BREAST CANCER

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

Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact
basement membrane and central tumor necrosis.

See Cutaneous Clues to Diagnosing Metastatic Cancer, a Critical Images slideshow, to help identify various
skin lesions that are cause for concern. Also, see the Breast Lumps in Young Women: Diagnostic
Approaches slideshow to help manage palpable breast lumps in young women.

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 and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are now
considered primary treatment for breast cancer. Surgical therapy may consist of lumpectomy or total
mastectomy. Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing
recurrence rates. 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.

Background
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women. In less-developed
countries, it is the leading cause of cancer death in women; in developed countries, however, it has been

surpassed by lung cancer as a cause of cancer death in women. [1] 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. [2] (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.)
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 asBreast
Cancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, andMammogram.

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 the 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, typespecific 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 [3] (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.[4]
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 12% 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.[5]
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.[6] This bimodal pattern may reflect the influence of age within the
different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier, whereas hormonesensitive, 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 two 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 theBRCA1 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 two 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 thePTEN, 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.[7] 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.[8] 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.[9, 10, 11, 12, 13] 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. [14, 15]
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.[16] Use of SERMs in women at increased risk for breast cancer has prevented
invasive ER-positive cancers.[17, 18, 19] 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.[20, 21] 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. [22]
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. [21] 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). [23, 24] 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.[25] 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.[25] Risk is greater among women taking combination HRT
than among those taking estrogen-only formulations.[26]
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%).[27] 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).[28]
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).[29]
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.[30] 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.[31] 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.[32, 33, 34] 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.[35, 36]
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.[35, 36] 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. [37]
Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast
disease or fibroadenoma, have not been associated with increased risk. [38]

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.[39, 40, 41, 42] 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 countries
are thought to be protective against breast cancer.[43]

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 [44, 45]
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 [46, 47]
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).[48, 49, 50] 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[51, 52, 53, 54] :

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. [54, 55] 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 [56] ; evidence
suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[57]
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 231,840 new cases of female invasive breast cancer are predicted to occur
in 2015, along with 2350 cases in men.[2] Among US women in 2015, in addition to invasive breast cancer,
60,290 new cases of in situ breast cancer are expected to occur; approximately 83% of these cases are
expected to be DCIS, and 12% are expected to be LCIS.[2]
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.[58] 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. [59]

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. [60, 61, 62, 63]
The reason for the decline has been extensively debated. Breast cancer rates decreased significantly after the
reports from the Million Women Study[64] and the Womens Health Initiative showing higher numbers of breast
cancers in women using combination HRT with estrogen and progestin for menopausal symptoms. The nearimmediate 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. [62]
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. [58,
61]
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.[65]
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. [5] This rise is
occurring in spite of very low use of HRT by this population [66] 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.[1]

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.[1]
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. [1]

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. [59]
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.[59]

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. [59]
According to the American Cancer Society (ACS), breast cancer rates among women from various racial and
ethnic groups are as follows [59] :

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.[2] The 2015 estimates are 40,730 expected breast cancer deaths (40,290 in
women, 440 in men).[2]

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:

One to three positive nodes 30-40%

Four to nine 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. [67] (See the Staging section in this
article as well as Medscape Reference article Breast Cancer 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.[68] (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 one component of invasive micropapillary ductal carcinoma. [69]
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 4871% and 3-year disease-free survival rate of 15-60%. [70] In most case series, large tumor size and advanced
stage have emerged as predictors of poor overall survival and prognosis. [71] 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%). [72, 73]

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 [74, 75] :

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

Differential Diagnoses

Breast Abscess and Masses

Breast, Fibroadenoma
Proceed to Workup

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. [76, 77] 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.[78]
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. [77, 79, 80]
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. [81] 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).[82, 83]
The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in women aged 5074 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%.[84]
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. [85, 86]
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.[87]
In contrast, since 2009 the USPSTF has recommended biennial screening mammography for women aged 5074 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).
[86]

