Breast Cancer 

Updated: Dec 04, 2019
Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS 

Overview

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. 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 d’orange

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.

HER2-targeted therapies have been investigated in combination with angiogenesis inhibitors, with promising results. HER2 overexpression is associated with an increase in VEGF levels in primary breast cancers. Dual blockade by antiangiogenic/HER2 agents (eg, neratinib) targeting HER2, and EGFR pathways produces greater inhibition of human breast cancer cell lines.[1]

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 many 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.[2] In the United States, breast cancer accounts for 30% of all cancers in women and is second only to lung cancer as a cause of cancer deaths.[3] (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 Treatment and Medication.)

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

Anatomy

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

Anatomy of the breast. 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, type-specific risk factors, and prevention and has had a substantial impact on treatment strategies and breast cancer research.

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

  • Luminal A
  • Luminal B
  • Basal-like
  • HER2-positive
Intrinsic subtypes of breast cancer. 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.[5]

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

  • Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to metastasize via lymphatics; this lesion accounts for 75% of breast cancers

  • Over the past 25 years, the incidence of lobular carcinoma in situ (LCIS) has doubled, reaching a current level of 2.8 per 100,000 women; the peak incidence is in women aged 40-50 years

  • Infiltrating lobular carcinoma accounts for fewer than 15% of invasive breast cancers

  • Medullary carcinoma accounts for about 5% of cases and generally occurs in younger women

  • Mucinous (colloid) carcinoma is seen in fewer than 5% of invasive breast cancer cases

  • Tubular carcinoma of the breast accounts for 1-2% of all breast cancers

  • Papillary carcinoma is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers

  • Metaplastic breast cancer accounts for fewer than 1% of breast cancer cases, tends to occur in older women (average age of onset in the sixth decade), and has a higher incidence in blacks

  • Mammary Paget disease accounts for 1-4% of all breast cancers and has a peak incidence in the sixth decade of life (mean age, 57 years)

Etiology

Epidemiologic studies have identified a number of risk factors that are associated with an increased risk of a woman developing breast cancer. Several risk factors have been found to be clinically useful for assessing a patient’s 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.[6]

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.[7] This bimodal pattern may reflect the influence of age within the different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier, whereas hormone-sensitive, slower-growing tumors tend to occur with advancing age.

Family history of breast cancer

A positive family history of breast cancer is the most widely recognized risk factor for breast cancer. The lifetime risk is up to 4 times higher if a mother and sister are affected, and it is about 5 times greater in women who have 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. However, identification of additional genetic variants associated with increased risk may prove valuable. Michailidou et al conducted a controlled genome-wide association study (GWAS) of breast cancer that included 122,977 cases of European ancestry and 14,068 cases of East Asian ancestry, and identified 65 new loci associated with overall breast cancer risk.[8] A GWAS by Milne et al identified 10 variants at 9 new loci that are associated with risk of estrogen receptor–negative breast cancer.[9]

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

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

  • Two or more relatives with breast or ovarian cancer
  • Breast cancer occurring in an affected relative younger than 50 years
  • Relatives with both breast cancer and ovarian cancer
  • One or more relatives with 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 the PTEN, TP53, MLH1, MLH2, CDH1, or STK11 gene.

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

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

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

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

The National Society of Genetics Counselors provides a Find a Genetic Counselor directory. The directory lists over 3300 counselors in the United States and Canada who will meet with patients in person or by phone, video conferencing, or other virtual methods.

Direct-to-consumer genetic testing

In March 2018 the US Food and Drug Administration (FDA) authorized the Personal Genome Service Genetic Health Risk (GHR) Report for BRCA1/BRCA2 (Selected Variants). This direct-to-consumer test analyzes DNA collected from a self-collected saliva sample for three specific BRCA1/BRCA2 breast cancer gene mutations that are most common in people of Ashkenazi Jewish descent. The FDA notes that more than 1,000 BRCA mutations have been identified, and the three mutations, detected by this testare not the most common BRCA1/BRCA2 mutations in the general population.[12]

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.[13, 14, 15, 16, 17] 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.[18, 19]

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.[20] Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers.[21, 22, 23] 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.[24, 25] 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.[26]

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.[25] 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).[27, 28] 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.[29] 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.[29] Risk is greater among women taking combination HRT than among those taking estrogen-only formulations.[30]

In the Women’s 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%).[31] 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).[32]

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 cancer—is 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).[33]

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.[34] 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.[35] 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.[36, 37, 38] 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.[39, 40]

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.[39, 40] 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.[41]

Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast disease or fibroadenoma, have not been associated with increased risk.[42]

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.[43, 44, 45, 46] 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 alcohol—the more common pattern in less industrialized countries—are thought to be protective against breast cancer.[47]

One such diet is the Mediterranean diet, which comprises a high intake of plant proteins, whole grains, fish, and monounsaturated fat, as well as moderate alcohol intake and low intake of refined grains, red meat, and sweets. The Netherlands Cohort Study, which included 62,573 women aged 55-69 years with more than 20 years of follow-up, found that close adherence to a Mediterranean diet is associated with lower risk for breast cancer—in particular, for types of breast cancer that carry a poorer prognosis in postmenopausal women.[48, 49]

Compared with women who reported the least adherence to a Mediterranean diet, women who most closely adhered to the diet had a 40% reduced risk for estrogen receptor–negative (ER-) breast cancer, (hazard ratio [HR], 0.60; ptrend = 0.032) and a 39% reduced risk for progesterone receptor–negative (PR-)/ER- disease (HR, 0.61; ptrend = 0.047). The study found no significant associations with the diet and the risk of ER+ disease or total breast cancer risk.[48, 49]

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[50, 51]

  • 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 hormone–binding globulin[52, 53]

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).[54, 55, 56] 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[57, 58, 59, 60] :

  • 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.[60, 61] 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[62] ; evidence suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[63]

A meta-analysis by Yuan et al found an increased risk of breast cancer in women who do long-term night shift work.  In North America and Europe, working the night shift was associated with a 32% increased risk for breast cancer overall (odds ratio [OR], 1.316). Risk increased in a dose-response fashion, rising 3.3% (OR, 1.033) Risk was even higher for nurses (OR, 1.577).[64, 65]

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 268,600 new cases of female invasive breast cancer are predicted to occur in 2019, along with 2670 cases in men.[3] Among US women in 2019, in addition to invasive breast cancer, 62,930 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.[3]

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.[66] 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.[67]

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.[68, 69, 70, 71]

The reason for the decline has been extensively debated. Breast cancer rates decreased significantly after the reports from the Million Women Study[72] and the Women’s Health Initiative showing higher numbers of breast cancers in women using combination HRT with estrogen and progestin for menopausal symptoms. The near-immediate decrease in the use of combination HRT for that purpose has been widely accepted as a primary explanation for the decrease in breast cancer rates.[70]

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.[66, 69] 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.[73]

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.[6] This rise occurred in spite of very low use of HRT by this population[74] 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 patterns—particularly fewer children and later age at first birth—may 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.[2]

In 2018, there were an estimated 2.09 million new cases of invasive breast cancer worldwide. The 2018 incidence of female breast cancer ranged from 25.9 cases per 100,000 in South Central Asia to 94.2 cases per 100,000 in Australia/New Zealand.[2]

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 62 years.[6]  Among women over the age of 50, breast cancer incidence rates were relatively stable from 2005-2014. In contrast, incidence rates, among women under age 50 have increased 0.2% per year since the mid-1990s.[67]

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.[67]

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.[67]

According to the American Cancer Society (ACS), breast cancer rates per 100,000 among women from various racial and ethnic groups are as follows[67] :

  • Non-Hispanic white: 128.7
  • Non-Hispanic black: 125.5
  • American Indian/Alaskan Native: 100.7
  • Hispanic/Latina: 91.9
  • Asian/Pacific Islander: 90.7

According to the ACS, death rates per 100,000 from breast cancer among women from various racial and ethnic groups are as follows:

  • Non-Hispanic white: 20.8
  • Non-Hispanic black: 29.5
  • American Indian/Alaska Native: 14.3
  • Hispanic/Latina: 14.2
  • Asian/Pacific Islander: 11.3

Among US women from 2006 through 2015, breast cancer death rates declined annually by 2.6% in American Indians/Alaskan Natives, 1.8% in non-Hispanic whites, NHWs, 1.5% in non-Hispanic blacks, 1.4% in Hispanics, and 0.9% in Asians/Pacific islanders.  Breast cancer death rates in black women began to exceed those in white women in the early 1980s, and the disparity remains large; in 2015, breast cancer death rates were 39% higher in black women than white women.[67]

Prognosis

From 1990 through 2015, death rates from breast cancer in the United States decreased 39%. The decrease occurred in both younger and older women, but has slowed among women younger than 50 since 2007.[67]  

The decrease in breast cancer death rates is thought to represent progress in both earlier detection and improved treatment modalities.[3] The 2018 estimates are 41,040 expected breast cancer deaths (40,920 in women, 480 in men).[3]

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
  • Estrogen receptor/progesterone receptor (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 receptor–positive 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.[75] (See the Staging section in this article as well as 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

  • Neratinib – A small-molecule oral tyrosine kinase inhibitor

  • Ado-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.[76] (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.[77]

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

For metaplastic breast cancer, the majority of published case series have demonstrated a worse prognosis than with infiltrating ductal carcinoma, even when adjusted for stage, with a 3-year overall survival rate of 48-71% and 3-year disease-free survival rate of 15-60%.[78] In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[79] 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%).[80, 81]

Cardiovascular disease

Cardiovascular disease (CVD) risk is increased in women with breast cancer. The increase is due in part to the cardiotoxic effects of some breast cancer treatments (eg, chemotherapy, radiotherapy, targeted therapy such as trastuzumab). In addition, breast cancer and CVD, share several risk factors, including smoking, obesity, and the typical Western diet.[82]

In older breast cancer survivors, risk for the development of the CVD risk factors obesity and dyslipidemia is higher than the risk of tumor recurrence. In the population of older postmenopausal women, breast cancer survivors are at higher risk for mortality attributable to CVD, compared with women without a history of breast cancer. The increased risk becomes manifest approximately 7 years after the diagnosis of breast cancer. [82]

 

 

 

Presentation

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[83, 84] :

  • 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 d’orange

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).

 

DDx

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

 

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 cancer−related 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.[85, 86] A review that used seven statistical models determined that the use of screening mammography reduced the rate of death from breast cancer by 28–65% (median, 46%).[85] A meta-analysis found that screening mammography reduces breast cancer mortality by about 20–35% in women 50–69 years old and slightly less in women 40–49 years old at 14 years of follow-up.[86]

In the UK Age trial, breast cancer mortality in the first 10 years after diagnosis was significantly lower (rate ratio [RR] 0.75) in women who received annual screening mammography from age 40-49 years than in those invited for screening at age 50 years and every 3 years thereafter. During the remainder of the 17-year follow-up period, however, reduction in breast cancer mortality was not evident (RR 1.02).[87]

In contrast, 25-year follow-up of 89,835 women in the Canadian National Breast Screening Study found that annual mammography in women aged 40-59 did not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Findings for women aged 40-49 and 50-59 were almost identical. Moreover, 22% (106/484) of invasive breast cancers detected by screening mammography were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.[88]

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.[89]

Mammography

Mammography is a low-dose x-ray−based modality used to image the breast. It is currently the best available population-based method for detecting breast cancer at an early stage.[86, 90, 91]

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 µm. 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.[92] 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).[93, 94]

The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in women aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged 40-49 years, the risk of death is decreased by 17%.[95]

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 woman’s 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.[96, 97]

At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS). In October 2015, the ACS updated its guidelines, which had previously recommended annual screening mammography, beginning at age 40 years for all women and continuing for as long as a woman is in good health, along with 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.[98]

The 2015 ACS recommendations for women at average risk of breast cancer are as follows[99] :

  • Women should begin regular screening mammography at age 45 years (strong recommendation)
  • Women aged 45-54 years should be screened annually (qualified recommendation)
  • Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)
  • Women should have the opportunity to begin annual screening at 40-44 years of age (qualified recommendation)
  • Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)
  • Clinical breast examination is not recommended for breast cancer screening in average-risk women at any age

Since 2009 the USPSTF has recommended biennial screening mammography for women aged 50-74 years (grade B recommendation). The USPSTF recommends against routine screening mammography in women aged 40-49 years because of high rates of false-negative findings, perceived harm of unnecessary biopsy, and concern for the harm associated with overdiagnosis and overtreatment (grade C recommendation).[97]

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.

Similarly, a 2015 review by the American College of Physicians (ACP) recommends the following strategies as the least intensive and having the highest value for asymptomatic women at average risk and in good health[100] :

  • Women 40-49 years of age: Discuss benefits and harms; if the patient requests screening, order biennial mammography

  • Women 50-74 years of age: Encourage mammography every 2 years

For women of any age, the ACP does not recommend the following low-value screening strategies[100] :

  • Annual mammography

  • MRI

  • Tomosynthesis

  • Regular systematic breast examination

In contrast to the ACP recommendation against the use of tomosynthesis (3D mammography) in breast cancer screening, the American College of Radiology (ACR) states that, “breast tomosynthesis has shown to be an advance over digital mammography, with higher cancer detection rates and fewer patient recalls for additional testing.” The ACR notes that further studies will be needed to determine which subgroups of women are likely to benefit most from tomosynthesis screening.[101]

In the Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study—a prospective population-based screening study in 9672 women that compared integrated 3D mammography with 2D mammography—3D mammography detected more cases of breast cancer than 2D mammography but increased the percentage of false-positive recalls in sequential screen-reading.[102] Thus, the benefit of significantly increased breast cancer detection with tomosynthesis screening must be weighed against the possible risk of overdiagnosis.

