is needed when the lymph nodes (N), the presence or absence of distant metas-
pathology finding is “nonconcordant” with the imaging find- tases (M) [see Table 3], and a “stage group” derived from the
ing (e.g., only adipose tissue when the imaging shows a solid T, N, and M categories [see Table 4]. The AJCC TNM system
mass). Surgical excision is also generally done when the is currently in its seventh edition, published for use in cases
biopsy shows certain otherwise benign lesions, the most com- diagnosed in 2010 and later [see Table 3]. The eighth edition
mon of which are atypical hyperplasia (ductal or lobular), lob- of the AJCC Cancer Staging Manual is planned for release in
ular carcinoma in situ (LCIS), radial scar, or intraductal late 2016 for use in cases diagnosed beginning January 2017.
papilloma. With these lesions, there is a small chance that Stage should be documented in the medical record at two
there is cancer in the tissue immediately surrounding the distinct points in treatment. Clinical stage is the initial cancer
biopsy-sampled tissue.32,33 The need for surgical excision for stage used in treatment planning and includes information
some of these benign findings on core biopsy remains an area gleaned from the history, the physical examination, and any
of active investigation and controversy.34 It is possible that in available imaging studies prior to the first course of treatment,
the near future we should be able to identify patients in whom whether that is surgery, systemic therapy, or radiation. Clini-
the risk that a specific type of benign lesion found by core cal stage is assigned on the available information; it is not
biopsy harbors a cancer is low enough to allow it to be mandatory to do advanced scan imaging to determine clinical
followed without surgical excision.35 stage. Pathologic stage is the clinical stage supplemented with
the findings from surgical resection (breast and lymph nodes).
When neoadjuvant therapy is used, the extent of disease after
Management of Breast Cancer
treatment is the posttreatment stage. The degree of response
Breast cancer management continues to evolve rapidly, and to neoadjuvant therapy may itself be a significant factor defin-
a review can only provide a foundation to understand ing prognosis. The rules and specifics of the TNM staging sys-
principles of treatment and the basics of current approaches. tem are detailed in the AJCC Cancer Staging Manual.36
Surgeons must remain current with relevant literature and
should refer to national guidelines in making treatment Primary Classes of Breast Cancer
decisions. The most comprehensive guidelines that are
Breast cancers are malignancy of the epithelial cells lining
updated at least annually are supplied by the National
the ductal and lobular system of the breast and emanate from
Comprehensive Cancer Network (NCCN) and are available at
the terminal ductal lobular unit [see Figure 2]. Proliferation of
http://www.nccn.org.30
these cells that fill the duct but do not penetrate through the
Surgical care cannot be done in a vacuum and must be inte-
intact basement membrane surrounding the duct or lobule is
grated with adjuvant therapies, including radiation and sys-
called noninvasive, intraductal, or in situ cancer. These
temic therapy. In many cases, adjuvant systemic therapy is
best administered before surgery (“neoadjuvant therapy”). account for about 20% of all cancers. Even with screening, by
Therefore, although it is not mandatory that every breast can- the time of diagnosis, most cancers exhibit infiltration or inva-
cer patient have a preoperative consultation with specialists in sion of the malignant cells through the basement membrane
each relevant discipline, it is incumbent upon the surgeon to into the surrounding stroma of the breast. These cancers are
ensure that the surgical care is appropriately coordinated and termed invasive or infiltrating cancers.
integrated in an overall breast cancer care plan. The significance of invasion through the basement mem-
Breast cancer management must address two major issues. brane is that these cancers have the potential to spread beyond
The first is the treatment of the local disease in the breast itself the breast. This is accomplished by invasion into surrounding
(“local therapy”). This is generally accomplished through surgi- blood vessels and lymphatic channels that course through the
cal resection with or without radiation. The second is prevention breast. Cancer cells may spread to lymph nodes in the region
of distant recurrence using adjuvant systemic therapy (chemo- (primarily in the axilla) or to other organs of the body
therapy, immunotherapy, and endocrine therapy) because any [see Figure 3].

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Table 3  American Joint Committee on Cancer (AJCC) TNM Staging System: T, N, and M Categories36
Primary tumor, clinical TX  Primary tumor cannot be assessed
(cT) and pathologic
T0  No evidence of tumor
(pT)
Tis  Carcinoma in situ
Tis  (DCIS) Ductal carcinoma in situ
Tis  (LCIS) Lobular carcinoma in situ
Tis  (Paget) Paget disease of the nipple with no tumor
T1 Tumor ≤ 2 cm
T1mic Tumor ≤ 0.1 cm
T1a  Tumor > 0.1–0.5 cm
T1b  Tumor > 0.5–1 cm
T1c  Tumor > 1–2 cm
T2  Tumor > 2–5 cm
T3  Tumor > 5 cm
T4  Tumor of any size with direct extension to chest wall and/or skin
T4a  Extension to chest wall, not including pectoralis muscle
T4b  Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to
the same breast
T4c  Both T4a and T4b
T4d  Inflammatory carcinoma
Regional lymph nodes, cNX  Regional lymph nodes cannot be assessed (e.g., previously removed)
clinical (cN)
cN0  No regional lymph node metastasis
cN1  Metastasis in movable ipsilateral axillary lymph node or nodes
cN2  Metastasis in ipsilateral axillary lymph nodes or in clinically detected ipsilateral internal mammary nodes in
the absence of clinically evident axillary lymph node metastasis
cN2a  Metastasis in ipsilateral axillary nodes fixed to one another (matted) or to other structures
cN2b  Metastasis only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically
evident axillary lymph node metastasis
cN3  Metastasis in ipsilateral infraclavicular lymph node(s) or in clinically detected ipsilateral internal mammary
lymph node or nodes and in the presence of clinically evident axillary lymph node metastasis or metastasis in
ipsilateral supraclavicular lymph node or nodes with or without axillary or internal mammary lymph node
involvement
cN3a  Metastasis in ipsilateral infraclavicular lymph node(s)
cN3b  Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
cN3c  Metastasis in ipsilateral supraclavicular lymph node(s)
Regional lymph nodes, pNX  Regional lymph nodes cannot be assessed (e.g., previously removed)
pathologic (pN)
pN0  No regional lymph node metastasis histologically
pN0(i−)  No regional lymph node metastasis histologically, negative IHC
pN0(i+)  Malignant cells in regional lymph node(s) ≤ 0.2 mm (detected by IHC, including isolated tumor cells)
pN0(mol−)  No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)
pN0(mol+)  No regional lymph node metastasis by IHC or histology, positive molecular findings (RT-PCR)
pN1  Metastasis in one to three axillary lymph nodes and/or in internal mammary nodes with microscopic disease
detected by sentinel lymph node dissection but not clinically detected
pN1mi  Micrometastases (> 0.2 mm and/or > 200 cells, none > 2.0 mm)
pN1a  Metastasis in one to three axillary lymph nodes, at least one metastasis > 2 mm
pN1b  Metastasis in internal mammary nodes with micrometastases or macrometastases; microscopic disease
detected by sentinel lymph node dissection but not clinically detected
pN1c  Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with micrometas-
tases or macrometastases detected by sentinel lymph node dissection but not clinically detected
pN2  Metastasis in four to nine lymph nodes or in clinically detected internal mammary lymph nodes in the
absence of axillary lymph node metastasis
pN2a  Metastasis in four to nine axillary lymph nodes (at least one tumor deposit > 2.0 mm)

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Table 3  American Joint Committee on Cancer (AJCC) TNM Staging System: T, N, and M Categories36
pN2b  Metastasis in clinically detected internal mammary lymph nodes in the absence of axillary lymph node
metastasis
pN3  Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically detected
ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes or
­metastasis in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases
or macrometastases detected by sentinel lymph node biopsy but not clinically detected or in ipsilateral supracla-
vicular lymph nodes
pN3a  Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm) or metastasis to the
infraclavicular lymph nodes
pN3b Metastasis in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more
positive axillary lymph nodes or in more than three axillary lymph nodes and in internal mammary lymph nodes
with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected
pN3c  Metastasis in ipsilateral supraclavicular lymph nodes
Distant metastases (M) M0  No clinical or radiographic evidence of distant metastases
cM0(+)  No clinical or radiographic evidence of distant metastases but deposits of molecularly or microscopically
detected tumor cells in blood, bone marrow, or nonregional nodes < 0.2 mm without symptoms or signs of m
­ etastases
M1  Distant detectable metastases as determined by classic clinical and radiologic means and/or histologically
proven > 0.2 mm
IHC = immunohistochemistry; RT-PCR = reverse transcriptase–polymerase chain reaction.
Clinical detection is defined as detection by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for
malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination.
Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without
subsequent axillary lymph node dissection is designated as “sn” for sentinel node (e.g., pN0(sn)).
“M” is classified as clinical M0 (cM0) unless there is clinical or radiologic evidence of metastases (classified as cM1) or pathologic confirmation of metastases (pM1). Imaging
staging tests are not required to classify a case as cM0. “MX” has no meaning and is not a category used in AJCC/TNM staging.

Noninvasive Cancer considerable discordance among pathologists—in other words,


(Carcinoma In Situ) a lesion called DCIS by one pathologist may be deemed atyp-
In situ lesions include ical hyperplasia by others.34 The standard treatment of these
ductal carcinoma in situ entities is vastly different despite the fact that there is overlap
(DCIS) and a benign in the histologic findings. This suggests that “stand­ard treat-
entity called lobular car- ment” leads some women to receive significant overtreatment.
cinoma in situ (LCIS). Surgeons should be aware of these issues and advise their
The hallmark is that the patients thoroughly.
neoplastic cells fill the lobular carcinoma in situ
duct or lobule and do
not penetrate the base- LCIS is not cancer in that it has no metastatic potential.
ment membrane. Rather, it is a benign lesion and does not require cancer treat-
The use of the term ment per se. Its presence indicates that an individual has a
carcinoma for these enti- higher risk than average of breast cancer in either breast over
ties is considered by a lifetime. The use of the term carcinoma to describe this entity
many to be misleading has long been challenged as it misleads physicians and causes
as the large majority of substantial unwarranted concern among patients. LCIS is
women with these enti- characterized by small uniform cells confined to the lobule of
ties will never progress the breast. It is generally a clinically and mammographically
to have an invasive can- occult lesion that is identified only incidentally when a biopsy
cer that has any meta- is performed for calcifications or a mass that proves to be
static or life-threatening some other benign lesion.
potential. They may be better classified as neoplastic lesions The primary issue for women with LCIS is that they have
analogous to the way carcinoma in situ of the uterine cervix an increased lifelong risk of subsequent invasive cancer of
has been classified as intraepithelial neoplasia. A recent approximately 0.5 to 0.75% per year.37 In addition, when LCIS
National Cancer Institute task force specifically called for is identified on a core-needle biopsy, there is some chance of
reclassification of these breast lesions without use of the term DCIS or invasive cancer in the surrounding tissue. Many
carcinoma.7 These controversies underscore the uncertainty advocate that women with a core biopsy showing LCIS should
regarding the natural history of these lesions and raise con- undergo surgical excision of the involved tissue, but others
cern that many of the standard treatments outlined below believe that this may be unwarranted.35,38,39
result in the overtreatment of many women with DCIS and Long-term follow-up shows that the large majority of
LCIS. Furthermore, within the spectrum of pathologic find- women with LCIS never develop invasive breast cancer.
ings of atypical hyperplasia (considered benign) and DCIS Therefore, ablative surgical therapy and radiation for LCIS are
(considered malignant), recent evidence shows that there is not necessary. Previously, LCIS was considered an indication

