Practice Essentials

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the
leading cause of cancer death among women.

Essential update: Bilateral mastectomy for breast cancer may increase survival rate in BRCA
mutation carriers

In a retrospective study of 390 women diagnosed with stage I or II breast cancer who were known or
likely carriers of a BRCA1 or BRCA2 mutation, Metcalfe and colleagues reported that bilateral
mastectomy was associated with a 48% reduction in breast cancer deaths. This figure was obtained
through multivariable analysis, after controlling for patient age at diagnosis, year of diagnosis,
treatment, and other prognostic factors. Patients, who were aged 65 or less, initially underwent
unilateral (346 women) or bilateral (44 women) mastectomy, with 137 of the unilateral patients later
undergoing mastectomy of the contralateral breast. Patients were followed for up to 20 years, with a
median follow-up period of 14.3 years.[1, 2, 3]

Signs and symptoms

Early breast cancers may be asymptomatic, and pain and discomfort are typically not present. If a lump
is discovered, the following may indicate the possible presence of breast cancer:

Change in breast size or shape

Skin dimpling or skin changes
Recent nipple inversion or skin change, or nipple abnormalities
Single-duct discharge, particularly if blood-stained
Axillary lump

See Clinical Presentation for more detail.

Diagnosis

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient
or health care provider.

Evaluation of breast cancer includes the following:

Clinical examination
Imaging
Needle biopsy

Physical examination

The following physical findings should raise concern:

Lump or contour change

Skin tethering
Nipple inversion
Dilated veins
Ulceration
Paget disease
Edema or peau dorange

If a palpable lump is found and possesses any of the following features, breast cancer may be present:

Hardness
 Irregularity
Focal nodularity
Fixation to skin or muscle

Screening

Early detection remains the primary defense in preventing breast cancer. Screening modalities include
the following:

Breast self-examination
Clinical breast examination
Mammography
Ultrasonography
Magnetic resonance imaging

Ultrasonography and MRI are more sensitive than mammography for invasive cancer in nonfatty
breasts. Combined mammography, clinical examination, and MRI are more sensitive than any other
individual test or combination of tests.

Biopsy

Core biopsy with image guidance is the recommended diagnostic approach for newly diagnosed breast
cancers. This is a method for obtaining breast tissue without surgery and can eliminate the need for
additional surgeries. Open excisional biopsy is the surgical removal of the entire lump.

See Workup for more detail.

Management

Surgery

Surgery is the primary treatment for breast cancer. Lumpectomy or total mastectomy may be indicated.

Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing
recurrence rates. Adjuvant treatment for breast cancer involves radiation therapy and a variety of
chemotherapeutic and biologic agents. There are 2 general approaches for delivering radiation therapy:

External-beam radiotherapy (EBRT)

Partial-breast irradiation (PBI)

Surgical resection with or without radiation is the standard treatment for ductal carcinoma in situ.

Pharmacologic agents

Hormone therapy and chemotherapy are the 2 main interventions for treating metastatic breast cancer.
Common chemotherapeutic regimens include the following:

Docetaxel
Cyclophosphamide
Doxorubicin
Carboplatin
Methotrexate
Trastuzumab

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for
reduction of breast cancer risk in high-risk women.
In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for
fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and
pamidronate may be added to the treatment regimen to increase bone mass. These agents are given
along with calcium and vitamin D supplementation.

See Treatment and Medication for more detail.

Image library

Anatomy of breast.

Background

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the
leading cause of cancer death in women.[4] In the United States, breast cancer accounts for 29% of all
cancers in women and is second only to lung cancer as a cause of cancer deaths.[5] (For discussion of
male breast cancer, see Breast Cancer in Men.)

Many early breast carcinomas are asymptomatic; pain or discomfort is not usually a symptom of breast
cancer. Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the
patient or healthcare provider.

The general approach to evaluation of breast cancer has become formalized as triple assessment:
clinical examination, imaging (usually mammography, ultrasonography, or both), and needle biopsy.
(See Workup.) Increased public awareness and improved screening have led to earlier diagnosis, at
stages amenable to complete surgical resection and curative therapies. Improvements in therapy and
screening have led to improved survival rates for women diagnosed with breast cancer.

Surgery and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are now
considered primary treatment for breast cancer. For many patients with low-risk early-stage breast
cancer, surgery with local radiation is curative. (See Treatment and Management.)

Surgery is considered primary treatment for breast cancer. Many patients with early-stage breast cancer
are cured with surgery alone. (See Treatment and Management.)

Adjuvant breast cancer therapies are designed to treat micrometastatic disease or breast cancer cells
that have escaped the breast and regional lymph nodes but do not yet have an established identifiable
metastasis. Depending on the model of risk reduction, adjuvant therapy has been estimated to be
responsible for 35-72% of the decrease in mortality.
Over the past 3 decades, extensive and advocate-driven breast cancer research has led to extraordinary
progress in the understanding of the disease. This has resulted in the development of more targeted and
less toxic treatments. (See Treatmentand Medication.)

For patient education information, see the Breast Cancer Health Center, as well as Breast Cancer,
Mastectomy, Breast Lumps and Pain, Breast Self-Exam, and Mammogram.

Anatomy

The breasts of an adult woman are milk-producing glands on the front of the chest wall. They rest on
the pectoralis major and are supported by and attached to the front of the chest wall on either side of
the sternum by ligaments. Each breast contains 15-20 lobes arranged in a circular fashion. The fat that
covers the lobes gives the breast its size and shape. Each lobe comprises many lobules, at the end of
which are glands that produce milk in response to hormones (see the image below).

Anatomy of breast.

Pathophysiology

The current understanding of breast cancer etiopathogenesis is that invasive cancers arise through a
series of molecular alterations at the cell level. These alterations result in breast epithelial cells with
immortal features and uncontrolled growth.

Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with distinct
natural histories and clinical behavior. The exact number of disease subtypes and molecular alterations
from which these subtypes arise remains to be fully elucidated, but these generally align with the
presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal
growth factor receptor 2 (HER2).

This view of breast cancer--not as a set of stochastic molecular events, but as a limited set of separable
diseases of distinct molecular and cellular origins--has altered thinking about breast cancer etiology,
type-specific risk factors, and prevention and has had a substantial impact on treatment strategies and
breast cancer research.

Evidence from The Cancer Genome Atlas Network (TCGA) confirms the following 4 main breast
tumor subtypes, with distinct genetic and epigenetic aberrations[6] (see the image below):

Luminal A
Luminal B
Basal-like
 HER2-positive Intrinsic subtypes of breast cancer.

It is noteworthy that the basal-like breast tumor subgroup shares a number of molecular characteristics
common to serous ovarian tumors, including the types and frequencies of genomic mutations. These
data support the evidence that some breast cancers share etiologic factors with ovarian cancer. Most
compelling are the data showing that patients with basal-type breast cancers show treatment
responsiveness similar to that of ovarian cancer patients.[7]

The various types of breast cancers are listed below by percentage of cases:

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a
tendency to metastasize via lymphatics; this lesion accounts for 75% of breast cancers
Over the past 25 years, the incidence of lobular carcinoma in situ (LCIS) has doubled,
reaching a current level of 2.8 per 100,000 women; the peak incidence is in women aged 40-
50 years
Infiltrating lobular carcinoma accounts for fewer than 15% of invasive breast cancers
Medullary carcinoma accounts for about 5% of cases and generally occurs in younger women
Mucinous (colloid) carcinoma is seen in fewer than 5% of invasive breast cancer cases
Tubular carcinoma of the breast accounts for 1-2% of all breast cancers
Papillary carcinoma is usually seen in women older than 60 years and accounts for
approximately 1-2% of all breast cancers
Metaplastic breast cancer accounts for fewer than 1% of breast cancer cases, tends to occur in
older women (average age of onset in the sixth decade), and has a higher incidence in blacks
Mammary Paget disease accounts for 1-4% of all breast cancers and has a peak incidence in
the sixth decade of life (mean age, 57 years)

Etiology

Epidemiologic studies have identified a number of risk factors that are associated with an increased
risk of a woman developing breast cancer. Several risk factors have been found to be clinically useful
for assessing a patients risk of breast cancer. Many of these factors form the basis of breast cancer risk
assessment tools currently being used in the practice setting.

Age and gender

Increasing age and female sex are established risk factors for breast cancer. Sporadic breast cancer is
relatively uncommon among women younger than 40 years but increases significantly thereafter. The
effect of age on risk is illustrated in the SEER (Surveillance, Epidemiology and End Results) data,
where the incidence of invasive breast cancer for women younger than 50 years is 44.0 per 100,000 as
compared with 345 per 100,000 for women aged 50 years or older. [8]
The total and age-specific incidence for breast cancer is bimodal, with the first peak occurring at about
50 years and the second occurring at about 70 years. [9] This bimodal pattern may reflect the influence of
age within the different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier,
whereas hormone-sensitive, slower-growing tumors tend to occur with advancing age.

Family history of breast cancer

A positive family history of breast cancer is the most widely recognized risk factor for breast cancer.
The lifetime risk is up to 4 times higher if a mother and sister are affected, and it is about 5 times
greater in women who have 2 or more first-degree relatives with breast cancer. The risk is also greater
among women with breast cancer in a single first-degree relative, particularly if the relative was
diagnosed at an early age (50 years). Despite a history indicating increased risk, many of these
families have normal results on genetic testing.

A family history of ovarian cancer in a first-degree relative, especially if the disease occurred at an
early age (< 50 years), has been associated with a doubling of breast cancer risk. This often reflects
inheritance of a pathogenic mutation in the BRCA1 or BRCA2 gene.

The family history characteristics that suggest increased risk of cancer are summarized as follows:

Two or more relatives with breast or ovarian cancer

Breast cancer occurring in an affected relative younger than 50 years
Relatives with both breast cancer and ovarian cancer
One or more relatives with 2 cancers (breast and ovarian cancer or 2 independent breast
cancers)
Male relatives with breast cancer
BRCA1 and BRCA2 mutations
Ataxia telangiectasia heterozygotes (quadrupled risk)
Ashkenazi Jewish descent (doubled risk)

A small percentage of patients, usually with a strong family history of other cancers, have cancer
syndromes. These include families with a mutation in the PTEN, TP53, MLH1, MLH2, CDH1, or
STK11 gene.

To aid in the identification of mutation carriers of BRCA1/2, a number of family historybased risk
assessment tools have been developed for clinical use, including the following:

BRCAPRO
Couch
Myriad I and II
Ontario Family History Assessment Tool (FHAT)
Manchester

All of these assessment tools are highly predictive of carrier status and aid in reducing testing costs for
the majority of mutation negative families.[10] BRCAPRO, the most commonly used model, identifies
approximately 50% of mutation-negative families, avoiding unnecessary genetic testing, and fails to
screen only about 10% of mutation carriers.