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 [88]
99m
Tc-tetrofosmin (also for myocardial perfusion imaging)

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.
99m

In several prospective studies, overall sensitivity of 99m 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.[3]

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% palpable, 50% impalpable,

83-92% in women older than 50 y;
decreases to 35% in dense breasts)

14-90% (90%
palpable)

10-50%

Initial investigation for symptomatic breast in women

older than 35 y and for screening; investigation of
choice for microcalcification

(94% palpable)

Ultrasonography

68-97% palpable

74-94% palpable

92% (palpable)

Initial investigation for palpable lesions in women

younger than 35 y

MRI

86-100%

21-97% (< 40%

primary cancer)

52%

Scarred breast, implants, multifocal lesions, and

borderline lesions for breast conservation; may be
useful in screening high-risk women

Scintigraphy

76-95% palpable, 52-91% impalpable

62-94% (94%
impalpable)

70-83% (83%
palpable, 79%
impalpable)

Lesions >1 cm and axilla assessment; may help predict

drug resistance

PET

96% (90% axillary metastases)

100%

Axilla assessment, scarred 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- and fielddependent)

<7

7-12

>12

C. Nuclear size and pleomorphism

Near normal; little

variation

Slightly enlarged; moderate

variation

Markedly enlarged; 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 welldeveloped glands invading fibrous stroma.

Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma, accounting for 1520% 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). [89]

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 four 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

T2

N1

M0

Stage IIB

T3

N0

M0

T0

N2

M0

T1

N2

M0

T2

N2

M0

T3

N1-2

M0

T4

N0

M0

T4

N1

M0

T4

N2

M0

Stage IIIC

Any T

N3

M0

Stage IV

Any T

Any N

M1

Stage IIIA

Stage IIIB

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.

Lymph node assessment

Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node
dissection (ALND) has also been considered necessary for staging and prognosis.
A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American
Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following
patients[90] :

Women with operable breast cancer and multicentric tumors

Women with DCIS who will be undergoing mastectomy
Women who previously underwent breast and/or axillary surgery

Women who received preoperative/neoadjuvant systemic therapy

According to the ASCO guidelines, sentinel lymph node biopsy should not be performed in patients with any of
the following:

Large or locally advanced invasive breast cancer (tumor size T3/T4)

Inflammatory breast cancer
DCIS (when breast-conserving surgery is planned)
Pregnancy
ASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy are as
follows:

ALND should not be performed in women with no sentinel lymph node (SLN) metastases
In most cases, ALND should not be performed in women with one to two metastatic SLNs who are
planning to undergo breast-conserving surgery with whole-breast radiotherapy

ALND should be offered to women with SLN metastases who will be undergoing mastectomy
The 2014 National Comprehensive Cancer Network (NCCN) breast cancer guidelines state that lymph node
dissection is optional in the following cases[67] :

Strongly favorable tumors

When no result would affect the choice of adjuvant systemic therapy
Elderly patients
Patients with comorbid conditions
Also see Breast Cancer Staging for summarized information.

Additional Testing
The 2014 NCCN guidelines recommend the following laboratory studies for all asymptomatic women with earlystage 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. [67, 91]

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.[92] (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 HER2gene 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 HER2gene 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.[93] 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).
See Breast Cancer Treatment Protocols for summarized information.