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Table 4  American Joint Committee on Cancer TNM Staging System: Anatomic Stage/Prognostic Groups36
Stage Group T N M
0 Tis N0 M0
1A T1 N0 M0
1B T0 or T1 N1mi M0
T0 N1 M0
IIA T1 N1 M0
T2 N0 M0
T2 N1 M0
IIB
T3 N0 M0
T0 N2 M0
T1 N2 M0
IIIA
T2 N2 M0
T3 N1 or N2 M0
IIIB T4 Any N M
IIIC Any T N3 M0
IV Any T Any N M1
1. Record clinical stage prior to initiation of treatment based on the physical examination and imaging. Advanced body imaging is not required to assign “clinical M0 (cM0).”
2. Record pathological stage based on clinical information prior to surgery and surgical findings, but only if surgery comes before systemic therapy or radiation.
3. Record posttherapy stage based on clinical and imaging information prior to treatment and on status after treatment for patients receiving presurgical (neoadjuvant) therapy.
4. Use clinical M status (cM0 or cM1) for both clinical stage group and pathologic stage group unless there is pathologic confirmation of distant metastases.

for bilateral mastectomy because of the risk of subsequent ductal carcinoma in situ
cancer. However, mastectomy is not indicated solely because The histologic hallmark of DCIS is the presence of
of LCIS. The risk of cancer is low enough, and the likelihood malignant-­appearing cells confined to the lumen of the breast
that it will be discovered on screening and successfully ductal system without invasion through the ductal basement
treated is high enough, that observation without aggressive membrane. DCIS is most often diagnosed because of the pres-
intervention is the best option for women with LCIS. Mas- ence of calcifications clustered in one area of the breast. The
tectomy may be performed in a few individuals in the con- calcifications suspicious for DCIS are most often linear (not
text of risk reduction for those at very high risk related to round), clustered in a single location of the breast, and aligned
additional factors such as inherited susceptibility (e.g., with in a ductal distribution pattern. The area of involvement in
known mutations in breast cancer–related genes).40 the breast with DCIS may not be limited to the extent of cal-
Women with LCIS should be counseled regarding lifetime cifications, and not all DCIS manifests as microcalcifications.
breast cancer risk and may benefit from consultation with It is uncertain whether all DCIS is a precursor to invasive
genetics professionals especially if they have a family history cancer and will therefore progress to invasive cancer if left
of breast and/or ovarian cancer. Women with a biopsy show- untreated.46 It is likely that some forms of what we call DCIS
ing LCIS may also consider risk-reducing chemoprevention are more akin to atypical ductal hyperplasia and serve pri-
with one of the selective estrogen receptor modulators marily as a marker of risk of developing a future breast can-
(SERMs), tamoxifen or raloxifene, or the aromatase inhibitor cer anywhere in the breast and not directly progressing to
exemestane. These reduce the risk of subsequent invasive invasive cancer at that specific site. It is hoped that research
cancer by about 50% with an acceptable toxicity profile.41–43 will identify which lesions currently classified as DCIS
Tamoxifen is the only chemoprevention agent approved for require ablative treatment and which are benign and require
use in premenopausal women. Raloxifene and exemestane no intervention. Unfortunately, despite extensive research, at
are the preferred agents in postmenopausal women. this point, there are no markers or other characteristics that
Pleomorphic LCIS is a very uncommon variant of LCIS can accurately define which DCIS may progress to invasive
characterized by cells confined to the breast lobule with var- cancer.47,48 Therefore, most women diagnosed with DCIS still
ied size, shape, and nuclear configuration. It has many of the undergo the current standard treatments, as outlined below.
histologic characteristics of DCIS but is clearly lobular in that However, there is intense interest in this issue because it is
it does not express the transmembrane protein E-cadherin. likely that many women currently treated for DCIS do not
Pleomorphic LCIS may behave similarly to DCIS with a pre- need aggressive treatment.7,49–51
dilection for local recurrence and progression to invasive can- DCIS encompasses a spectrum of histologic subtypes all
cer. Because it is quite uncommon, there are limited data on characterized by malignant-appearing cells confined to the
its behavior and outcome. However, many experts believe lumen of the breast ducts. However, the appearance ranges
that there is sufficient anecdotal evidence to support treating from bland uniform cells growing from the wall of the duct
pleomorphic LCIS as we treat DCIS (see below) with wide or bridging the duct (papillary, cribriform) to cells filling the
excision to negative margins and consideration of adjuvant entire duct [see Figure 4]. These cells also vary in nuclear mor-
radiation therapy.44,45 phology, ranging from low-grade, uniform-appearing nuclei

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Figure 2  Structure of breast.

to varying size and shape and large nuclei (high grade) and Treatment
also in the presence or absence of central necrosis within the
The overall cancer-specific survival for women with DCIS
duct. The combination of high nuclear grade and central
approaches 100% irrespective of the subtype of DCIS and the
necrosis is termed comedo DCIS or comedocarcinoma.
type of treatment.46 Mastectomy is effective in DCIS, but in
The primary clinical relevance of the DCIS subtypes is that
most cases, breast-conserving therapy (BCT) is the most rea-
they may have different potential for local recurrence after
sonable and appropriate approach because it provides the
breast-conserving surgery. The presence of high-grade cells same very low risk of cancer-related death.
or comedonecrosis is not an indication of any metastatic The primary purpose of breast surgery with DCIS is to
potential and does not itself warrant systemic therapy or prevent progression of the DCIS to invasive cancer and the
lymph node staging but may denote a higher risk of future recurrence of cancer at the original site—so-called local recur-
recurrence in the breast. This may impact on the decision to rence. Local recurrence can occur after mastectomy or BCT.
use radiation after breast-conserving surgery. Recurrence in the skin of the mastectomy site or on the chest

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Figure 3  Impact of basement membrane invasion: invasive cancer.

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Figure 4  Histologic subtypes of ductal carcinoma in situ.

wall muscle (local recurrence) is very uncommon, with a risk BCT for DCIS consists of surgical excision (lumpectomy or
of about 0.5 to 3%.52 The risk of local recurrence with wide excision) of the DCIS with some surrounding normal
breast-conserving surgery is related to a number of patient breast tissue to achieve a negative margin. It is often supple-
factors, including age, the histologic features of the DCIS, the mented by radiation therapy to the breast. The choice between
size of the DCIS, the extent of surgery, and the use of radia- BCT and mastectomy is influenced by the size of the area of
tion and antiestrogen endocrine therapy. Younger women involvement, the size of the breast, and the location of the
have a slightly higher risk of local recurrence. DCIS. There is no specific size of a lesion that mandates

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Figure 5  Specimen mammogram of breast cancer–localizing wire. Note the malignant-appearing calcifications in the center of the specimen and
unrelated vascular calcifications in the periphery of the tissue.

mastectomy, and the use of wide excision with a generous tissue around the end of the wire. To confirm removal of the
resection of breast tissue can be accomplished in most women. area of concern, an x-ray image or specimen mammogram is
The use of breast-conserving surgery has been expanded to obtained during surgery [see Figure 5]. An alternate technique
women previously thought to require mastectomy for larger for localizing the area for excision is placement of an iodine-
or extensive DCIS through the use of so-called oncoplastic 125-labeled seed that is identified with a radioactive detector
surgery.53,54 This allows resection of larger sections of the breast during surgery.55
and rebuilding of the breast to provide an excellent cosmetic The specimen then must be carefully oriented so that if the
outcome. Reconstruction of the breast mound is available to cancer is close to one margin, the pathologist can identify the
most women who require or choose mastectomy for DCIS. specific margin (e.g., anterior, posterior, medial, lateral, supe-
Breast reconstruction may be performed at the same time as rior, inferior). This is most commonly accomplished by paint-
the mastectomy using implant techniques or tissue transfer ing the surface of the tissue with ink, using a separate color of
using a variety of tissue flaps (see below). ink for each of the six margins [see Figure 6]. The pathologist
A key factor to successful BCT for DCIS is obtaining a neg- can see this thin line of ink microscopically and determine the
ative surgical margin. The margin is defined as the distance distance in millimeters of cancer cells from the margin.
measured in millimeters between the edge of the surgical Another surgical technique to evaluate margins is to
specimen and the closest tumor cells. The margin status may remove separate surgical specimens from each margin after
affect the risk of local recurrence in DCIS and invasive cancer. removal of the cancer. For each margin, a “shave” of the sur-
gical cavity a few millimeters thick is obtained. Any cancer in
Surgical Considerations these shave specimens defines a positive margin, and the
At surgery, it is imperative that the breast lumpectomy absence is defined as negative. One randomized trial with
excision specimen be properly handled to allow determina- invasive cancer showed a lower rate of reexcision and posi-
tion of whether the cancer abuts the edge of the resected tis- tive margins with this technique.56
sue (margin). The first step is proper identification of the area A positive margin is one where cancer cells are present at
to be removed. Because DCIS is not palpable, the mammo- the edge of the resected tissue. Because the DCIS may extend
gram or other images must be used to identify the area to be beyond the area of calcifications seen on mammography, the
removed. This is most commonly done by inserting a fine rate of positive margins on the initial excision for DCIS range
wire into the breast to the area of the cancer, termed wire is as high as 20 to 25%. Women who have a positive margin
localization or needle localization. The surgeon removes the on the initial excision for DCIS should undergo repeat surgery

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Figure 6  Breast cancer wide excision specimen painted with six colors of ink to orient the specimen for pathologic analysis of surgical margins.

to obtain a negative margin. On occasion, even with such Choice of Breast Surgery
reexcision, the DCIS extends to the new margin, and further Most women with DCIS can be treated with breast-­
reexcision is needed. Some of these women ultimately require conserving surgery—commonly referred to as “lumpec-
mastectomy. tomy”—often combined with breast radiation. Some women
The definition of a negative margin is an area of ongoing require mastectomy for DCIS. The most common indication
discussion.57,58 The clinical trials of local therapy in DCIS from for mastectomy is extensive DCIS involving a large portion of
the National Adjuvant Breast and Bowel Project (NSABP) dis- the breast or documented in multiple locations in the breast.
cussed below used the definition of a negative margin as the However, the definition of “extensive” is not always clear-cut.
absence of the ink used to paint the surgical margin on any For many patients, the choice between mastectomy and
cancer cells (no ink on the tumor). In women treated without breast conservation may be difficult. As DCIS is rarely a
radiation, the lowest recurrence rates are among women with threat to life, the small long-term risk of a second breast
a full 1 cm margin of normal tissue around the DCIS.59 How- malignancy is inevitably incorporated into this decision.
ever, removing this much breast tissue may leave a significant Some women with disease treatable by breast conservation
breast defect. In conjunction with radiation, a margin of 2 mm still select mastectomy. The choice may also be influenced by
is required to obtain optimal rates of local recurrence with the risk of developing a subsequent second breast cancer
DCIS.60 However, a recent guideline primarily focused on related to family history and biologically defined inherited
invasive cancer reiterated that there are no concrete data susceptibility. Some patients elect mastectomy to avoid radi-
showing that any distance of tissue for a negative margin ation as well. Patients should receive careful counseling
greater than “no ink on the tumor” provides any lower risk regarding surgical options, a personalized surveillance plan,
of recurrence.61 It is not clear if this recommendation applies and reassurances regarding the long-term outlook for women
to DCIS or if a margin of 2 mm or greater is warranted. with DCIS.62

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Radiation Therapy Lymph Node Surgery


