Breast Cancer

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Practice Essentials

Breast cancer is the common term for a set of breast tumor subtypes with distinct molecular and cellular origins and clinical behavior. Most of these are epithelial tumors of ductal or lobular origin (see the image below). Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women.



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

See Oncology Decision Point for expert commentary on breast cancer treatment decisions and related guidelines. Also see the following Medscape–Memorial Sloan Kettering e-tumor boards:

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:

See Presentation for more detail.

Diagnosis of breast cancer

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:

Physical examination

The following physical findings should raise concern:

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

Screening

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

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.

Breast self-examination is no longer recommended. Instead, breast awareness is recommended; women should be familiar with how their breasts normally look and feel, and report any changes promptly to their health care provider.[2, 3] Most guidelines also recommend against clinical breast examination for screening.[3, 4]

Biopsy

Core biopsy with image guidance is the recommended diagnostic approach for newly diagnosed breast cancers. This obtains 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 of breast cancer

Surgery, radiation therapy, and adjuvant hormone or chemotherapy when indicated are considered primary treatment. Surgical therapy may consist of lumpectomy or total mastectomy with sentinel lymph node biopsy (SLNB) or complete axillary lymph node dissection (ALND). Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing recurrence rates. Adjuvant systemic therapies (eg, hormonal therapy, chemotherapy, targeted therapies), when indicated, are recommended on the basis of tumor biology, stage, and gene expression assay results, as well as individual patient factors such as comorbidities and personal preferences.

Pharmacologic agents

Pharmacologic treatment for breast cancer is typically selected according to the molecular characteristics of the tumor and the disease stage. Agents used (alone or in combination) include the following[5] :

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. For patient education information, see the Breast Cancer Resource Center.

Prevention

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women. Aromatase Inhibitors are also approved for risk reduction in postmenopausal women. Prophylactic mastectomy is also an option for risk reduction.

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.[6] In the United States, breast cancer is the most common cancer in women and is second only to lung cancer as a cause of cancer deaths in women.[7] (For discussion of male breast cancer, see Breast Cancer in Men.)

Many early breast cancers 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 for 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 have not yet established an identifiable metastasis. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the decrease in cancer recurrence.

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.)

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).



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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 four main breast tumor subtypes, with distinct genetic and epigenetic aberrations[8] (see the image below):



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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 cancers.[9]

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

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 used in clinical practice.

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.[11]

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.[12, 13] It has been proposed that this bimodal pattern may reflect the influence of age within the different tumor subtypes; poorly differentiated, high-grade disease tends to occur earlier, whereas hormone-sensitive, slower-growing tumors tend to occur with advancing age.

However, a review of Carolina Breast Cancer Study data found that the bimodal peaks occurred regardless of molecular characteristics, although estrogen receptor (ER)-negative cases (as well as those with borderline, low, and intermediate ER expression) had a predominant early-onset peak, while cases with high ER expression had a predominant late-onset peak. In addition, basal-like, HER2-enriched, and luminal B cancers had predominant early-onset peaks with minor late-onset peaks, whereas luminal A cases had the most pronounced peak in late-onset cases.[13]

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.[14] A GWAS by Milne et al identified 10 variants at 9 new loci that are associated with risk of estrogen receptor–negative breast cancer.[15] A similar study by Ahearn et al identified 85 variants associated with at least one tumor feature, including 32 variants associated with triple-negative disease.{ref 212}

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:

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:

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 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 test are not the most common BRCA1/BRCA2 mutations in the general population.[16]

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.[17, 18, 19, 20, 21] 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.[22, 23]

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.[24] Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers.[25, 26] 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.[27, 28] 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.[29]

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.[28] 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).[30, 31] 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.[32] 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.[32] Risk is greater among women taking combination HRT than among those taking estrogen-only formulations.[33, 34]

A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer of 58 international studies that included 143,887 postmenopausal women with invasive breast cancer and 424,972 without breast cancer concluded the following about menopausal HRT and breast cancer[35] :

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 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%).[36] Fewer women died of breast cancer in the estrogen-only arm.

A 23% reduction in breast cancer diagnosis in women assigned to estrogen-only HRT persisted over 16 years of cumulative follow-up in two WHI trials in more than 10,000 women (hazard ratio [HR] 0.77, 95% CI 0.62-0.92); most of the reduction was due to fewer diagnoses of estrogen receptor–positive/progesterone receptor–negative disease. In addition, breast cancer deaths were 44% lower with estrogen-only HRT (HR 0.56, 95% CI 0.34-0.92).[36]  

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. For more information, see Menopausal Hormone Replacement Therapy.