For more discussion of tomosynthesis, see Mammography in Breast Cancer.

For women whose mammogram reveals dense breast tissue, 21 US states have laws requiring that the women be notified and be advised to discuss supplemental imaging with their provider. However, a prospective cohort study found that only a minority of women with dense breasts have high interval cancer rates. The authors concluded that supplemental imaging should not be justified on the basis of breast density alone .[103]

Kerlikowske et al reported that women at high risk can be identified by combining 5-year breast cancer risk, as determined with the Breast Cancer Surveillance Consortium (BCSC) risk calculator, with breast density as categorized with the Breast Imaging Reporting and Data System (BI-RADS).[103]

High interval cancer rates were observed for women with a 5-year BCSC risk of 1.67% or greater and extremely dense breasts or a 5-year risk of 2.50% or greater and heterogeneously dense breasts. However, study participants who met those criteria accounted for only 24% of all women with dense breasts.[103]

The highest rate of advanced-stage breast cancer, >0.4 case per 1000 examinations, was seen in women with 5-year BCSC risk of 2.50% or greater and heterogeneously or extremely dense breasts. Such patients comprised 21% of all women with dense breasts.[103]

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.)

In an observational study by Buist et al that included more than 2 million screenings in over 800,000 women, MRI screening for breast cancer was associated with higher rates of subsequent biopsy but a lower yield of cancer findings. In women with a breast cancer history, biopsy rates were more than twofold higher after MRI than after mammography alone; in women with no history of breast cancer, biopsy rates were more than fivefold higher.[104]

In women with a past history of breast cancer, ductal carcinoma in situ or invasive disease was found in 404.6 per 1000 biopsies  following mammography versus 267.7 per 1000 biopsies following MRI, a significant difference. Yield was nonsignificantly higher after mammography in women without a history of breast cancer: 279.3 versus 214.6 per 1000, respectively.[104]

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)

  • Patient’s 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[105]

  • 99m Tc-tetrofosmin (also for myocardial perfusion imaging)

  • 99m Tc-methylene diphosphonate (MDP; for bone scintigraphy)

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

In several prospective studies, overall sensitivity of99m Tc-sestamibi scintimammography in the detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values were 89% and 84%, respectively. Similar numbers have been demonstrated for99m Tc-tetrofosmin and99m Tc-MDP scintimammography.[4]

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%

(94% palpable)

Initial investigation for symptomatic breast in women older than 35 y and for screening; investigation of choice for microcalcification

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. For full discussion, see Breast Cancer Histology.

All of the following features are 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 field-dependent)

< 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. Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.
Breast cancer. Intraductal carcinoma, noncomedo ty 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. Enlargem Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.
Breast cancer. Lobular carcinoma in situ. Enlargem 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- Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.

Infiltrating lobular carcinoma

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

Medullary carcinoma

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

  • Sheets of anaplastic tumor cells with scant stroma

  • Moderate or marked stromal lymphoid infiltrate

  • Histologic circumscription or a pushing border

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

Mucinous carcinoma

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

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

Breast cancer. Colloid (mucinous) carcinoma. Nests 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 papillar 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).[106]

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) provides two principal groups for breast cancer staging: anatomic, which is based on extent of cancer as defined by tumor size (T), lymph node status (N), and distant metastasis (M); and prognostic, which includes anatomic TNM plus tumor grade and the status of the biomarkers human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). The prognostic stage group is preferred for patient care and is to be used for reporting of all cancer patients in the United States.[107]

In turn, prognostic stages are divided into clinical and pathological groups. Pathological stage applies to patients who have undergone surgery as the initial treatment for breast cancer. It includes all information used for clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological prognostic stage does not apply to patients who received neoadjuvant therapy (systemic agents or radiation prior to surgical resection).[75]  

See the tables below.

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

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

Tis (DCIS)

Ductal carcinoma in situ

Tis (Paget)

Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized on the basis of the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted

T1

Tumor ≤ 20 mm in greatest dimension

T1mi

Tumor ≤ 1 mm in greatest dimension

T1a

Tumor > 1 mm but ≤ 5 mm in greatest dimension (round any measurement >1.0-1.9 mm to 2 mm)

T1b

Tumor > 5 mm but ≤ 10 mm in greatest dimension

T1c

Tumor > 10 mm but ≤ 20 mm in greatest dimension

T2

Tumor > 20 mm but ≤ 50 mm in greatest dimension

T3

Tumor > 50 mm in greatest dimension

T4

Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules), not including invasion of dermis alone

T4a

Extension to chest wall, not including only pectoralis muscle adherence/invasion

T4b

Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma

T4c

Both T4a and T4b

T4d

Inflammatory carcinoma

Regional lymph nodes (N)

Clinical

cNX

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

cN0

No regional lymph node metastasis (on imaging or clinical examination)

cN1

Metastasis to movable ipsilateral level I, II axillary lymph node(s)

cN1mi

Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

cN2

Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases

cN2a

Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures

cN2b

Metastases only in ipsilateral internal mammary nodes and in the absence of axillary lymph node metastases

cN3

Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s), with or without level I, II axillary node involvement, or in ipsilateral internal mammary lymph node(s) with level I, II axillary lymph node metastasis; or metastases in ipsilateral supraclavicular lymph node(s), with or without axillary or internal mammary lymph node involvement

cN3a

Metastasis in ipsilateral infraclavicular lymph node(s)

cN3b

Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

cN3c

Metastasis in ipsilateral supraclavicular lymph node(s)

Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy, respectively.

Pathologic (pN)

pNX

Regional lymph nodes cannot be assessed (for example, previously removed, or not removed for pathologic study)

pN0

No regional lymph node metastasis identified histologically, or isolated tumor cell clusters (ITCs) only. Note: ITCs are defined as small clusters of cells ≤ 0.2 mm, or single tumor cells, or a cluster of < 200 cells in a single histologic cross-section; ITCs may be detected by routine histology or by immunohistochemical (IHC) methods; nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated

pN0(i)

No regional lymph node metastases histologically, negative IHC

pN0(i+)

ITCs only in regional lymph node(s)

pN0(mol-)

No regional lymph node metastases histologically, negative molecular findings (reverse transcriptase polymerase chain reaction [RT-PCR])

pN0(mol+)

Positive molecular findings by RT-PCR; no ITCs detected 

pN1

Micrometastases; or metastases in 1-3 axillary lymph nodes and/or in internal mammary nodes; and/or in clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy

pN1mi

Micrometastases (200 cells, > 0.2 mm but none > 2.0 mm)

pN1a

Metastases in 1-3 axillary lymph nodes (at least 1 metastasis > 2.0 mm)

pN1b

Metastases in ipsilateral internal mammary lymph nodes, excluding ITCs, detected by sentinel lymph node biopsy

pN1c

Metastases in 1-3 axillary lymph nodes and in internal mammary sentinel nodes (ie, pN1a and pN1b combined)

pN2

Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases

pN2a

Metastases in 4-9 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm)

pN2b

Clinically detected* metastases in internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary lymph nodes

pN3

Metastases in ≥ 10 axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes; or in > 3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes 

pN3a

Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes

pN3b

pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging) or pN2a in the presence of pN1b

pN3c

Metastases in ipsilateral supraclavicular lymph nodes

*"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis on the basis of FNA biopsy with cytologic examination.

Distant metastasis (M)

M0

No clinical or radiographic evidence of distant metastasis

cM0(i+)

No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastase

cM1

Distant metastases detected by clinical and radiographic means 

pM1

Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases > 0.2 mm 

Table 5. Histologic grade (Open Table in a new window)

Histologic grade (G)

GX

Grade cannot be assessed

G1

Low combined histologic grade (favorable)

G2

Intermediate combined histologic grade (moderately favorable)

G3

High combined histologic grade (unfavorable)

Table 6. Anatomic stage/prognostic groups (Open Table in a new window)

Stage

T

N

M

0

Tis

N0

M0

IA

T1

N0

M0

IB

T0

N1mi

M0

 

T1

N1mi

M0

IIA

T0

N1

M0

 

T1

N1

M0

 

T2

N0

M0

IIB

T2

N1

M0

 

T3

N0

M0

IIIA

T0

N2

M0

 

T1

N2

M0

 

T2

N2

M0

 

T3

N1

M0

 

T3

N2

M0

IIIB

T4

N0

M0

 

T4

N1

M0

 

T4

N2

M0

IIIC

Any T

N3

M0

IV

Any T

Any N

M1

Notes:

  • T1 includes T1mi.
  • T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
  • T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.
  • M0 includes M0(i+)
  • The designation pM0 is not valid; any M0 is clinical.
  • If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is considered stage IV and remains stage IV regardless of response to neoadjuvant therapy.
  • Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.
  • Staging following neoadjuvant therapy is designated with “yc” or “yp” prefix to the T and N classification. No anatomic stage group is assigned if there is a complete pathologic response (pCR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

Table 7. Clinical prognostic stage (Open Table in a new window)

TNM

Grade

HER2

ER

PR

Stage

Tis N0 M0

Any

Any

Any

Any

0

T1 N0 M0

T0 N1mi M0

T1 N1mi M0

G1

Positive

Positive

Positive

IA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IB

G2

Positive

Positive

Positive

IA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IB

G3

Positive

Positive

Positive

IA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IB

Negative

Positive

Negative

T0 N1 M0

T1 N1 M0

T2 N0 M0

G1

Positive

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

G2

Positive

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

IIB

G3

Positive

Positive

Positive

IB

IIA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IIB

Negative

Positive

Negative

T2 N1 M0

T3 N0 M0

G1

Positive

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

IIB

Negative

Positive

Positive

IIA

Negative

IIB

Negative

Positive

Negative

G2

Positive

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

IIB

Negative

Positive

Positive

IIA

Negative

IIB

Negative

Positive

Negative

IIIB

G3

Positive

Positive

Positive

IB

Negative

IIB

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IIIA

Negative

Positive

Negative

IIIB

T0 N2 M0

T1 N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

G1

Positive

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

IIIB

G2

Positive

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

IIIB

G3

Positive

Positive

Positive

IIB

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IIIB

Negative

Positive

Negative

IIIC

T4 N0 M0

T4 N1 M0

T4 N2 M0

Any T N3 M0

G1

Positive

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IIIC

G2

Positive

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IIIC

G3

Positive

Positive

Positive

IIIB

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IIIC

Negative

Positive

Negative

Any T Any N M1

Any

Any

Any

Any

IV

ER=estrogen receptor; PR=progesterone receptor

Table 8. Pathological prognostic stage (Open Table in a new window)

TNM

Grade

HER2

ER

PR

Stage

Tis N0 M0

Any

Any

Any

Any

0

T1 N0 M0

T0 N1mi M0

T1 N1mi M0

G1

Positive

Positive

Positive

IA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

G2

Positive

Positive

Positive

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IB

G3

Positive

Positive

Positive

IA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

Negative

Positive

Negative

IB

T0 N1 M0

T1 N1 M0

T2 N0 M0

G1

Positive

Positive

Positive

IA

Negative

IB

Negative

Positive

Negative

IIA

Negative

Positive

Positive

IA

Negative

IB

Negative

Positive

Negative

IIA

G2

Positive

Positive

Positive

IA

Negative

IB

Negative

Positive

Negative

IIA

Negative

Positive

Positive

IA

Negative

IIA

Negative

Positive

Negative

G3

Positive

Positive

Positive

IA

IIA

Negative

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIA

Negative

Positive

Negative

T2 N1 M0

T3 N0 M0

G1

Positive

Positive

Positive

IA

Negative

IIB

Negative

Positive

Negative

Negative

Positive

Positive

IA

Negative

IIB

Negative

Positive

Negative

G2

Positive

Positive

Positive

IB

Negative

IIB

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIB

Negative

Positive

Negative

G3

Positive

Positive

Positive

IB

Negative

IIB

Negative

Positive

Negative

Negative

Positive

Positive

IIA

Negative

IIB

Negative

Positive

Negative

IIIA

T0 N2 M0

T1 N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

G1

Positive

Positive

Positive

IB

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIIA

Negative

Positive

Negative

G2

Positive

Positive

Positive

IB

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

IB

Negative

IIIA

Negative

Positive

Negative

IIIB

G3

Positive

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

Negative

Positive

Positive

IIA

Negative

IIIA

Negative

Positive

Negative

IIIC

T4 N0 M0

T4 N1 M0

T4 N2 M0

Any T N3 M0

G1

Positive

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

Negative

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

G2

Positive

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

Negative

Positive

Positive

IIIA

Negative

IIIB

Negative

Positive

Negative

IIIC

G3

Positive

Positive

Positive

IIIB

Negative

Negative

Positive

Negative

Negative

Positive

Positive

Negative

IIIC

Negative

Positive

Negative

Any T Any N M1

Any

Any

Any

Any

IV

ER=estrogen receptor; PR=progesterone receptor

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[108] :

  • 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

National Comprehensive Cancer Network (NCCN) recommendations differ from those of ASCO in that the NCCN considers that women with clinical stage as high as IIIA T3, N1, M0 may be candidates for SLN biopsy. In addition, the NCCN concluded that there is insufficient evidence to make recommendations for or against SLN biopsy in pregnant patients; the NCCN recommends that decisions regarding use of SLN biopsy in pregnancy be individualized. However, isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid appears to be safe.[75]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following cases[75] :

  • 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 NCCN guidelines[75] recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I–IIB):

  • Complete blood count (CBC) with differential
  • Comprehensive metabolic panel, with liver function tests (LFTs) and alkaline phosphatase

Additional studies indicated in specific settings include the following:

  • Bone scan, in patients with localized bone pain or alkaline phosphatase elevation
  •  Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast, in patients with elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis
  • Chest diagnostic CT with contrast, in patients with pulmonary symptoms

For women with clinical stage lllA (T3, N1, M0) disease, tests to consider are as follows:

  • CBC
  • Comprehensive metabolic panel, including LFTs and alkaline phosphatase
  • Chest diagnostic CT with contrast
  • Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast
  • Bone scan or sodium fluoride PET/CT (category 2B)
  • FDG PET/CT (optional)

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.[109] (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 transcriptase–polymerase 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 > 2.2 or HER2 gene copy > 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 < 1.8 or HER2 gene copy < 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-PCR–based 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.[110] 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

 

Treatment

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).