Large-scale randomized clinical trials in North America DCIS does not spread beyond the breast; therefore, lymph
and Europe demonstrated the effectiveness of BCT and the node surgery is not necessary for DCIS. However, in 10 to
impact of radiation in minimizing the risk of local recurrence 20% of cases where there are only calcifications seen on imag-
in DCIS.63 Trials conducted in the 1980s and 1990s by large ing and DCIS on the needle biopsy, an invasive cancer will
cooperative oncology research groups, including the NSABP be identified in the final surgical resection specimen. Because
and the European Organization for Research and Treatment lymph node surgery may be necessary for those for whom
of Cancer (EORTC), compared wide excision alone versus the excision shows invasive cancer, some surgeons have
wide excision plus radiation therapy.64–68 Every study reported advocated lymph node surgery in all women with DCIS
long-term overall cancer-specific survival approaching 100% found by needle biopsy.
irrespective of treatment. However, women treated by This is not appropriate in most cases because women
breast-conserving surgery without radiation had a higher rate undergoing BCT can undergo sentinel lymph node biopsy
of recurrence in the same breast (local recurrence) than those (SLNB, described below under treatment of invasive cancer)
treated with radiation. The rate of local recurrence in the first at a subsequent surgical procedure with the same level of
trial, conducted in the 1980s (NSABP B-17 study), was over accuracy as if done at the time of excision if an invasive can-
30% without radiation and about 12% with radiation.64 This cer is identified in the final surgical specimen [see the discus-
60% relative reduction in the risk of local recurrence with the sion of SLNB in the section on invasive cancer, below]. SLNB
use of postoperative radiation is consistent across other stud- carries some risk of long-term morbidity. Every prospective
ies. Recurrences are mostly in proximity to the site of the orig- study demonstrates that women with SLNB have a signifi-
inal DCIS. In one half to two thirds of cases, the recurrence is cant risk, averaging about 6%, of at least mild permanent
DCIS but is invasive cancer in the remainder.69,70 swelling of the arm called lymphedema.81–83 Therefore, with
The standard radiation treatment is breast radiation ther- breast-conserving surgery for DCIS, SLNB should not be per-
apy to the entire breast to a dose of about 50 Gy coupled with formed at the time of surgical excision and should be reserved
only for those for whom the excision reveals invasive cancer.
an additional 15 Gy administered to the site of the surgical
Exceptions to this rule include cases where initial evalua-
excision (termed a boost). The use of whole breast radiation
tion prior to excision shows the presence of a mass suspicious
reduces the risk to a low level that may in some cases be
for invasive cancer on imaging or on physical examination or
reduced even further by use of an antiestrogen hormonal
when the DCIS is in the axillary tail of the breast and excision
agent (tamoxifen or an aromatase inhibitor; see below).
may preclude subsequent SLNB because of interruption of
Because most local recurrences occur in the breast tissue
lymphatic flow to the axilla. Another exception is when mas-
close to the original DCIS, it is possible that radiation admin-
tectomy is used for DCIS, SLNB is appropriate because mas-
istered only to the affected region of the breast may be as
tectomy may preclude subsequent SLNB due to disruption of
effective as whole breast radiation therapy. Techniques for
lymphatic flow and would therefore commit women to full
administering so-called accelerated partial breast irradiation
axillary lymph node dissection (ALND) if invasive cancer
(APBI) therapy allow treatment to be delivered over a much were identified in the mastectomy specimen.
shorter period of time (as short as 5 days or even a single
intraoperative dose), making it an attractive alternative.71–73 Adjuvant Systemic Therapy
However, as of 2015, there are limited long-term data demon- In women who undergo radiation with DCIS, clinical trials
strating the effectiveness of APBI in DCIS and some data have shown that adjuvant endocrine therapy reduces the risk
showing a higher rate of local recurrence with APBI, so its of local recurrence. The NSABP B-17 trial showed that tamox-
use remains controversial.73–75 ifen reduced local recurrence by 40% after lumpectomy and
Substantial research has focused on identification of those radiation.84 A subsequent trial (NSABP B-35) comparing the
women with DCIS who may not require radiation after aromatase inhibitor anastrozole with tamoxifen in postmeno-
breast-conserving surgery. Some evidence from nonrandom- pausal women after excision and radiation for DCIS showed
ized series suggests that for some subsets of women with an additional 27% reduction in local recurrence and new
DCIS, most notably those with a small area (size) of DCIS breast cancers with anastrozole.85 Therefore, anastrozole is a
coupled with a low or intermediate nuclear grade and a clear option in place of tamoxifen in postmenopausal women.
greater width of the resection margin, the risk of local recur- The use of endocrine treatment in DCIS must be balanced
rence with surgery alone is substantially less than 10%—a against the toxicity of the selected drug, recognizing that
rate low enough to warrant omission of radiation.76–78 How- endocrine therapy is not lifesaving in this situation. There are
ever, subset analysis of the randomized trials has been unable no data supporting the use of endocrine therapy in women
to identify any group of women for whom radiation does not treated for DCIS with mastectomy, but it may be considered
reduce the risk of local recurrence.63 This remains an area of because of its potential impact on reducing the risk of a can-
active research, with investigators trying to identify molecu- cer in the contralateral breast.
lar profiles and other features that identify those cases of
DCIS likely to have a local recurrence and/or progress to paget disease of the breast
invasive cancer.79 The use of radiation or the decision to omit Paget disease of the nipple is an uncommon presentation of
radiation therapy with DCIS requires careful counseling of breast cancer. The hallmark of Paget disease is eczematous
the patient coupled with multidisciplinary input.80 changes directly in the nipple, often with beet red and ulcerated

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skin on the nipple and surrounding areola. This is due to lobular carcinoma may be more insidious because of the infil-
malignant cells called Paget cells occurring in the nipple skin trative nature of the disease, making it more difficult to detect
that have a characteristic “fried egg” microscopic appearance. by mammographic or clinical means.
In most cases of Paget disease, there is DCIS or invasive can-
cer in the underlying breast. Molecular Classification
Women with pagetoid changes in the nipple are often mis- Breast cancers are also classified by biologic or molecular
diagnosed as having benign skin conditions and are treated characteristics. These provide information about the likeli-
with topical steroids. If such treatments are used and the hood of developing distant metastases and long-term prog-
lesion does not resolve, or if there is any clinical suspicion of nosis, as well as information on sensitivity to specific drugs
Paget disease, a biopsy of the affected skin is needed. If the to help guide therapy. One of the key characteristics is the
biopsy shows Paget disease, then the breast should be care- microscopic grade of the cancer. Grade is generally classified
fully imaged by mammography. MRI may be useful if the as 1, 2, or 3, corresponding, respectively, to low, intermediate,
breast is dense or the mammogram is negative. If a breast and high grade. The pathologist classifies grade on the basis
lesion is found, it too should be biopsied. of the microscopic appearance. The most reliable way of
Treatment is generally based on the type (in situ or invasive) defining grade that pathologists should use for all breast can-
of primary tumor in the breast. Both the cancer in the breast cers is the modified Bloom-Scarf-Richardson grade, also
and the nipple should be treated. This may be accomplished referred to as the Nottingham grade.88 In this system, the
in many cases with removal of the nipple in continuity with pathologist assigns a level of 1, 2, or 3 to each of three char-
the breast cancer, followed by radiation.86 Mastectomy is still acteristics of the cancer: nuclear pleomorphism, tubule for-
often used but may be reserved for cases with more extensive mation, and mitotic count. The sum of these individual
involvement.87 Lymph node surgery with SLNB is warranted features assigns a score from 3 to 9. A score of 3 to 5 is grade
only with invasive cancer or mastectomy. Adjuvant systemic
therapy is administered by standard guidelines based on the
stage and biomarker expression found in the invasive cancer.

Invasive Breast Cancer


classification
The majority of breast
cancers are classified as
invasive or infiltrating,
characterized by the epi-
thelial cells invading
through the basement
membrane of the duct or
lobule. Properties that
allow basement mem-
brane invasion also
allow the malignant
cells to invade surround-
ing blood vessels or
lymphatic channels and
therefore carry the pos-
sibility of spread to dis-
tant sites. Most have
probably not spread as
assessed by long-term survival without distant metastases.
However, the treatment of invasive breast cancer must
include both the local treatment of the breast and consider-
ation of adjuvant drug therapy because of the potential for
distant spread.
The majority of breast cancer arises from the ductal compo-
nent of the terminal ductal lobular unit and is termed inva-
sive ductal cancer. An additional 10 to 15% arise within the Figure 7  Microscopic appearance of invasive ductal and invasive
lobule, termed invasive lobular cancer, which is character- lobular cancer. (a) Invasive ductal cancer showing nests of tumor cells
with formation of tubules. Note two large ducts at the top of the image
ized by small cells infiltrating in a linear fashion through the
showing a component of cancer cells confined to the duct: ductal carci-
breast stroma [see Figure 7]. Invasive lobular carcinoma car-
noma in situ. (b) Invasive lobular cancer showing an infiltrating process
ries the same risk of distant metastases as invasive ductal of lines of small single cells (often termed Indian filing). These are lin-
carcinoma. Therefore, the treatment and prognosis are those ear groups of cells one cell layer–thick surrounding benign ducts in the
of a comparably staged invasive ductal carcinoma. However, center of the image.

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invasive cancer. Some pathologists may overuse assignment