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. (SeeSurgical Treatment of Breast Cancer.)
In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically nodenegative 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.[94]
In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary
radiotherapy.[94] 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. [95, 96]

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[97, 98] :

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. [67]
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[99] :

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.
[100, 101, 102]
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. [103]

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.[104]
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. [105, 106]

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[4]:

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.
The benefit of radiation therapy for women with 1-3 positive ALNs has been uncertain. Nonetheless, a metaanalysis of 22 clinical studies found that among women with 1-3 positive nodes (1314 patients) following
mastectomy and axillary dissection for early breast cancer, postmastectomy radiotherapy reduced the breast
cancer mortality rate by 20% and reduced the recurrence rate by 32%. These benefits were similar among
women with 1, 2, or 3 positive nodes. Mean follow-up was 11 years. Radiotherapy also benefited patients with
4 or more positive nodes, while no benefit was seen for those with node-negative disease. Among women with
4 or more positive nodes, radiotherapy reduced breast cancer mortality by 13% and overall recurrence by 21%.
[107, 108]

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 cancerrelated 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. (SeeAdjuvant 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 breastconserving 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 BRCA1and 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) forBRCA1 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 forBRCA1 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. [17] 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.
According to evidence-based guidelines from the American Society of Clinical Oncology (ASCO), the HER2 targeted drugs trastuzumab, pertuzumab, and taxane should be used as first-line therapy for patients with
advanced HER2 -positive breast cancer (except in patients with a contraindication to taxane). [114, 115]These
guidelines provide indications not only for first-line HER2 -targeted therapy but also for second- and third-line
treatment.
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 theAJCC 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 B27 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. [116]
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 two main interventions: hormone therapy and
chemotherapy.

Hormone therapy
For patients who have hormone receptor (ER and/or PR)positive disease without a life-threatening component
(eg, massive liver metastases) or systemic symptoms requiring immediate palliation for comfort, in general,
hormone manipulation is the initial treatment of choice. Response rates are higher with chemotherapy, but so is
the incidence of potentially dangerous toxicity, and there is no evidence that patients live longer as a result of
receiving initial chemotherapy.
For ERpositive metastatic breast cancer, the American Society of Clinical Oncology (ASCO) recommends
using endocrine therapy rather than chemotherapy as first-line treatment, except in patients with immediately
life-threatening disease or if there are concerns about endocrine resistance. The recommendation is part of an
ASCO clinical practice guideline on the use of chemotherapy and targeted therapy for women with human
epidermal growth factor 2 (HER2)-negative (or unknown) advanced breast cancer, with recommendations
based on a systematic review of 79 studies.[117]
A trial of hormone manipulation alone can assess whether hormone therapy is effective, which is impossible to
determine if it is given together with cytotoxic chemotherapy. This is especially important when the patient has
relapsed disease, because the benefit of second-line hormone manipulation is nearly 50%, and failure to
benefit from an initial trial with endocrine therapy correlates with second-line failure. Common hormone
therapies and dosages are listed in Table 5, below.
Table 5. Hormone Agents Used in Breast Cancer (Open Table in a new window)

Agent

Dose and Schedule

Postmenopausal
Tamoxifen

Or

20 mg PO every day

Aromatase inhibitor

Anastrozole

1 mg PO every day

Letrozole

2.5 mg PO every day

Exemestane

25 mg PO every day

Or

Fulvestrant

500 mg IM loading dose followed

by 250 mg IM every month

Or

Megestrol

40 mg PO 4 times a day

Premenopausal
Tamoxifen

20 mg PO every day

Or

Aromatase inhibitor + LHRH*

Leuprolide

7.5 mg IM depot q28d

22.5 mg IM q3mo

30 mg IM q4mo

Goserelin

3.6 mg SC depot q28d

10.8 mg SC q3mo

Megestrol

40 mg PO 4 times a day

*LHRH = luteinizing hormonereleasing hormone.