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).[37]

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.[38] 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.[39] 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.[40, 41, 42] 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.[43, 44]

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.[43, 44] 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.[45]

Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast disease or fibroadenoma, have not been associated with increased risk.[46]

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.[47, 48, 49, 50] 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.[51]

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.[52]

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.[52]

Obesity

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

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

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).[57, 58, 59] 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[60, 61, 62] :

Alcohol consumption has been linked with breast cancer.[63, 64, 65] Regular consumption of alcoholic beverages can prevent the absorption of nutrients, contribute to weight gain, and raise the levels of estrogen.[64]

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.[62, 66] 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[67] ; evidence suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[68]

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 316,950 new cases of invasive breast cancer in women are predicted to occur in 2025, along with 2800 cases in men.[7] Among US women in 2025, in addition to invasive breast cancer, 59,080 new cases of ductal carcinoma in situ (DCIS) are expected to be diagnosed.[7]

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.[69]

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.[70, 71, 72, 73]

The reason for the decline has been extensively debated. Breast cancer rates decreased significantly after the reports from the Million Women Study[74] 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.[72]

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.[69, 71] 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.[75]

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.[11] This rise occurred in spite of very low use of HRT by this population[76] 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:

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.[6]

In 2022, there were an estimated 2.3 million new cases of female breast cancer worldwide. The 2022 incidence rates of female breast cancer ranged from 26.7 cases per 100,000 in middle Africa and south central Asia to 100.3 cases per 100,000 in Australia/New Zealand.[6]

Age-related demographics

The incidence rate of breast cancer increases with age, from 2% of cases in women 20-34 years of age to over 70% of cases in women 45-74 years of age. The median age of women at the time of breast cancer diagnosis is 63 years.[11]  

In 2012-2021, the incidence rate of invasive breast cancer rose by 1.4% per year in women ages 20-49 years and by 0.4% per year in women older than 50 years. Rates of ductal carcinoma in situ remained stable in both age groups.[77]  A study of invasive breast cancer in women age 20 to 49 years, using data from Surveillance, Epidemiology, and End Results (SEER) from 2000-2019, reported that the annual percentage increase in breast cancer was 0.24 (95% CI, 0.05-0.42) between 2000 and 2016 but rose to 3.76 (95% CI, 1.39-6.19) from 2016 onward. During that time, the incidence rates of stages I and IV breast cancers rose, but those of stage II and III breast cancer decreased.[78]

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, however, African Americans have a higher incidence. According to the American Cancer Society (ACS), breast cancer rates per 100,000 among women from various racial and ethnic groups are as follows[77] :

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

Among US women from 2013 through 2022, breast cancer death rates declined by 1.4% per year in Black women, by 1% per year in White women, and by 0.7% per year in Hispanic women, but was stable in Asians/Pacific Islanders and American Indians/Alaskan Natives. Breast cancer death rates in Black women began to exceed those in White women in the early 1980s; the disparity peaked in 2011, when death rates were 44% higher in Black than in White women, and then decreased only slightly, to 36% in 2022.[77]

Compared with the White population of the US, those with African ancestry have a higher incidence rate of breast cancer before age 40 years in women, and a higher incidence of breast cancer in men. They are more likely to present with advanced breast cancer and to have a biologically aggressive disease such as triple-negative breast cancer. Their mortality rate is 40% higher.[79]

Studies based on The Cancer Genome Atlas, which characterize tumor DNA and protein expression, support the clinical studies that report higher likelihood of aggressive breast cancer with poorer outcomes in US women with African ancestry. In contrast, women of Asian ancestry tend to have breast tumors with favorable immune microenvironments and may experience better disease-free survival compared with US Whites.[80]

 

 

 

Prognosis

From 1989 through 2022, death rates from breast cancer in the United States decreased 44%. The decrease was 1.9% per year from 1998 through 2010, then slowed to 1.2% per year from 2010 through 2022.[77]  

The decrease in breast cancer death rates is thought to represent progress in both earlier detection and improved treatment modalities.[7] The 2025 estimates are 42,680 expected breast cancer deaths (42,170 in women, 510 in men).[7]

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:

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:

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.[81] (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:

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. (See Breast Cancer and HER2.)

Molecular profiling assays

In patients with early breast cancer—ER-positive, HER2-negative, and node-negative or with 1-3 positive nodes—genetic testing of the tumor can be used to determine the risk of recurrence, and the likely benefit from chemotherapy. Multiple assays that have been developed and validated for this purpose; see Workup/Tumor Genetic Testing.

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.

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.[82]

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%.[83] In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[84] 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 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%).[85, 86]

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, hormonal therapies, targeted therapy such as trastuzumab). In addition, breast cancer and CVD, share several risk factors, including smoking, obesity, and the typical Western diet.[87]

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.[87]

 

 

History

Many early breast cancers 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) guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women are as follows[88] :

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:

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:

Rapid onset (within 6 months) of thickening or edema of the skin of the breast (eg, peau d'orange), erythema, and symmetrical enlargement of the affected breast, with or without a palpable mass, are hallmarks of inflammatory breast cancer—a rare condition that accounts for only 1-5% of breast cancers. Inflammatory breast cancer tends to occur in women younger than 40 years of age and in those who are overweight or obese, and is more common in women of African, South Asian, and Arabic descent.[89]

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

A complete examination includes assessment for lymphatic and distant metastases; in descending order of frequency, distant metastases are to bone, lung, liver, and brain.[90] Thus, the assessment should include the axillae and supraclavicular fossae, 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:

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

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:

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 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.[91, 92] 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%).[91] 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.[92]

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).[93]

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.[94]  

A large-scale, population-based, observational study by García-Albéniz et al concluded that continuing annual breast cancer screening past age 75 years did not result in substantial reductions in 8-year breast cancer mortality compared with stopping screening. The study used data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008.[95]

In women aged 70 to 74 years, continued screening resulted in a slightly reduced 8-year rate of breast cancer death: 2.7 deaths per 1,000 women, compared with 3.7 for those who stopped screening. In those aged 75 to 84 years, comparable figures were 3.8 versus 3.7 deaths per 1,000 women (hazard ratio, 1.00 [CI, 0.83 to 1.19]).[95] Although breast cancer was diagnosed more often in women who continued screening, that did not translate to a significant reduction in deaths because breast cancer treatment is less successful in older women.[96]

A number of screening modalities exist for breast cancer, including mammography, ultrasonography, and MRI. Breast self-examination is no longer recommended for screening. Instead, breast awareness is recommended; women should be familiar with how their breasts normally look and feel, and report any changes promptly to their health care provider.[2, 3] Most guidelines also recommend against clinical breast examination.[3, 4, 97] (See Breast Cancer Screening.)