Table 5  Nottingham Grading System for
of these subtypes in cases where only a small portion of the
Invasive Breast Cancer tumor has the requisite characteristics. Because of the poten-
Feature of Cancer Assigned Score tial overuse of these subgroup terms and the therapeutic
Tubule formation implication, great care should be taken in making treatment
  Majority of tumor (> 75%) 1 decisions based on pathology reports assigning these sub-
groups. The surgeon is best advised to review the findings
  Moderate degree (10–75%) 2
carefully and dialogue with the interpreting pathologist
  Little or none (< 10%) 3 before acting.
Mitotic count Inflammatory breast cancer is a variant of invasive ductal
  0–9 mitoses/10 HPF 1 cancer characterized by rapid onset and skin edema and ery-
  10–19 mitoses/10 HPF 2
thema encompassing over one third of the breast.97 It has an
especially high likelihood of subsequent metastases and
  20 or more mitoses/10 HPF 3
death. It often correlates with the histologic finding of dermal
Nuclear pleomorphism lymphatics clogged by tumor cells, but the diagnosis of
  Small regular, uniform 1 inflammatory cancer is made clinically based on the skin
  Moderate size and variation 2 appearance. Skin biopsy showing dermal lymphatic involve-
ment is not necessary to classify a cancer as inflammatory.36,97
  Marked nuclear variation 3
A complete and understandable pathology report is the
Combined Histologic Grade Total Score
cornerstone of breast cancer treatment. Ambiguity can lead to
  Low (I) 3–5 misclassification and inappropriate treatment. Pathology
  Intermediate (II) 6–7 findings for breast and all cancers should be reported using
  High (III) 8–9 structured documents according to the templates provided
HPF = high-power field.
by the College of American Pathologists (http://www.cap.
org). Surgeons should be sure that testing for their patients is
performed and reported in accordance with these standards.
1, 6 to 7 is grade 2, and 8 to 9 is grade 3, with a corresponding
worsening prognosis with increasing grade [see Table 5]. treatment
The other key markers in breast cancer are the hormone The treatment of invasive breast cancer includes treatment
receptors for estrogen and progesterone and the level of of the breast itself with surgery or surgery and radiation
expression or amplification of the HER-2/neu gene.30 These (termed local therapy) and consideration of drugs to reduce
should be tested in all invasive breast cancers. They provide the chance of death from distant metastases (termed systemic
key prognostic and predictive information about the sensitiv- therapy). Historically, surgery has been the initial step in
ity of the cancer to specific drugs. It is expected that biologic treatment. However, increasingly, treatment begins with sys-
classification of breast cancers beyond these three markers temic chemotherapy or endocrine therapy before surgery
will ultimately allow a higher degree of personalization of (termed neoadjuvant therapy). Coordinating the local and
both local and systemic treatment.89–94 systemic therapies is critical to achieve optimal outcomes.
In 2015, there was increasing use of genomic sequencing of
breast and other cancers to identify specific molecular defects Local Therapy: Surgery and Radiation
that may be targeted with drugs or other therapies. Although The primary goal of local therapy of breast cancer is erad-
currently clinical practice relies primarily on the hormone ication of the primary tumor to prevent progression and fur-
receptors and HER-2, the surgeon is well advised to stay cur- ther dissemination of the disease and to minimize the risk of
rent in this field as changes may impact the type of surgery local recurrence. In addition, surgery to remove regional
and the timing of surgery vis-à-vis systemic therapy. lymph nodes for pathologic examination provides staging
Certain histologic subtypes of invasive ductal cancer that and prognostic information, guides systemic treatment, and
account for about 15% of cases may have a higher or lower provides regional control in the common regional nodal
propensity to spread and a different prognosis than that of basins. Although surgery is still most often the initial treat-
typical invasive ductal cancer. These include tubular carci- ment of breast cancer, neoadjuvant therapy should be consid-
noma, mucinous (colloid) carcinoma, medullary carcinoma, ered in cases of large tumors, those with lymph node
metaplastic carcinoma, and inflammatory carcinoma. Tubular involvement, or cancers with particular aggressive features
and mucinous carcinomas may have a lower rate of lymphatic such as HER-2 overexpression or amplification.
metastases and a generally better prognosis than typical duc-
tal cancers.95,96 Medullary cancer, characterized by extensive Breast surgery  Historically, local treatment for resectable
lymphoid cell infiltration within the tumor, was historically breast cancers meant mastectomy. One can argue that the
considered a cancer with a better prognosis. However, the development of the operation of radical mastectomy was the
term can be overapplied based on pathologic criteria, and single most important advance in the treatment of breast
most cancers classified as medullary are actually high-grade cancer. At the time it was developed in the late 1800s by pio-
cancers with a poor prognosis. Standard guidelines do not neering surgeons including William Halsted, most women
assign medullary cancer to a good prognosis subgroup.30 Met- presented with breast cancers that were locally advanced and
aplastic cancer is an epithelial cancer with elements of squa- were likely to progress to painful and infected chest wall
mous differentiation. It has a worse prognosis than typical tumors. Radical mastectomy provided temporary or even

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permanent control of the cancer in the breast. Although many 1978 by the NSABP B-06 trial on which women with cancers
still progressed with metastatic cancer at some point, radical 4 cm or less in size were randomly assigned to receive mas-
mastectomy controlled symptoms, eradicated the cancer in tectomy, lumpectomy alone, or lumpectomy plus radiation
the breast, and provided most with a high-quality life for therapy.99 Long-term follow-up on this trial demonstrated no
some time free of the progressing, locally infiltrative cancer.98 difference in overall survival between the three groups [see
The ability to treat breast cancer effectively led to women Figure 8]. However, with lumpectomy alone, the cancer
presenting with smaller cancers. Today, the number of recurred in the same breast in 40% of women. Radiation
women with these terrible advanced local tumors is small, reduced the rate of local recurrence to approximately 12%.
and the classic radical mastectomy is rarely required. How- On the basis of this finding, coupled with those of other stud-
ever, it was not until the 1960s that the so-called “Halstedian” ies, lumpectomy plus radiation therapy became an accepted
thesis that breast cancers progressed in a stepwise fashion standard in the 1980s and was widely used thereafter.
from the breast (local) to lymph nodes (regional) to distant Subsequent studies in more recent decades in which women
disease (metastases) was proven incorrect and that the need had therapy under current standards of pathology, surgery,
for the extended radical procedures was questioned. and radiation and received stage- and biomarker-appropriate
In the 1970s and 1980s, landmark clinical trials demon- adjuvant systemic therapy have extended the initial findings
strated that breast cancer is a systemic disease with the possi- supporting breast conservation. As outlined below, local
bility of disseminated disease even at the smallest size primary recurrence with BCT is as low as, or even lower than, that
tumor and that removal of the tumor without mastectomy with mastectomy. Indeed, recent population studies suggest
provided a long-term outcome equivalent to mastectomy. The that survival may be better with breast-conserving surgery
first of these studies, the NSABP B-04 study, compared radi- than with mastectomy.100
cal mastectomy with removal of the breast, pectoralis muscle, This review does not provide detailed information on the
and all regional lymph nodes to simple mastectomy without technical performance of breast surgery. For this the reader
removal of the pectoralis muscle or lymph nodes. This study is directed to search this publication for breast procedures
showed that extended surgery and lymph node removal and to the American College of Surgeons’ 2015 publication
do not improve survival. This was followed immediately in Operative Standards for Cancer Surgery.101

100 Mastectomy

Lumpectomy

80 Lumpectomy+Radiation
Percent Surviving

60

40

20

0
2 5 8 12 16 20

Years from Diagnosis

Figure 8  Overall survival from the NSABP B-06 Study; p = .57 for three-way comparison among treatment groups. Adapted from Fisher
B et al.99

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to neoadjuvant systemic therapy and patients with a history


Table 6  Relative Indications for Mastectomy of previous radiation treatments to the breast, as with a pre-
Extensive invasive or in situ cancer with failed breast-conserving vious breast cancer or other cancers, such as Hodgkin lym-
surgery phoma. Mastectomy may also be needed if surgical margins
Positive margins despite reexcision (no absolute limit on number remain positive despite reexcision (often more than one reex-
of reexcisions)
cision). BCT is not advised for inflammatory breast cancer
Multicentric cancer (more than one cancer) in separate
quadrants/separated by 5 cm because of the likelihood of microscopic multicentric cancer
Diffuse microcalcifications related to cancer (e.g., extensive DCIS within the breast and within the skin of the breast.
component)
Large cancer in relation to size of breast (consider neoadjuvant Oncoplastic breast surgery  One of the reasons often cited
therapy)
for mastectomy is the need to resect a large area of the breast,
Previous radiation to ipsilateral breast where radiation would
provide excessive dose to chest wall with the resulting poor appearance of the breast. Over the last
Patient preference, especially with inherited susceptibility; careful 10 years, a new area of breast surgery has evolved that applies
counseling required plastic surgery principles to reconfiguring the breast after re-
DCIS = ductal carcinoma in situ. section of a large specimen. This is called oncoplastic breast
surgery.53,54 A variety of techniques allow preservation of the
breast and its normal sensation and appearance where previ-
Margins with BCT  Successful BCT requires surgical exci- ously mastectomy was performed. This may be done inde-
sion of the cancer to obtain negative margins of resection pendently by a qualified and experienced breast surgeon or in
around the tumor. As with DCIS, major clinical trials testing collaboration with a plastic surgeon.
BCT defined a negative margin as no ink on the tumor
[see Figure 6]. In 2013, a task force sponsored by the Society of Breast reconstruction  Women treated with mastectomy
Surgical Oncology (SSO) and the American Society for Thera- may consider reconstruction of the breast mound performed
peutic Radiation Oncology (ASTRO) concluded a detailed either at the time of mastectomy (immediate reconstruction)
analysis of available data on the impact of margin width on or at a later time (delayed reconstruction).102 Immediate recon-
recurrence and published a guideline recommending that the struction is reasonable in women with early-stage breast cancer.
only margin width required to provide optimal low risk of However, the potential need for postmastectomy radiation
local recurrence is no ink on the tumor.61 The task force also must be considered in reconstruction planning.103 Although
cautioned that aggressive surgery to obtain wider margins satisfactory cosmetic outcomes may be obtained even with
provides no improvement in the risk of local recurrence and radiation to the implant, radiation increases the rate of painful
may be harmful by requiring repeated surgeries, potentially contracture. Decisions regarding immediate breast reconstruc-
producing inferior cosmetic results and leading more women tion should be made in collaboration with the entire multidis-
to otherwise unnecessary mastectomy. ciplinary treatment team. Conversely, delayed reconstruction
Therefore, BCT should provide a negative margin defined requires that the woman live without the reconstructed breast
by no ink on the tumor. If there is cancer (invasive or DCIS) at for a period of 1 to 2 years and may be more difficult to per-
the resection margin, additional surgery to remove more tissue form because there is less skin remaining from the original
at this margin is necessary. A specific exception where a pos- mastectomy to be used in reconstruction. However, more
itive microscopic margin may be acceptable is at the chest wall advanced cancers, such as those invading the skin or chest
where the pectoralis fascia has been taken and anteriorly at wall (T4) or extensive node involvement, are best treated by
the skin. Otherwise, if a negative margin cannot be obtained mastectomy without immediate reconstruction.
with lumpectomy, including with a second or occasionally a Options for breast reconstruction include prosthetic recon-
third operation for reexcision, mastectomy is necessary. struction with an implant or tissue expander generally placed
Unfortunately, a substantial percentage of women require beneath the pectoralis major muscle or transfer of autologous
more than one operation on the breast to achieve a negative tissue from another region in the body.102 Implant reconstruc-
margin. Careful management and attention to detail limit the tion is generally simpler and quicker to perform but may not
need for reexcision. Factors that minimize the need for reex- leave as attractive an aesthetic result. Complications of
cision include obtaining a diagnosis before any surgery implant reconstruction include contracture around the
through the use of needle biopsy, careful preoperative plan- implant (that may be exacerbated if radiation is necessary)
ning and imaging localization, and careful collaboration with and infection resulting in loss of the implant.
the radiologist and pathologist in intraoperative management Autologous tissue reconstruction often leaves a superior cos-
of the surgical specimen. metic result but at the cost of more complex surgery, longer
A majority of women with cancers less than 5 cm in size recovery, and the potential for complications at the site of the
may be treated with BCT. However, some require mastec- donor tissue. The most common donor sites are the rectus
tomy [see Table 6]. None of the indications for mastectomy are abdominis muscle (transverse rectus abdominis myocutaneous
absolute, but they need to be carefully considered in counsel- [TRAM] flap), the more superficial fat and skin from the
ing women. These relative indications include the presence of abdominal wall (deep inferior epigastric perforator [DIEP]
separate cancers in distinct parts of the breast separated by at flap), and the lattissimus dorsi muscle flap. These flaps may be
least 5 cm of normal breast tissue, termed multicentric cancer. used in conjunction with complete sparing of most of the skin
This occurs in 2 to 5% of cases. Other indications for mastec- of the breast (skin-sparing mastectomy), which provides for a
tomy include a very large tumor in relation to the size of the superior cosmetic outcome. In general, the nipple and areola
breast that is not amenable to or does not respond sufficiently are resected with mastectomy. In select circumstances such as

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Figure 9  Anatomy of the axilla. (a) The levels of the axilla are defined by the surrounding muscles and the axillary vein. Level I are nodes later-
al to the pectoralis muscle. Level II nodes reside between the lateral to medial border of the pectoralis minor muscle. Level III nodes are those
medial to the pectoralis minor muscle to the thoracic inlet. Most but not all sentinel nodes are in level I. (b) Key structures to recognize and protect
in axillary surgery.