Notably, a significant portion of ovarian cancers not previously considered familial can be attributed to
BRCA1 or BRCA2 mutations.[11] This finding has led to the suggestion that women with nonmucinous
invasive ovarian cancers may benefit from genetic testing to determine mutation status independent of
a strong history or no history of breast cancer.

The National Institutes of Health (NIH) provides a Cancer Genetics Services Directory. This is a partial
listing of professionals who provide services related to cancer genetics, including cancer risk
assessment, genetic counseling, and genetic susceptibility testing.
Reproductive factors and steroid hormones

Late age at first pregnancy, nulliparity, early onset of menses, and late age of menopause have all been
consistently associated with an increased risk of breast cancer. [12, 13, 14, 15, 16] Prolonged exposure to
elevated levels of sex hormones has long been postulated as a risk factor for developing breast cancer,
explaining the association between breast cancer and reproductive behaviors. [17, 18]

Clinical trials of secondary prevention in women with breast cancer have demonstrated the protective
effect of selective estrogen receptor modulators (SERMs) and aromatase inhibitors on recurrence and
the development of contralateral breast cancers.[19] Use of SERMs in women at increased risk for breast
cancer has prevented invasive ER-positive cancers.[20, 21, 22] These data support estradiol and its receptor
as a primary target for risk reduction but do not establish that circulating hormone levels predict
increase risk.

A number of epidemiologic and pooled studies support an elevated risk of breast cancer among women
with high estradiol levels.[23, 24] The Endogenous Hormones and Breast Cancer Collaborative Group
(EHBCG) reported a relative risk of 2.58 among women in the top quintile of estradiol levels. [25]

Upon thorough review of the collective data, the Breast Cancer Prevention Collaborative Group
(BCPCG) prioritized additional factors that might be included in the validation phase of a risk
prediction model and gave a high priority score to free plasma estradiol levels. [24] At present, routine
measurement of plasma hormone levels is not recommended in the assessment of breast cancer risk.

One of the most widely studied factors in breast cancer etiology is the use of exogenous hormones in
the form of oral contraceptives (OCs) and hormone replacement therapy (HRT). [26, 27] The overall
evidence suggests an approximately 25% greater risk of breast cancer among current users of OCs. The
risk appears to decrease with age and time since OC discontinuance. For OC users, risk returns to that
of the average population risk about 10 years after cessation.

Data obtained from case-control and prospective cohort settings support an increased risk of breast
cancer incidence and mortality with the use of postmenopausal HRT. [28] Increased risk of breast cancer
has been positively associated with length of exposure, with the greatest risk being observed for
hormonally responsive lobular, mixed ductal-lobular, and tubular cancers.[28] Risk is greater among
women taking combination HRT than among those taking estrogen-only formulations.[29]

In the Womens Health Initiative (WHI) trial, the incidence of invasive breast cancer was 26% higher
in women randomly assigned to combination HRT than in those assigned to placebo. In contrast, the
use of estrogen (conjugated equine estrogen) alone in women who had undergone hysterectomy was
associated with a 23% (but not significant) decrease in breast cancer risk in comparison with placebo at
initial reporting.

On extended follow-up (median, 11.8 years), estrogen-only therapy for 5-9 years in women with
hysterectomy was associated with a significant 23% reduction in the annual incidence of invasive
breast cancer (0.27%; placebo, 0.35%). [30] Fewer women died of breast cancer in the estrogen-only
arm. These findings contrast with those reported from large observational case-control and prospective
cohort studies, where estrogen alone was associated with increased risk (though the increase was
consistently less than that associated with combined HRT use). [31]

To aid the medical community in the application of HRT, a number of agencies and groups have
published recommendations for HRT use in the treatment of menopause and associated bone loss. At
present, HRT is not recommended for prevention of cardiovascular disease or dementia or, more
generally, for long-term use to prevent disease.

Recommendations differ slightly by agency and by country. US and non-US evidence-based treatment
recommendations can be found at the National Guidelines Clearinghouse Web site.

When prescribing HRT, the clinician should provide a discussion of the most current evidence and an
assessment of the potential benefit and harm to the patient. Because of the known risk of endometrial
cancer with estrogen-only formulations, the US Food and Drug Administration (FDA) currently
advises the use of estrogen-plus-progesterone HRT for the management of menopausal symptoms in
women with an intact uterus tailored to the individual patient, at the lowest effective dose for the
shortest time needed to abate symptoms.

There are currently no formal guidelines for the use of HRT in women at high risk for breast cancer (ie,
women with a family history of breast cancer, a personal history of breast cancer, or benign breast
disease). Only a few studies have evaluated the effect of HRT after a diagnosis of breast cancer. The
largest of these, the HABITS (Hormonal replacement therapy After Breast canceris IT Safe?) study
was stopped early because unacceptable rates of breast cancer recurrence and contralateral disease with
2 years of HRT use (hazard ratio, 3.5).[32]

In another randomized clinical trial, no increase in the risk of breast cancer recurrences was observed
in women at a median follow up of 4.1 years.[33] Use of progesterone-containing HRT was limited by
intermittent use, with continuous exposure avoided.

Combination formulations containing estrogen plus progesterone are contraindicated in women with a
prior history of invasive disease, a history of ductal or lobular carcinoma in situ, or a strong family
history of breast cancer. This recommendation poses a significant challenge when confronted with a
patient suffering severe menopausal symptoms.

Many new treatments for menopausal symptoms have been suggested (eg, clonidine, venlafaxine,
gabapentin, and combination venlafaxine plus gabapentin). To date, no randomized clinical trials
among women at increased risk of breast cancer or women with a history of breast cancer have
assessed the overall efficacy or risks associated with these treatments. [34] Use of these agents is
controversial and should target the severity of menopausal symptoms.

Other hormone-based approaches (eg, low-dose vaginal estrogen for vaginal and urinary symptoms,
including dyspareunia) are generally considered to be safer, particularly in patients receiving SERMs.
However, these agents may also carry a slight increased risk, in that they are capable of raising
estradiol levels, at least transiently, depending on the dose and frequency of administration. Little
evidence supports the benefit of commonly used dietary isoflavones, black cohosh, or vitamin E.

Prior breast health history

A history of breast cancer is associated with a 3- to 4-fold increased risk of a second primary cancer in
the contralateral breast.[35, 36, 37] The presence of any premalignant ductal carcinoma in situ (DCIS) or
LCIS confers an 8- to 10-fold increase in the risk of developing breast cancer in women who harbor
untreated preinvasive lesions.[38, 39]

A history of breast biopsy that is positive for hyperplasia, fibroadenoma with complex features,
sclerosing adenosis, and solitary papilloma have been associated with a modest (1.5- to 2-fold) increase
in breast cancer risk.[38, 39] In contrast, any diagnosis of atypical hyperplasia that is ductal or lobular in
nature, especially in a woman under the age of 45 years, carries a 4- to 5-fold increased risk of breast
cancer, with the increase rising to 8- to 10-fold among women with multiple foci of atypia or
calcifications in the breast.[40]

Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative
breast disease or fibroadenoma, have not been associated with increased risk. [41]

Lifestyle risk factors

The wide variability of breast cancer incidence around the world (eg, the nearly 5-fold difference
between Eastern Africa and Western Europe) has long been attributed to differences in dietary intake
and reproductive patterns.[42, 43, 44, 45] In general, rates differ according to the level of industrial
development: there are more than 80 cases per 100,000 in developed countries, compared with fewer
than 40 per 100,000 in less developed countries.
As with cancers of the colon and prostate, diets that are rich in grains, fruits, and vegetables; low in
saturated fats; low in energy (calories); and low in alcoholthe more common pattern in less
industrialized countriesare thought to be protective against breast cancer.[46]

Obesity

Increased risk of postmenopausal breast cancer has been consistently associated with the following:

Adult weight gain of 20-25 kg above body weight at age 18[47, 48]
Western dietary pattern (high energy content in the form of animal fats and refined
carbohydrates)
Sedentary lifestyle
Regular, moderate consumption of alcohol (3-5 alcoholic beverages per week)

The Western lifestyle (ie, chronic excess energy intake from meat, fat, and carbohydrates and lack of
exercise) strongly correlates with development of the following:

Obesity, particularly abdominal obesity

Chronic hyperinsulinemia
Higher production and availability of insulinlike growth factor (IGF)-1
Increased levels of endogenous sex hormones through suppression of sex hormonebinding
globulin[49, 50]

Studies of dietary fat, total energy, and meat intake levels have largely been inconsistent in population
studies of adult women with regard to risk of breast cancer. In contrast, epidemiologic studies have
more consistently found a positive relation between breast cancer risk and early-life exposures such as
diet, obesity, and body size (including height).[51, 52, 53] The mechanism of this relation is unknown.

Environmental risk factors

A number of environmental exposures have been investigated in relation to breast cancer risk in
humans, including the following[54, 55, 56, 57] :

Tobacco smoke (both active and passive exposure)

Dietary (eg, charred and processed meats)
Alcohol consumption
Environmental carcinogens (eg, exposure to pesticides, radiation, and environmental and
dietary estrogens)

Of these environmental exposures, only high doses of ionizing radiation to the chest area, particularly
during puberty, have been unequivocally linked with an increased risk of breast cancer in adulthood.[57,
58]
Because of the strong association between ionizing radiation exposure and breast cancer risk,
medical diagnostic procedures are performed in such a way as to minimize exposure to the chest area,
particularly during adolescence.

Women with a history of radiation exposure to the chest area should be examined and counseled
regarding their risk of breast cancer on the basis of the timing and dose of the previous exposure. A
patient treated for Hodgkin lymphoma with Mantel radiation that includes the breasts in the radiation
field has a 5-fold higher risk of developing breast cancer. This risk increases markedly for women
treated during adolescence[59] ; evidence suggests that cumulative risk increases with age as a function
of age of exposure and type of therapy.[60]

Current evidence does not support a significant and reproducible link between other environmental
exposures and breast cancer risk. Thus, a number of factors remain suspect but unproven.

Epidemiology
United States statistics

In the United States, approximately 232,340 new cases of female invasive breast cancer are predicted
to occur in 2013, along with 2240 cases in men. [5] Among US women in 2011, in addition to invasive
breast cancer, 57,650 new cases of in situ breast cancer were expected to occur; approximately 83% of
these cases were expected to be DCIS, and 11% were expected to be LCIS. [61]

The incidence of breast cancer in the United States increased rapidly from 1980 to 1987, largely as a
consequence of the widespread use of mammography screening, which led to increased detection of
asymptomatic small breast tumors. After 1987, the increase in overall rates of invasive breast cancers
slowed significantly, specifically among white women aged 50 years or older.