In a randomized study, Mehta et al found that combination treatment with anastrozole and fulvestrant was
superior to either anastrozole alone or sequential anastrozole and fulvestrant treatment in patients with
hormone-receptor-positive metastatic breast cancer.[118]

Chemotherapy
Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single-agent regimens. Combination
therapy is currently considered up front, depending on the patient's performance status, because of higher
response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen
should be to prolong survival while maintaining a good quality of life.
When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of
cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit.
Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single
agent, but this practice has not been widely adopted, because the combination is more toxic and the study
designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the
other drug component of the initial therapy at the time of relapse.
A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is
combined with a targeted agent other than hormone therapy. These targeted agents often have very low
response rates when given as monotherapy, but they provide added benefit when given in combination with
cytotoxic chemotherapy. A list of targeted chemotherapeutic agents is provided in Table 6, below, followed by
Table 7, showing combination regimens for breast cancer.
Table 6. Targeted Chemotherapy for Metastatic Breast Cancer (Open Table in a new window)

Drug

Class

Dose/Schedule

Overall Response Rate (ORR)

Toxicity

Capecitabine

Oral fluoropyrimidine

1250 mg/m/d PO for 2 weeks with 1 wk

off

30%

Rash, hand-foot syndrome,

diarrhea, mucositis

Docetaxel

Doxorubicin

Antimicrotubule

75-100 mg/m IV q3wk

30-68%

Myelosuppression, alopecia,

or

skin reaction, mucositis,

40 mg/m/wk X IV for 6 wk with 2 wk off

and fluid retention

Anthracycline

45-60 mg/m IV q3wk

35-50%

Myelosuppression, nausea/

(antitumor antibiotic)

or

vomiting, mucositis, diarrhea

20 mg/m IV qwk (not to

cardiotoxicity, alopecia

exceed a cumulative dose

of 450-500 mg/m)

Doxil (liposomal

Anthracycline

encapsulated

20 mg/m IV q2wk

Less cardiotoxicity, neutropenia, alopecia, stomatitis, handfoot

or
syndrome

doxorubicin)

Epirubicin

35-40 mg/m IV q4wk

Anthracycline

90 mg/m IV q3wk (not

35-50%

Myelosuppression, mucositis, nausea, vomiting,

cardiotoxicity

to exceed cumulative dose

of 900 mg/m)

Gemcitabine

Antimetabolite

725 mg/m/wk IV for 3 wk

Myelosuppression, nausea/

then 1 wk off

vomiting, flulike syndrome,

or

elevated LFTs

1 g/m/wk

IV X 2 then 1 wk off

Nab-paclitaxel

Antimicrotubule

80-100 mg/m/wk IV X 3 then 1 wk off

58-62%

or

33%

Less neuropathy, and allergic reaction

260 mg/m IV q3wk

Paclitaxel

Antimicrotubule

80 mg/m/wk IV

25-50%

or

Myelosuppression, alopecia,

neuropathy, allergic reaction

175 mg/m IV over 3 hours q3wk

Trastuzumab

Monoclonal antibody

4 mg/kg loading dose, then 2

10-15%

mg/kg weekly or

Fever, allergic reaction,

cardiotoxicity/congestive heart failure

8 mg/kg

loading dose, then 6 mg/kg

q3wk

Pertuzumab

Monoclonal antibody

840 mg IV loading dose,

80.2% (objective response rate)

then 420 mg q3wk

Fever, allergic reaction,

cardiotoxicity/congestive heart failure

Give with trastuzumab and docetaxel

Palbociclib

CDK inhibitor

125 mg/day PO for 3 weeks with 1 wk off

Data are not available for ORR

Give with letrozole

Mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole
group

Neutropenia, leukopenia, thrombocytopenia, anemia,

stomatitis

Vinorelbine

Vinca alkaloid

20 mg/m/wk IV

35-45%

Myelosuppression, nausea/

vomiting, constipation, fatigue,

stomatitis, anorexia

Table 7. Combination Regimens for Metastatic Breast Cancer (Open Table in a new window)

Chemotherapy

Dose and Schedule

Cycle

Capecitabine

1250 mg/m bid days 1-14

Repeat cycle every 21 days

Docetaxel

75 mg/m day 1

May decrease capecitabine dose

XT

to 850-1000 mg/m to reduce

toxicity risk

XP

Capecitabine

825 mg/m bid days 1-14

Paclitaxel

175 mg/m day 1

Repeat cycle every 21 days

XN

Capecitabine

1000 mg/m bid days 1-14

Repeat cycle every 21 days

Navelbine

25 mg/m days 1 and 8

Gemcitabine[119]