 In early-stage breast cancer, tumor gene-expression assays can be used to determine the likelihood of recurrence and thus the potential benefit of adjuvant chemotherapy. For example, with a commercially available 21-gene assay, a recurrence score of 0 to 10 is prognostic for a 2% rate of distant recurrence at 10 years that is unlikely to be improved by adjuvant chemotherapy. A high score, which has variably been defined as 26 or 31 or higher, is predictive of chemotherapy benefit.[111]

The prospective Trial Assigning Individualized Options for Treatment (TAILORx) studied the outcome in 9719 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer who had a midrange recurrence score of 11 to 25. At 9 years, patients treated with chemoendocrine therapy or endocrine therapy alone had similar rates of invasive disease–free survival, freedom from disease recurrence, and overall survival. Chemotherapy offered some benefit only in women 50 years of age or younger with a recurrence score of 16 to 25, who represented 46% of this age group.[111]

A secondary analysis of the TAILORx data confirmed that there is a cohort of these women who benefit from chemotherapy. In the women with a recurrence score of 26 to 100, who received adjuvant chemotherapy in addition to endocrine therapy, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93% at 5 years; in comparison, the expected rate in this population of women, if treated with endocrine therapy alone, is 79% at 5 years.[112]

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. (See Surgical Treatment of Breast Cancer.)

In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axillae who were undergoing either breast conservation or mastectomy with SLN mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND) in women with a positive SLN.[113]

In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy.[113] 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 radiotherapy—in 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.[114, 115]

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[116, 117] :

  • 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.[75]

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[118] :

  • Age ≥45 years for all tumor types
  • All invasive subtypes or DCIS
  • Total tumor size (invasive and DCIS) ≤ 3 cm
  • T stage Tis, T1, T2 (≤ 3 cm) 
  • Margins; No tumor on ink for invasive tumors or tumors involved with DCIS;  ≥2 mm for DCIS 
  • Node negative 
  • Multifocal acceptable if total span of tumors is ≤3 cm
  • Estrogen receptor positive or negative
  • Focal lymphovascular invasion
  • No genetic mutations

Potential complications of PBI are catheter placement followed by removal secondary to any of the following:

  • Inadequate skin spacing
  • Infection
  • Seroma
  • Fibrosis
  • Chronic pain
  • Disease recurrence

An observational study using data from the SEER–Medicare 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.[119, 120, 121] 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.[122]

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.[122]

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.[123, 124]

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[5] :

  • 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 meta-analysis 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%.[125, 126]

Systemic Adjuvant Therapy for Breast Cancer

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

Emerging data suggest that adjuvant therapy with bisphosphonates may prevent disease recurrence and prolong survival. The Early Breast Cancer Trialists' Collaborative Group found that in postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy produced highly significant reductions in recurrence (rate ratio [RR] 0.86, P=0.002), distant recurrence (RR 0.82, P=0.0003), bone recurrence (RR 0.72, P=0.0002), and breast cancer mortality (RR 0.82, P=0.002). In premenopausal women, bisphosphonate treatment had no apparent effect on any outcome.[127]

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.

However, an observational study of 108,196 women with DCIS found that although lumpectomy with radiotherapy or mastectomy reduced the risk for invasive recurrence at 10 years, that approach did not reduce breast cancer-specific mortality.[128] The low mortality from DCIS—by 20 years after diagnosis, 3.3% of the study patients had died from breast cancer—has prompted calls for reconsideration of the treatment approach to DCIS. Instead, the current aggressive approach could be reserved for patients with risk factors for death from breast cancer (eg, age younger than 35 years at diagnosis, African-American ethnicity). These patients constitute approximately 20% of DCIS cases.[129, 130]

For the majority of patients with DCIS, other approaches might be considered, such as endocrine therapy with tamoxifen/raloxifene or aromatase inhibitors. Women at lowest risk might simply be followed with observation and prevention strategies such as diet, exercise, alcohol moderation, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens.[129, 130]

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

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated with breast-conserving surgery and radiation for DCIS. A retrospective study found that patients with ER-positive DCIS who were treated with tamoxifen showed significant decreases in subsequent breast cancer at 10 years.[131]

Adjuvant tamoxifen also reduces the risk of contralateral breast cancer.[132, 133] In a study by Phillips et al, tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry the BRCA1 and BRCA2 mutations. The analysis used pooled observational cohort data from 3 studies and included 1583 BRCA1 and 881 BRCA2 mutation carriers. Of these, 383 (24%) and 454 (52%), respectively, took tamoxifen after being diagnosed with breast cancer.[132, 133]

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< 0.001) for BRCA1 carriers and an HR of 0.33 (P< 0.001) for BRCA2 carriers. When the analysis was limited to prospective data, the effect was reduced, with an HR for BRCA1 carriers of 0.58 (P = 0.1) and an HR for BRCA2 mutation carriers of 0.48 (P =0.07).[132, 133]

A clinical trial comparing anastrozole with tamoxifen as adjuvant therapy in postmenopausal women with DCIS, given for 5 years, found that on median follow-up of 9 years, anastrozole provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age.[134]

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.[21] 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.[135] 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).[136, 137] 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 the AJCC Cancer Staging Handbook differ from those in its predecessors in ways that are relevant to the patient groups discussed here: women with T3 tumors were previously considered to have stage III disease and are so reported in the older literature; women with resectable tumors who are found to have 4 or more involved axillary lymph nodes after initial surgery, formerly called stage II, are currently grouped as IIIA.

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

Inflammatory breast cancer

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

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

In Western countries, the frequency of IBC is low—1-2% of all breast cancers—but in some parts of the world, such as northern Africa, it is much higher, for reasons that are not known. IBC tends to occur at a younger age than LABC does. Pathologically, IBC was originally associated with the classic finding of involvement of subdermal lymphatic vessels, though this finding is not in itself diagnostic of IBC (it may occur with LABC as a secondary phenomenon).

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

Locally advanced breast cancer

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

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

Evaluation of lymph nodes and response

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

Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-negative result, or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection.[138]

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 ER–positive 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.[139]

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

20 mg PO every day

Or

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 on days 1, 15, 29, and once monthly thereafter

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 hormone–releasing 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.[140]

In the international, double-blind phase III MONARCH 2 trial, 669 patients were randomized in a 2:1 ratio to abemaciclib (a CDK inhibitor) plus fulvestrant or fulvestrant plus placebo. Patients received 500 mg of fulvestrant plus placebo or 150 mg of abemaciclib twice daily. The median progression-free survival was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group. The overall response rates among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.[141]

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

Abemaciclib CDK inhibitor

200 mg PO BID continue until disease progression

19.7% Diarrhea, fatigue, neutropenia and nausea

Capecitabine

Oral fluoro-pyrimidine

1250 mg/m²/d PO for 2 weeks with 1 wk off

30%

Rash, hand-foot syndrome,

diarrhea, mucositis

Docetaxel

Antimicrotubule

75-100 mg/m² IV q3wk

or

40 mg/m²/wk X IV for 6 wk with 2 wk off

30-68%

Myelosuppression, alopecia,

skin reaction, mucositis,

and fluid retention

Doxorubicin

Anthracycline

(antitumor antibiotic)

45-60 mg/m² IV q3wk

or

20 mg/m² IV qwk (not to

exceed a cumulative dose

of 450-500 mg/m²)

35-50%

Myelosuppression, nausea/

vomiting, mucositis, diarrhea

cardiotoxicity, alopecia

Doxil (liposomal

encapsulated

doxorubicin)

Anthracycline

20 mg/m² IV q2wk

or

35-40 mg/m² IV q4wk

 

Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot

syndrome

Epirubicin

Anthracycline

90 mg/m² IV q3wk (not

to exceed cumulative dose

of 900 mg/m²)

35-50%

Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity

Gemcitabine

Antimetabolite

725 mg/m²/wk IV for 3 wk

then 1 wk off

or

1 g/m²/wk

IV X 2 then 1 wk off

 

Myelosuppression, nausea/

vomiting, flulike syndrome,

elevated LFTs

Nab-paclitaxel

Antimicrotubule

80-100 mg/m²/wk IV X 3 then 1 wk off

or

260 mg/m² IV q3wk

58-62%

33%

Less neuropathy, and allergic reaction

Olaparib PARP inhibitor 300 mg PO BID 59.9% Anemia, fatigue, nausea, and vomiting

Paclitaxel

Antimicrotubule

80 mg/m²/wk IV

or

175 mg/m² IV over 3 hours q3wk

25-50%

Myelosuppression, alopecia,

neuropathy, allergic reaction

Pertuzumab

Monoclonal antibody

840 mg IV loading dose,

then 420 mg q3wk

Give with trastuzumab and docetaxel

80.2% (objective response rate)

Fever, allergic reaction,

cardiotoxicity/congestive heart failure

Palbociclib

CDK inhibitor

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

Give with letrozole

Data are not available for ORR

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

Neutropenia, leukopenia, thrombocytopenia, anemia, stomatitis

Ribociclib CDK inhibitor

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

Give with letrozole

Mean PFS was 16 months in the letrozole group and 25.3 months for ribociclib QT prolongation, hepatobiliary toxicity, neutropenia, alopecia, diarrhea, vomiting, constipation, fatigue, anorexia
Talazoparib PARP inhibitor 1 mg PO qDay 62.6% Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite

Trastuzumab

or biosimilars of trastuzumab
Monoclonal antibody

Combination therapy: 4 mg/kg IV once, then 2 mg/kg weekly for 12-18 weeks, then 6 mg/kg q3weeks to total 52 weeks

Single agent: 8 mg/kg IV once, then 6 mg/kg q3weeks to total 52 weeks
10-15% Fever, allergic reaction, cardiotoxicity/congestive heart failure

Vinorelbine

Vinca alkaloid

20 mg/m²/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

XT

Capecitabine

Docetaxel

1250 mg/m² bid days 1-14

75 mg/m² day 1

Repeat cycle every 21 days

May decrease capecitabine dose

to 850-1000 mg/m² to reduce

toxicity risk

XP

Capecitabine

Paclitaxel

825 mg/m² bid days 1-14

175 mg/m² day 1

Repeat cycle every 21 days

XN

Capecitabine

Navelbine

1000 mg/m² bid days 1-14

25 mg/m² days 1 and 8

Repeat cycle every 21 days

     

Gemcitabine[142]

Paclitaxel

1250 mg/m² days 1 and 8

175 mg/m² day 1

Repeat cycle every 21 days

Carboplatin[143]

Paclitaxel

AUC of 6 day 1

200 mg/m² day 1

Repeat cycle every 21 days

Carboplatin[144]

Docetaxel

AUC of 6 day 1

75 mg/m² day 1

Repeat cycle every 21 days

Palbociclib[145]

Letrozole

125 mg PO once daily days 1-21

2.5 mg PO once daily 

days 1-28

Repeat cycle every 28 days

Palbociclib

Fulvestrant

125 mg PO once daily days 1-21

500 mg IM on days 1, 15, 29 and once monthly thereafter 

Repeat cycle every 28 days

Ribociclib[146]

Letrozole

600 mg PO once daily days 1-21

2.5 mg PO once daily days 1-28

Repeat cycle every 28 days

Paclitaxel[147]

90 mg/m² day 1, 8, and 15

Repeat cycle every 28 days

Abemaciclib

Fulvestrant[141]

150 mg PO BID

500 mg IM on Days 1, 15 and 29 and once monthly thereafter

Repeat cycle every 28 days

Ribociclib[148]

Fulvestrant

600 mg PO once daily days 1-21

500 mg IM on Days 1, 15 and 29 and once monthly thereafter
Repeat cycle every 28 days

HER2-positive metastatic breast cancer regimens

Trastuzumab

Paclitaxel

4 mg/kg loading dose then

2 mg/kg weekly

80 mg/m² IV weekly

 

Trastuzumab

Docetaxel

8 mg/kg loading dose then

6 mg/kg day 1

100 mg/m² IV day 1

Repeat cycle every 21 days

Trastuzumab

Vinorelbine

4 mg/kg loading dose then

2 mg/kg weekly

25 mg/m² day 1 weekly

 

Lapatinib

Capecitabine

1250 mg PO daily

2000 mg/m² daily days 1-14

Repeat cycle every 21 days

Paclitaxel

Lapatinib

175 mg/m2

1500 mg/d

Repeat cycle every 3 weeks

AUC = area under the curve (systemic exposure)

References for chemotherapy regimens: XT,[149] XP,[150] XN,[150] HER2-positive metastatic breast cancer regimens[151, 152, 153, 154]

 

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.[155]

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%.