Incidence over this period of time varied dramatically by histologic type. Common ductal carcinomas
increased modestly from 1987 to 1999, whereas invasive lobular and mixed ductal-lobular carcinomas
increased dramatically during this time period.[62] For women under the age of 50, breast cancer rates
have remained stable since the middle to late 1980s. Rates of DCIS have stabilized since 2000.[61]

Whereas a decline in invasive breast cancer rates was evident as early as 1999, rates decreased
dramatically in women aged 50 years or older between 2001 and 2004. During this same period, no
significant change was observed in the incidence of ER-negative cancers or cancers in women younger
than 50 years. The decline in rates from 2001 to 2004 was greatest between 2002 and 2003 and was
limited to non-Hispanic whites.[63, 64, 65, 66]

The reason for the decline has been extensively debated. Breast cancer rates decreased significantly
after the reports from the Million Women Study[67] and the Womens Health Initiative showing higher
numbers of breast cancers in women using combination HRT with estrogen and progestin for
menopausal symptoms. The near-immediate decrease in the use of combination HRT for that purpose
has been widely accepted as a primary explanation for the decrease in breast cancer rates. [65]

However, Jemal and Li argued that the decline in breast cancer incidence started earlier than the
reduction in combination HRT use and that the decline is due in part to a saturation in
mammographic screening mammography that produced a plateau in incidence when such screening
stabilized in the late 1990s.[62, 64] Saturation of the population would be predicted to reduce the pool of
undiagnosed or prevalent cases.

For women aged 69 years or older, breast cancer rates started to decline as early as 1998, when
screening first showed a plateau. This observation is consistent with the prediction that if widespread
screening and earlier detection are effective, they should result in a peak incidence among women
during the sixth and seventh decades of life, followed by a decline. This is exactly the pattern now
being reported for screened populations.[68]

The second observation noted by Jemal et al was that despite evidence for a plateau effect, screening
saturation alone could not explain the dramatic declines or the pattern of decline. The decline in
incidence was observed only for ER-positive tumors and not for ER-negative ones; these findings
support the competing hypothesis that exposure to HRT as estrogen in combination with synthetic
progesterone promoted the growth of undetected tumors.

Under this scenario, withdrawal of combination HRT at the population level may have resulted in
regression or a slowing of tumor growth. The latter, it has been argued, would result in a delay in
detection. Overall, incidence figures from 2005-2009, for which the most recent data are currently
available, suggest that overall new breast cancer case rates have remained fairly stable since the initial
drop.

It is notable, however, that the annual percentage change from 2005 to 2009 increased in women aged
65-74 years by 2.7% during this period, rates that parallel 2001 incidence figures for this age group. [8]
This rise is occurring in spite of very low use of HRT by this population[69] and suggests that the drop
in combination HRT use immediately after 2002 may not have resulted in a sustained decrease in new
breast cancer cases.
At present, it is unclear whether decreased use of combination HRT has resulted in a sustained
reduction in the incidence of breast cancer at the population level or has shifted the age at which
preexisting disease would become detectable. Longer-term follow-up of post-2002 trends in relation to
combination HRT use are needed to address this question.

International statistics

The final decades of the 20th century saw worldwide increases in the incidence of breast cancer, with
the highest rates reported in Westernized countries. Reasons for this trend are largely attributed to
introduction of screening mammography. Changes in reproductive patternsparticularly fewer
children and later age at first birthmay also have played a role, as may changes in lifestyle factors,
including the following:

Western dietary patterns

Decreased physical activity
Rising obesity rates
More widespread use of exogenous hormones for contraception and treatment of menopausal
symptoms

The beginning of the 21st century saw a dramatic decrease in breast cancer incidence in a number of
Westernized countries (eg, the United Kingdom, France, and Australia). These decreases paralleled
those noted in the United States and reflected similar patterns of mammography screening and
decreased use of combination HRT.[4]

In 2008, there were an estimated 1.38 million new cases of invasive breast cancer worldwide. The 2008
incidence of female breast cancer ranged from 19.3 cases per 100,000 in Eastern Africa to 89.9 cases
per 100,000 in Western Europe.[4]

With early detection and significant advances in treatment, death rates from breast cancer have been
decreasing over the past 25 years in North America and parts of Europe. In many African and Asian
countries (eg, Uganda, South Korea, and India), however, breast cancer death rates are rising. [4]

Age-related demographics

The incidence rate of breast cancer increases with age, from 1.5 cases per 100,000 in women 20-24
years of age to a peak of 421.3 cases per 100,000 in women 75-79 years of age; 95% of new cases
occur in women aged 40 years or older. The median age of women at the time of breast cancer
diagnosis is 61 years.[61]

Rates of in situ breast cancer stabilized among women 50 years and older in the late 1990s; this is
consistent with the proposed effects of screening saturation. However, the incidence of in situ breast
cancer continues to increase in younger women.[61]

Race- and ethnicity-related demographics

In the United States, the incidence of breast cancer is higher in non-Hispanic whites than in women of
other racial and ethnic groups. Among women younger than 40 years, African Americans have a higher
incidence. In addition, a larger proportion of African-American women are diagnosed with larger,
advanced-stage tumors (>5 cm) and are more likely to die of breast cancer at every age. [61]

According to the American Cancer Society (ACS), breast cancer rates among women from various
racial and ethnic groups are as follows[61] :

Non-Hispanic white: 125.4/100,000

African American: 116.1/100,000
Hispanic/Latina: 91.0/100,000
American Indian/Alaska Native: 89.2/100,000
 Asian American/Pacific Islander: 84.9/100,000

According to the ACS, death rates from breast cancer among women from various racial and ethnic
groups are as follows:

Non-Hispanic white: 23.9/100,000

African American: 32.4/100,000
Hispanic/Latina: 15.3/100,000
American Indian/Alaska Native: 17.6/100,000
Asian American/Pacific Islander: 12.2/100,000

Breast cancer death rates among women in most racial and ethnic groups in the US have been declining
since the early 1990s, except in American Indian and Alaska Native populations, among whom rates
have remained stable.

Prognosis

Death rates from breast cancer in the United States have decreased steadily in women since 1990.
Breast cancer mortality fell by 24% between 1990 and 2000 for women aged 30-79 years. The largest
decrease in mortality has been seen in women younger than 50 years (3.3% per year) compared with
those aged 50 years and older (2.0% per year).

The decrease in breast cancer death rates is thought to represent progress in both earlier detection and
improved treatment modalities.[5] The 2013 estimates are 39,920 expected breast cancer deaths (39,510
women, 410 men).[5]

Prognostic and predictive factors

Numerous prognostic and predictive factors for breast cancer have been identified by the College of
American Pathologists (CAP) to guide the clinical management of women with breast cancer. Breast
cancer prognostic factors include the following:

Axillary lymph node status

Tumor size
Lymphatic/vascular invasion
Patient age
Histologic grade
Histologic subtypes (eg, tubular, mucinous [colloid], or papillary)
Response to neoadjuvant therapy
ER/PR status
HER2 gene amplification or overexpression

Cancerous involvement of the lymph nodes in the axilla is an indication of the likelihood that the breast
cancer has spread to other organs. Survival and recurrence are independent of level of involvement but
are directly related to the number of involved nodes.

Patients with node-negative disease have an overall 10-year survival rate of 70% and a 5-year
recurrence rate of 19%. In patients with lymph nodes that are positive for cancer, the recurrence rates at
5 years are as follows:

1-3 positive nodes 30-40%

4-9 positive nodes 44-70%
>10 positive nodes 72-82%
Hormone receptorpositive tumors generally have a more indolent course and are responsive to
hormone therapy. ER and PR assays are routinely performed on tumor material by pathologists;
immunohistochemistry (IHC) is a semiquantitative technique that is observer- and antibody-dependent.

This prognostic information can guide physicians in making therapeutic decisions. Pathologic review
of the tumor tissue for histologic grade, along with the determination of ER/PR status and HER2 status,
is necessary for determining prognosis and treatment. Evaluation of lymph node involvement by means
of sentinel lymph node biopsy or axillary lymph node dissection is generally necessary as well. [70] (See
Staging.)

HER2

In the past, HER2 overexpression was associated with a more aggressive tumor phenotype and a worse
prognosis (higher recurrence rate and increased mortality), independent of other clinical features (eg,
age, stage, and tumor grade), especially in patients who did not receive adjuvant chemotherapy.
Prognosis has improved with the routine use of HER2-targeted therapies, which consist of the
following:

Trastuzumab Monoclonal antibody

Pertuzumab Monoclonal antibody
Lapatinib A small-molecule oral tyrosine kinase inhibitor
Trastuzumab-emtansine An antibody-drug conjugate directed specifically to the HER2
receptor

HER2 status has also been shown to predict response to certain chemotherapeutic agents (eg,
doxorubicin). Retrospectively analyzed results from clinical trials have shown that HER2-positive
patients benefit from anthracycline-based regimens, perhaps because of the frequent coamplification of
topoisomerase II with HER2. Preliminary data also suggest that HER2 positivity may predict response
to and benefit from paclitaxel in the adjuvant setting.[71] (See Breast Cancer and HER2.)

Prognosis by cancer type

DCIS is divided into comedo (ie, cribriform, micropapillary, and solid) and noncomedo subtypes, a
division that provides additional prognostic information on the likelihood of progression or local
recurrence. Generally, the prognosis is worse for comedo DCIS than for noncomedo DCIS (see
Histology).

Approximately 10-20% of women with LCIS develop invasive breast cancer within 15 years after their
LCIS diagnosis. Thus, LCIS is considered a biomarker of increased breast cancer risk.

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to
metastasize via lymphatic vessels. Like ductal carcinoma, infiltrating lobular carcinoma typically
metastasizes to axillary lymph nodes first. However, it also has a tendency to be more multifocal.
Nevertheless, its prognosis is comparable to that of ductal carcinoma.

Typical or classic medullary carcinomas are often associated with a good prognosis despite the
unfavorable prognostic features associated with this type of breast cancer, including ER negativity,
high tumor grade, and high proliferative rates. However, an analysis of 609 medullary breast cancer
specimens from various stage I and II National Surgical Adjuvant Breast and Bowel Project (NSABP)
protocols indicates that overall survival and prognosis are not as good as previously reported. Atypical
medullary carcinomas also carry a poorer prognosis.