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.[92, 98, 99]

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.

Advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems.[100] CAD systems have been developed to help the radiologist identify mammographic abnormalities. Tomosynthesis mammography is a method of creating a three-dimensional image of the breast from x-ray cross-sections. Mammography with tomosynthesis increases cancer detection rates in asymptomatic patients.[101, 102]

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).[103]

The US Preventive Services Task Force (USPSTF) reports that reduction in breast cancer mortality due to screening mammography varies with patient age. With screening mammography, relative risk (RR) of breast cancer mortality was 0.92 for women aged 39 to 49 years, 0.86 for those aged 50 to 59 years, 0.67 for those aged 60 to 69 years, and 0.80 for those aged 70 to 74 years. Risk of advanced breast cancer was reduced for women aged 50 years or older (RR 0.62) but not those aged 39 to 49 years (RR 0.98).[104]

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 two 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.[105, 106]

At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS). In 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.[107, 108]

Current ACS recommendations for women at average risk of breast cancer are as follows[108, 3] :

Since 2009 the USPSTF has recommended biennial screening mammography for women aged 50-74 years. However, in April 2024 the USPSTF released updated recommendations, as follows[106] :

Similarly, a 2019 review by the American College of Physicians (ACP) provides the following guidance statements regarding screening of asymptomatic women at average risk and in good health[4] :

Tomosynthesis (3D mammography) has gained a role in breast cancer screening. American College of Radiology (ACR) considers tomosynthesis indicated in woman at low, intermediate, and high risk of breast cancer, and notes that compared with 2D mammography alone, tomosynthesis results in higher cancer detection rates and lower rates of recall for benign findings, and that these advantages may be especially pronounced in women under age 50, and those with dense breasts or certain lesion types (eg, spiculated masses, asymmetries).[109]  

A retrospective review of breast cancer screening in 385,503 women that included 542,945 tomosynthesis screens and 261,359 digital mammography screens demonstrated that in nearly all age groups and races, tomosynthesis is associated with improved patient screening metrics, compared with digital mammography: lower recall rates, higher cancer detection rates, and improved positive predictive value for recall.[110]

National Comprehensive Cancer Network (NCCN) guidelines recommend considering tomosynthesis as part of screening, although the NCCN notes that studies have yet to determine whether tomosynthesis improves breast cancer–specific mortality.[2]

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.[111] 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.

Increased breast density reduces the sensitivity of mammography, and is an independent risk factor for breast cancer. On mammography, the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS) classifies breast density as follows, based on the proportion of fibroglandular tissue compared with fat and its potential for masking noncalcified lesions[109] :

The US Food and Drug Administration requires mammography facilities to notify patients about the density of their breasts. The reports should describe the patient's breasts as either “not dense” (ie, category A or B) or “dense” (ie, category C or D).[112]  The American College of Radiology offers recommendations on the use of digital breast tomosynthesis, ultrasound, and MRI to supplement mammography, based on the patient's breast cancer risk and degree of density.[113]

However, a prospective cohort study found that only a minority of women with dense breasts have high interval cancer rates. 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 BI-RADS. 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.[114]

Ultrasonography

Ultrasonography has become a widely available and useful adjunct to mammography in the clinical setting. 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.

An American College of Radiology practice parameter lists the following as appropriate indications for diagnostic sonography of the breast and axilla[115] :

In a systematic review and meta-analysis by Sood et al, data from low- and middle-income countries showed that ultrasound had a diagnostic sensitivity of 89.2% and specificity of 99.1% for detection of breast cancer. These authors concluded that ultrasound has potential use as a primary detection tool for breast cancer in low-resource settings where mammography is unavailable.[116]

Magnetic Resonance Imaging

The principal indications for MRI of the breast are screening for breast cancer in women at increased risk, staging of known cancer, and evaluation of response to neoadjuvant chemotherapy. Breast MRI is based on T1-weighted contrast-enhanced imaging, but multiparametric assessment, including T2-weighted, ultrafast, and diffusion-weighted imaging, may be used to improve the characterization of lesions.[117]

MRI is used in conjunction with mammography for breast cancer screening in women at increased risk.[2, 118] For example, guidelines from the American College of Radiology (ACR) recommend supplemental screening with contrast-enhanced breast MRI for women with the following risk factors[119] :

The ACR also recommends consideration of additional surveillance with MRI in women with histories of breast cancer and those with atypia at biopsy, especially if other risk factors are present.