small tumors located in the periphery of the breast or for breast axilla, and because of the potential morbidity of internal
cancer risk-reducing surgery, mastectomy that preserves the mammary lymph node dissection, surgical evaluation of
nipple (nipple-sparing mastectomy) is reasonable.104–107 women with breast cancer is generally limited to the axilla.
Many factors impact the choice to do reconstruction, the The axilla contains an average of 15 to 20 lymph nodes
timing of reconstruction, and the type of reconstruction. extending under the axillary vein medially toward the thoracic
Patient factors affecting reconstruction planning include breast inlet [see Figure 9]. Until 15 years ago, evaluating these nodes
size, body habitus, recent or ongoing tobacco use, diabetes, required dissection of the entire axillary contents. Although
and obesity. In addition, factors related to the cancer itself, ALND is a safe operation, it carries substantial risk of long-
such as stage, risk of recurrence, and the likelihood of the need term morbidity related to disruption of the lymphatic flow
for postmastectomy radiation, also impact these decisions. from the arm and permanent swelling, termed lymph-
edema,112–114 as well as paresthesias due to irritation or inter-
Lymph node surgery  The presence of metastases in ruption of the intercostobrachial nerves in the axilla.
regional lymph nodes is a key prognostic factor used in Lymphedema is a chronic lifelong condition that ranges from
making treatment decisions. In addition, removing lymph minimal effects to disabling swelling. The risk of lymphedema
nodes prevents recurrence risk in the regional lymph node is 10 to 15% with axillary dissection alone and substantially
basin. However, treatment of lymph nodes does not itself affect higher when radiation is also required after node dissection.82,115
survival. Surgery for removal of regional lymph nodes is the
only accurate way to determine if nodes are involved with Sentinel lymph node biopsy  During the 1990s, investiga-
cancer. Noninvasive testing of the regional lymph nodes with tors tested the hypothesis that lymphatic flow from a tumor
PET, MRI, and ultrasound imaging has insufficient sensitivity drained through a definable pathway and that drainage to the
and specificity to replace surgical resection.108 Therefore, if the axilla could be mapped using radioactive or large colloidal
nodal status is needed for staging to plan subsequent systemic particle tracers. The premise is that the tracers are trapped in
or radiation treatment, surgical evaluation of regional nodes the first few lymph nodes identified by these mappings, that
remains a key component of breast cancer care.109 these are the same nodes to which cancer spreads, and that the
Lymph from the breast drains primarily through the axil- presence or absence of cancer in these sentinel nodes defines
lary lymph nodes.110 A small fraction of lymph drainage from the status of the entire axillary lymph node basin. Testing
the breast is through other pathways, including direct drain- proved this hypothesis correct.116,117 Therefore, to determine if
age through the supraclavicular nodes and the internal mam- the axillary nodes are positive, only a few lymph nodes must
mary chain.111 Because the majority of drainage is through the be removed, and full ALND is not necessary for those with

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negative sentinel nodes. Morbidity, including the risk of It is unclear to what extent the low rate of axillary recurrence
lymphedema and paresthesias, is markedly lower with SLNB in the ACOSOG Z0011 study was due to radiation of part of
than with axillary dissection. However, SLNB is not risk free. the axilla. In 2014, the findings of a review of the extent of
Lymphedema still occurs even with SLNB, with rates of mea- radiation administered to the breast on the study were pub-
surable lymphedema on average about 6% compared with lished showing that about 20% of the patients had radiation to
15 to 20% with axillary dissection.81,83 the axilla beyond what was allowed in the protocol.119 It is
SLNB is appropriate for any woman with an invasive can- unlikely that this could impact the overall findings of the study,
cer and clinically negative nodes. Those with clinically posi- but the editorial accompanying the article recommended more
tive nodes are not candidates for SLNB and should have full detailed analysis of the ACOSOG Z0011 findings.120
ALND or neoadjuvant therapy. If there is a question about Microscopic lymph node involvement  A key factor for surgeons
the clinical status of lymph nodes, involvement of nodes may is to understand the prognostic significance of the microscopic
be confirmed before surgery using ultrasound-guided needle lymph node involvement. The prognosis in breast cancer is
biopsy (core-needle biopsy or FNA). It may also be consid- better when there is minimal cancer in the lymph nodes com-
ered for women with local recurrence after previous pared with larger and more extensive deposits. There are two
breast-conserving surgery and radiation who had a previous classes of microscopic lymph node involvement as codified in
SLNB, although the accuracy of SLNB in this setting has the AJCC staging system: isolated tumor cells (ITCs) defined
never been fully proven. as small clusters of cells measuring 0.2 mm or less and
SLNB is performed by injecting a radiolabeled sulfur col- micrometastases defined as tumor deposits from 0.2 to 2 mm.
loid and/or blue dye (isosulfan blue or methylene blue) into ITCs have minimal or no prognostic impact and are classified
the breast either into the periareolar skin and under the are- as negative nodes (N0(i+)).121,122 Micrometastases are classified
ola or around the tumor (peritumoral). Many surgeons per- as positive with a “mi” descriptor (N1mi).
form SLNB with either radioactive colloid or blue dye tracer, SLNB with neoadjuvant therapy  SLNB can be performed ei-
and others recommend using both in all cases. Over a few ther before neoadjuvant chemotherapy is initiated or after
minutes, this drains to and is trapped in the first few lymph completion of chemotherapy. With both approaches, sentinel
nodes that drain the breast lymph. The tracer(s) are found in nodes that are identified appear to provide accurate informa-
an average of three lymph nodes that are removed and exam- tion on node status. Most surgeons perform SLNB after neo-
ined for metastases. adjuvant therapy in those with clinically negative nodes and
The agents used for SLNB are safe. Isosulfan blue adminis- omit axillary dissection when the sentinel lymph node is neg-
tration has about a 0.5% risk of immediate anaphylaxis with ative. At the current time, ALND remains the standard when
hypotension and an occasional case with rapid onset of hives. sentinel lymph nodes are positive after neoadjuvant therapy.
Methylene blue may cause skin necrosis in a few cases. These As discussed below, neoadjuvant chemotherapy may result in
blue dyes should not be used in pregnancy because of the a major shrinkage or in some cases complete eradication of
potential teratogenic effects. However, radioactive sulfur col- the cancer in the breast and nodes (termed a pathologic com-
loid is generally considered safe to use in pregnancy because plete response [pCR]). A recent ACOSOG study examined the
the radiation dose to the fetus is exceedingly low, although feasibility of SLNB after neoadjuvant chemotherapy in
safety data are relatively limited. patients initially presenting with positive lymph nodes.123 In
Management of patients with a positive SLNB has histori- women with a negative sentinel node after chemotherapy,
cally been to perform complete axillary dissection. This is still 12% had other positive lymph nodes (12% false negative rate).
the standard when performing a mastectomy, although this Additional studies are ongoing to determine if omission of
may change in the next few years. The practice has changed axillary dissection is appropriate when a pCR in the nodes is
because of randomized trials of axillary dissection compared obtained with neoadjuvant therapy.
with no further axillary surgery for those with limited axil-
lary node involvement. The most notable trial is American Radiation  Radiation to the area of the breast is necessary
College of Surgeons Oncology Group (ACOSOG) Z0011.118 In in most cases of cancers treated by BCT to reduce the chance
this study, women treated with breast-conserving surgery of recurrence in the breast area (local recurrence). Radiation is
who had one or two positive sentinel nodes were random- also necessary for select cases treated with mastectomy.
ized between completion ALND and no additional axillary Radiation with mastectomy  Mastectomy should be supple-
surgery. The large majority of these patients received adju- mented with radiation when the cancer is over 5 cm in size,
vant radiation to the breast as well as adjuvant endocrine when surgical resection margins are close or positive, or when
therapy and/or chemotherapy. There was no difference in lymph nodes are involved.124 The “textbook” standard is that
local, axillary, or distant recurrence or in survival between radiation is indicated with four or more positive nodes. How-
these groups. Primarily on the basis of this study, it is now ever, radiation should be considered even when only one to
accepted that axillary dissection is not necessary for women three nodes are involved. Meta-analyses of available random-
with one or two positive sentinel nodes treated with ized trials published in 2014 showed improved survival with
breast-conserving surgery, systemic therapy, and whole postmastectomy radiation therapy even with one to three
breast radiation.117 Women treated with breast-conserving positive nodes, although the absolute level of improvement
surgery with more than two positive sentinel nodes or those may be very small, with very limited nodal involvement.125,126
with bulky or matted axillary nodes should still have full The potential need for radiation after mastectomy may
axillary dissection. affect decisions regarding immediate breast reconstruction.103