Palbociclib (Ibrance) is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 used for first-line treatment for ER-positive, HER2-negative metastatic breast cancer in postmenopausal women, in combination with the aromatase inhibitor letrozole.[156]  A phase II study in which progression-free survival (PFS) for women receiving palbociclib and letrozole was 20.2 months, versus 10.2 months for those on letrozole alone (P = 0.0004).[156, 157]

The CDK 4,6 inhibitor ribociclib (Kisqali) was approved by the FDA in March 2017 for postmenopausal HR+/HER- advanced or metastatic breast cancer in combination with letrozole. Approval was based on interim analysis results from the phase III MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer (n=668). Ribociclib plus letrozole yielded a PFS rate of 63% with a duration of 19.3 months, compared with a rate of 42.2% and a duration of 14.7 months with letrozole alone.[146]  

Since those data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone, according to a company statement.[158]

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 fourth-line 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.

PARP Inhibitors

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. In January 2018, the FDA expanded approval of olaparib to include treatment of BRCA-mutated, HER2-negative metastatic breast cancer in patients who have been previously treated with chemotherapy. Olaparib (which had previously been approved for treatment of BRCA-mutated ovarian cancer) is the first PARP inhibitor approved to treat breast cancer, and the first drug of any kind approved to treat certain patients with BRCA-mutated metastatic breast cancer.[159]

Approval was based on the OlympiAD clinical trial, which was the first phase III trial to demonstrate that PARP inhibitors are superior to chemotherapy for this class of patients. In this trial, patients with a germline BRCA mutation and HER2-negative metastatic breast cancer were assigned to receive either olaparib 300 mg PO BID (n=205) or standard therapy (n=92). Standard therapy was a choice of single-agent chemotherapy, which consisted of 21-day cycles of capecitabine (2500 mg/m2 PO on days 1-14), vinorelbine (30 mg/m2 IV on days 1 and 8), or eribulin (1.4 mg/m2 IV on days 1 and 8). Median progression-free survival (PFS) was significantly longer in those who received olaparib compared with standard therapy (7.0 months vs 4.2 months; hazard ratio, 0.58; P = 0.0009).[160]

The objective response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group. Overall survival and median time to death did not differ significantly between the 2 treatment arms after a median follow-up of 14 months (45.9% vs 47.4%; 19.3 months vs 19.6 months).[160]

In October 2018, talazoparib, another PARP inhibitor, was approved for patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Approval was based on the phase III EMBRACA trial (n=431), which talazoparib reduced the risk of disease progression or death by 46% compared with chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. Patients were randomized in a 2:1 ratio to receive talazoparib or physician’s choice of chemotherapy (PCT), which included eribulin, gemcitabine, vinorelbine, and/or capecitabine. [161]

The ORR was 62.6% in the talazoparib group and 27.2% in the PCT group (p < 0.001). Clinical benefit rate at 24 weeks was 68.6% in the talazoparib group and 36.1% in the PCT group. OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib. The median OS was 22.3 months with the PARP inhibitor compared with 19.5 months with chemotherapy.[161]

Treatment of HER2-positive metastatic breast cancer

See HER2 Breast Cancer for more information on this topic.

Treatment of triple-negative metastatic breast cancer

Unresectable metastatic triple-negative breast cancer (ie, estrogen receptor–, progesterone receptor–, and HER2 receptor–negative) is aggressive and carries a poor prognosis. However, combination therapy with the programmed cell death ligand–1 (PDL1) inhibitor atezolizumab plus nanoparticle albumin-bound (nab)–paclitaxel has been shown to prolong PFS in these patients.[162]  In March 2019, FDA approved atezolizumab in combination with nab-paclitaxel for triple-negative breast cancer.[163]

Approval was based on the phase III IMpassion130 trial in patients with untreated metastatic triple-negative breast cancer, in which intention-to-treat analysis showed median PFS of 7.2 months with atezolizumab plus nab-paclitaxel versus 5.5 months with placebo plus nab-paclitaxel (hazard ratio [HR] for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); in patients with PDL1-positive tumors, median PFS was 7.5 months and 5.0 months, respectively (HR, 0.62; 95% CI, 0.49 to 0.78; P< 0.001).[162]

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 had 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.[164] Some of the highlights of the expert panel’s 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.[132, 133]

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.[165] Arthritis and hot flashes were more common in women treated with the aromatase inhibitor.

ASCO guidelines recommend the following[164] :

  • 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

Prophylactic Mastectomy

Prophylactic mastectomy is an option for women found to be at extremely elevated risk for breast cancer. Either total mastectomy or subcutaneous (nipple-sparing) mastectomy may be performed.[166]

Genetic factors that place a woman at very high risk of developing breast cancer include the following[166] :

  • Strong family history of breast and/or ovarian cancer
  • Pathogenic mutation in BRCA1 or BRCA2
  • High-penetrance mutation in another gene associated with breast cancer risk (eg, TP53, PTEN)

The National Comprehensive Cancer Network (NCCN) recommends that in general, the only women who should consider risk-reduction mastectomy are those with a genetic mutation that confers a high risk for breast cancer, a compelling family history, or possibly a personal history of receiving thoracic radiation therapy before 30 years of age. The NCCN notes that while risk-reduction mastectomy had previously been considered for lobular carcinoma in situ (LCIS), risk-reduction therapy is currently the preferred approach for LCIS.[167]

In retrospective studies with median follow-up periods of 13-14 years, bilateral risk-reduction mastectomy decreased the risk of developing breast cancer by at least 90% in women at moderate to high risk and in those with known BRCA1/2 mutations. In women with deleterious mutations in other genes that are associated with a 2-fold or greater risk for breast cancer but without a compelling family history of breast cancer, the value of risk-reducing mastectomy is unknown.[167]

Woman who are considering prophylactic mastectomy should meet with a range of specialists to discuss the risks and benefits of surgery, including its potential psychosocial effects, as well as the nonsurgical options for reducing risk of breast cancer.These may include a breast health specialist, medical social worker, or cancer clinical psychologist or psychiatrist. Early consultation with a reconstructive surgeon is recommended for those considering either immediate or delayed breast reconstruction.[166, 167]

Contralateral prophylactic mastectomy

A consensus statement from the American Society of Breast Surgeons (ASBrS) recommends that women with unilateral breast cancer who are at average risk should be discouraged from undergoing a contralateral prophylactic mastectomy (CPM), because most of those women, with the possible exception of BRCA carriers, will not obtain a survival benefit, and CPM doubles the risk of surgical complications.[168]

However, the ASBrS advises that the final decision whether or not to proceed with contralateral prophylactic mastectomy   is a result of the balance between benefits and risks of CPM and patient preference.

The ASBrS concluded that CPM should be considered for patients with any of the following significant risk factors for contralateral breast cancer:

  • BRCA1/2 mutations
  • Strong family history (in patient who have not undergone genetic testing)
  • Mantle chest radiation before age 30 years

The ASMBrS suggests that CPM can be considered for women with factors that place them at lower risk. These include women who are carriers of a non-BRCA gene (eg, CHEK-2, PALB2, p53, CDH1) and those with a strong family history of breast cancer but who are themselves BRCA negative and have no family member with known BRCA.

Other reasons for considering CPM, according to the ASMBrS, include the following:

  • To limit contralateral breast surveillance (dense breasts, failed surveillance, recall fatigue)
  • To improve reconstructed breast symmetry
  • To manage risk aversion
  • To manage extreme anxiety (although that may be better managed through psychological support strategies)

The ASMBrS recommends discouraging CPM not only in average-risk women with unilateral breast cancer, but in those with any of the following:

  • Advanced index cancer (eg, inflammatory breast cancer, T4 or N3 disease, stage IV disease)
  • High risk for surgical complications (eg, due to comorbidities such obesity, smoking, diabetes)
  • Negative BRCA test results, despite a family history of BRCA carriage

Finally, the ASMBrS recommends against CPM in men with breast cancer, even if they are BRCA carriers.

Long-Term Monitoring

Follow-up guidelines

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

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

 

NCCN

ASCO

History and physical examination

Year 1, every 3-4 mo

Year 2, every 4 mo

Year 3-5, every 6 mo

Year 6+, annually

Year 1-3, every 3-6 mo

Year 4-5, every 6-12 mo

Year 6+, annually

Breast self-examination

No recommendation

Counseled to perform monthly breast self-examination

Mammography

6 mo after post-BCS radiation therapy

Annually thereafter

6 mo after definitive radiation therapy

Every 6-12 mo for surveillance of abnormalities

Annually if stability of abnormalities is achieved

Pelvic examination

Annually, for women on tamoxifen

Annual exam if uterus present

Regular gynecologic follow-up

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

Table. (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.)

Monitoringof 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 patient’s 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.

Monitoringof radiation-induced heart disease

According to a new consensus statement from the European Association of Cardiovascular Imaging and the American Society of Echocardiography, patients treated with radiotherapy to the chest for Hodgkin's disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10 years to detect radiation-induced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times higher in patients treated with radiation for breast cancer.[169, 170]

Recommendations of the statement include the following[169, 170] :

  • 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[171] :

  • 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

Rehabilitation

A systematic review of 37 systematic reviews of rehabilitation interventions for women after breast cancer treatment found the strongest evidence in support of exercise/physical activity and yoga. Overall, the review identified five rehabilitation areas and reached the following conclusions[172] :

  • Exercise and physical activity improved outcomes such as shoulder mobility, lymphedema, pain, fatigue, and quality of life (QoL).
  • Yoga significantly improved QoL and reduced anxiety, depression, sleep disturbance, fatigue, and gastrointestinal symptoms.
  • Complementary and alternative medicine (CAM; tai chi, acupoint stimulation, massage) had positive effects on nausea, pain, fatigue, anger, and anxiety; however, those results need to be interpreted with caution because of low methodological quality in the studies reviewed.
  • Lymphedema treatment: Resistance training had positive effects on volume reduction and muscle strength.
  • Psychosocial interventions (eg, cognitive-behavioral therapy) had positive effects on QoL, anxiety, depression, and mood disturbance.
 

Guidelines

Guidelines Summary

Guideline contributor: Kathy D Miller, MD Professor of Medicine and Ballve-Lantero Scholar, Indiana University School of Medicine; Co-Leader, Breast Cancer Program, Indiana University Melvin and Bren Simon Cancer Center

Breast Cancer Screening

Guidelines on breast cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • U.S. Preventive Services Task Force (USPSTF)
  • American College of Obstetricians and Gynecologists (ACOG)
  • European Commission Initiative on Breast Cancer (ECIBC)

The guidelines differ in their recommendations regarding breast self-examination and clinical breast examination, use of screening mammography in women 40-49 years old, age at which to discontinue screening mammography, and magnetic resonance imaging (MRI) mammography. All three guidelines recommend routine screening mammography in asymptomatic, average-risk women aged 50 to 74, but differ with regard to frequency of screening.

American Cancer Society screening guidelines

The ACS updated its guidelines for breast cancer screening in average-risk women in October 2015.[173] At this time, the ACS is in the process of updating the breast cancer screening guidelines for women at high risk, which were last updated in 2007.[174]

Breast examination

It is acceptable for women to choose not to do breast self-examination (BSE) or to do BSE regularly (monthly) or irregularly. Beginning in their early 20s, women should be told about the benefits and limitations of BSE. Whether a woman ever performs BSE, the importance of prompt reporting of any new breast symptoms to a health professional should be emphasized. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination

The ACS does not recommend clinical breast examination for breast cancer screening in average-risk women at any age

Mammography

ACS recommendations are as follows[173] :

  • Women should begin regular screening mammography at age 45 years (strong recommendation)
  • Women aged 45-54 years should be screened annually (qualified recommendation)
  • Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)
  • Women should have the opportunity to begin annual screening at 40-44 years  of age (qualified recommendation)
  • Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)

Breast MRI Screening as an Adjunct to Mammography

The ACS recommends annual MRI screening along with mammography, based on evidence from nonrandomized screening trials and observational studies, in women with the following risk factors[175] :

  • BRCA mutation
  • First-degree relative of  BRCA carrier, but untested
  • Lifetime risk ∼20–25% or greater, as defined by BRCAPRO or other models that are largely dependent on family history

The ACS recommends annual MRI screening, based on expert consensus opinion that considers evidence of lifetime risk for breast cancer, in women with the following risk factors[175] :

  • Radiation to chest between age 10 and 30 years
  • Li-Fraumeni syndrome or first-degree relatives with the syndrome
  • Cowden and Bannayan-Riley-Ruvalcaba syndromes or first-degree relatives with those syndromes

The ACS found insufficient evidence to recommend for or against MRI screening in women with the following risk factors[175] :

  • Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family history
  • Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)
  • Atypical ductal hyperplasia (ADH)
  • Heterogeneously or extremely dense breast on mammography
  • Personal history of breast cancer, including ductal carcinoma in situ (DCIS)

The ACS recommends against MRI screening (based on expert consensus opinion) in women at < 15% lifetime risk.