Overall, patients with mucinous carcinoma have an excellent prognosis, with better than 80% 10-year
survival. Similarly, tubular carcinoma has a low incidence of lymph node involvement and a very high
overall survival rate. Because of the favorable prognosis, these patients are often treated with only
breast-conserving surgery and local radiation therapy.
Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a
good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype,
even though approximately 70% of cases are ER-positive. A retrospective review of 1400 cases of
invasive carcinoma identified 83 cases (6%) with at least 1 component of invasive micropapillary
ductal carcinoma.[72]

Additionally, lymph node metastasis is frequently seen in this subtype (incidence, 70-90%), and the
number of lymph nodes involved appears to correlate with survival.

For metaplastic breast cancer, the majority of published case series have demonstrated a worse
prognosis than with infiltrating ductal carcinoma, even when adjusted for stage, with a 3-year overall
survival rate of 48-71% and 3-year disease-free survival rate of 15-60%.[73] In most case series, large
tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[74]
Nodal status does not appear to impact survival in metaplastic breast cancer.

Paget disease of the breast is associated with an underlying breast cancer in 75% of cases. Breast-
conserving surgery can achieve satisfactory results, but at the risk of local recurrence. Poor prognostic
factors include a palpable breast tumor, lymph node involvement, histologic type, and an age of less
than 60 years. Paget disease with a palpable mass usually has an invasive component and a lower 5-
year survival rate (20-60%). Those that do not have an underlying palpable mass have a higher 5-year
survival rate (75-100%)

History

Many early breast carcinomas are asymptomatic, particularly if they were discovered during a breast-
screening program. Larger tumors may present as a painless mass. Pain or discomfort is not usually a
symptom of breast cancer; only 5% of patients with a malignant mass present with breast pain.

Often, the purpose of the history is not diagnosis but risk assessment. A family history of breast cancer
in a first-degree relative is the most widely recognized breast cancer risk factor.

The US Preventive Services Task Force (USPSTF) has updated its 2005 guidelines on risk assessment,
genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF
recommendations are as follows[77, 78] :

Women who have family members with breast, ovarian, tubal, or peritoneal cancer should be
screened to identify a family history that may be associated with an increased risk for
mutations in the breast cancer susceptibility genes BRCA1 or BRCA2
Women who have positive screening results should receive genetic counseling and then
BRCA testing if warranted
Women without a family history associated with an increased risk for mutations should not
receive routine genetic counseling or BRCA testing

Physical Examination

If the patient has not noticed a lump, then signs and symptoms indicating the possible presence of
breast cancer may include the following:

Change in breast size or shape

Skin dimpling or skin changes (eg, thickening, swelling, or redness)
Recent nipple inversion or skin change or other nipple abnormalities (eg, ulceration,
retraction, or spontaneous bloody discharge)
Nipple discharge, particularly if bloodstained
Axillary lump
To detect subtle changes in breast contour and skin tethering, the examination must include an
assessment of the breasts with the patient upright with arms raised. The following findings should raise
concern:

Lump or contour change

Skin tethering
Nipple inversion
Dilated veins
Ulceration
Mammary Paget disease
Edema or peau dorange

The nature of palpable lumps is often difficult to determine clinically, but the following features should
raise concern:

Hardness
Irregularity
Focal nodularity
Asymmetry with the other breast
Fixation to skin or muscle (assess fixation to muscle by moving the lump in the line of the
pectoral muscle fibers with the patient bracing her arms against her hips)

A complete examination includes assessment of the axillae and supraclavicular fossae, examination of
the chest and sites of skeletal pain, and abdominal and neurologic examinations. The clinician should
be alert to symptoms of metastatic spread, such as the following:

Breathing difficulties
Bone pain
Symptoms of hypercalcemia
Abdominal distention
Jaundice
Localizing neurologic signs
Altered cognitive function
Headache

The clinical evaluation should include a thorough assessment of specific risk factors for breast cancer
(see Breast Cancer Risk Factors).

Diagnostic Considerations

The differential diagnosis includes the following:

Circumscribed breast lesions Benign breast disease (eg, fibroadenomas and cysts), breast
cancer, breast lymphoma, and metastasis to the breast from other primary sites (eg,
neuroendocrine or extramedullary acute myeloid leukemia)
Skin thickening Inflammatory carcinoma and mastitis
Stellate lesions Breast cancer, traumatic fat necrosis, a radial scar, and a hyalinized
fibroadenoma
Dilated ducts with or without nipple discharge Papilloma, ductal carcinoma, duct ectasia,
and fibrocystic disease

Approach Considerations

Breast cancer evaluation should be an ordered inquiry that begins with symptoms and a general clinical
history. This is followed by a sequence that has become formalized as triple assessment, which
includes the following components:
 Clinical examination
Imaging (usually mammography, ultrasonography, or both)
Needle biopsy

This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a diagnosis
can be obtained with the minimum degree of invasiveness and, consequently, the minimum amount of
discomfort to the patient. Because the more invasive investigations also tend to be the most expensive,
this approach is usually the most economical.

The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the
most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate degree of
breast conservation while minimizing the need for reoperation.

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient
or healthcare provider. Mammographic features suggestive of malignancy include asymmetry,
microcalcifications, and a mass or architectural distortion. If any of these features are identified,
diagnostic mammography along with breast ultrasonography should be performed before a biopsy is
obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.

Breast Cancer Screening

Whereas early detection has been advocated as a primary defense against the development of life-
threatening breast cancer, questions have been raised in the past few years regarding the age at which
to initiate, the modality to use, the interval between screenings, whether to screen older women, and
even the impact on breast cancerrelated deaths. It is widely believed that breast tumors that are
smaller or nonpalpable and that present with a favorable tumor marker profile are more treatable when
detected early.

A survival benefit of early detection with mammography screening has been demonstrated. [79, 80] A
number of screening modalities exist for breast cancer, including clinical breast examination,
mammography, ultrasonography, and MRI. (See Breast Cancer Screening.)

In December 2013, the US Food and Drug Administration (FDA) issued a warning that nipple aspirate
tests are not an effective screening tool for breast cancer or other breast diseases and should not be used
in place of mammography, other imaging tests, or biopsy. The agency is concerned that the test, which
involves analysis of fluid aspirated from a woman's breast with a pump device, could lead to false-
positive or -negative results if fluid analysis alone is used as a screen.[81]

A warning against the use of nipple aspiration for breast cancer screening is also found in the National
Comprehensive Cancer Networks (NCCNs) 2013 guidelines. In addition, the NCCN guidelines state
that the test is currently being evaluated for clinical usefulness.

Mammography

Mammography is a low-dose x-raybased modality used to image the breast. It is currently the best
available population-based method for detecting breast cancer at an early stage. [80, 82, 83]

Mammography is used both for screening to detect a cancer and for diagnostic workup of patients after
a tumor is detected. Screening mammography is performed in asymptomatic women, whereas
diagnostic mammography is performed in symptomatic women (ie, when a breast lump or nipple
discharge is present or when an abnormality is found during screening mammography).

Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at less
than 100 m. Mammography often detects a lesion before it is palpable by clinical breast examination
and, on average, 1 to 2 years before noted by breast self-examination.
Recent advances in mammography include the development of digital mammography and the increased
use of computer-aided diagnosis (CAD) systems.[84] CAD systems have been developed to help the
radiologist identify mammographic abnormalities.

Digital mammography allows the image to be recorded and stored. With computer technology, digital
mammogram images can be magnified and the image modified to improve evaluation of specific areas
in question. Digital images can be transmitted electronically, decreasing the time to second opinion
without the risk of losing the film.

In a cohort study of women aged 50-74 years, which used data from the Ontario Breast Screening
Program, computed radiography (CR) was 21% less effective than digital direct radiography (DR) for
breast cancer detection; however, DR was equivalent to screen-film mammography (SFM).[85, 86]

The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in women
aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged 40-49
years, the risk of death is decreased by 17%.[87]

Screening mammography

Although mammography guidelines have been in place for more than 30 years, 20-30% of women still
do not undergo screening as indicated. The 2 most significant factors governing a womans decision to
undergo mammography are physician recommendation and access to health insurance. Nonwhite
women and those of lower socioeconomic status remain less likely to obtain mammography services
and more likely to present with life-threatening, advanced stage disease.[88, 89]

At present, the most widely accepted recommendations in the United States come from the American
Cancer Society (ACS), which recommends annual screening mammography, beginning at age 40 years
for all women and continuing for as long as a woman is in good health. The ACS recommends clinical
breast examinations about every 3 years for women in their 20s and 30s and every year for women 40
and over, with monthly breast self-examination as an option for women starting in their 20s. [90]

In contrast, since 2009 the USPSTF has recommended biennial screening mammography for women
aged 50-74 years (grade B recommendation). The USPSTF recommends against routine screening
mammography in women aged 40-49 years because of high rates of false-negative findings, perceived
harm of unnecessary biopsy, and concern for the harm associated with overdiagnosis and overtreatment
(grade C recommendation).[89]

Instead of routine screening for women 40-49 years old, the USPSTF recommends that clinicians
provide screening to selected patients in this age range, depending on individual circumstances and
patient preferences. The USPSTF further concluded that for most individuals without signs or
symptoms, there is likely to be only a small benefit from screening.

Finally, the USPSTF recommends against teaching breast self-examination and concludes that the
current evidence is insufficient to assess the benefits and harms of clinical breast examination in
women aged 40 years or older or the benefits and harms of screening mammography in women aged
75 years or older.

Diagnostic mammography

Diagnostic mammography is more expensive than screening mammography. It is used to determine the
exact size and location of breast abnormalities and to image the surrounding tissue and lymph nodes.
Women with breast implants or a personal history of breast cancer may require the additional views
used in diagnostic mammography as part of their routine screening examination.

A ductogram (or galactogram) is sometimes helpful for determining the cause of nipple discharge. In
this specialized examination, a fine plastic tube is placed into the opening of the duct in the nipple. A
small amount of contrast medium is injected, which outlines the shape of the duct on a mammogram
and shows whether a mass is present inside the duct.
Ultrasonography

Ultrasonography has become a widely available and useful adjunct to mammography in the clinical
setting. It is generally employed to assist the clinical examination of a suspicious lesion detected on
mammography or physical examination. As a screening tool, ultrasonography is limited by a number of
factors, most notably its failure to detect microcalcifications and its poor specificity (34%).

Originally, ultrasonography was used primarily as a relatively inexpensive and effective method of
differentiating cystic breast masses, which did not require sampling, from solid breast masses, which
were usually examined with biopsy; in many cases, the results of these biopsies were benign. However,
it is now well established that ultrasonography also provides valuable information about the nature and
extent of solid masses and other breast lesions and can often provide useful information regarding the
staging of the axilla.