However, 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.[120]

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.[120]

Breast MRI may be performed when breast cancer is suspected but other imaging studies have yielded equivocal results.[118] In a study of 1441 women with dense breasts who underwent screening, abbreviated breast MRI was associated with a significantly higher rate of invasive breast cancer detection compared with digital breast tomosynthesis.[121]

For more information, see Magnetic Resonance Mammography.

Imaging Studies for Staging

Imaging studies used for staging breast cancer include positron emission tomography (PET) and scintimammography.

Using a wide range of labeled metabolites (eg, fluorinated glucose [18-fluorodeoxyglucose; 18FDG]), PET can detect metabolic activity, vascularization, oxygen consumption, and tumor receptor status. In combination with computed tomography (CT) to assist in anatomic localization, PET (PET-CT) 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.

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

In several prospective studies, overall sensitivity of 99mTc-sestamibi scintimammography in the detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values were 89% and 84%, respectively. Similar numbers have been demonstrated for 99mTc-tetrofosmin and 99mTc-MDP scintimammography.[8]

 

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



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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.

HER2 Testing

Testing for human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression is essential in breast cancer, to identify tumors that may benefit from HER2-targeted therapies. The American Society of Clinical Oncology (ASCO) and the  College of American Pathologists (CAP) have published 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. The guidelines were first published in 2007, updated in 2018, and reaffirmed in 2023.[123, 124, 125] (See Breast Cancer and HER2.)

The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

In breast cancer specimens with equivocal (IHC 2+) results, the ASCO/CAP guidelines advise that the pathologist must order a reflex test of the same specimen, using in situ hybridization (ISH) to test for HER2 amplification; or order a new test on a new specimen, if available, using ICH or ISH. The disinction is important because patients with breast cancers that are IHC 3+ or IHC 2+ with ISH amplified may be eligible for several therapies that disrupt HER2 signaling pathways, while patients with IHC 1+ or IHC 2+ with ISH not-amplified can be treated with the antibody-drug conjugate trastuzumab-deruxtecan.[124, 125]

HER2 ISH testing involves the ratio of HER2 to chromosome 17 centromere [HER2/CEP17] and gene copy number. Results are classified as follows:

For cases in which ISH testing yields contradictory or intermediate results (eg, HER:CEP17 ratio < 2.0, average HER2 copy number ≥ 4.0 to < 6.0), ASCO guidelines provide a set of algorithms to guide classification.

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:

On the basis of ER and PR (hormone receptor) and HER2 results, breast cancer is classified as one of the following types[5] :

That classification helps guide the selection of drug regimens.

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)



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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).



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



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Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth patter....

Table 3. Ductal Carcinoma in Situ Subtypes



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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, to 3.19 per 100,000 persons/year; the peak incidence is in women aged ≥50 years.[10]



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Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.



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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 75-85% 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.



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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:

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.



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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; 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.



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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).[126]

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 Black women. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.

A wide variety of histologic patterns includes the following:

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 three stage groups for breast cancer: anatomic, clinical prognostic, and pathological prognostic. Anatomic staging, which is based on extent of cancer as defined by tumor size (T), lymph node status (N), and distant metastasis (M), is intended for use in settings where biomarker analysis is not available.

Clinical prognostic staging 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). Pathological prognostic stage includes all information used for clinical prognostic staging plus findings at surgery and pathological findings from surgical resection. Pathological prognostic stage does not apply to patients who received neoadjuvant therapy (systemic or radiation therapy prior to surgical resection). The prognostic stage groups are preferred for patient care and are to be used for reporting of all cancer patients in the United States.[127, 128]

See the tables below.

Table 4. TNM Classification for Breast Cancer



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Table 5. Histologic grade



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Table 6. Anatomic stage/prognostic groups



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Notes:

Table 7. Clinical prognostic stage



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Table 8. Pathological prognostic stage



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Lymph node assessment

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

A 2017 update on SLNB for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that SLNB may be offered to the following patients[129] :

According to the ASCO guidelines, SLNB should not be performed in patients with any of the following:

Additional ASCO guidelines advise that SLNB is not required in patients age ≥ 70 years with clinically node-negative (T1N0) early-stage invasive breast cancer that is hormone receptor positive and HER2 negative.[130]

ASCO recommendations regarding ALND in patients who have undergone SLNB are as follows:

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 SLNB. 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 SLNB in pregnancy be individualized. However, isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid appears to be safe.[81]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following cases[81] :

Also see Breast Cancer Staging for summarized information.

Additional Testing

The NCCN guidelines[81] recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I–IIB):

Additional studies indicated in specific settings include the following:

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

Tumor Molecular Testing

In patients with early breast cancer—ER positive, HER2 negative, and node negative or with 1-3 positive nodes—genetic testing of the tumor can be used to determine the risk of recurrence and the likely benefit from chemotherapy. Commercially available assays that have been developed and validated for this purpose include the following[131] :

Assays that are limited to estimating risk of recurrence include the following[131] :

Oncotype DX

Oncotype DX is a reverse transcription polymerase chain reaction (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, a recurrence score (RS) can be calculated that correlates with the likelihood of distant recurrence at 10 years. The Oncotype DX RS has been shown to predict benefit from chemotherapy and hormonal therapy, as follows:

MammaPrint

MammaPrint 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. MammaPrint test results are reported as either a low-risk or a high-risk RS. A low-risk score indicates a 10% risk of cancer recurrence within 10 years without any additional treatments after surgery. A high-risk score indicates a 29% risk of recurrence within 10 years without any additional treatments after surgery.