Finally, the ACS advises that screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. Payment should not be a barrier.

USPSTF screening guidelines

In 2016, the USPSTF released updated recommendations on breast cancer screening, but did not update its 2009 recommendations for breast examination. In its 2016 statement, the USPSTF encouraged patients to be aware of changes in their bodies and discussing these changes with clinicians.[176]

The 2009 breast examination recommendations are as follows[97] :

  • No requirement for clinicians to teach women how to perform BSE (Grade D recommendation)

  • Insufficient current evidence to assess the additional benefits and harms of clinical breast examination (CBE) beyond screening mammography in women 40 years or older

The 2016 screening mammography recommendations are as follows[176] :

  • No requirement for routine screening mammography in women aged 40 to 49 years (Grade C recommendation); the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms

  • Biennial screening mammography for women between the ages of 50 and 74 years (Grade B recommendation)

  • Insufficient current evidence to assess the additional benefits and harms of screening mammography in women 75 years or older

  • Insufficient current evidence to assess the additional benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer

  • Insufficient current evidence to assess the additional benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging, DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram

BCRA-related cancer

In 2013, the USPSTF issued updated guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows[177] :

  • 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

ACOG screening guidelines

The ACOG released guidelines for breast cancer risk assessment and screening in average-risk women in 2017.[178] For women at average risk, ACOG categorizes its recommendations as follows:

  • Level A – Based on good and consistent scientific evidence
  • Level B – Based on limited or inconsistent scientific evidence
  • Level C – Based primarily on consensus and expert opinion

ACOG recommends that health care providers periodically assess patients' breast cancer risk by reviewing the history (level B). Breast cancer risk factors include the following:

  • Family history of breast cancer, ovarian cancer, or other hereditary breast and ovatrians syndrome-associated cancer (eg, prostate cancer, pancreatic cancer)
  • Known deleterious gene mutation
  • Prior breast biopsy with atypical hyperplasia (lobular or ductal) or lobular carcinoma in situ
  • Early menarche
  • Late menopause
  • Nulliparity
  • Prolonged interval between menarche and first pregnancy
  • Menopausal hormone therapy with estrogen and progestin (decreased risk with progestin alone)
  • Not breastfeeding
  • Increasing age
  • Certain ethnicities (eg, higher likelihood of BRCA mutation in Ashkenazi Jewish women)
  • Higher body mass index
  • Alcohol consumption
  • Smoking
  • Dense breasts on mammography
  • Prior exposure to high-dose therapeutic chest irradiation at age 10-30 years

Women whose initial history indicates a potentially increased risk of breast cancer should have further risk assessment (level B), using the Gail model or another of the validated assessment tools available online, such as the BRCAPRO, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, International Breast Cancer Intervention Studies (IBIS, also known as Tyrer–Cuzick), or the Claus model.

Breast examination

Women should be counseled about breast self-awareness (ie, awareness of the normal appearance and feel of their breasts) and encouraged to notify their health care provider if they experience a change (level C). However, breast self-examination is not recommended (level B).

Clinical breast examination remains a recommended part of the evaluation of women who are at high risk or have symptoms. Screening clinical breast examination may be offered to asymptomatic, average-risk women on the following schedules, in the context of an informed, shared decision-making approach that recognizes the uncertainty of its benefits and the possibility of adverse consequences (level C):

  • For women aged 25–39 years, clinical breast examinations may be offered every 1–3 years.
  • For women aged 40 years and older, clinical breast examination may be offered annually

Mammography

The decision about the age to begin mammography screening should be made through a shared decision-making process that includes information about the potential benefits and harms. Recommendations (level A) for average-risk women are as follows:

  • Screening mammography should be offered starting at age 40 years.

  • If patient desires, after counseling, initiate mammography at age 40-49 years.

  • Women should begin screening mammography by no later than age 50 years.

  • Mammography may be performed every 1 or 2 years; biennial screening mammography, particularly after age 55 years, is a reasonable option to reduce the frequency of harms, as long as patient counseling includes a discussion that with decreased screening comes some reduction in benefits.

  • Continue screening mammography until age 75 years; beyond that age, the decision to discontinue screening should be based on a shared decision-making process that includes a discussion of the woman's health status and longevity.

ACOG considers that age alone should not be the basis to continue or discontinue screening. Beyond age 75 years, the decision to discontinue screening mammography should be based on a shared decision-making process informed by the woman’s health status and longevity (level C).

ECIBC screening guidelines

The European Commission Initiative on Breast Cancer (ECIBC) screening guidelines include the following recommendations for women age 40-74 years who are at average risk of breast cancer[179] :

  • Age 40-44: no screening 
  • Age 45-49: screening every 2 or 3 years
  • Age 50-69: screening every 2 years
  • Age 70-74: screening every 3 years

In addition, for asymptomatic women with an average risk for breast cancer, screening with digital mammography is recommended over DBT for breast cancer screening. The guidelines also suggest that screening with digital mammography alone is preferred over screening with both DBT and digital mammography.[179]

For women with dense breast tissue and negative mammography findings, ECIBC suggests not implementing tailored screening with automated breast ultrasound system (ABUS), hand-held ultrasound (HHUS), or MRI.[179]

 

 

Pharmacologic Interventions for Breast Cancer Risk Reduction

Guidelines for pharmacologic intervention in women who are at increased risk for breast cancer, but do not have a personal history of breast cancer, have been issued by the American Society of Clinical Oncology (ASCO)[180] and the U.S. Preventive Services Task Force (USPSTF).[181] The guidelines differ in their classification of increased risk and in their inclusion of women with lobular carcinoma in situ (LCIS).

American Society of Clinical Oncology

ASCO has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, and aromatase inhibitors) for breast cancer risk reduction.[180]

ASCO guidelines recommend the following[180] :

  • 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 three 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

ASCO guidelines recommend that discussions with patients and health care providers should include both the risks and benefits of pharmacologic breast cancer risk reduction in the preventive setting.

Tamoxifen

ASCO guidelines recommend that use of tamoxifen, 20 mg per day orally for 5 years, should be discussed as an option to reduce the risk of invasive breast cancer (BC), specifically ER-positive BC, in women 35 years of age or older who are premenopausal or postmenopausal and have a 5-year projected absolute breast cancer risk ≥ 1.66% or with LCIS. Risk reduction benefit continues for at least 10 years.[180]

ASCO guidelines advise that tamoxifen not be used in the following cases[180] :

  • In women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack or during prolonged immobilization

  • In combination with hormone therapy

  • In women who are pregnant, may become pregnant, or are nursing mothers

Raloxifene

ASCO guidelines recommend that raloxifene should be discussed as an option to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women who are age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS. Raloxifene is given in a dosage of 60 mg/ day orally for 5 years; it can be used for longer than 5 years in women with osteoporosis, in whom BC risk reduction is a secondary benefit.[180]

ASCO guidelines advise that raloxifene not be used in the following cases[180] :

  • For BC risk reduction in premenopausal women

  • In women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack or during prolonged immobilization

Exemestane

Exemestane is not FDA approved for breast cancer risk reduction. However, ASCO guidelines recommend that it should be discussed as an alternative to tamoxifen and/or raloxifene to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS or atypical hyperplasia. It should not be used for BC risk reduction in premenopausal women. Exemestane is given in a dosage of 25 mg per day orally for 5 years.[180]

USPSTF guidelines

The USPSTF updated its guidelines for primary breast cancer risk reduction in 2019.[181]  The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors.

The USPSTF recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (eg, atypical ductal or lobular hyperplasia and lobular carcinoma in situ). The recommendation does not apply to women with a current or previous diagnosis of breast cancer or ductal carcinoma in situ..[181]

Lymph Node Biopsy and Dissection

Guidelines for sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) have been issued by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).

American Society of Clinical Oncology

A 2014 update on SLNB for patients with early-stage breast cancer by ASCO advises that SLNB may be offered to the following patients[182] :

  • 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, SLNB 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 SLNB 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

National Comprehensive Cancer Network

The 2017 NCCN guidelines recommend that SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate candidate for SLNB.[75] Candidates include patients with clinical stage I, IIA, IIB, and IIIA T3, N1, M0 who are clinically node negative at the time of diagnosis, as well as those who are clinically node positive but have negative results on fine needle aspiration or core biopsy.

The NCCN recommends axillary dissection level I/II if the sentinel node is not identified or if the sentinel node is positive but the patient fails to meet all the following criteria:

  • T1 or T2 tumor
  • Only one or two positive sentinel lymph nodes
  • Breast-conserving therapy
  • Whole-breast radiation therapy planned
  • No preoperative chemotherapy

If the patient does meet all those criteria, the NCCN recommends against further axillary surgery. In addition, no further axillary surgery is a category 1 recommendation for patients with a negative sentinal lymph node. The NCCN guidelines state that lymph node dissection is optional in the following cases:

  • Strongly favorable tumors
  • When the result would not affect the choice of adjuvant systemic therapy
  • Elderly patients
  • Patients with comorbid conditions

Finally, for patients with clinically negative axillae who are undergoing mastectomy and for whom radiation therapy is planned, the NCCN states that axillary radiation may replace axillary dissection level I/II for regional control of disease.

In contrast with ASCO, the NCCN concluded that insufficient data exist on which to base recommendations regarding the use of SLNB in pregnant women. The NCCN advises that whether to use SLNB in pregnancy should be an individualized decision, but cites a review recommending that SLNB should not be offered to pregnant women under 30 weeks' gestation. If SLNB is used, the NCCN advises that isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy, but radiolabeled sulfur colloid appears to be safe.[75]

 

Lumpectomy Margins

In 2016, the Society of Surgical Oncology, American Society for Radiation Oncology and American Society of Clinical Oncology released a consensus guideline that addresses margins for breast-conserving surgery with whole-breast radiation therapy (WBRT) in ductal carcinoma in situ (DCIS). Key recommendations include[183] :

  • A positive margin is associated with a significant increase in ipsilateral breast tumor recurrence (IBTR); this increased risk is not nullified by the use of WBRT
  • Negative margins halve the risk of IBTR  and a 2 mm margin minimizes the risk of IBTR compared with smaller negative margins.
  • More widely clear margins do not significantly decrease IBTR compared with 2 mm margins.
  • Negative margins < 2 mm alone are not an indication for mastectomy; clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm.

The following consensus guideline, released in 2014 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.[184] :

  • Positive margins are associated with at least a two-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

Radical Mastectomy

According to National Comprehensive Cancer Network (NCCN) guidelines, mastectomy with level I/II axillary lymph node dissection is the recommended procedure in patients who respond to neoadjuvant chemotherapy. Other NCCN indications for mastectomy include the following[75] :

  • Prior radiation therapy to the breast or chest wall

  • Radiation therapy contraindicated by pregnancy (except patients in the third trimester who can receive radiation postpartum)

  • Inflammatory breast cancer

  • Diffuse suspicious or malignant-appearing microcalcifications

  • Widespread disease that is multicentric, located in more than one quadrant, and cannot be removed through a single incision with negative margins

  • A positive pathologic margin after repeat re-excision and suboptimal cosmetic outcome

Relative indications for mastectomy include the following:

  • Active connective tissue disease involving skin (eg, scleroderma, lupus)

  • Tumors greater than 5 cm in diameter

  • Focally positive margin

Patients who are younger than 35 years of age or premenopausal with known BRCA1/2 mutations have an increased risk of local recurrence. Prophylactic bilateral mastectomy may be considered for risk reduction.

Postmastectomy Radiation Therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), recommend that postmastectomy radiation therapy be performed according to the following criteria[185] :

  • Positive postmastectomy margins

  • Primary tumors >5 cm

  • Involvement of ≥4 lymph nodes

Patients with more than four 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.