This imaging technique is also useful in the guidance of biopsies and therapeutic procedures; research
is currently under way to evaluate its role in cancer screening.

Magnetic resonance imaging

In an effort to overcome the limitations of mammography and ultrasonography, MRI has been explored
as a modality for detecting breast cancer in women at high risk and in younger women. A combination
of T1, T2, and 3-D contrast-enhanced MRI techniques has been found to possess high sensitivity
(approximating 86-100% in combination with mammography and clinical breast examination) to
malignant changes in the breast. (See Magnetic Resonance Mammography.)

Indications for MRI

The high cost and limited availability of MRI, as well as the difficulties inherent in performing and
interpreting the studies with high false-positive rates, necessitate that the use of this modality be
carefully considered before it is recommended in a patient. The following are current indications for
MRI:

Characterization of an indeterminate lesion after a full assessment with physical examination,

mammography, and ultrasonography
Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node
Evaluation of suspected multifocal or bilateral tumor
Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality
Evaluation of suspected extensive high-grade intraductal carcinoma
Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma of
unknown origin
Monitoring of the response to neoadjuvant chemotherapy
Detection of recurrent breast cancer

Contraindications for MRI

Conversely, in a number of situations, MRI is contraindicated, usually because of physical constraints

that prevent adequate patient positioning. Additional contraindications include the following:

Contraindication to gadolinium-based contrast media (eg, allergy or pregnancy)

Patients inability to lie prone
Marked kyphosis or kyphoscoliosis
Marked obesity
Extremely large breasts
Severe claustrophobia

Relative contraindications also exist. These are essentially based on the high sensitivity but limited
specificity of the technique. MRI may not be useful for the following:
 Cancer-phobic patients at average or low risk of disease for breast cancer, because of the
psychological stress associated with false-positive findings
Assessment of mammographically detected microcalcifications

Nuclear imaging

The following 3 radiotracers are commonly used for breast imaging or scintimammography in either
clinical practice or research:

Technetium-99m (99m Tc)-sestamibi (for myocardial perfusion imaging); this was the first
radiopharmaceutical agent to be approved by the US Food and Drug Administration (FDA)
for use in scintimammography[91]
99m
Tc-tetrofosmin (also for myocardial perfusion imaging)
99m
Tc-methylene diphosphonate (MDP; for bone scintigraphy)

Scintimammography is not indicated as a screening procedure for the detection of breast cancer.
However, it may play a role in various specific clinical indications, as in cases of nondiagnostic or
difficult mammography and in the evaluation of high-risk patients, tumor response to chemotherapy,
and metastatic involvement of axillary lymph nodes.

In several prospective studies, overall sensitivity of99m Tc-sestamibi scintimammography in the

detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values
were 89% and 84%, respectively. Similar numbers have been demonstrated for 99m Tc-tetrofosmin
and99m Tc-MDP scintimammography.[6]

Positron Emission Tomography

Using a wide range of labeled metabolites (eg, fluorinated glucose [ 18 FDG]), positron emission
tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption, and
tumor receptor status.

When PET is combined with computed tomography (CT) to assist in anatomic localization (PET-CT),
scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph node
metastasis for the purposes of staging locally advanced and inflammatory breast cancer before
initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.

Accuracy of Breast Imaging Modalities

The different techniques used in breast imaging vary with respect to sensitivity, specificity, and
positive predictive value (see Table 1 below).

Table 1. Accuracy of Breast Imaging Modalities (Open Table in a new window)

Modality Sensitivity Specificity PPV Indications

Mammography 63-95% (>95% 14-90% (90% 10-50% Initial investigation for
palpable, 50% palpable) symptomatic breast in women
impalpable, 83-92% in older than 35 y and for
women older than 50 screening; investigation of
y; decreases to 35% in (94% choice for microcalcification
dense breasts) palpable)

Ultrasonography 68-97% palpable 74-94% 92% Initial investigation for

palpable (palpable) palpable lesions in women
younger than 35 y
MRI 86-100% 21-97% (< 52% Scarred breast, implants,
40% primary multifocal lesions, and
cancer) borderline lesions for breast
conservation; may be useful in
screening high-risk women
Scintigraphy 76-95% palpable, 52- 62-94% (94% 70-83% (83% Lesions >1 cm and axilla
91% impalpable impalpable) palpable, 79% assessment; may help predict
impalpable) drug resistance
PET 96% (90% axillary 100% Axilla assessment, scarred
metastases) breast, and multifocal lesions
MRI = magnetic resonance imaging; PET = positron emission tomography; PPV = positive predictive
value.

Breast Biopsy

Percutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance is the
recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can minimize the
need for operative intervention (and subsequent scarring, and provide accurate pathologic diagnosis for
appropriate management.

Excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive
margins. Open excisional biopsy is reserved for lesions where the diagnosis remains equivocal despite
imaging and core biopsy assessment or for benign lesions that the patient chooses to have removed.
Because wide clearance of the lesion is usually not the goal in diagnostic biopsies, unnecessary
distortion of the breast is thereby avoided. Ongoing audit is essential to help reduce an excessive
benign-to-malignant biopsy ratio.

Histology

Breast cancers usually are epithelial tumors of ductal or lobular origin. The following features are all
important in deciding on a course of treatment for any breast tumor:

Size
Status of surgical margin
Presence or absence of estrogen receptor (ER) and progesterone receptor (PR)
Nuclear and histologic grade
Proliferation
Vascular invasion
Tumor necrosis
Quantity of intraductal component
HER2 status

Histologic grade

Histologic grade is the best predictor of disease prognosis in carcinoma in situ, but it is dependent on
the grading system used, such as the Van Nuys classification (high-grade, low-grade comedo, low-
grade noncomedo). The grading of invasive carcinoma is also important as a prognostic indicator, with
higher grades indicating a worse prognosis (see Table 2 below).

Table 2. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) (Open Table in
a new window)

Score
1 >2 >3
A. Tubule formation >75% 10-75% < 10%
B. Mitotic count/HPF (microscope- < 7 7-12 >12
and field-dependent)
C. Nuclear size and pleomorphism Near normal; little Slightly enlarged; Markedly enlarged;
variation moderate variation marked variation
Grade I cancer if total score (A + B + C) is 3-5
Grade II cancer if total score (A + B + C) is 6 or 7
Grade III cancer if total score (A + B + C) is 8 or 9
HPF = high-power field.

Ductal carcinoma in situ

Increased use of screening mammography has resulted in a dramatic increase in the detection of ductal
carcinoma in situ (DCIS). Approximately 64,000 cases of DCIS are diagnosed annually in the United
States. About 90% of DCIS cases are identified on mammography as suspicious calcifications: linear,
clustered, segmental, focal, or mixed distribution.

DCIS is broadly divided into 2 subtypes: comedo (ie, cribriform, micropapillary, and solid; see the first
image below) and noncomedo (see the second image below). The likelihood of progression or local
recurrence, as well as the prognosis, varies in accordance with the DCIS subtype present (see Table 3
below).

Breast cancer. Intraductal carcinoma, comedo type.

Distended duct with intact basement membrane and central tumor necrosis.

Breast cancer. Intraductal carcinoma, noncomedo

type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth
pattern.

Table 3. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)

DCIS Characteristic Comedo Noncomedo

Nuclear grade High Low
Estrogen receptor Often negative Positive
Distribution Continuous Multifocal
Necrosis Present Absent
Local recurrence High Low
Prognosis Worse Better
DCIS = ductal carcinoma in situ.

Lobular carcinoma in situ

Lobular carcinoma in situ (LCIS) arises from the terminal duct apparatus and shows a rather diffuse
distribution throughout the breast, which explains its presentation as a nonpalpable mass in most cases
(see the images below). Over the past 25 years, the incidence of LCIS has doubled, currently standing
at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.

Breast cancer. Lobular carcinoma in situ.

Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Breast cancer. Lobular carcinoma in situ.

Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Infiltrating ductal carcinoma

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor (accounting for 75% of
breast cancers) and has a tendency to metastasize via lymphatic vessels. This lesion has no specific
histologic characteristics other than invasion through the basement membrane (see the image below).
DCIS is a frequently associated finding on pathologic examination.

Breast cancer. Infiltrating ductal carcinoma. Low-

grade carcinoma with well-developed glands invading fibrous stroma.

Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma,
accounting for 15-20% of invasive breast cancers. Histologically, it is characterized by the "single-file"
arrangement of small tumor cells. Like ductal carcinoma, infiltrating lobular carcinoma typically
metastasizes to axillary lymph nodes first. However, it also has a tendency to be multifocal and have
discontinuous areas of involvement, making mammographic and even MRI staging imprecise.

Medullary carcinoma

Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most
patients present with a bulky palpable mass and axillary lymphadenopathy. Diagnosis of this type of
breast cancer depends on the following histologic triad:

Sheets of anaplastic tumor cells with scant stroma

Moderate or marked stromal lymphoid infiltrate
Histologic circumscription or a pushing border

DCIS may be observed in the surrounding normal tissues. Medullary carcinomas are typically high-
grade lesions that are negative for ER, PR, and HER2 and that commonly demonstrate mutation of
TP53.

Mucinous carcinoma

Mucinous (colloid) carcinoma is another rare histologic type, seen in fewer than 5% of invasive breast
cancer cases. It usually presents during the seventh decade of life as a palpable mass or appears
mammographically as a poorly defined tumor with rare calcifications.

Mucin production is the histologic hallmark. There are 2 main types of lesions, A and B, with AB
lesions possessing features of both. Type A mucinous carcinoma represents the classic variety, with
larger quantities of extracellular mucin (see the image below), whereas type B is a distinct variant with
endocrine differentiation.

Breast cancer. Colloid (mucinous) carcinoma. Nests

of tumor cells in pool of extracellular mucin.

DCIS is not a frequent occurrence in this setting, though it may be found. Most cases are ER- and PR-
positive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express
glycoproteins MUC2 and MUC6.

Tubular carcinoma

Tubular carcinoma of the breast is an uncommon histologic type, accounting for only 1-2% of all
breast cancers. Characteristic features of this type include a single layer of epithelial cells with low-
grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.

Tubular components make up more than 90% of pure tubular carcinomas and at least 75% of mixed
tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a
very high overall survival rate. Because of its favorable prognosis, patients are often treated with only
breast-conserving surgery and local radiation therapy.