1250 mg/m days 1 and 8

Paclitaxel

175 mg/m day 1

Carboplatin[120]

AUC of 6 day 1

Paclitaxel

200 mg/m day 1

Carboplatin[121]

AUC of 6 day 1

Docetaxel

75 mg/m day 1

Palbociclib[122]

125 mg PO once daily days 1-21

Letrozole

2.5 mg PO once daily days 1-28

Paclitaxel[123]

90 mg/m day 1, 8, and 15

HER2-positive metastatic breast cancer regimens

Trastuzumab

4 mg/kg loading dose then

Paclitaxel

2 mg/kg weekly

80 mg/m IV weekly

Repeat cycle every 21 days

Repeat cycle every 21 days

Repeat cycle every 21 days

Repeat cycle every 28 days

Repeat cycle every 28 days

Trastuzumab

8 mg/kg loading dose then

Docetaxel

6 mg/kg day 1

Repeat cycle every 21 days

100 mg/m IV day 1

Trastuzumab

4 mg/kg loading dose then

Vinorelbine

2 mg/kg weekly

25 mg/m day 1 weekly

Lapatinib

1250 mg PO daily

Capecitabine

2000 mg/m daily days 1-14

Paclitaxel

175 mg/m2

Lapatinib

1500 mg/d

Repeat cycle every 21 days

Repeat cycle every 3 weeks

AUC = systemic exposure.

References for chemotherapy regimens: XT,[124] XP,[125] XN,[125] HER2-positive metastatic breast cancer regimens[126, 127, 128, 129]

The initial choice of chemotherapy is highly influenced by the patient's personal history of previous drug
exposure. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a
higher risk of developing resistance, and there is a relationship between cumulative lifetime total dose of
doxorubicin and the risk of potentially fatal cardiomyopathy.
It is important to realize that if 1 year or more has elapsed since completion of adjuvant therapy, a patient's
tumor is likely to respond to a previously given drug or combination as though that drug or combination had
never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane
(docetaxel or paclitaxel) in the adjuvant setting.
Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may
be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering
neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further
administration problematic. Substitution of one taxane for another is possible, depending on the nature of the
chronic toxicity.
If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then
changing the schedule of administration can be effective. At least one third of breast cancer patients with
taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is
administered on a weekly schedule at a lower dose.
The Cancer and Leukemia Group B (CALGB) 9840 trial reported an improved overall response rate (ORR) in
patients receiving weekly dosing of paclitaxel (40%) compared with every-3-week paclitaxel (28%), as well as
improved median time to progression (9 mo vs 5 mo). However, care should be taken in watching for
progression of adverse effects, especially neuropathy.
In addition to taxanes and anthracyclines, a variety of other chemotherapeutic agents can be used as single
agents or in combination with taxanes. Capecitabine (Xeloda) is an oral agent that essentially represents a
sustained-release formulation of the older antimetabolite fluorouracil (5-FU) and provides the convenience of
self-administration.
Drugs such as capecitabine have very little associated myelosuppression, and they are often chosen when the
patient's bone marrow has been damaged by previous therapy or when there is a desire to coadminister a
myelosuppressive agent for more rapid effect. As a single agent, capecitabine has an ORR of 25-30%, with
minimal toxicity. When combined with a taxane, an ORR of 40-50% has been observed, along with a median
overall survival benefit of 3-15 months.
Another antimetabolite, gemcitabine (Gemzar), is typically given in combination with paclitaxel, based on
results from a phase III trial comparing paclitaxel with the combination regimen in locally advanced breast
cancer (LABC) and metastatic breast cancer. A total of 529 patients were randomized to receive paclitaxel 175
mg/m2 on day 1 plus gemcitabine 1250 mg/m2 on days 1 and 8, or receive the same dose of paclitaxel alone
every 3 weeks. ORR (41% vs 26%) and overall survival (18.6 mo vs 15.8 mo) were significantly higher with the
paclitaxel/gemcitabine arm than with paclitaxel alone.[130]
Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin in the mitotic spindle and is administered
intravenously, usually on a weekly basis. Vinorelbine is often used as a single agent following treatment with a
taxane or anthracycline, yielding an ORR of 25%. However, when used as a first- or second-line agent,
vinorelbine can have ORRs of up to 40%.