For women with invasive breast cancer who receive whole-breast irradiation (WBI), updated guidelines from the American Society of Radiation Oncology (ASTRO) recommend the use of hypofractionated WBI regardless of patient age, chemotherapy history, or tumor stage. The 2018 update expands the indications for WBI; previous guidelines, from 2011, recommended the treatment for patients aged 50 and older whose disease was less advanced (T1–2, N0) and who had not undergone chemotherapy. For WBI with or without inclusion of the low axilla, the preferred scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions.[186]

Treatment of HER2-Positive Breast Cancer

Evidence-based guidelines from the American Society of Clinical Oncology (ASCO) for treatment of HER2 -positive breast cancer, which are largely adapted from the 2015 Cancer Care Ontario (CCO) clinical practice guidelines, are as follows[187, 188, 189] :

  • Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer (>1 cm)

  • Trastuzumab plus chemotherapy may be considered in small (≤1 cm), node-negative tumors in patients with HER2-positive T1a-b N0 disease

  • In high-risk HER2-positive disease, the recommended regimen is sequential anthracycline and taxanes given concurrently with trastuzumab; or docetaxel, carboplatin, and trastuzumab for six cycles

  • For lower-risk node-negative HER2-positive disease, an alternative regimen is paclitaxel and trastuzumab in combination once weekly for 12 weeks, with trastuzumab then given for 1 year

  • In patients with high-risk disease and when a taxane is contraindicated, the optimal dose of an anthracycline three-drug regimen that contains cyclophosphamide is recommended, with a cumulative dose of doxorubicin ≥240 mg/m² or epirubicin ≥600 mg/m², but no higher than 720 mg/m²; the cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m²

  • Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen

  • For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable chemotherapy alternative to doxorubicin-cyclophosphamide

  • Concurrent administration of trastuzumab with the anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity, but trastuzumab should be preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen

  • Second-line treatment, for patients whose disease progresses during or after first-line treatment with HER2-targeted agents, is with ado-trastuzumab emtansine (T-DM1)

  • T-DM1 can be used as third-line treatment if the cancer progresses during or after second-line treatment, in patients who have not previously received the drug

Hormonal Adjuvant Therapy

In 2016, the American Society of Clinical Oncology (ASCO) issued an updated clinical practice guideline on adjuvant endocrine therapy for premenopausal women with hormone receptor–positive breast cancer.  ASCO recommends high-risk women receive adjuvant endocrine therapy with ovarian suppression but lower-risk patients should not.[190]

Specific recommendations include [190] : 

  • Women with stage II or stage III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression in addition to endocrine therapy

  • Women with stage I or II breast cancers at higher risk of recurrence, who might consider chemotherapy, may also be offered ovarian suppression in addition to endocrine therapy

  • Women with stage I breast cancers not warranting chemotherapy should receive endocrine therapy but not receive ovarian suppression

  • Women with node-negative cancers 1 cm or less (T1a, T1b) should receive endocrine therapy but not receive ovarian suppression

  • Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor

In its 2014 practice guidelines, ASCO addressed postmenopausal women and recommended they be offered adjuvant endocrine therapy with one of the following treatments[191, 192] :

Postmenopausal patients should be offered adjuvant endocrine therapy with one of the following treatments[191, 192] :

  • Tamoxifen for 10 years

  • An aromatase inhibitor for 5 years

  • Tamoxifen for 5 years, then switching to an aromatase inhibitor for up to 5 years

  • Tamoxifen for 2-3 years, then switching to an aromatase inhibitor for up to 5 years

Postmenopausal patients who are intolerant of either tamoxifen or an aromatase inhibitor should be offered an alternative adjuvant endocrine therapy. Patients who have received an aromatase inhibitor but discontinued treatment at less than 5 years may be offered tamoxifen for a total of 5 years. Patients who have received tamoxifen for 2-3 years should be offered an aromatase inhibitor for up to 5 years, for a total duration of up to 7-8 years of adjuvant endocrine therapy.[191, 192]

Breast Cancer in Young Women

Guidelines on the management of breast cancer in young women from the European School of Oncology (ESO) and the European Society of Medical Oncologists (ESMO), and endorsed by the European Society of Breast Specialists (EUSOMA), include 75 statements.[193] Among them are the following recommendations:

  • There is no clear role for routine screening by any imaging technique for early breast cancer detection in healthy, average-risk young women. However, in young women with a cancer predisposition syndrome (germline mutation in a known cancer predisposition gene), significant family history, or prior personal history of ionizing radiation to the chest, consideration may be given to screening breast MRI.
  • In young women with the diagnosis of either invasive disease or preinvasive lesions who are not high-risk mutation carriers, there is no evidence that performing risk-reducing bilateral mastectomy leads to improved overall survival (OS)
  • In patients with triple-negative breast cancer (TNBC) or BRCA-associated tumors, the incorporation of platinum agents increases pathologic complete response (pCR) rates and may be considered when neoadjuvant chemotherapy is indicated. Data on the impact of incremental increases in pCR on long-term outcome are inconclusive.
  • The use of platinum derivatives has potential additional impact on fertility and increased toxicity that may compromise standard duration and dosing of systemic treatment, and this needs to be clearly communicated to patients.
  • For patients with TNBC not achieving a pCR after standard neoadjuvant regimens, the routine addition of adjuvant chemotherapy (such as capecitabine or metronomiccyclophosphamide and methotrexate [CM]) is not recommended; however, it may be considered in highly selected patients, as in other age groups
  • It is recommended that young women with ER-positive advanced breast cancer have adequate ovarian suppression or ablation and then be treated in the same way as postmenopausal women with endocrine agents and targeted therapies, such as an aromatase inhibitor or fulvestrant plus a cyclin-dependent kinase (CDK) 4/6 inhibitor or exemestane with everolimus.
  • Olaparib monotherapy may be considered in women with advanced breast cancer harboring a germline BRCA mutation in early lines of therapy.
  • All patients with hormone receptor–positive disease should receive adjuvant endocrine therapy (ET). Tamoxifen alone for 5 years is indicated for low-risk patients. Tamoxifen for 10 years should be considered in high-risk patients, if tolerated. The addition of a gonadotropin-releasing hormone (GnRH) agonist (or ovarian ablation) to tamoxifen is indicated in patients at higher risk who remain premenopausal after chemotherapy.
  • Young women with stage I or II breast cancer who cannot take tamoxifen (due to contraindications or severe side effects) may receive a GnRH agonist alone, oophorectomy, or an aromatase inhibitor + GnRH agonist.

Follow-up for Breast Cancer Survivors

The National Comprehensive Cancer Network (NCCN)[75]  and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO)[194]  have issued guidelines on followup care for breast cancer survivors. The guidelines differ principally in the timing of care. See the table below.

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

 

NCCN

ACS/ASCO

History and physical examination

Year 1, every 3-4 mo

Year 2, every 4 mo

Year 3-5, every 6 mo

Year 6+, annually

Year 1-3, every 3-6 mo

Year 4-5, every 6-12 mo

Year 6+, annually

Signs of recurrance

No recommendation

Educated and counseled about signs and symptoms 

Mammography

6 mo after post-BCS radiation therapy

Annually thereafter

Annually 

MRI No recommendation

Not recommended for routine screening unless patient

meets high-risk criteria for increased surveillance

Pelvic examination

Annually, for women on tamoxifen

Annual exam if uterus present

No recommendation

Routine blood tests

Not recommended

Not recommended

Imaging studies

Not recommended

Not recommended

Tumor marker testing

Not recommended

No recommendation

Use of Biomarkers to Guide Adjuvant Systemic Therapy

A guideline from the American Society of Clinical Oncology (ASCO) advises that the only biomarkers that can guide choices of specific treatment regimens in breast cancer are as follows[195] :

  • Estrogen receptor (ER)
  • Progesterone receptor (PR)
  • Human epidermal growth factor receptor 2 (HER2)

ASCO recommendations regarding further biomarker use include the following[195] :

  • The Oncotype DX 21-gene recurrence score may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with HER2-positive or triple-negative (ER,PR, HER2 negative) breast cancer
  • The EndoPredict 12-gene risk score may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
  • The MammaPrint (Agendia) 70-gene assay should not be used in patients with triple-negative breast cancer; in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer; or in patients with HER2-positive breast cancer
  • PAM50 risk of recurrence score may be used, in combination with other clinicopathologic variables, in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
  • The Breast Cancer Index may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
  • The Mammostrat (Clarient) five-protein assay should not be used in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer or in patients with HER2-positive or triple-negative breast cancer.
  • Immunohistochemistry 4 may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with HER2-positive or triple-negative breast cancer
  • Urokinase plasminogen activator and plasminogen activator inhibitor type 1 may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, they should not be used in patients with HER2-positive breast cancer or triple-negative breast cancer
  • Circulating tumor cells should not be used to guide decisions on adjuvant systemic therapy
  • Tumor-infiltrating lymphocytes should not be used in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer or in patients with HER2-positive or triple-negative breast cancer
  • Protein encoded by the MKI67 gene should not be used to guide the selection of adjuvant chemotherapy
  • CYP2D6 polymorphisms or p27 expression determined by immunohistochemistry should not be used to guide the selection of adjuvant tamoxifen
  • Protein encoded by the immunohistochemistry MKI67 gene labeling index should not be used to guide the selection of adjuvant aromatase inhibitors
  • For patients with ER/PR-positive, HER2-negative (node-negative) breast cancer who have had 5 yr of endocrine therapy without evidence of recurrence, clinicians should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or immunohistochemistry 4) to guide decisions on extended endocrine therapy
  • Clinicians should not use microtubule-associated protein Tau messenger (m)RNA expression or mRNA expression determined by immunohistochemistry or HER1/epidermal growth-factor receptor expression by immunohistochemistry to guide the selection of adjuvant taxanes
  • Clinicians should not use TOP2A gene amplification or TOP2A protein expression determined by immunohistochemistry and should not use HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 to guide the selection of adjuvant anthracyclines
 

Medication

Medication Summary

Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents. It is designed to treat micrometastatic disease (or breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer−related morbidity and mortality.

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.

Bevacizumab, a humanized monoclonal antibody that inhibits angiogenesis, had been approved for use in combination therapy for metastatic breast cancer. In November 2011, however, the US Food and Drug Administration (FDA) revoked its approval for this indication, after concluding that bevacizumab had not been shown to be safe and effective for that use.[75]  

In December 2013, Hoffmann-La Roche, manufacturer of capecitabine (Xeloda), an oral agent for the treatment of breast and colorectal cancers, reported that in rare cases, patients using the drug may develop potentially fatal cutaneous disease, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Signs and symptoms of severe skin reactions may include flu-like symptoms, fever, itching, mouth sores, and burning eyes, as well as a painful, red or purplish rash that causes the skin to shed.[196]

Fulvestrant (Faslodex) was approved by the FDA for hormone receptor (HR)-positive, HER2-negative locally-advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy.

The approval is based on results from the phase III FALCON trial, a total of 462 treatment-naïve patients were randomly assigned to 500 mg of fulvestrant on days 0, 14, 28 or 1 mg daily of anastrozole. Eligible patients had received no prior endocrine therapy, although treatment with 1 prior chemotherapy. 

Data from FALCON showed that fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole. Overall response rate and clinical benefit rate did not differ significantly between groups. Fulvestrant resulted in a median duration of response of 20 months as compared with 13.2 months with anastrozole. Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole. Expected duration of response also favored fulvestrant, as did expected duration of clinical benefit.[197]

Alpelisib (Piqray) is a phosphatidylinositol-3-kinase (PI3K) inhibitor approved by the FDA in May 2019. It is indicated in combination with fulvestrant for treatment of men and postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. 

Approval for alpelisib was supported by the SOLAR-1 trial (n=572). Results demonstrated that adding alpelisib to fulvestrant significantly prolonged median PFS (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation.[198]

Palbociclib and ribociclib are cyclin-dependent kinases (CDK) 4, 6 inhibitors indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Approval of palbociclib for initial endocrine-based therapy in postmenopausal women was based on the phase II trial (PALOMA-1) which measured median progression-free survival (PFS) duration. The mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group.[145]

The approval of palbociclib for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy was based on the PALOMA-3 trial (n=521). PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo. vs 3.8 mo.).[199]

Approval of ribociclib was based on interim analysis results from the pivotal phase 3 MONALEESA-2 trial in postmenopausal women who received no prior systemic therapy for their advanced breast cancer. The trial demonstrated that ribociclib plus the aromatase inhibitor letrozole reduced the risk for progression or death compared with letrozole alone. The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63% with a duration of 19.3 months in the ribociclib group and 42.2% with a duration of 14.7 months in the letrozole alone group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively.[146]  Since these data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination vs 16 months with letrozole alone, according to a company statement.

A third inhibitor, abemaciclib was FDA approved in September 2017. Approval was based on results from the MONARCH 1 and 2 trial. The Monarch 1 trial studied the safety and efficacy of abemaciclib as a stand-alone treatment in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. Abemaciclib was administered at 200 mg orally twice daily until disease progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.The investigator-assessed, confirmed ORR was 19.7%, which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months.[200]

In February 2018, the FDA also approved this CDK inhibitor for use in combination with an aromatase inhibitor for frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Approval was based on data from the MONARCH 3 trial; a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor (NSAI) in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. The addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the NSAI alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer. In the study, the median progression-free survival was 28.2 months in the abemaciclib arm versus 14.8 months with the NSAI alone. In those with measurable disease, the ORR was 55.4% with the CDK4/6 inhibitor and 40.2% in the control arm. The median duration of response was 27.4 months for the abemaciclib arm compared with 17.5 months in the control arm.[201]

 

Antineoplastics, Antimicrotubular

Class Summary

Use of antimicrotubular therapy may be considered in patients who have received at least 2 chemotherapeutic regimens for metastatic disease.