In the MINDACT trial, follow-up after almost 9 years showed that among women with high clinical risk breast cancer, those with a MammaPrint low-risk RS had excellent distant metastasis–free survival when treated with endocrine therapy alone; adding chemotherapy provided only a 2.6% benefit, regardless of nodal positivity. Furthermore, exploratory analysis suggested that the benefit of adding chemotherapy may be limited to women younger than 50 years, and could possibly be due to chemotherapy-induced ovarian function suppression, in which case reinforced endocrine therapy might obviate chemotherapy.[136]

Prosigna

Prosigna, previously known as PAM50, is a 50-gene assay. The relative expression of those genes is used to calculate an RS ranging from 0 to 100. Node-negative patients are classified as low risk (RS 0–40), intermediate risk (RS 41-60) or high risk (RS 61-100) Node-positive patients are classified as low risk (RS 0–40) or high risk (RS 41–100). Prosigna may be used for predicting outcome and aiding adjuvant therapy decision-making in HR-positive, HER2-negative breast cancer that is either lymph node–negative or lymph node–positive (1–3 metastatic nodes).[137, 138, 139, 140] It may be superior to Oncotype DX for predicting late distant recurrence after 5 years of endocrine therapy.[141]

Endopredict

Endopredict is an 11-gene assay that has been shown to predict outcome patients with in ER-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy, as well as in those with HER2-negative lymph node–positive disease who receive adjuvant chemotherapy.[140, 142, 143] The Endopredict RS score has been used in combination with nodal status and tumor size to create a comprehensive risk score, EPclin, which can predict the likelihood of distant recurrence in patients with ER-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.[144]

Breast Cancer Index

The Breast Cancer Index (BCI) is an 11-gene assay that has prognostic value for detecting early and late recurrences in patients with ER-positive, HER2-negative and lymph node–negative breast cancer treated with adjuvant endocrine therapy. Thus, BCI may be of value for identifying patients in this setting who may not require extended endocrine therapy beyond 5 years of treatment.[131, 145]

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 to provide necessary prognostic information.

Preoperative (neoadjuvant) chemotherapy is used in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. It may allow less extensive surgery (eg, permit breast-conserving surgery in patients who are not candidates for that on initial presentation, or obviate axillary lymph node dissection in patients who present with node-positive breast cancer). In patients with triple-negative (estrogen receptor, progesterone receptor, and HER2) or HER2-positive disease, response to neoadjuvant therapy can guide the selection of adjuvant therapy.[5] The American Society of Clinical Oncology has published a guideline on the optimal use of neoadjuvant therapy for women with invasive nonmetastatic breast cancer.[146]

Race may affect response to neoadjuvant therapy. In a review of Black and White women treated with neoadjuvant endocrine therapy, Black women were more likely to benefit than White women if treated at an earlier disease stage, but were less likely to benefit than White women if treated at a later disease stage. The study included 3521 White women and 365 Black women with stage I-III hormone receptor–positive breast cancer.[147]

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 adding adjuvant chemotherapy to endocrine therapy. Commercially available assays have demonstrated efficacy for this in women with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer—either axillary node negative or with 1-3 positive lymph nodes (see Workup/Additional Testing).[131]

Despite marked advances in the treatment of early-stage breast cancer, many women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease at presentation. There are two main interventions for metastatic breast cancer: hormone therapy and chemotherapy. Increasingly, chemotherapy is combined with agents targeted to specific tumor mutations. Although treatments for metastatic breast cancer continue to improve, there remains no cure once distant metastases develop.

See Breast Cancer Treatment Protocols for summarized information. See Oncology Decision Point for expert commentary on breast cancer treatment decisions and related guidelines. To view multidisciplinary tumor board case discussions, see the Memorial Sloan Kettering e-Tumor Boards HR+/HER2- Metastatic Breast Cancer and Recurrent Metaplastic Triple Negative Breast Cancer.

Treatment of Early Breast Cancer

Early breast cancer includes ductal carcinoma in situ and stage I, stage IIA, stage IIB, and stage IIIA breast cancers. European Society for Medical Oncology (ESMO) guidelines on early breast cancer include the following treatment recommendations[148] :

In 2021, the US Food and Drug Administration approved abemaciclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, for adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence and a Ki-67 score ≥20%, as determined by an FDA-approved test. Abemeciclib is given in combination with endocrine therapy (tamoxifen or an aromatase inhibitor).

Approval for this indication was based on results from the monarchE trial, in which invasive disease–free survival at 2 years was 92.2% with abemaciclib plus endocrine therapy versus 88.7% with endocrine therapy alone. In monarchE, high risk was defined as having ≥ 4 positive axillary lymph nodes, or having 1-3 positive axillary lymph nodes and one or more of the following features: histologic grade 3 disease, tumor size > 5 cm, or Ki-67 index > 20%.[149]

Also in 2021, the FDA approved pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1), for the treatment of patients with high-risk, early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. Approval was based on findings in the KEYNOTE-522 trial (n=1174), in which the pathological complete response rate  \was 63% for patients who received pembrolizumab plus chemotherapy, versus 56% for patients who received chemotherapy alone.[150, 151]