Papillary carcinoma

Papillary carcinoma of the breast (see the image below) encompasses a spectrum of histologic
subtypes. There are 2 common types: cystic (noninvasive form) and micropapillary ductal carcinoma
(invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts
for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast
and can present as bloody nipple discharge. They are strongly ER- and PR-positive.

Breast cancer. Papillary carcinoma. Solid papillary

growth pattern with early cribriform and well-developed thin papillary fronds.

Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a
good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype
similar to that of infiltrating ductal carcinoma, even though about 70% of cases are ER-positive. A
retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least 1
component of invasive micropapillary ductal carcinoma. Additionally, lymph node metastasis is seen
frequently in this subtype (70-90% of cases).[92]

Metaplastic breast cancer

Metaplastic breast cancer (MBC) accounts for fewer than 1% of breast cancer cases. It tends to occur in
older women (average age of onset in the sixth decade) and has a higher incidence in blacks. It is
characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.

A wide variety of histologic patterns includes the following:

Spindle-cell carcinoma
Carcinosarcoma
Squamous cell carcinoma of ductal origin
Adenosquamous carcinoma
Carcinoma with pseudosarcomatous metaplasia
Matrix-producing carcinoma

This diverse group of malignancies is identified as a single entity on the basis of a similarity in clinical
behavior. Compared with infiltrating ductal carcinoma, MBC tumors are larger, faster-growing,
commonly node-negative, and typically negative for ER, PR, and HER2.

Mammary Paget disease

Mammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak
incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of
the nipple-areola complex and is composed of the histologic hallmark Paget cells within the basement
membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed
between the keratinocytes singly or as a cluster of cells.
Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or
erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with
symptoms of itching, tingling, burning, or pain. In situ or invasive breast cancer is found in
approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast
examination and mammographic evaluation, with additional imaging, including breast MRI, if the
mammogram is negative.

Breast Cancer Staging

The American Joint Committee on Cancer (AJCC) staging system groups patients into 4 stages
according to the TNM system, which is based on tumor size (T), lymph node status (N), and distant
metastasis (M). (See Table 4 below.)

Table 4. TNM Staging System for Breast Cancer (Open Table in a new window)

Stage Tumor Node Metastases

Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T0 N1 M0

T1 N1 M0

T2 N0 M0

Stage IIB T2 N1 M0

T3 N0 M0

Stage IIIA T0 N2 M0

T1 N2 M0

T2 N2 M0

T3 N1-2 M0

Stage IIIB T4 N0 M0
 T4 N1 M0

T4 N2 M0

Stage IIIC Any T N3 M0

Stage IV Any T Any N M1

Primary tumor (T)

Tumor size definitions are as follows:

Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor
Tis DCIS
Tis LCIS
Tis Paget disease of the nipple with no tumor (Paget disease associated with a tumor is
classified according to the size of the tumor)
T1 Tumor 2 cm in greatest diameter
T1mic Microinvasion 0.1 cm in greatest diameter
T1a Tumor >0.1 but not >0.5 cm in greatest diameter
T1b Tumor >0.5 but not >1 cm in greatest diameter
T1c Tumor >1 cm but not >2 cm in greatest diameter
T2 Tumor >2 cm but not >5 cm in greatest diameter
T3 Tumor >5 cm in greatest diameter
T4 Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as
described below
T4a Extension to the chest wall, not including the pectoralis
T4b Edema (including peau dorange) or ulceration of the skin of the breast or satellite skin
nodules confined to the same breast
T4c Both T4a and T4b
T4d Inflammatory disease

Regional lymph nodes (N)

Clinical regional lymph node definitions are as follows:

Nx Regional lymph nodes cannot be assessed (eg, previously removed)

N0 No regional lymph node metastasis
N1 Metastasis in movable ipsilateral axillary lymph node(s)
N2 Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent
ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node
metastasis
N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures
N2b Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the
absence of clinically evident axillary lymph nodes
N3 Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without
axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph
node(s) and in the presence of axillary lymph node
N3a Metastasis in ipsilateral infraclavicular lymph node(s)
N3b Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c Metastasis in ipsilateral supraclavicular lymph node(s)
Distant metastasis

Metastases are defined as follows:

Mx Distant metastasis cannot be assessed

M0 No distant metastasis
M1 Distant metastasis

The 5-year survival rates are highly correlated with tumor stage, as follows:

Stage 0, 99-100%
Stage I, 95-100%
Stage II, 86%
Stage III, 57%
Stage IV, 20%

This prognostic information can guide physicians in making therapeutic decisions. Pathologic review
of the tumor tissue for histologic gradealong with determination of ER, PR, and HER2 statusis
necessary for determining prognosis.

Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node
dissection has also been considered necessary for staging and prognosis.

The 2012 National Comprehensive Cancer Network (NCCN) breast cancer guidelines state that lymph
node dissection is optional in the following cases[70] :

Strongly favorable tumors

When no result would affect the choice of adjuvant systemic therapy
Elderly patients
Patients with comorbid conditions

Additional Testing

The 2012 NCCN guidelines recommend the following laboratory studies for all asymptomatic women
with early-stage breast cancer (stages I and II):

Complete blood count (CBC) with differential

Liver function tests (LFTs) and alkaline phosphatase

In addition imaging studies (eg, chest x-ray, chest CT, or CT of the abdomen and pelvis) can be
considered for women with stage III (locally advanced or inflammatory breast cancer) or symptomatic
disease. Tumor markers (carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may also be
obtained in these patients.[70, 93]

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2
testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP
have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should
initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest;
Dako, Glostrup, Denmark) for HER2 protein expression. [94] (See Breast Cancer and HER2.)

The scoring method for HER2 expression is based on the cell membrane staining pattern and is as
follows:
 3+ Positive for HER2 protein expression; uniform intense membrane staining of more than
30% of invasive tumor cells
2+ Equivocal for HER2 protein expression; complete membrane staining that is either
nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells, or
uniform intense membrane staining in 30% or less of tumor cells
1+ Weak or incomplete membrane staining in any tumor cells
0 Negative for HER2 protein expression; no staining

Breast cancer specimens with equivocal IHC results should undergo validation with a HER2 gene
amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on
FISH alone for determining HER2 status.

In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal
IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are
seen in fewer than 3% of invasive breast cancer specimens and those that had previously been
considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC < 3+/FISH positive) have
been observed in approximately 4% of specimens. Currently, no data support excluding this group
from treatment with trastuzumab.

Newer methodologies for establishing HER2 status, including reverse transcriptasepolymerase chain
reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have been developed. The HER2
CISH PharmDX Kit (Dako Denmark A/S, Glostrup, Denmark) was approved by the FDA in November
2011. The interpretation for HER2 FISH testing (ratio of HER2 to chromosome 17 centromere
[HER2/CEP17] and gene copy number) is as follows:

Positive HER2 amplification HER2:CEP17 ratio is greater than 2.2 or HER2 gene copy is
greater than 6.0
Equivocal HER2 amplification HER2:CEP17 ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0
Negative HER2 amplification HER2:CEP17 ratio is less than 1.8 or HER2 gene copy of less
than 4.0

Molecular profiling assays

The Onco type Dx assay (Genomic Health, Inc, Redwood City, CA) has been approved by the US Food
and Drug Administration (FDA) for women with early-stage ER-positive, node-negative breast cancer
treated with tamoxifen, where the recurrence score (RS) correlated with both relapse-free interval and
overall survival. This assay is an RT-PCRbased assay of 21 genes (16 cancer genes and 5 reference
genes) performed on paraffin-embedded breast tumor tissue.

By using a formula based on the expression of these genes, an RS can be calculated that correlates with
the likelihood of distant recurrence at 10 years. Breast tumor RSs and risk levels are as follows:

< 18, low risk

18-30, intermediate risk
>30, high risk

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20
studies, the Onco type Dx assay was shown retrospectively to predict benefit from chemotherapy and
hormonal therapy in hormone-sensitive, node-negative tumors.[95] Similarly, among women with 1- to
3-node-positive, hormone receptor-positive disease, the Onco type Dx recurrence score was a
significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in
RS.

Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with
the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In
contrast, women with a high RS had a significant improvement in DFS with the addition of
chemotherapy to hormonal therapy (tamoxifen).
The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still
controversial. The Trial Assigning Individualized Options for Treatment [TAILORx], a large,
prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is
addressing this important question.

The MammaPrint assay (Agendia, The Netherlands) is a genetic test that measures the activity of 70
genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer. It was
approved for use by the FDA in 2007 and is an alternative platform to Oncotype DX. MammaPrint test
results are reported as either a low-risk or a high-risk RS:

A low-risk score means that the cancer has a 10% risk of coming back within 10 years without
any additional treatments after surgery
A high-risk score means that the cancer has a 29% risk of coming back within 10 years
without any additional treatments after surgery

Approach Considerations

Surgery is considered primary treatment for early-stage breast cancer; many patients are cured with
surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with
negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and
axillary lymph nodes (ALNs) to provide necessary prognostic information.

Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells
that have escaped the breast and regional lymph nodes but which have not yet had an established
identifiable metastasis). Adjuvant treatment for breast cancer involves radiation therapy and systemic
therapy (including a variety of chemotherapeutic, hormonal and biologic agents).

Treatment of Invasive Breast Cancer

Surgical treatment of invasive breast cancer may consist of lumpectomy or total mastectomy. In breast
cancer patients who have clinically negative nodes, surgery typically includes sentinel lymph node
(SLN) dissection for staging the axilla. (See Surgical Treatment of Breast Cancer.)

In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically
node-negative axillae who were undergoing either breast conservation or mastectomy with SLN
mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND)
in women with a positive SLN.[96]

In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received
axillary radiotherapy.[96] After 5 years of follow-up, the axillary recurrence rate was 0.54% in the
ALND group and 1.03% in the radiotherapy group, and there were no significant differences between
the groups with respect to either disease-free survival (86.9% vs 82.7%) or overall survival (93.3% vs
92.5%). The rate of lymphedema in the ALND group after 5 years, however, was twice the rate seen in
the radiotherapy group (28% vs 14%).