Eribulin (Halaven)

Eribulin inhibits the growth phase of microtubules, leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death. It is indicated for metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or the metastatic setting.

Docetaxel (Taxotere, Docefrez)

Docetaxel is indicated for use in combination with doxorubicin and cyclophosphamide for adjuvant treatment of operable node-positive breast cancer. It is also indicated for locally advanced or metastatic breast cancer after failure of prior chemotherapy. It is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division and leading to cell death.

Paclitaxel (Taxol)

Paclitaxel is indicated for adjuvant treatment of node-positive breast cancer; it is administered sequentially after doxorubicin-containing combination chemotherapy. Dose-dense regimens (ie, more frequent administration) are currently being studied and resulting disease-free interval examined. Mechanisms of action are tubulin polymerization and microtubule stabilization, which, in turn, inhibit mitosis and may result in the breakage of chromosomes.

Ixabepilone (Ixempra)

Ixabepilone is a semisynthetic analogue of epothilone B that inhibits microtubules, halting cell division in the mitotic phase and resulting in cell death. It is used mostly in combination with capecitabine in patients with recurrent or metastatic breast cancer in whom therapy with other first-line agents (eg, an anthracycline and a taxane) has failed.

Antineoplastics, Alkylating

Class Summary

Alkylating agents constitute one of the earliest classes of antineoplastic agents used to treat cancer. They work by cross-linking DNA, which impedes cellular growth. They can be used alone or in combination with other chemotherapeutic agents.

Carboplatin

Carboplatin is an analogue of cisplatin. It is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the action of these drugs in the G1 and S phases.

Carboplatin has the same efficacy as cisplatin but a better toxicity profile. Its main advantages over cisplatin include less nephrotoxicity and ototoxicity, absence of a need for extensive prehydration, and reduced likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is chemically related to nitrogen mustards. It can be used as a single agent or in various combination chemotherapy regimens for recurrent or metastatic breast cancer.

Cyclophosphamide is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type of reaction. The mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Antineoplastics, Anthracycline

Class Summary

Anthracyclines work in multiple ways, including intercalation between DNA base pairs and inhibition of type II topoisomerase function, resulting in inhibition of cell replication and transcription. They also work by inhibition of DNA helicase, resulting in DNA cleavage.

Doxorubicin

Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix.

This agent is also a powerful iron chelator. The iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Maximum toxicity occurs during the S phase of the cell cycle.

Epirubicin (Ellence)

Epirubicin is indicated as a part of adjuvant therapy in patients with evidence of axillary-node tumor involvement after resection of primary breast cancer.[142] It can be used as a single agent, but such use is much less common in the setting of recurrent or metastatic disease. Epirubicin is a cell cycle phase inhibitor–nonspecific anthracycline derivative of doxorubicin with maximum cytotoxic effects on the S and G2 phases of the cell cycle.

Calcium Metabolism Modifiers

Class Summary

Bisphosphonates are complementary to chemotherapy and hormone therapy because they may lessen the damage to bone from metastatic disease. Bisphosphonates inhibit osteoclast function and reduce the resorption of bone. An intravenous bisphosphonate should be used in combination with oral calcium citrate and vitamin D supplementation in bone metastasis, according to the National Comprehensive Cancer Network (NCCN) guidelines.[75]

Pamidronate (Aredia)

Pamidronate disodium is a bone resorption inhibitor that absorbs calcium phosphate crystals and prevents the dissolution of this mineral. It also inhibits osteoclast activity in the bone.

Zoledronic Acid (Zometa, Reclast)

Zoledronic acid inhibits bone resorption by acting on osteoclasts or osteoclast precursors. It may be superior to pamidronate in patients with lytic bone metastases.

Antineoplastics, Antimetabolite

Class Summary

Antimetabolite therapy can stop cancer cell growth and cell division by interfering with DNA replication of these cells. These drugs are often first-line agents for breast cancer.

Capecitabine (Xeloda)

Capecitabine is a pyrimidine analogue that, in combination with docetaxel, is indicated for metastatic breast cancer after the failure of prior anthracycline-containing chemotherapy.

Monotherapy with capecitabine is indicated for the treatment of patients with metastatic breast cancer that either is resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or is resistant to paclitaxel in a situation where further anthracycline therapy is not indicated.[143] It is the preferred first-line agent for human epidermal growth receptor 2 (HER2)-positive disease, along with trastuzumab.

Gemcitabine (Gemzar)

Gemcitabine is a pyrimidine analogue that is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is cell-cycle specific for the S phase. Gemcitabine, in combination with paclitaxel, is indicated as a first-line treatment for metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy (unless anthracyclines were clinically contraindicated).

Methotrexate (Trexall)

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Methotrexate is indicated alone or in combination with other anticancer agents for the treatment of breast cancer.

Antineoplastics, Vinca Alkaloid

Class Summary

Monoclonal antibodies have been engineered to react against specific antigens on cancer cells, thereby potentially helping to enhance the patient’s immune response and prevent cancer cell growth.

Vinorelbine (Navelbine)

Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during the G2 phase of cell division, thereby inhibiting mitosis. This agent is a preferred first-line agent, with trastuzumab, for HER2-positive breast cancer. It is also used alone to treat recurrent or metastatic disease.

Monoclonal Antibodies

Class Summary

Monoclonal antibodies have been engineered to react against specific antigens on cancer cells, which can help to enhance the patient’s immune response and prevent cancer cell growth. The combination of both HER2 receptor antibodies (pertuzumab plus trastuzumab) is superior to either agent alone.

ado-trastuzumab emtansine (Kadcyla)

Ado-trastuzumab emtansine is an HER2-targeted antibody (trastuzumab) covalently linked to a microtubule inhibitor (DM1, a maytansine derivative). It is indicated for the treatment of HER2-positive metastatic breast cancer after prior trastuzumab and taxane therapy. It is also indicated for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment.

Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death

Denosumab (Prolia, Xgeva)

Denosumab is a monoclonal antibody that specifically targets RANK ligand, an essential regulator of osteoclasts. This agent is indicated to prevent skeletal-related events (ie, bone fractures, spinal cord compression, or hypercalcemia) in patients with bone metastases from solid tumors whose expected survival exceeds 3 months.

Osteonecrosis of the jaw in patients receiving denosumab has often been associated with dental procedures. Consequently, patients should undergo a dental examination before the initiation of denosumab therapy to determine whether they might benefit from preventive dentistry procedures.

Trastuzumab (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, trastuzumab-dkst, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-qyyp)

Trastuzumab is a monoclonal antibody that binds to extracellular HER2. It mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2.

It is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer, as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, as part of a treatment regimen with docetaxel and carboplatin, or as a single agent following multimodality anthracycline based therapy. This agent is also used for HER2-overexpressing metastatic breast cancer as first-line treatment in combination with paclitaxel OR as a single agent for patients who have received 1 or more chemotherapy regimens for metastatic disease.

The combination of trastuzumab and an anthracycline is associated with significant cardiac toxicity.

Pertuzumab (Perjeta)

Pertuzumab is a monoclonal antibody that binds to the extracellular domain of the HER2 receptor. It is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. It is also the first drug approved for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer . Pertuzumab was also indicated the adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

Trastuzumab/hyaluronidase (Herceptin Hylecta)

Trastuzumab is a monoclonal antibody which binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER-2). It mediates antibody-dependent cellular cytotoxicity by inhibiting proliferation of cells which overexpress HER-2 protein. It is indicated in combination with chemotherapy in patients with HER2-positive early breast cancer, in combination with paclitaxel in patients with metastatic HER2-positive breast cancer as a frontline treatment, and alone for patients with metastatic disease who have received at least 1 prior chemotherapy regimen. Administered SC over 2-5 minutes.

Tyrosine Kinase Inhibitors

Class Summary

Tyrosine kinase inhibitors play an important role in the modulation of growth factor signaling. They are commonly combined with other forms of chemotherapy or radiation therapy.

Lapatinib (Tykerb)

Lapatinib is a 4-anilinoquinazoline kinase that inhibits the intracellular tyrosine kinase domains of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2). This agent is indicated in combination with capecitabine for advanced or metastatic breast cancer in patients with tumors that overexpress HER2 and for which previous therapy (ie, anthracycline, taxane, and trastuzumab) was not effective.

This agent is also used in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer tumors that overexpress the HER2 receptor, for whom hormonal therapy is indicated.[145]

Neratinib (Nerlynx)

Tyrosine kinase inhibitor indicated for extended adjuvant therapy following trastuzumab-based therapy with early stage HER2 overexpressed/amplified breast cancer. It irreversibly binds to EGFR, HER2, and HER4. In vitro, inhibition reduces EGFR and HER2 autophosphorylation, subsequently inhibits signal transduction pathways and demonstrates antitumor activity in overexpressed EGFR and/or HER2 carcinoma cells; neratinib human metabolites (M3, M6, M7, and M11) inhibits EGFR, HER2 and HER4 activity.

Aromatase Inhibitors

Class Summary

Aromatase inhibitors play a role in adjuvant therapy in breast cancer. These agents work by inhibiting aromatase, the enzyme responsible for converting other steroid hormones into estrogen. All 3 selective aromatase inhibitors (anastrozole, letrozole, and exemestane) have similar antitumor efficacy and similar toxicity profiles.

Anastrozole (Arimidex)

Anastrozole significantly lowers serum estradiol concentrations by inhibiting the conversion of adrenally generated androstenedione to estrone. It is used as first-line treatment of breast cancer in postmenopausal women with hormone receptor–positive or hormone receptor–unknown locally advanced or metastatic disease. It is also used to treat advanced breast cancer in postmenopausal women with disease progression after tamoxifen therapy.

Letrozole (Femara)

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits the conversion of androgens to estrogens. Letrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer. It is also used for first-line treatment of postmenopausal women with hormone receptor–positive or hormone receptor–unknown locally advanced or metastatic breast cancer.

Letrozole is also indicated for treatment of advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy and for extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.[146]

Exemestane (Aromasin)

Exemestane elicits irreversible steroidal aromatase inactivation by acting as a false substrate for the aromatase enzyme. It binds irreversibly to the aromatase enzyme active site, causing inactivation (ie, suicide inhibition). It significantly lowers circulating estrogen concentrations in postmenopausal women.

Exemestane differs from tamoxifen in that it inhibits estrogen production, whereas tamoxifen inhibits estrogen at the receptor site. It may be superior to tamoxifen for breast cancer chemoprevention, with a better safety profile. However, exemestane is not yet indicated for this application by the American Society of Clinical Oncology (ASCO). It is indicated for advanced breast cancer in postmenopausal women whose disease has progressed after tamoxifen therapy. Off-label use of exemestane is suggested as an alternative to tamoxifen or raloxifene in the 2013 ASCO guidelines to reduce the risk of ER-positive breast cancer in high-risk postmenopausal women.[135]

CDK Inhibitors

Class Summary

Palbociclib and ribociclib are cyclin-dependent kinases (CDK) 4, 6 inhibitors indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Palbociclib (Ibrance)

Palbociclib is a cyclin dependent kinases (CDK) 4, 6 inhibitor. It reduces cellular proliferation of ER-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. It is indicated in combination with letrozole for treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. It is also approved for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy.

Ribociclib (Kisqali)

CDK 4, 6 inhibitor. CDK inhibitors block cellular proliferation of G1 into S phase of the cell cycle. It is indicated in combination with an aromatase inhibitor (eg, letrozole) as initial endocrine-based therapy for postmenopausal women with HR+/HER- advanced or metastatic breast cancer.

Abemaciclib (Verzenio)

CDK 4, 6 inhibitor. These kinases are activated upon binding to D cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. In ER-positive breast cancer cells, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. It is indicated for HR+/HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy as either monotherapy or in combination with fulvestrant. It is also indication for the frontline treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor.

Antineoplastics, PARP Inhibitors

Class Summary

This class of agents is thought to augment cytotoxic therapy without increasing side effects and to kill cancer cells with DNA repair defects as a single agent. The genomic instability of some tumor cells allows poly (ADP-ribose) polymerase (PARP) inhibitors to have selectivity for the tumor cells over normal cells.

Olaparib was the first PARP inhibitor approved for breast cancer. Its approval was based on the first phase 3 randomized trial that demonstrated PARP inhibitors were superior to chemotherapy for patients with HER2-negative metastatic breast cancer with a BRCA mutation.[160]

Olaparib (Lynparza)

Indicated for deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, in patients who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.

Talazoparib (Talzenna)

Indicated for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.

Antineoplastics, Estrogen Receptor Antagonist

Class Summary

Selective estrogen receptor modulators (SERMs) stimulate or inhibit the estrogen receptors of various target tissues. Examples of SERMs include tamoxifen, raloxifene, and toremifene.

Tamoxifen (Soltamox)

Tamoxifen is a nonsteroid with potent antiestrogenic effects in the breast; however, it may be an estrogen agonist in the uterus. CYP2C19 heterozygous*2 carriership may be a predictive factor for longer survival in patients with breast cancer who are taking tamoxifen.[147] Tamoxifen is considered the gold standard for prevention of breast cancer in high-risk women, as adjuvant treatment for breast cancer, and in metastatic breast cancer.