In September 2024, the FDA approved the CDK4/6 inhibitor ribociclib in combination with an aromatase inhibitor for the adjuvant treatment of HR-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence. Approval was based on results from the NATALEE trial, in which invasive disease-free survival at 3 years was 90.4% with ribociclib plus an aromatase inhibitor (letrozole or anastrozole) and 87.1% with an aromatase inhibitor alone (hazard ratio for invasive disease, recurrence, or death, 0.75; P = 0.003). Distant disease–free survival and recurrence-free survival were also superior in the ribociclib arm.[152]

In 2022, the FDA approved adjuvant olaparib (Lynparza) for BRCA-mutated HER2-negative high-risk early breast cancer in adults who have undergone treatment with chemotherapy before or after surgery. Approval was based on the phase 3 OlympiA trial (n=1836), which patients treated with olaparib 300 mg twice daily showed improvement in invasive disease-free survival (DFS), reducing the risk of breast cancer recurrence by 42% compared with the placebo group (hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; P < 0.0001). The 3-year distant DFS was 87.5% in the olaparib group and 80.4% in the placebo group (HR for distant disease or death, 0.57; P < 0.001).[153]

American Society of Clinical Oncology (ASCO) guidelines, updated in 2024, include the following recommendations on selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer[154] :

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.[155]

In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy.[155] 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.[156]

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[157] :

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.[81]

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 adverse 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 adverse 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[158] :

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

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.[159, 160] 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 two 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.[161, 162]

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.[161]

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.[161, 162]

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[163] :

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%.[164]

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.[165]

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.[166] 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.[167]

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.[167]

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.[168]

Adjuvant tamoxifen also reduces the risk of contralateral breast cancer.[169] 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.[169]

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).[169]

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.[170]

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.[25] 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 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 results in NeoSphere, a randomized trial that compared a number of neoadjuvant 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.[171]  The 5-year follow-up results of NeoSphere continued to demonstrate the benefit of this regimen.[172]

Evidence-based guidelines from the American Society of Clinical Oncology (ASCO) recommend HER2-targeted therapy for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. The ASCO guidelines recommend trastuzumab, pertuzumab, and a taxane for first-line treatment and trastuzumab emtansine for second-line treatment. For third-line treatment, the guidelines recommend offering other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) and pertuzumab if the patient has not previously received it.[173]

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.[174]

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:

Systemic Treatment of Metastatic Breast Cancer

Despite marked advances in the treatment of early-stage breast cancer, 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. Increasingly, chemotherapy is combined with agents targeted to specific tumor mutations.

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, hormone manipulation is generally 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 therapy for women with human epidermal growth factor 2 (HER2) negative (or unknown) advanced breast cancer, published in 2016 and updated in 2014 and 2023.[175, 176, 177]

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 9, below.

Table 9. Hormone Agents Used in Breast Cancer



View Table

See Table

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.[178]

Fulvestrant

Fulvestrant (Faslodex), an estrogen antagonist, is 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.

Approval was based on results from the phase III FALCON trial (n = 462), in which fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole, and 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. Overall response rate and clinical benefit rate did not differ significantly between the drugs.[179]  

Elacestrant

In 2023, elacestrant (Orserdu), the first oral selective ER degrader, was approved for men or postmenopausal women with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. Approval was based on the phase III EMERALD trial, which compared elacestrant (n = 239) with standard of care (n = 238) and in which PFS was prolonged in all patients who received elacestrant (P = 0.002), including those with ESR1 mutation (P = 0.0005).[180] Current ASCO guidelines recommend routine testing for emergence of ESR1 mutations in patients with ER-positive, HER2-negative metastatic breast cancer who experience recurrence or progression on endocrine therapy.[177]

CDK inhibitors

Cyclin dependent kinases (CDK) 4,6 inhibitors reduce cellular proliferation of ER-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Three agents in this class are approved for first- and second-line use in advanced or metastatic breast cancer: palbociclib, ribociclib, and abemaciclib. CDK 4,6 inhibitors are generally used in combination with an aromatase inhibitor.

Palbociclib

Palbociclib is approved for use in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Approval of palbociclib for this indication was based on the phase II PALOMA-1 trial, in which mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group.[181]

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), in which PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo. vs 3.8 mo.).[182]

Ribociclib

Ribociclib is indicated for initial endocrine-based therapy of advanced or metastatic HR+/HER2- breast cancer, in combination with an aromatase inhibitor; and in combination with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy.[183]

Approval of ribociclib for initial therapy was based on interim analysis of the phase III MONALEESA-2 trial, in which the risk for progression or death was lower with ribociclib plus letrozole compared with letrozole alone. After 18 months, the PFS was 63% with a duration of 19.3 months in the ribociclib/letrozole 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.[184]  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.[185]

Abemaciclib

Abemaciclib has the following indications for the treatment of HR+/HER- advanced or metastatic breast cancer:

Approval for first-line use was based on data from the MONARCH 3 trial, in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46%. Median PFS was 28.2 months in the abemaciclib arm versus 14.8 months with the aromatase inhibitor alone. The median duration of response was 27.4 months for the abemaciclib arm compared with 17.5 months in the control arm.[186] Final overall survival results of MONARCH 3, with a median follow-up of 8.1 years, showed that the PFS benefit was sustained. The overall survival benefit, however, while clinically meaningful, did not reach statistical significance.[187]

Approval of abemaciclib for second-line use was based on results from the MONARCH 1 and 2 trials. The Monarch 1 trial demonstrated the safety and efficacy of abemaciclib as a stand-alone treatment in heavily pretreated patients, with confirmed objective response rate of 19.7%, clinical benefit rate of 42.4%, median PFS of 6.0 months, and median overall survival of 17.7 months.[188] In MONARCH 2, median PFS was 16.4 months with fulvestrant plus abemaciclib versus 9.3 months with fulvestrant alone, and the overall response rates in patients with measurable disease were 48.1% and 21.3% in the abemaciclib/fulvestrant and control arms, respectively.[189]

Chemotherapy and targeted therapy

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 selecting a treatment regimen should be to prolong survival while maintaining a good quality of life.