Ten-year follow-up results from the multicenter UK Standardization of Breast Radiotherapy (START)
trials confirm that 3-week hypofractionated adjuvant radiotherapyin which lower total doses of
radiotherapy are delivered in fewer, larger doses (fractions)is as effective and safe as the
international standard 5-week regimen for women with early-stage breast cancer following primary
surgery. Additionally, the hypofractionated regimen may cause less damage to surrounding normal
breast tissue.[97, 98]

Lumpectomy margins

The following consensus guideline, released by the Society of Surgical Oncology and the American
Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast
irradiation (WBI) in stages I and II invasive breast cancer [99, 100] :
 Positive margins are associated with at least a 2-fold increase in ipsilateral breast tumor
recurrence (IBTR)
Negative margins optimize IBTR; this risk is not significantly lowered by wider margin
widths
IBTR rates are reduced with the use of systemic therapy; in patients who do not receive
adjuvant systemic therapy, margins wider than no ink on tumor are not needed
Biologic subtypes do not indicate the need for margins wider than no ink on tumor
Margin width should not determine the choice of WBI delivery technique, fractionation, and
boost dose.
Wider negative margins than no ink on tumor are not indicated for patients with invasive
lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for
reexcision; the significance of pleomorphic LCIS at the margin is not clear
Young age is associated with an increased risk for IBTR after breast-conserving therapy, an
increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and
pathologic features; an increased margin width does not nullify the increased risk for IBTR in
young patients
An extensive intraductal component (EIC) identifies patients who may have a large residual
ductal carcinoma in situ (DCIS) burden after lumpectomy; when margins are negative, there is
no evidence of an association between an increased risk for IBTR and EIC

Postlumpectomy radiation therapy

The purpose of radiation therapy after breast-conserving surgery is to eradicate local subclinical
residual disease while reducing local recurrence rates by approximately 75%. On the basis of results
from several randomized controlled studies, irradiation of the intact breast is considered standard of
care, even in the lowest-risk disease with the most favorable prognostic features.[70]

There are 2 general approaches used to deliver radiation therapy: conventional external-beam
radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy (WBRT) consists
of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a
boost dose specifically directed to the area in the breast where the tumor was removed.

Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin
desquamation. Late toxicity (lasting 6 months after treatment) may include persistent breast edema,
pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis,
cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma
(0.5%).

PBI is employed in early-stage breast cancer after breast-conserving surgery as a way of delivering
larger fraction sizes while maintaining a low risk of late effects. Techniques that can deliver this
therapy include interstitial brachytherapy (multiple catheters placed through the breast) and
intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]).

Treatment is typically administered twice daily for 5 days. In several nonrandomized studies, these
techniques have shown low local recurrence rates comparable to those of EBRT.

The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when
patients are being considered for treatment with accelerated PBI [101] :

Age 45 years
Invasive ductal carcinoma or ductal carcinoma in situ (DCIS)
Total tumor size (invasive and DCIS) 3 cm
Negative microscopic surgical margins of excision
ALN- or SLN-negative

Potential complications of PBI are catheter placement followed by removal secondary to inadequate
skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence.
An observational study using data from the SEERMedicare linked database on 35,947 women aged
66 years and older who had invasive breast cancer (79.9%) or DCIS (20.1%) determined that standard
EBRT was associated with a higher 5-year breast preservation rate than either lumpectomy alone or
brachytherapy was.[102, 103, 104] However, the study data did not reflect use of the newest forms of
brachytherapy, a limitation that may reduce the real-world applicability of these findings.

Single-dose radiotherapy

According to 2 major studies, single-dose radiotherapy delivered during or soon after surgery for breast
cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local
recurrence.[105]

In the TARGIT-A trial, more than 3400 patients with early breast cancer were randomized to either 1
intraoperative dose of 20 Gy using a spherical applicator or EBRT delivered according to standard
schedules over several weeks. Breast cancer mortality overall was similar in the TARGIT and EBRT
groups (2.6% vs 1.9%), but there were significantly fewer non-breast-cancer deaths with TARGIT than
with EBRT (1.4% vs 3.5%). Overall mortality rates were 3.9% with TARGIT and 5.3% with
EBRT.[106]

In the ELIOT study, 1305 patients were randomized after lumpectomy to receive either intraoperative
radiotherapy or EBRT. The 5-year event rate for ipsilateral breast tumor recurrence was 4.4% with
ELIOT and 0.4% with EBRT. Overall survival at 5 years was similar in the 2 groups (34 vs 31 deaths),
and there was no significant difference between groups in the rate of breast-cancer-related deaths.[107,
108]

Postmastectomy radiation therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), along
with several prospective, randomized clinical trials, recommend that postmastectomy radiation therapy
be performed according to the following criteria[7] :

Positive postmastectomy margins

Primary tumors >5 cm
Involvement of 4 lymph nodes

Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation
therapy at doses of 45-50 Gy to the axillary and supraclavicular regions. For patients in whom ALND
shows no node involvement, axillary radiation therapy is not recommended.

Meta-analyses have shown that postmastectomy radiation therapy combined with regional nodal
radiation therapy significantly decreases the rate of local relapse and breast cancer mortality. Currently,
the benefit of radiation therapy for women with 1-3 positive ALNs is uncertain, and studies are
ongoing.

Systemic Adjuvant Therapy for Breast Cancer

Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells
that have escaped the breast and regional lymph nodes but which have not yet had an established
identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing
breast cancer-related morbidity and mortality. Depending on the model of risk reduction, adjuvant
therapy has been estimated to be responsible for 35-72% of the reduction in mortality. (See Adjuvant
Therapy for Breast Cancer.)

Treatment of Carcinoma in Situ

Ductal carcinoma in situ

Currently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant
radiation and hormonal therapies are often reserved for younger women, patients undergoing
lumpectomy, or those with the comedo subtype.

In the United States, approximately 30% of women with DCIS are treated with mastectomy with or
without reconstruction, 30% with conservative surgery alone, and 40% with conservative surgery
followed by WBRT. ALND or SLND is not routinely recommended for patients with DCIS. Studies
have identified metastasis to the ALNs in 10% of patients.

In DCIS, WBRT is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by
approximately 60%. Roughly 50% of local recurrences are invasive breast cancer. Meta-analyses of
randomized controlled trials have demonstrated slightly higher rates of contralateral breast cancer with
radiation therapy than with observation (3.85% vs 2.5%) after surgery for DCIS. Studies comparing
accelerated PBI given over 5 days to standard WBRT are currently under way.

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated
with breast-conserving surgery and radiation for DCIS. A retrospective study found that patients with
ER-positive DCIS who were treated with tamoxifen showed significant decreases in subsequent breast
cancer at 10 years.[109]

Adjuvant tamoxifen also reduces the risk of contralateral breast cancer. [110, 111] In a study by Phillips et
al, tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry the
BRCA1 and BRCA2 mutations. The analysis used pooled observational cohort data from 3 studies and
included 1583 BRCA1 and 881 BRCA2 mutation carriers. Of these, 383 (24%) and 454 (52%),
respectively, took tamoxifen after being diagnosed with breast cancer. [110, 111]

Overall, there were a total of 520 contralateral breast cancer cases during 20,104 person-years of
observation. Contralateral breast cancer developed in 520 women (24% of BRCA1 and 17% of BRCA2
mutation carriers), and 100 of these cases occurred after the patients' entry into the cohort. An analysis
that included both retrospective and prospective data found a hazard ratio (HR) of 0.38 (P < .001) for
BRCA1 carriers and an HR of 0.33 (P < .001) for BRCA2 carriers. When the analysis was limited to
prospective data, the effect was reduced, with an HR for BRCA1 carriers of 0.58 (P = .1) and an HR for
BRCA2 mutation carriers of 0.48 (P = .07).[110, 111]

A clinical trial evaluating the role of the aromatase inhibitor anastrozole as adjuvant therapy in DCIS
has met its accrual. The trial is comparing anastrozole with tamoxifen, given for 5 years. The estimated
primary completion date is March 2014.[112]

Lobular carcinoma in situ

Overall, treatment options for lobular carcinoma in situ (LCIS) include observation and close follow-up
care with or without tamoxifen and bilateral mastectomy with or without reconstruction. There is no
evidence of therapeutic benefit from local excision, axillary dissection, radiotherapy, or chemotherapy.
LCIS in the breast of a woman with ductal or lobular cancer does not require further immediate surgery
on the opposite breast. Mirror biopsy of the contralateral breast, once advocated for treatment of LCIS,
is now mainly of historic interest.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively studied the
efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS. [20] The
researchers found a 55% risk reduction in women treated with tamoxifen.

Treatment of Locally Advanced and Inflammatory Breast Cancer

Originally, the reason for grouping locally advanced breast cancer (LABC) with inflammatory breast
cancer (IBC) was the recognition that both diseases had little or no chance of cure from local therapy
alone and were therefore considered inoperable. The definition of locally advanced disease has now
broadened to include patients who are technically operable but who have large primary tumors (>5
cm).
It is important to recognize, however, that the reasons for using neoadjuvant therapy in women with
large primary tumors, in whom the goal is to increase the possibility of breast-conserving surgery, are
different from the reasons in women with disease that meets the original criteria of LABC or IBC, for
whom the administration of systemic treatment is essential to make definitive local treatment possible
with the intent of cure.

In September 2013, the FDA approved pertuzumab for neoadjuvant treatment in combination with
trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early
stage breast cancer (either greater than 2 cm in diameter or node positive). Approval was based on a
randomized trial that compared a number of regimens with and without pertuzumab in women with
HER2-positive breast cancer. In the trial, 39.3% of patients treated with pertuzumab, trastuzumab, and
docetaxel (n = 107) achieved a pathologic complete response (pCR) compared with 21.5% of patients
treated with trastuzumab and docetaxel (n = 107) at the time of surgery. [113] A confirmatory trial will
provide long-term outcomes and is expected to be completed in 2016.

Overall, the prognosis is better for women with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer
than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d). Disease-free survival
(DFS) and overall survival are typically better for stage IIB and IIIA patients; however, the likelihood
of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized
surrogate for long-term outcome, is inversely related to tumor size. Thus, the relative proportions of
patients in each category are important.

It is also important to recognize that staging criteria in the seventh edition of the AJCC Cancer Staging
Handbook differ from those in its predecessors in ways that are relevant to the patient groups discussed
here: women with T3 tumors were previously considered to have stage III disease and are so reported
in the older literature; women with resectable tumors who are found to have 4 or more involved
axillary lymph nodes after initial surgery, formerly called stage II, are currently grouped as IIIA.

The revised staging system is better for defining prognostic subgroups. However, the practical
relevance of grouping together all patients who typically receive upfront chemotherapy remains, in
that their treatment outcomes are usually reported as a function of the particular neoadjuvant program
employed.

Inflammatory breast cancer

IBC is a clinical diagnosis that implies presentation with the cardinal signs of inflammation (calor
[warmth], rubor [redness], tumor [mass]) involving the breast, although the warmth may be subtle and
the mass may not be appreciated as something discrete. Indeed, even when a localized mass is apparent
in IBC, the true extent of the disease (as shown by performing skin biopsies from the surrounding
normal-appearing skin) is usually greater than is apparent on physical examination.