As with hormone therapy, the likelihood of benefit from chemotherapy is related to the success achieved with
the previous regimen. Although there are occasional gratifying responses to a drug used in the third- or fourthline setting of metastatic breast cancer, they are the exception rather than the rule. Thus, patient
characteristics, previous treatments, and the expected toxicity of these regimens must be taken into account.

Treatment of HER2-positive metastatic breast cancer

See HER2 Breast Cancer for more information on this topic.

Antiangiogenic therapy in metastatic breast cancer

Angiogenesis is recognized as a key process in the progression and metastasis of breast cancer. Bevacizumab
(Avastin) is a humanized mAb directed against vascular endothelial growth factor (VEGF), which exerts an
independent effect on the process of new blood vessel formation in tumors (angiogenesis). Bevacizumab was
approved by the FDA as a first-line therapy for HER2-negative metastatic breast cancer patients, based on
results from the phase III ECOG 2100 trial.
However, on November 18, 2011, the FDA officially rescinded its approval of bevacizumab because the drug
has not been shown to be safe and effective for this use. The decision is based on the totality of data, including
3 trials in first-line treatment of metastatic breast cancer (E2100, AVADO, and RIBBON-1), as well as the EVF
2119 trial for second-line treatment in this setting.
The bevacizumab data review found that patients treated with bevacizumab did not live any longer than
patients who were not taking it, but they were at greater risk of adverse effects, including those unique to
bevacizumab, such as gastrointestinal perforations, which can be life threatening. Other serious and potentially
life-threatening effects include the risk of stroke, wound-healing complications, and organ damage or failure;
bevacizumab has also been linked with the neurological condition reversible posterior leukoencephalopathy
syndrome (RPLS).

Adjunctive bisphosphonate therapy in metastatic breast cancer

See Bone Health and Breast Cancer Management for more information on this topic

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. [131] 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. [132] Arthritis and hot flashes were more common in women
treated with the aromatase inhibitor.
ASCO guidelines recommend the following[131] :

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)

History and physical examination

NCCN

ASCO

Year 1, every 3-4 mo

Year 1-3, every 3-6 mo

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 radiation therapy

6 mo after definitive radiation therapy

Annually thereafter

Every 6-12 mo for surveillance of abnormalities

Annually if stability of abnormalities is achieved

Pelvic examination

Annually, for women on tamoxifen

Regular gynecologic follow-up

Annual exam if uterus present

Patients on tamoxifen should be advised to report any vaginal bleeding

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 radiationinduced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times higher in patients treated with
radiation for breast cancer.[133, 134]
Recommendations of the statement include the following[133, 134] :

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

Integrative Therapy
The Society for Integrative Oncology has released clinical practice guidelines on the use of integrative
therapies as supportive care in patients treated for breast cancer. Recommendations include the following [135] :

Meditation, yoga, and relaxation with imagery may be useful for alleviating anxiety and mood disorders
(grade A evidence)
Stress management, yoga, massage, music therapy, energy conservation, and meditation may reduce
stress, improve mood, decrease fatigue, and improve quality of life (grade B evidence)
Acetyl-L-carnitine for the prevention of taxane-induced neuropathy may increase neuropathy and
should not be used (grade H [likely harmful])
Evidence of benefit is weak or lacking for many interventions