In a patient with 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 approach, which is becoming increasingly common, is to combine a cytotoxic chemotherapeutic agent 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 10, below, followed by Table 11, showing combination regimens for breast cancer.

Table 10. Targeted Chemotherapy for Metastatic Breast Cancer



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Table 11. Combination Regimens for Metastatic Breast Cancer



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The choice of chemotherapy for recurrent disease is highly influenced by the patient's previous drug exposure. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a higher risk of doxorubicin resistance. However, 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.

Toxicity is also a consideration. There is a relationship between cumulative lifetime total dose of doxorubicin and the risk of potentially fatal cardiomyopathy. 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.[203]

Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin in the mitotic spindle and is administered intravenously, usually on a weekly basis. Vinorelbine is often used as a single agent following treatment with a taxane or anthracycline, yielding an ORR of 25%. However, when used as a first- or second-line agent, vinorelbine can have ORRs of up to 40%.

As with hormone therapy, the likelihood of benefit from chemotherapy is related to the success achieved with the previous regimen. Although there are occasional gratifying responses to a drug used in the third- or 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.

PI3K inhibitors

Alpelisib (Piqray) is a phosphatidylinositol-3-kinase (PI3K) inhibitor approved by the FDA in 2019. It is indicated in combination with fulvestrant for treatment of men and postmenopausal women with HR-positive, 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), in which 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.[204]

In October 2024 the FDA approved the PI3K inhibitor inavolisib. It is indicated in combination with the CDK4/6 inhibitor palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or completion of adjuvant endocrine therapy. Approval was supported by INAVO120, a randomized, double-blind, placebo-controlled, multicenter trial in 325 patients, in which median PFS was 15.0 months in the inavolisib/palbociclib/fulvestrant arm compared with 7.3 months in the placebo/palbociclib /fulvestrant arm.[205]

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.[206]

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).[207]

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).[207]

In 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. [208]

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.[208]  

AKT Inhibitor

Capivasertib is an adenosine triphosphate (ATP)–competitive inhibitor of all 3 AKT isoforms (AKT1/2/3). AKT (protein kinase B [PKB]) is the collective name of a set of 3 serine/threonine-specific protein kinases. Inhibition of AKT prevents phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. Capivasertib is indicated in combination with fulvestrant for HR+/HER2- locally advanced or metastatic breast cancer with at least 1 PIK3CA/AKT1/PTEN-alteration, following progression on 1 or more endocrine-based regimen in the metastatic setting, or recurrence during, or within 12 months after completing, adjuvant therapy. 

Approval was based on the randomized CAPIitello-291 phase 3 trial in 708 patients with advanced breast cancer, 489 (69.1%) of whom had previously received a CDK4/6 inhibitor. In the overall study population, median progression-free survival (PFS) was 7.2 months in the patients receiving capivasertib plus fulvestrant, compared with 3.6 months in those receiving fulvestrant plus placebo (P < 0.001). In the 289 study subjects who had AKT pathway alterations, median PFS was 7.3 months with capivasertib-fulvestrant versus 3.1 months with placebo-fulvestrant (P < 0.001).[209]   

Daropotamab deruxtecan

Datopotamab deruxtecan is an antibody-drug conjugate approved by the FDA in January 2025 for second-line treatment of unresectable or metastatic, hormone receptor–positive, HER2-negative breast cancer.[210]  It consists of a humanized IgG1 antibody against trophoblast cell surface antigen 2 (Trop-2) attached to deruxtecan, which is a topoisomerase I inhibitor. It binds to Trop-2 on tumor cells and undergoes internalization; in the cell, lysosomal enzymes release the deruxtecan, whcih causes DNA damage and apoptotic cell death.

Approval was based on results from the ongoing phase 3 TROPION-Breast01 trial, which is comparing datopotamab deruxtecan with investigator's choice of standard-of-care chemotherapy in 732 patients. In TROPION-Breast01, median PFS was 6.9 months in the datopotamab deruxtecan arm and 4.9 months in the chemotherapy arm (P < 0.0001).[211]

Treatment of HER2-positive metastatic breast cancer

ASCO guidelines recommend HER2-targeted therapy for patients with HER2-positive advanced breast cancer, except those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Recommended regimens are as follows[212] :

ASCO notes that for third-line treatment, there is insufficient evidence to recommend one regimen over another, but options include regimens with the following:

Optimal duration of chemotherapy is at least 4-6 months or until maximum response. HER2-targeted therapy can continue until progression or unacceptable toxicities.

For patients with breast cancer that is HER2-positive and ER- or PR-positive, recommended options are standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.