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Reconstruction may complicate radiation dosimetry and Partial breast radiation  Recent clinical research has focused
uniform dose delivery over the entire field and increase the on limiting the extent and time required to deliver radiation to
volume of treated tissue, including the lung and heart. In addi- the breast. Most recurrences occur at or near the primary
tion, radiation may compromise the cosmetic result of recon- tumor site. Only about 15% of new events in the treated breast
struction through contracture of the scar capsule around an occur outside this area and are most likely a new second pri-
implant and/or loss of tissue volume within an autologous mary cancer. Limiting radiation to the site of the primary
tissue flap. The potential need for radiation after mastectomy cancer might provide local control equivalent to whole breast
should be discussed with all women having mastectomy for radiation therapy. APBI has a key advantage: it may be deliv-
invasive breast cancer. Referral to a plastic surgeon specializ- ered in a much shorter time frame, generally two fractions a
ing in reconstruction and to a radiation oncologist before sur- day over only 5 days. Another purported advantage is that if
gery can allow for detailed discussion about the risks and there is a second disease event in the affected breast, this may
benefits to immediate versus delayed reconstruction for the be treated by a repeat lumpectomy rather than mastectomy,
although there are no data to support this thesis.
patient who is likely to require postmastectomy radiation.
There are a number of techniques to deliver APBI.135 The
Radiation with BCT  Radiation is generally administered in
technique with the longest-term follow-up, albeit in a limited
all cases with BCT. Radiation reduces the risk of local recur-
number of patients, is multicatheter brachytherapy.136 This tech-
rence compared with lumpectomy alone by as much as 70%.
nique is cumbersome, unsightly, and seldom used. Alternative
This is true regardless of the size of the cancer. Subset analysis
techniques for delivery of APBI include three-­ dimensional
of large clinical trials and limited clinical trials in women with
CT–directed external-beam radiation or brachytherapy using a
small cancers have not identified any group of small cancers
radiation seed in a multilumen catheter placed in the lumpec-
for which radiation does not reduce the risk of local recur- tomy site. A single dose of radiation administered during
rence. Although the initial studies of BCT showed no impact of surgery (intraoperative radiation therapy [IORT]) may also be
radiation on survival, more recent data suggest that radiation sufficient.137,138
with BCT improves both local recurrence and survival.43,100,127 Long-term data from controlled clinical trials demonstrat-
One group where radiation may be omitted after breast-­ ing the safety and effectiveness of these techniques are lim-
conserving surgery is women age 70 and over with cancers ited.72,133,135,139 Data from noncontrolled series with relatively
that are hormone receptor positive and 2 cm or smaller and short-term follow-up show promising findings, albeit per-
who have clinically negative axillary lymph nodes. Two clin- haps with a slightly higher local recurrence compared with
ical trials demonstrated that radiation offers little or no clini- standard radiation.74,75 Large clinical trials are ongoing,
cal advantage in this situation. A Cancer and Leukemia including a study by the NSABP. As of 2015, APBI or IORT
Group B (CALGB) study in the 1990s randomly assigned is being used by many surgeons but is often limited to those
women meeting these criteria to lumpectomy with radiation with lower risks of local recurrence based on guidelines from
and tamoxifen or to lumpectomy with tamoxifen only.128,129 the American Society of Breast Surgeons, American
There was no difference in long-term survival at a median Brachytherapy Society, or ASTRO.140–142 There are reports
follow-up of 12 years. Local recurrence occurred in 2% with from some analyses of administrative and other data that the
radiation and 10% without radiation. However, ultimately, cosmetic outcome may be inferior with APBI.143 The use of
the outcome was not impacted by this slightly higher rate of APBI has decreased in the last few years. The overall safety
local recurrence. Most women treated initially without radia- and efficacy of APBI are uncertain, and we must await fur-
tion could be treated with a repeat lumpectomy (with or with- ther trial results before broad application of this technique.
out radiation), whereas those who received radiation initially Whole breast radiation therapy is safe and well tolerated and
all had mastectomy. Therefore, omission of radiation is rea- remains the gold standard.30,144–146
sonable in this group. A trial of lumpectomy with adjuvant Side effects of breast radiation  The immediate effects of radi-
hormone therapy with or without radiation in the United ation include skin reaction and occasional skin breakdown.
Kingdom for women age 65 and over with estrogen receptor– This is generally readily managed. Fatigue is another com-
positive tumors under 3 cm showed a local recurrence rate of mon issue during radiation. The most serious long-term effect
is a slight increased risk in coronary artery disease presenting
4% without radiation and 1.3% with radiation.130 There was
years or decades after breast radiation for left-sided cancers,
no difference in survival. A similar trial conducted in Canada
but this added risk is very low. Less significant effects include
for women age 50 and over demonstrated local recurrence
tenderness and potentially volume loss in the treated breast,
rates of about 15% among women between ages 50 and 70,
breast lymphedema, pneumonitis, and an increase in the risk
lending caution to omitting radiation for younger women.131
of rib fractures in the treated field. In addition, a serious but
Historically, the standard radiation treatment after very rare effect is an angiosarcoma in the treated field.
breast-conserving surgery is treatment of the entire breast to
a dose of about 50 Gy, with an additional boost of radiation management of the contralateral breast
to the primary tumor site of 15 Gy, taking about 7 weeks Women with breast cancer have a risk of second malignan-
overall. For women with relatively smaller breasts and body cies, including the risk of developing a contralateral primary
habitus, an alternative is administration of the entire radia- breast cancer. Outside the setting of inherited susceptibility
tion dose in 16 fractions over about 3 weeks, termed hypo­ (mutations in the BRCA1 or BRCA2 or other breast cancer–
fractionation.132–134 Hypofractionated whole breast radiation related genes), the chance of developing a contralateral pri-
has equivalent efficacy and provides substantial time and mary breast cancer is about 10% over 20 to 30 years.99
cost savings for the patient and for the health care system. Endocrine therapy for treatment of hormone-positive breast

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cancer further reduces the risk of a contralateral breast. Since situation is the same as for women without inherited suscep-
the average woman diagnosed with breast cancer is in her 50s tibility.151 However, the women are at increased risk for
or 60s, and most of these contralateral breast cancers will be developing a second primary cancer in the same breast, a risk
effectively treated, the risk that a woman with a breast cancer that approaches 50%, especially in women under age 50 at the
will succumb to a new contralateral breast cancer in her life- initial diagnosis.150 There are some emerging data that women
time is far outweighed by both the risk of death from the with inherited susceptibility who undergo bilateral mastec-
current breast cancer and the long-term risk of death from tomy when treated for a breast cancer may have slightly
other causes. Therefore, prophylactic treatment of the contra- improved long-term survival.152 The choice of bilateral mas-
lateral breast is generally not necessary. tectomy must be carefully considered in the context of the
Lobular cancer was historically thought to convey a much risk of metastases from the index cancer (e.g., those with
higher risk of a contralateral breast cancer compared with advanced cancers may have less to gain from mastectomy)
ductal cancer. However, any added risk of contralateral can- and the patient’s age. Women in their 60s or above with a
cer in a woman with lobular cancer is relatively small. A BRCA1 or BRCA2 mutation have a substantially lower risk
recent population study from the Netherlands showed that of a contralateral breast cancer over their lifetime than women
over 10 years, the risk of a contralateral breast cancer was in their 30s or 40s and gain little or no advantage from
3.5% with ductal cancer and 4.1% with lobular cancer.147 mastectomy.
Therefore, the presence of lobular compared with ductal can-
cer should have little bearing on the consideration of contra- treatment of local recurrence after mastectomy
lateral prophylactic treatment.147,148 or breast-conserving surgery
Careful counseling can largely allay a woman’s fears of the Local recurrence after surgical treatment of breast cancer
impact of the risk of a second cancer. For young women, or occurs with both mastectomy and BCT. When performed by
those with a family history suggesting inherited susceptibil- experienced surgeons with careful pathologic control, appro-
ity, referral for genetics evaluation and possible testing is priate radiation, and stage-appropriate adjuvant systemic
warranted to help identify those who may benefit from con- therapy, the rate of local recurrence with BCT is as low as 1 to
tralateral prophylactic mastectomy and/or risk management 5%. Biomarker-appropriate adjuvant systemic therapy is also
and preventive measures for other cancer types (e.g., ovarian, a key factor in minimizing the risk of local recurrence.153
gastric). Local recurrences are also a significant issue among women
However, some women, especially those undergoing mas- treated with mastectomy. This risk is about 2 to 5% for
tectomy for the index cancer, may request contralateral mas- women with negative lymph nodes and ranges as high as
tectomy regardless of a defined low risk and despite careful 25% for women with multiple positive lymph nodes who do
counseling. Recent observational studies demonstrate that not receive radiation.154,155 In general, mastectomy provides
the number of women undergoing prophylactic contralateral no benefit over breast-conserving surgery measured by the
mastectomy increased significantly over the last decade. For risk of local recurrence.
example, in New York State, the rate of contralateral mastec- Local recurrence is a serious event regardless of the type of
tomy among those treated with mastectomy rose from about initial surgery. These women have a higher risk of develop-
4% of women treated in 1995 to 15% in 2005.149 The rising rate ing distant metastases compared with women with similar-­
of contralateral prophylactic mastectomy has been the subject stage cancer who do not suffer local recurrence. It has
of recent study, with proposed reasons including improved previously been generally cited that radiation only impacts
reconstruction outcomes, increasing use of breast MRI, and
the risk of local recurrence and not overall survival. How-
increased awareness of hereditary cancer syndromes.
ever, meta-analysis of all available data for women treated
choice of breast surgery in women with breast with BCT and mastectomy demonstrates that radiation ther-
cancer inherited susceptibility apy not only reduces the risk of local failure but also improves
survival.127 The best estimate is that radiation saves one life
The issues in selection of breast cancer surgery are different
for every four local recurrences prevented. Radiation is there-
for women with inherited susceptibility from breast cancer–
related genes. The most common are BRCA1 and BRCA2, but fore recommended for women who have a risk of local failure
recent research and the use of next-generation sequencing over 10% regardless of the type of primary surgery.
tools are showing a broader spectrum of breast cancer genes The accepted treatment for local recurrence after BCT is
involved in breast cancer inherited susceptibility.11 Women mastectomy. This is because the recurrence may be multifocal
with inherited susceptibility are generally younger at the and because full-dose radiation is difficult to administer
time of the initial breast cancer diagnosis and have a higher safely a second time due to cumulative tissue toxicity. In care-
risk of developing a second cancer in the same (ipsilateral) or fully selected patients, repeat lumpectomy with additional
contralateral breast. The risk of a contralateral breast cancer whole breast or partial breast radiation may be performed,
is dependent on the age at which they are diagnosed with but most consider this an investigational approach.
their first breast cancer: 25 to 50% for those under age 50 at Local recurrence after mastectomy is more difficult to treat
the initial diagnosis, 15 to 20% for those over age 50, and and carries a more serious prognosis. Treatment usually
lower for those over age 60.150 includes resection of a local recurrence in the skin, muscle, or
Women who have inherited susceptibility with a known regional nodes if possible, followed by radiation to the chest
mutation in BRCA1, BRCA2, or other breast cancer–related wall and regional nodes. If previously treated with radiation,
genes also often choose mastectomy or bilateral mastectomy. targeted radiation may be used despite the very high cumu-
The overall survival for women treated with BCT in this lative dose with related toxicity.

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The role for additional adjuvant systemic therapy after markers are the estrogen receptor, the progesterone receptor
local recurrence is uncertain, although there are some limited (collectively referred to as hormone receptors), and HER-2/neu
data supporting its use.156 Many oncologists will deliver addi- protein expression or gene amplification. Other markers are
tional systemic treatment based on the type of previous treat- described, but their utility in defining prognosis and treatment
ment and the nature and extent of the local recurrence. is unproven. These include Ki-67 and the androgen receptor. In
making these assessments, it must be recognized that a sub-
selection of breast-conserving therapy versus stantial fraction of women with negative lymph nodes will
mastectomy develop metastatic disease and require systemic therapy.36
The decision between BCT and mastectomy is a complex In stage I and stage II cancer, it is not necessary to perform
and difficult one for women with breast cancer. From a tech- staging studies such as bone scanning, CT, PET, and MRI in
nical standpoint, BCT is possible in the large majority of all women. These are not sensitive at detecting this micro-
women with breast cancer: more than 90% of women with scopic metastatic disease; they are negative in most cases, yet
tumors under 2 cm in size (T1) may undergo BCT. However, these individuals have the same risk of future development
many other factors in addition to the technical ability to per- of metastatic cancer as those who do not have scans. Further-
form BCT affect the decision. Ultimately, the individual more, there is a substantial chance of false positive scans,
patient is the determinant of whether or not she will have a requiring extensive evaluation, further invasive studies, and
mastectomy. Her choice may be influenced by perceptions or a delay in initiation of treatment.
values based on personal or family experiences, real or per- Adjuvant systemic therapy for breast cancer consists of two
ceived increased risks of recurrent cancer based on the family major classes of drugs: endocrine drugs that block synthesis
history, willingness to pursue radiation treatment, ability to (aromatase inhibitor) or the effect of circulating estrogen
comply with imaging surveillance, and other factors.62 (SERM) on breast cancers that express estrogen and proges-
Counseling women regarding the choice of surgery is one terone receptors and systemic cytotoxic chemotherapy. The
of the most important tasks for the treating surgeon.157 Sur- discussion below provides general concepts of the use of
geons need to learn the skills of nondirective counseling and adjuvant systemic therapy based on stage and biomarker sta-
must incorporate other professionals and resources into their tus. Specific treatment recommendations change regularly
practice. Careful study of the decision-making process has with accumulating evidence, so advice regarding the exact
shown that physicians are not necessarily fully sensitive to regimens appropriate for a given case is not possible in a
their patient’s concerns or to their styles of decision mak- review such as this. The best available treatments are codified
ing.158,159 This has led to the development of decision aid sup- in widely accepted and regularly updated practice guidelines
port tools and to the recognition of the need for developed and updated annually by the American Society of
multidisciplinary counseling, especially in more complex sit- Clinical Oncology (ASCO), NCCN, and others.30
uations or those associated with questions surrounding
inherited susceptibility and genetics.160 Timing of Adjuvant Systemic Therapy: Before or After
One of the key factors in this process is the recognition that Surgery?
breast cancer treatment is not an emergency. There are no The standard treat-
data that treatment initiated within a few days of diagnosis ment for breast cancer
improves outcome compared with treatment delayed a rea- has been to perform
sonable period of time, measured in a number of weeks or breast and axillary sur-
even months. Women should be provided with the opportu- gery as the initial step in
nity to seek additional counseling, research information on treatment and use the
their own, and obtain second opinions if they so desire. Inclu- information from surgery
sion of professionals of other disciplines, including radiation (pathologic stage) to
oncology, plastic surgery, medical oncology, radiology, psy- define the best adjuvant
chology, social work, nursing, and genetics, may be war- systemic therapy. How-
ranted. Unfortunately, there are data suggesting that surgeons ever, mounting evidence
do not appropriately coordinate services with other disci- supports delaying surgery
plines in breast cancer care.161 until after completion of
systemic therapy. Presur-
adjuvant systemic therapy gical therapy—so-called
Women with invasive cancer need to consider systemic neoadjuvant therapy—
drugs in addition to treating the breast because of the risk of was first investigated in
developing distant metastases. These metastases develop the 1970s and 1980s
from microscopic dissemination of cancer cells prior to diag- mostly for those with
nosis. The decision depends on both the estimated risk of large, potentially unre-
developing metastatic disease and the degree of benefit that sectable cancers. Neoad-
treatment may provide. These risks are estimated by analyz- juvant chemotherapy often reduced the size and extent of the
ing features of the cancer, including the size of the invasive cancer more than 50%, with 15 to 25% having complete dis-
component of the cancer, the presence or absence of regional appearance of cancer clinically. Half of those women had no
lymph node metastases, the grade of the cancer, and the pres- viable tumor identified pathologically (pCR). Neoadjuvant
ence or absence of specific biomarkers associated with prog- chemotherapy is now the accepted standard treatment for
nosis and response to treatment. The three clinically used locally advanced and inflammatory breast cancers (stage III).