IBC was originally described as having an erysipeloid border. However, only a minority of cases have
this component of a raised edge.

In Western countries, the frequency of IBC is low1-2% of all breast cancersbut in some parts of
the world, such as northern Africa, it is much higher, for reasons that are not known. IBC tends to
occur at a younger age than LABC does. Pathologically, IBC was originally associated with the classic
finding of involvement of subdermal lymphatic vessels, though this finding is not in itself diagnostic of
IBC (it may occur with LABC as a secondary phenomenon).

These tumors are more likely to stain negatively by IHC for ER and PR and somewhat more likely to
be positive for HER2 overexpression. In addition, both angiogenesis and lymphangiogenesis appear to
be increased by microvessel density or RNA-based gene expression arrays.

Locally advanced breast cancer

LABC is more common in the US than IBC is; by the definition used here, it may account for 10-15%
of patients (this drops to about 5% if one uses the older, stricter definition that includes inoperability).
Epidemiologically, LABC is associated with lower socioeconomic class and, probably for that reason,
with black race in the United States.

LABC encompasses both relatively indolent neglected tumors and those that have grown rapidly as a
result of their inherent biology. In most case series, LABC has a better long-term outcome than IBC
does, even when only inoperable cases are considered.

Evaluation of lymph nodes and response

Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy before
initiating chemotherapy. Those with clinically negative nodes may undergo sentinel lymph node biopsy
before they start treatment, or else sentinel node determination may be delayed until after treatment is
completed.

Theoretically, it should be preferable to perform sentinel node sampling up front, because

chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-
negative result, or altered lymphatic drainage in large tumors might affect accuracy of the procedure.
However, data from the NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node
biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative
rate for patients undergoing initial resection.[114]

In general, the best single test for evaluating the status of measurable tumor is ultrasonography
(preferably done by the same operator). The mass often appears larger on physical examination than on
ultrasonography, which can more effectively discriminate hypoechoic masses from surrounding stroma
or hematoma. In IBC, magnetic resonance imaging (MRI) may be an important adjunct to response
assessment. The role of positron emission tomography (PET) in routine assessment of response must
be determined on a case-by-case basis.

No current imaging technique appears to be highly accurate for the prediction of pCR. Thus, the
purposes of regular size assessment are as follows:

To exclude continuation of therapy in a patient with a growing tumor (seen in < 5% with the
initial treatment)
To suggest when maximal response of grossly evident disease has been achieved (this may be
the optimal time to proceed to resection

Systemic Treatment of Metastatic Breast Cancer

Marked advances are being made in the treatment of early-stage breast cancer, but many women still
develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease
at presentation. Although treatments for metastatic breast cancer continue to improve, there remains no
cure once distant metastases develop.

Furthermore, although occasional patients with metastatic breast cancer benefit from surgical resection
for an isolated recurrence and many require radiation therapy for palliation at a specific site (or
definitive treatment of brain metastasis), in general, recurrent or metastatic breast cancer must be
approached systemically so that the therapeutic effect reaches all sites of disease. There are 2 main
interventions: hormone therapy and chemotherapy. (See Adjuvant Therapy for Breast Cancer.)

Surgical Treatment of Metastatic Breast Cancer

As modern systemic chemotherapy has become more effective, some patients with intact primary
tumors and metastasis can have long-term stable distant disease or even no evidence of residual
metastatic disease after treatment. There is increasing interest in the role of surgical intervention for the
intact primary tumor of these metastatic breast cancer patients. Several single-institution cohort and
retrospective studies have concluded that surgical resection of the intact primary tumor may provide a
survival advantage.
It is still unknown whether a selection bias affects the findings of a survival advantage in favor of
surgery. However, the dogmatic belief that one should never operate in the setting of metastatic disease
has certainly been dispelled in favor of critical evaluation of whether surgically achieved local control
can lead to improved survival as a part of multimodal treatment. An ongoing prospective randomized
clinical trial, E2108, is addressing the role of surgery for the primary tumor in metastatic setting.

Pharmacologic Reduction of Breast Cancer Risk

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for
reduction of breast cancer risk in high-risk women. Two NSABP trials (P1 and P2) showed that
tamoxifen reduced the risk of DCIS and invasive breast cancer by 30-50%. In the NSABP P2
prevention trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer
but was 30% less effective than tamoxifen in reducing the risk of DCIS.

ASCO has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen,
raloxifene, and aromatase inhibitors) for breast cancer risk reduction. [115] Some of the highlights of the
expert panels literature review are as follows.

Tamoxifen use for 5 years reduces risk of breast cancer for at least 10 years in premenopausal women,
particularly ER-positive invasive tumors. Women 50 years or younger have few adverse effects with
tamoxifen, and vascular/vasomotor adverse effects do not persist after treatment.

As noted earlier, in an analysis that used pooled observational cohort data from 3 studies and included
1583 BRCA1 and 881 BRCA2 mutation carriers, adjuvant tamoxifen reduced the risk for contralateral
breast cancer recurrences in women who carry these mutations. [110, 111]

Tamoxifen and raloxifene are equally effective in reducing the risk of ER-positive breast cancer in
postmenopausal women. Raloxifene is associated with lower rates of thromboembolic disease, benign
uterine conditions, and cataracts than tamoxifen is. The evidence does not allow determination of
whether either agent decreases mortality from breast cancer.

Exemestane, an aromatase inhibitor, has also been found to be effective at reducing the incidence of
invasive breast cancers in postmenopausal women at moderately increased breast cancer risk. In the
NCIC- led MAP.3 trial, exemestane decreased the incidence of invasive breast cancer by 65% and that
of invasive plus in situ breast cancer by 53% as compared with placebo. [116] Arthritis and hot flashes
were more common in women treated with the aromatase inhibitor.

ASCO guidelines recommend the following[115] :

For premenopausal or postmenopausal women with increased risk for breast cancer, offer
tamoxifen (20 mg/day for 5 years) to reduce the risk of invasive ER-positive breast cancer
In postmenopausal women, raloxifene (60 mg/day for 5 years) may also be considered
Off-label use of exemestane (25 mg/day for 5 years) should be discussed as an alternative to
reduce the risk in postmenopausal women
All 3 agents should be discussed (including risks and benefits) with women aged 35 years or
older without a personal history of breast cancer who are at increased risk of developing
invasive breast cancer

Long-Term Monitoring

Follow-up guidelines

There is no consensus among oncologists as to appropriate and optimal follow-up for long-term breast
cancer survivors. The majority of relapses, both local and distant, occur within the first 3 years,
especially in higher-risk and ER-negative patients. The 2007 ASCO guidelines do not support the use
of tumor biomarkers, including CEA, CA15.3, and CA27.29, for monitoring patients for recurrence
after primary breast cancer therapy. ASCO and NCCN have both provided recommendations for
surveillance in the adjuvant setting (see Table 5 below).

Table 5. Follow-up Recommendations for Breast Cancer Survivors (Open Table in a new window)

NCCN ASCO
History and physical Year 1, every 3-4 mo Year 1-3, every 3-6 mo
examination

Year 2, every 4 mo Year 4-5, every 6-12 mo

Year 3-5, every 6 mo Year 6+, annually

Year 6+, annually

Breast self-examination No recommendation Counseled to perform monthly breast self-

examination
Mammography 6 mo after post-BCS 6 mo after definitive radiation therapy
radiation therapy

Every 6-12 mo for surveillance of

Annually thereafter abnormalities

Annually if stability of abnormalities is

achieved

Pelvic examination Annually, for women on Regular gynecologic follow-up

tamoxifen

Patients on tamoxifen should be advised to

Annual exam if uterus report any vaginal bleeding
present

Routine blood tests Not recommended Not recommended

Imaging studies Not recommended Not recommended
Tumor marker testing Not recommended Not recommended

ASCO guidelines for monitoring bone density

(Open Table in a new window)

Women aged 65 years
Woman aged 60-64 years with 1 of the following:

1. Family history of osteoporosis

2. Low body weight

3. Prior nontraumatic fracture

4. Other risk factors (eg, smoking, sedentary lifestyle)

Postmenopausal women on aromatase inhibitors

Premenopausal women who develop treatment related premature menopause

Postoperative imaging

Women who have had surgery for breast cancer may still require breast cancer screening with
mammography. If a woman had a total mastectomy, then the other breast requires yearly follow-up,
because there is still a higher risk that cancer will develop in the remaining breast. If the woman had a
subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself requires follow-
up mammography.

The first mammogram is best performed 6 months postoperatively to provide a baseline for the new
postoperative and postirradiation changes. Thereafter, mammography may be performed every 6-12
months for screening and follow-up. (See Postsurgical Breast Imaging.)

Monitoring of metastatic disease

Recommendations for monitoring disease response in the metastatic setting vary. In general, monthly
evaluations consisting of a history and physical examination to evaluate progression of disease and
toxicities are reasonable.

Measurement of tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with
diagnostic imaging, history, and physical examination for monitoring patients on active therapy.
CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients, whereas CEA
levels correlate in 40% of patients.

However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for
monitoring response to treatment. Caution should be used in the interpretation of rising CEA, CA15.3,
or CA27.29 levels during the first 4-6 weeks of a new therapy; spurious early rises may occur.

Standardized guidelines for imaging are not yet established; the choice and timing of imaging
procedures should be tailored to each patients specific needs. In general, computed tomography (CT)
of the chest, abdomen, and pelvis; MRI; bone scanning; or PET-CT is performed when symptoms
change or tumor markers rise.

Monitoring of radiation-induced heart disease

According to a new consensus statement from the European Association of Cardiovascular Imaging
and the American Society of Echocardiography, patients treated with radiotherapy to the chest for
Hodgkin's disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10
years to detect radiation-induced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times
higher in patients treated with radiation for breast cancer. [117, 118]

Recommendations of the statement include the following[117, 118] :

Before starting radiotherapy to the chest, patients should have a baseline echocardiogram to
evaluate cardiac morphology and function, and identify any abnormalities
After radiotherapy, patients should have a yearly physical exam
Modifiable CVD risk factors should be corrected
Patients who have a cardiac abnormality or are asymptomatic but at high risk of CVD should
have an initial transthoracic echocardiogram screening test five years after radiation treatment
Asymptomatic patients who are not at high risk of CVD should have an initial screening
echocardiogram 10 years after radiation treatment
After an initial screening electrocardiogram, patients should have an echocardiogram every
five years
When the findings from an echocardiogram are equivocal, cardiac computed tomography
(CT), cardiac magnetic resonance (CMR), and nuclear cardiology can be used to confirm and
evaluate the extent of RIHD