Raloxifene (Evista)

Raloxifene is a selective nonsteroidal benzothiophene ER modulator. It is indicated for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis. In addition, it is indicated for risk reduction in postmenopausal women at high risk for invasive breast cancer.

Toremifene (Fareston)

Toremifene is a nonsteroidal triphenylethylene derivative that binds to estrogen receptors. It may exert estrogenic activities, antiestrogenic activities, or both. It is indicated for metastatic breast cancer in postmenopausal women with ER-positive or ER-unknown tumors.[148]

PD-1/PD-L1 Inhibitors

Class Summary

PD-L1 is expressed on the surface of activated T cells under normal conditions; binding PDL1 inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PDL1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

Atezolizumab (Tecentriq)

Monoclonal antibody to programmed cell death ligand-1 protein (PDL1). It blocks the interaction between PDL-1 and its ligands. It is indicated in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥11% of the tumor area), as defined by an FDA-approved test.

PI3K Inhibitors

Alpelisib (Piqray)

PI3K inhibitor indicated in combination with fulvestrant for treatment of men and postmenopausal women with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

 

Questions & Answers

Overview

What is breast cancer?

What are the signs and symptoms of breast cancer?

What is included in the evaluation of breast cancer?

Which physical findings suggest breast cancer?

What features of a palpable lump suggest breast cancer?

How is breast cancer screening performed?

What is the role of biopsy in the workup of breast cancer?

How is breast cancer treated?

What are the chemotherapy regimens used to treat breast cancer?

What is the role of drug treatment for breast cancer?

What is breast cancer?

What is the anatomy relevant to breast cancer?

What is the pathophysiology of breast cancer?

How is breast cancer categorized?

What are the types of breast cancer?

What causes breast cancer?

What is the role of age in the etiology of breast cancer?

What is the role of family history in the etiology of breast cancer?

Which family history factors increase the risk for breast cancer?

How is family history–based risk for breast cancer assessed?

What is the role of reproductive factors in the etiology of breast cancer?

What is the role of estradiol in the etiology of breast cancer?

What is the role of oral contraceptives (OCs) in the etiology of breast cancer?

What is the role of hormone replacement therapy (HRT) in the etiology of breast cancer?

What are guidelines for HRT in women at high risk of breast cancer?

How should menopausal symptoms be treated in women at high risk of breast cancer?

Which history findings increase the risk for a second primary breast cancer occurrence?

What is the role of lifestyle factors in the etiology of breast cancer?

What is the role of obesity in the etiology of breast cancer?

Which Western lifestyle factors increase the risk for breast cancer?

Which environmental factors increase the risk for breast cancer?

What is the prevalence of breast cancer in the US?

What are the historical trends in the incidence of breast cancer in the US?

What is the role of HRT in the incidence of breast cancer in the US?

What is the global prevalence of breast cancer?

Which age groups have the highest prevalence of breast cancer?

What are the racial predilections of breast cancer?

How do the mortality rates for breast cancer vary among racial and ethnic groups?

What is the association between breast cancer and cardiovascular disease (CVD)?

What is the prognosis of breast cancer?

What are the prognostic and predictive factors for breast cancer?

What are the survival rates for breast cancer?

What is the prognosis of breast cancer following HER2-targeted therapies?

What is the prognosis of DCIS breast cancer?

What is the prognosis of LCIS breast cancer?

What is the prognosis of infiltrating ductal carcinoma breast cancer?

What is the prognosis of medullary carcinoma breast cancer?

What is the prognosis of mucinous carcinoma breast cancer?

What is the prognosis of cystic papillary carcinoma breast cancer?

What is the prognosis of metaplastic breast cancer?

What is the prognosis of mammary Paget disease?

Presentation

Which clinical history findings are characteristic of breast cancer?

What are the USPSTF guidelines on risk assessment for BRCA-related breast cancer?

What are the signs and symptoms of breast cancer?

Which breast exam findings suggest breast cancer?

How are palpable lumps characterized in breast cancer?

What are the signs and symptoms of metastatic breast cancer?

DDX

Which conditions should be included in the differential diagnosis of breast cancer?

What are the differential diagnoses for Breast Cancer?

Workup

What is the triple assessment algorithm for breast cancer diagnosis?

What is the efficacy of breast cancer screening in the early detection of breast cancer?

Which modalities are used to screen for breast cancer?

What is the role of mammography in the workup of breast cancer?

Which factors affect a women&#39;s decision to undergo a breast cancer screening mammogram?

What are the ACS guidelines for breast cancer screening?

What are the USPSTF guidelines for breast cancer screening?

What are the ACP guidelines for breast cancer screening?

What are the ACR guidelines for breast cancer screening?

What is the efficacy of 3D mammography for breast cancer screening?

How does breast density affect the risk for breast cancer?

What is the role of diagnostic mammography in the evaluation of breast cancer?

What is the role of ultrasonography in the workup of breast cancer?

What is the role of MRI in the workup of breast cancer?

When is MRI indicated for the diagnosis of breast cancer?

When is MRI contraindicated for the diagnosis of breast cancer?

Which radiotracers are used in scintimammography for the diagnosis of breast cancer?

What are contraindications for scintimammography in the workup of breast cancer?

What is the role of PET scanning in the workup of breast cancer?

What is the accuracy of breast imaging modalities for the diagnosis of breast cancer?

What is the role of breast biopsy in the diagnosis of breast cancer?

What are the histologic findings of lobular carcinoma in situ breast cancer?

What are the histologic findings of infiltrating ductal carcinoma breast cancer?

What are the histologic findings of medullary carcinoma breast cancer?

Which tumor features affect treatment selection for breast cancer?

What are the histologic grades for breast cancer?

What are the histologic characteristics of DCIS breast cancer?

What are the histologic findings of infiltrating lobular carcinoma breast cancer?

What are the histologic findings of mucinous carcinoma breast cancer?

What are the histologic findings of tubular carcinoma breast cancer?

What are the histologic findings of papillary carcinoma breast cancer?

What are histologic findings of metaplastic breast cancer?

What are the histologic findings of mammary Paget disease?

What is the AJCC staging system for breast cancer?

How is the primary tumor (T) in breast cancer staged?

How are regional lymph nodes (N) in breast cancer staged?

How is distant breast cancer metastasis staged?

What are the survival rates by stage for breast cancer?

According to ASCO guidelines, which patients with breast cancer should be offered sentinel lymph node (SLN) biopsy?

What are the contraindications for sentinel lymph node (SLN) biopsy in breast cancer?

What are the ASCO guidelines for axillary lymph node dissection (ALND) in breast cancer?

What are the NCCN guidelines for sentinel lymph node (SLN) biopsy in breast cancer?

What are the NCCN guidelines for axillary lymph node dissection (ALND) in breast cancer?

What are the NCCN guidelines for evaluation of asymptomatic women with early-stage breast cancer (stages I–IIB)?

What are the NCCN guidelines for evaluation of women with clinical stage IIIA (T3, N1, M0) breast cancer?

How is HER2 testing performed in the evaluation of breast cancer?

What is the role of molecular profiling assays in the workup of breast cancer?

What is the MammaPrint assay for breast cancer?

Treatment

How is breast cancer treated?

How is invasive breast cancer treated?

What are the guidelines for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer?

What is the role of post lumpectomy radiation therapy in the treatment of breast cancer?

What are the ASBrS selection criteria for treatment of breast cancer with accelerated partial breast irradiation (PBI)?

What are the potential complications of partial breast irradiation (PBI) in the treatment of breast cancer?

What is the efficacy of external-beam radiotherapy (EBRT) in the treatment of breast cancer?

What is the role of single-dose radiotherapy in the treatment of breast cancer?

What are the ASCO criteria for postmastectomy radiation therapy in the treatment of breast cancer?

What is the efficacy of radiation therapy for the treatment of invasive breast cancer?

What is the role of systemic adjuvant therapy in the treatment of breast cancer?

How is DCIS breast cancer treated?

What is the role of WBRT in the treatment of DCIS breast cancer?

What is the role of tamoxifen in the treatment of DCIS breast cancer?

How is LCIS breast cancer treated?

How is locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) treated?

What is the prognosis of locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) following treatment?

What is inflammatory breast cancer (IBC)?

What is locally advanced breast cancer (LABC)?

How are lymph nodes evaluated in locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC)?

What are the systemic treatments for metastatic breast cancer?

What is the role of hormone therapy in the treatment of metastatic breast cancer?

What is the role of chemotherapy in the treatment of metastatic breast cancer?

Which chemotherapy agents are used in the treatment of metastatic breast cancer?

What is the role of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of metastatic breast cancer?

What is the efficacy of combination therapy in the treatment of triple-negative breast cancer?

What is the role of antiangiogenic therapy in the treatment of metastatic breast cancer?

What is the role of surgery for the treatment of metastatic breast cancer?

What is the role of tamoxifen and raloxifene for the reduction of breast cancer risk?

What are the ASCO guidelines for the pharmacologic reduction of breast cancer risk?

What is the role mastectomy in the prevention of breast cancer?

What are the ASBrS recommendations for contralateral prophylactic mastectomy (CPM) in the treatment of breast cancer?

What are the differences between the NCCN and ASCO guidelines for the long-term monitoring of breast cancer survivors?

What are ASCO guidelines for monitoring bone density following the treatment for breast cancer?

What is the role of postoperative imaging in the long-term monitoring of breast cancer?

What is the role of postoperative imaging in the monitoring of metastatic breast cancer?

How is radiation-induced heart disease monitored in patients with breast cancer?

What are Society for Integrative Oncology guidelines for use of integrative therapy in breast cancer?

Guidelines

Which organizations have issued guidelines on breast cancer screening?

What are the ACS guidelines for breast self-exam (BSE)?

What are ACS guidelines breast cancer mammogram screening?

What are ACS guidelines for the use of MRI in breast cancer screening?

What are the USPSTF guidelines for breast self-exam (BSE)?

What are the USPSTF guidelines for breast cancer screening?

What are the USPSTF guidelines for BRCA-related breast cancer screening?

How are the ACOG guidelines for breast cancer screening categorized?

According to ACOG guidelines, which breast cancer risk factors should be periodically assessed in women?

What are the ACOG guidelines for clinical breast exam to screen for breast cancer?

What are the ACOG recommendations for breast cancer screening mammography?

Which organizations have issued guidelines for pharmacologic intervention for breast cancer risk reduction?

What are the ASCO guidelines on pharmacologic interventions for breast cancer risk reduction?

What are the ASCO recommendations for use of tamoxifen in breast cancer risk reduction?

What are the ASCO recommendations for use of raloxifene in breast cancer risk reduction?

What are the ASCO recommendations for use of exemestane in breast cancer risk reduction?

What are the USPSTF guidelines on pharmacologic interventions for breast cancer risk reduction?

Which organizations have issued guidelines for sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) in the treatment of breast cancer?

What are the ASCO guidelines for the use of sentinel lymph node biopsy (SLNB) in the treatment of breast cancer?

What are the ASCO guidelines for the use of axillary lymph node dissection (ALND) in the treatment of breast cancer?

What are the NCCN guidelines on the use of sentinel lymph node biopsy (SLNB) for the treatment of breast cancer?

What are the NCCN guidelines for axillary lymph node dissection (ALND) in the treatment of breast cancer?

What are the NCCN guidelines for use of sentinel lymph node biopsy (SLNB) in the treatment of breast cancer during pregnancy?

What are the guidelines for breast-conserving surgery with whole-breast radiation therapy (WBRT) in ductal carcinoma in situ (DCIS) breast cancer?

What are the guidelines for breast-conserving surgery with whole-breast radiation therapy (WBRT) in stages I and II invasive breast cancer?

What are the NCCN guidelines for radical mastectomy in the treatment of breast cancer?

What are the ASCO guidelines for postmastectomy radiation therapy in the treatment of breast cancer?

What are the ASCO treatment guidelines for HER2-positive breast cancer?

What are the ASCO guidelines for the use of hormonal adjuvant therapy in the treatment of premenopausal women with breast cancer?

What are the ASCO guidelines for adjuvant endocrine therapy in the treatment of postmenopausal women with breast cancer?

What are guidelines on the treatment of breast cancer in young women?

Which organizations issued guidelines on follow-up care for breast cancer survivors?

What are ASCO guidelines for use of biomarkers in the treatment of breast cancer?

Medications

What is the role of adjuvant therapies in the treatment of breast cancer?

Which medications are used in the adjuvant treatment of breast cancer?

Which medications in the drug class Antineoplastics, Estrogen Receptor Antagonist are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, PARP Inhibitors are used in the treatment of Breast Cancer?

Which medications in the drug class CDK Inhibitors are used in the treatment of Breast Cancer?

Which medications in the drug class Aromatase Inhibitors are used in the treatment of Breast Cancer?

Which medications in the drug class Tyrosine Kinase Inhibitors are used in the treatment of Breast Cancer?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, Vinca Alkaloid are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Breast Cancer?

Which medications in the drug class Calcium Metabolism Modifiers are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, Anthracycline are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Breast Cancer?

Which medications in the drug class Antineoplastics, Antimicrotubular are used in the treatment of Breast Cancer?

Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Breast Cancer?

Which medications in the drug class PI3K Inhibitors are used in the treatment of Breast Cancer?