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These findings with locally advanced breast cancer led to (e.g., anastrozole, letro-
studies of neoadjuvant chemotherapy with smaller cancers.162 zole, exemestane),
Large-scale studies, most notably the NSABP B-18 study, which block peripheral
demonstrated similar cancer responses.163 Neoadjuvant ther- synthesis of estrogen.
apy did not convey any survival advantage over chemother- Because ovarian pro-
apy administered postoperatively. However, women treated duction of estrogen is
with neoadjuvant chemotherapy were more likely to have not affected by aro-
BCT, and the rate of local recurrence was not increased. Fur- matase inhibitors, these
thermore, the degree of response to neoadjuvant therapy is drugs are only effective
itself of significant prognostic importance.163–165 Those women in postmenopausal
who achieve a major response, especially those who achieve women.170 Recent clini-
a pCR in the tumor, are more likely to have long-term sur- cal trials in postmeno-
vival compared with those who do not.162 Because of the pausal women
prognostic significance of response to neoadjuvant therapy, demonstrated that aro-
in 2013, the Food and Drug Administration approved the use matase inhibitors are
of pCR as an end point for clinical trials to assess the effec- superior to tamoxifen in
tiveness of new drugs or drug combinations in breast cancer. preventing recurrence
This may speed the process of identifying effective drugs in of breast cancer and
breast cancer therapy.166 have a slightly improved
Neoadjuvant endocrine therapy may also be of value in safety profile over
select cases.167,168 A response to neoadjuvant chemotherapy is tamoxifen. Tamoxifen
most likely among women with high-grade and endocrine remains the drug of
receptor–negative cancers. Cancers that are endocrine recep- choice in premenopausal women. These drugs are remark-
tor positive are less likely to respond to neoadjuvant chemo- ably safe and effective, with only rare serious side effects.
therapy. However, these tumors may respond to neoadjuvant With only a few exceptions, all women with hormone recep-
endocrine therapy with similar benefits in terms of surgical tor–positive breast cancers should receive prolonged endo-
treatment. With endocrine therapy, the time to maximal crine therapy. At least 5 years of therapy is warranted. There
tumor response is longer than with chemotherapy; it may is an increasing body of evidence that many should continue
take 6 months to achieve a maximum tumor response prior therapy for at least 10 years.171–173
to surgery. Some women with hormone receptor–positive breast can-
It is also reasonable to administer neoadjuvant therapy to cers should also consider adding systemic chemotherapy to
any woman who would otherwise receive systemic treatment the endocrine therapy. A large body of evidence from clinical
for breast cancer. In general, neoadjuvant therapy is adminis- trials shows that survival in some cases may be improved by
tered to those with larger T2 cancers (those over 3 to 4 cm in the addition of chemotherapy to endocrine therapy.174,175
size) and T3 cancers in an effort to allow breast-conserving However, the magnitude of benefit over the benefit of endo-
surgery. Increasingly, it is also used with even smaller tumors, crine therapy alone may be small. For otherwise healthy
especially those that are HER-2 positive or triple negative. In women who have positive lymph nodes, additional chemo-
addition, neoadjuvant therapy is the treatment of choice for therapy may be strongly considered. For those with negative
those with cancer that involves the skin or chest wall (T4), who nodes, the benefit varies according to the characteristics of
have extensive lymph node involvement clinically, or who the cancer. It must be clearly recognized that for women with
have inflammatory cancer. Regardless of the final surgery type hormone receptor–positive breast cancer, chemotherapy is
and the degree of tumor response, women with locally used in addition to endocrine therapy and not instead of
advanced breast cancer should receive surgery and radiation.169 endocrine therapy.
Genomic profiling of cancers or evaluation of the expres-
adjuvant therapy with hormone receptor–positive sion of multiple genes allows for the stratification of women
cancer with hormone receptor–positive breast cancer by risk of dis-
Most women with hormone receptor–positive breast cancer tant disease. It also identifies some who get no benefit and,
should receive antiestrogen (endocrine) therapy for up to conversely, those who get a major benefit from adding che-
10 years, with some women also benefiting from chemotherapy. motherapy to endocrine therapy.176–178 The most widely used
Endocrine therapy reduces mortality and the risk of second or genomic profiling system in breast cancer in 2015 is Onco-
contralateral breast cancer. Endocrine therapy has less imme- typeDx. Those women with a low OncotypeDx recurrence
diate toxicity and is a good option for some women as their score benefit from adjuvant endocrine therapy and get no
only systemic therapy. However, adjuvant endocrine therapy further improvement from adding chemotherapy. Conversely
is effective only for women whose tumors express hormone those with a high recurrence score have a dramatic reduction
receptors. This includes premenopausal women and post- in recurrence risk by adding chemotherapy. Ongoing studies
menopausal women with hormone receptor–positive cancers. are examining the chemotherapy benefit in the intermediate-­
The latter still have low levels of circulating estrogens from risk group. This profiling test is validated for use in women
nonovarian sources (adipose tissue and adrenal glands). with invasive cancer that is hormone receptor positive,
There are two primary classes of endocrine drugs: SERMs HER-2/neu negative, and lymph node negative. A small
(e.g., tamoxifen), which are competitive inhibitors of the body of retrospective data suggests that it provides similar
estrogen receptor in breast cancer, and aromatase inhibitors predictive information in those with positive nodes. As of

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2015, major clinical trials are under way to determine the negative cancers). This type of breast cancer is more common
utility of this assay in those with positive nodes. in younger women, those of African American ancestry, and
There are other genomic profiling tests available on the those with inherited susceptibility. These cancers have an
market that are less widely used in the United States, includ- increased risk of both local and distant recurrence. Women
ing the 70-gene assay marketed under the name MammaPrint with these cancers should receive neoadjuvant or adjuvant
and the PAM50 gene expression signature, which may also chemotherapy, but it may not be as effective as it is in other
prove useful in a variety of breast cancers.179,180 Other genomic-­ cancers. There is active ongoing clinical research to define
based prognostic and predictive systems in development are improved approaches in this setting, including the use of
likely to further identify those requiring chemotherapy, those platinum-based chemotherapy drugs (e.g., cisplatinum).
that will not, and the specific drug or targeted agents that will Clinical trials over the last three decades have defined the
likely be effective for a given cancer. most effective drugs in breast cancer. Chemotherapy drugs
are most effective when used in combination with other
adjuvant therapy with hormone receptor–negative drugs. The most effective drugs in breast cancer are the anth-
and/or her-2-positive cancer racyclines, of which the most widely used agent is doxorubi-
Endocrine therapy is not effective in women with hormone cin, cyclophosphamide, and the taxanes (paclitaxel and
receptor–negative breast cancer. For these women, the only docetaxil). Readers are referred to large-scale meta-analysis
treatment to reduce the risk of distant metastases is cytotoxic of the value of adjuvant chemotherapy and endocrine ther-
chemotherapy. Unless otherwise contraindicated by serious apy, to recent reviews on the subject, and to updated practice
comorbidities, women with cancers over 1.0 cm and negative guidelines for the current recommended therapies.174,175,185
hormone receptors should receive chemotherapy.30 Although Decisions regarding adjuvant systemic therapy are complex
those with tumors under 1 cm have a lower risk of distant for both patients and their physicians. To aid these decisions,
metastases, they still derive some benefit from added chemo- there are mathematical models that incorporate relevant prog-
therapy, and it should be considered based on the full spec- nostic factors and provide individualized risk of distant recur-
trum of patient and tumor characteristics. Women with rence and benefit from treatment. The most widely used
negative hormone receptors and positive nodes should receive models are Adjuvant! (https://www.adjuvantonline.com) and
chemotherapy unless otherwise contraindicated. Women CancerMath.net (http://cancer.lifemath.net/).186–188 Finally,
with hormone receptor–negative and/or HER-2-positive can- women should be offered the opportunity to participate in one
cers should be considered for neoadjuvant therapy for any of the many ongoing clinical trials that will help define even
cancer at least 2 cm in size or with clinically positive nodes. better adjuvant therapies, improve outcomes, and reduce the
Breast cancers that express the HER-2/neu protein have a short- and long-term toxicity of therapy.
higher risk of developing distant metastases in the absence of
stage iv breast cancer and metastatic breast
treatment. Agents have been developed that target this pro-
cancer
tein and have a significant therapeutic effect. When given in
conjunction with chemotherapy in both the adjuvant setting A small fraction of
and in patients with metastatic cancer, they improve the out- breast cancers have dis-
come for those with HER-2-positive cancers. The first and tant metastases (stage
most widely studied and used of these drugs is the monoclo- IV) at the time of initial
nal antibody trastuzumab. It is safe and effective when given cancer presentation. A
much larger number of
in combination with chemotherapy. The administration of
women develop meta-
standard chemotherapy coupled with a year of trastuzumab
static breast cancer years
reduces the risk of distance metastatic disease by about half
after initial treatment.
over the rate seen with chemotherapy alone and reduces can-
When a patient presents
cer mortality by about 30%.181,182 Women with HER-2-positive
with stage IV cancer at
breast cancer should receive chemotherapy and trastuzumab.
the initial diagnosis, it is
A number of other anti-HER-2 agents are available and may generally necessary to
be used in conjunction with trastuzumab or in those whose obtain tissue from both
tumors recur or progress after trastuzumab. Combining these the primary tumor and
with trastuzumab may increase the efficacy with a higher rate the suspected metastatic
of pCR with neoadjuvant chemotherapy.183 Based on this, the site to confirm the diag-
standard accepted regimens for neoadjuvant therapy in nosis and obtain hor-
HER-2-positive cancers include the combination of chemo- mone receptor and
therapy drugs and dual anti-HER-2 drugs with trastuzumab HER-2/neu information.
and pertuzumab. Similarly, in the treatment of metastatic dis- For those who develop
ease, use of combined anti-HER-2 therapy improves survival metastatic cancer after
over trastuzumab alone, as demonstrated in the CLEOPLA- initial treatment, it is best to biopsy a metastatic site to con-
TRA study, which recently demonstrated that chemotherapy firm the diagnosis and to repeat estrogen receptor, progester-
plus the combination of trastuzumab and pertuzumab one receptor, and HER-2 staining on the metastatic cancer. In
improves survival for women with metastatic cancer.184 15% of distant recurrences, the metastasis will have different
The most difficult situation is when estrogen receptor, receptor status from the primary tumor. This is even more
progesterone receptor, and HER-2/neu are negative (triple important now that next-generation genomic sequencing on

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the tumor may identify a specific target for which a proven Surgery for distant metastases, including liver and lung
or investigational drug is available. metastases in breast cancer, is usually futile, although it is
Metastatic breast cancer is generally incurable, and treat- sometimes considered in young women. Unfortunately, these
ment is targeted at preventing disease progression for the metastases are seldom isolated, and virtually all will recur
longest time possible while maintaining a high quality of life. without any survival advantage from the resection.
Those with metastatic cancer must know and understand Finally, it is important to communicate clearly with the
that, ultimately, the goal of treatment of metastatic cancer is patient about the overall palliative goal of therapy and to
palliative: to prolong high-quality life. They must understand help her deal with symptoms and the psychological issues of
that they will need to balance the potential benefits with the this diagnosis. Early consultation with a palliative care spe-
symptoms of therapy and recognize that they will eventually cialist and a palliative care team helps many women. Pallia-
reach a point where treatment is likely futile. However, cur- tive care consultation does not preclude the use of aggressive
rent treatments for metastatic cancer now often provide many therapy for metastatic cancer, and the partnership of the pal-
years of quality of life. It is clearly worth considering ongoing liative specialist and oncology treatment team is of great
systemic therapy and to switch sequentially to different ther- value to the patient. Hospice services are also critical for
apies to achieve this goal. patients as they approach the end of life. Honest communica-
First-line treatment of stage IV and recurrent metastatic tion about the potential benefits of treatment is critical to eas-
cancer is generally systemic therapy.30 In the absence of symp- ing the suffering and burden of end-of-life care.
tomatic or aggressive visceral disease, those with hormone
receptor–positive tumors are best treated with oral endocrine Special Circumstances
therapy or in some cases intramuscular endocrine therapy
with the estrogen receptor blocker fulvestrant. Many may have There are a number of special circumstances that are
long progression-free intervals and a high quality life with uncommon but occur frequently enough to deserve separate
limited treatment-related toxicity. Those with hormone recep- discussion. These include adenocarcinoma presenting in axil-
tor–negative cancers may begin with systemic chemotherapy. lary lymph nodes with no obvious known primary tumor,
For those with stage IV cancer at presentation and where breast cancer in pregnancy, and breast cancer in men.
the metastases are identified before the primary tumor in the axillary node with adenocarcinoma cancer,
breast is removed, there is generally no reason to do surgery. primary unknown
Systemic treatment often provides a major response in the
breast and achieves sufficient local control for the duration of A small number of women present to their physician with
the woman’s life. For those women fortunate to have pro- an axillary node containing metastatic adenocarcinoma and
longed survival but in whom the primary tumor does prog- no detectable primary cancer in the breast (occult breast pri-
ress, surgery and/or radiation may be used for local control mary). This is almost always breast cancer. Mammography
and to preserve quality of life. will often reveal the primary breast cancer, and MRI finds
Data from population cancer registries suggest that women many of these cancers not seen on mammography.193 How-
who present with metastatic disease who undergo surgery at ever, in a few cases, even MRI will be negative. In a woman,
the time of diagnosis have longer survival than those who do this is still virtually always a breast cancer despite the negative
not have surgery.189–191 However, this finding is most likely a breast imaging, even if the hormone receptors are negative.
selection bias in that women with a lower burden of disease Extensive whole body imaging to search for another source
are more likely to have undergone surgery before discovery of adenocarcinoma is not indicated. The woman should
of the metastatic cancer and are therefore more likely to sur- receive therapy assuming that this is a breast cancer.
vive longer. There are two small randomized trials showing In the past, mastectomy was used for all women with an
that surgery in those with metastatic disease provides no occult breast primary presenting with a positive axillary
improvement in survival. A randomized trial in the United node. Recent data show that mastectomy is not necessary.
States examining whether surgery for the primary tumor in These patients can undergo ALND with stage- and biomarker-­
the breast impacts survival in women with stage IV breast appropriate adjuvant systemic therapy and radiation to the
cancer completed accrual in 2015 and will be reported in a breast.194,195 The systemic therapy may be administered before
number of years.192 (neoadjuvant) or after surgery. Those with large or bulky
axillary nodes should receive neoadjuvant chemotherapy
surgical treatment of local recurrence and before surgery. In place of mastectomy, whole breast radia-
distant metastases tion is administered after completing systemic therapy, as
Surgical resection of local or regional recurrence of breast with other women undergoing breast-conserving surgery.
cancer in the absence of distant metastases is generally per-
formed when feasible. Breast local recurrence after BCT is breast cancer in pregnancy
generally amenable to surgical resection. Recurrent cancer in Breast cancer is uncommon in young women but may
the axillary nodes can be resected and is useful if metastatic occur during childbearing years. Therefore, breast cancer
evaluation shows no other disease. Resection of supraclavic- may occur during pregnancy and is the second most common
ular nodes is generally not of value. Treatment of local recur- cancer associated with pregnancy. Women in this age group
rence after mastectomy generally includes resection of visible are generally not undergoing routine breast cancer screening,
disease if it is limited and treatment with radiation whether and changes in the breast associated with pregnancy can
the disease is or is not resected. Radiation is also an important mask the presence of a mass. Therefore, breast cancer diag-
tool with regional lymph node recurrences. nosis is often delayed. Women with a suspicious mass during

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pregnancy should be evaluated aggressively. Imaging can adjuvant systemic therapy using the same criteria as for
generally be done with mammography and ultrasonography, women. Most breast cancers in men are hormone receptor
and biopsy should be performed as in any other woman with positive, and endocrine therapy is effective. Chemotherapy
a suspicious breast lesion. should be added based on the same criteria as with women.
The principles of treatment are the same as in any woman Survival when matched stage for stage with women is the
with breast cancer.196–198 The only limitation is that chemo- same, although, overall, men have a worse prognosis because
therapy cannot be administered during the first trimester and men tend to present with cancer at a higher stage.
radiation cannot be administered until after delivery. How-
ever, neither of these issues limits aggressive treatment of
Follow-up after Breast Cancer Treatment
women with breast cancer during pregnancy. Termination of
the pregnancy is not necessary, although some women diag- Patients who have been treated for invasive breast cancer
nosed early during the pregnancy choose to do so. are at risk for developing distant metastases, local recurrence,
Older texts suggested that mastectomy is the preferred and a contralateral or ipsilateral new breast cancer. Most recur-
treatment in women with breast cancer during pregnancy. rences occur within the first 5 to 10 years, with the peak at 4 to
However, now the same choices are available to women with 6 years. Recurrences with estrogen receptor–negative cancers
cancer during pregnancy because the radiation is generally on average are earlier than with estrogen receptor–positive
delayed until after chemotherapy and therefore is timed to cancers. Occasionally, women develop distant metastases well
occur after delivery of the child. Therefore, breast conserva- beyond 10 years after diagnosis.
tion can be used safely during pregnancy. Similarly, chemo- Follow-up for breast cancer only requires periodic careful
therapy may be used safely during pregnancy after the first history, physical examination, and breast imaging. Women
trimester. There are extensive data demonstrating the safety with breast cancer often assume that careful and aggressive
of chemotherapy for both the mother and the fetus. SLNB imaging screening is warranted to allow early detection of
may also be performed during pregnancy using radioactive metastases on the assumption that early detection will pro-
sulfur colloid alone. The estimated radiation dose to the fetus vide a better chance of a successful outcome. Unfortunately,
is exceedingly low and considered safe.199 Isosulfan blue and there is no such entity as early metastatic cancer. Once breast
methylene blue have potential teratogenic effects and are cancer metastases are established to the extent that they are
contraindicated during pregnancy. detectable, there is no therapy that is curative, and treatment
Women who have breast cancer at a young age or during is largely palliative, as discussed previously above. Because
pregnancy may wish to have additional children. Decades of this, national guidelines recommend against imaging or
ago, they were advised against this because of concern that serologic testing for metastatic disease on a periodic basis as
hormonal changes associated with pregnancy could promote it does not provide any survival advantage to a woman with
recurrence. Studies have shown that women who choose breast cancer. This question has been tested in randomized
to have children after breast cancer treatment have no clinical trials of extensive testing versus simple follow-up for
additional risk of breast cancer recurrence and death.200,201 local recurrence only combined with evaluation of any symp-
Fertility preservation options, including oocyte and embryo toms suggestive of metastatic disease. These studies showed
cryopreservation, are available, and consultation with a no survival advantage to the extensive testing group despite
reproductive endocrinologist should be offered to any woman detection of metastatic disease an average of 3 months earlier
diagnosed with breast cancer who has not completed her than in the simple follow-up group.208,209
childbearing.200,202–204 Screening women for evidence of local recurrence with
both invasive and in situ cancer may be of value. This should
breast cancer in men include mammography of the ipsilateral breast in women
Breast cancer occurs in men, but with an incidence less treated with breast conservation, contralateral mammogra-
than 1% that of women (lifetime risk for men about one in phy for all women, and a careful history and physical exam-
1,000). No screening for men is warranted. Any mass in the ination. Mammography should be done annually, with the
breast should be fully evaluated. Most masses prove to be history and physical examination done every 6 to 12 months.
gynecomastia. Breast cancer in a younger man may be indic- The role of breast MRI in breast cancer follow-up is unclear.
ative of inherited susceptibility from breast cancer–associated Women should maintain a primary care provider to be sure
genes within that family, particularly related to BRCA2. Care- that other regular medical care is provided.
ful family history and counseling regarding this risk should
cancer survivorship
be provided with strong consideration of genetic testing for
any man with breast cancer. In addition to covering medical issues in cancer follow-up,
The treatment of breast cancer in men follows the same surgeons should provide ongoing resources to help women
principles as in women.205,206 Surgery is generally mastectomy adjust to the cancer diagnosis, deal with psychological issues,
because often the tumor is directly under the nipple-areola address cancer genetic and family concerns, and identify
complex and overall smaller breast size. However, studies other long-term sequelae of cancer.210 Patients should be pro-
have been published demonstrating similar outcomes with vided with a written treatment summary and a “survivorship
breast conservation.207 care plan” for their ongoing care. Patients should be encour-
Radiation indications are the same as for women: large aged to seek individual counseling and participate in support
tumors, skin and/or chest wall involvement, and nodal groups as they see the need and to gain the value of engagement
involvement. SLNB and ALND should be performed using in the vast array of support and advocacy activities available
the same indications as in women. Men should also receive in most communities.211 Long-term effects of cancer care are

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common. Recently, a number of organizations established   17. Eberl MM, Fox CH, Edge SB, et al. BI-RADS classification
guidelines for many domains of survivorship care that pro- for management of abnormal mammograms. J Am Board
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