See HER2 Breast Cancer for more information on this topic.

Treatment of triple-negative metastatic breast cancer

Unresectable metastatic triple-negative breast cancer (TNBC; ie, estrogen receptor–negative, progesterone receptor–negative, and HER2 receptor–negative) is aggressive and carries a poor prognosis. Consequently, it is important to have multiple treatment options. 

Sacituzumab govitecan-hziy

In 2020, the FDA granted accelerated approval to the first antibody-drug conjugate, sacituzumab govitecan-hziy (Trodelvy), for metastatic TNBC in patients who have received at least two prior therapies for metastatic disease. The FDA granted regular approval to sacituzumab govitecan-hziy in 2021. Initial approval was based on the IMMU-132-01 trial; regular approval was based on results of the phase III ASCENT trial (n=529), in which median PFS was 4.8 months (95% CI: 4.1, 5.8) in patients receiving sacituzumab govitecan, compared with 1.7 months (95% CI: 1.5, 2.5) in those receiving chemotherapy (HR 0.43; 95% CI: 0.35, 0.54; P < 0.0001).[213]

Pembrolizumab

In 2020 the FDA approved pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1), in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC that expresses PD-L1 with a Combined Positive Score (CPS) ≥10, as determined by an FDA-approved test. Approval was based on the results of the KEYNOTE-355 trial, in which the addition of pembrolizumab to chemotherapy with nanoparticle albumin-bound (nab)–paclitaxel or gemcitabine plus carboplatin reduced the risk of disease progression or death by 35%, compared with chemotherapy alone.[214]

Atezolizumab plus nab-paclitaxel

In 2019, the FDA approved combination therapy with the programmed cell death ligand–1 (PDL1) inhibitor atezolizumab plus nab-paclitaxel for TNBC. Approval was based on the phase III IMpassion130 trial in patients with untreated metastatic TNBC, 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).[215]

Subsequently, however, the phase III IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in PD-L1–positive patients. Interim overall survival results in IMpassion131 also favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1–positive and the total study population. In 2021, the indication for atezolizumab in combination with nab-paclitaxel for PD-L1–positive TNBC) was voluntarily withdrawn by the manufacturer.[216]

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.

In contrast, the prospective randomized EA2108 clinical trial concluded that in patients with newly diagnosed metastatic breast cancer, locoregional treatment with surgery, accompanied by radiotherapy when indicated, does not improve survival. In this study, which included 256 patients, the 3-year overall survival (OS) rate was 67.9% for patients who received continued systemic therapy and 68.4% for those in the locoregional therapy arm; median OS was 53.1 months versus 54.9 months, respectively (P = 0.57). The use of locoregional therapy was associated with improved locoregional control, but that had no overall impact on patients' quality of life.[217]

Bone Health Management

Attention to bone health is an important aspect of managing breast cancer in women. Many women with breast cancer are postmenopausal and therefore at increased risk for osteoporosis. In addition, some of the agents used for the treatment of breast cancer  (chemotherapy and aromatase inhibitors) have adverse effects on bone. Finally, bone is the most common site of metastasis in breast cancer. Metastasis to bone causes pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as contributing to mortality

Increasing evidence indicates that in postmenopausal women with early breast cancer, adjuvant bisphosphonate treatment not only improves bone density but also decreases bone metastasis and improves overall survival.[218] In patients with metastatic breast cancer, bisphosphonates and denosumab have been shown to delay skeletal-related events, including fractures; hypercalcemia; and increased need for radiation, surgery, or pain medication.[219]

An updated guideline from the American Society of Clinical Oncology (ASCO)–Ontario Health (Cancer Care Ontario (CCO) recommends discussing early initiation of adjuvant bisphosphonate therapy with all patients with primary breast cancer who are postmenopausal (natural or therapy-induced) and are candidates for adjuvant systemic therapy. The guideline suggests that the Predict tool may aid in decision making by providing an estimate of the benefit of adjuvant bisphosphonate therapy in a given patient. Agents recommended by ASCO-CCO for reducing breast cancer recurrence include oral clodronate, oral ibandronate, and intravenous zoledronic acid.[220]

Denosumab, a monoclonal antibody that targets the receptor activator of nuclear factor kappa-B ligand (RANKL), is approved for increasing bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer. However, the ASCO-CCO guidelines do not recommend using denosumab to to prevent breast cancer recurrence, as studies have not shown that it consistently reduces breast cancer recurrence in patients with early-stage breast cancer.

Vitamin D

Vitamin D supplementation may be indicated in women treated for breast cancer, to aid with bone mineral density.[221]  A double-blind, placebo-controlled, randomized phase II trial by Restelli et al found that high-dose vitamin D supplements improved aromatase inhibitor–induced musculoskeletal symptoms in women on adjuvant anastrozole for breast cancer.[222] Vitamin D also appeared to have a positive effect on bone loss on these patients.

Vitamin D supplementation may offer benefits beyond bone health. Some evidence suggests that low vitamin D status enhances the risk for development or progression of breast cancer.[223]  A study from Thailand reported that vitamin D deficiency (25[OH]D concentration below 16 ng/mL was independently associated with poor survival in breast cancer patients.[224] A study from Ireland determined that all-cause mortality was lower in women who began vitamin D supplementation after breast cancer diagnosis, compared with nonusers of vitamin D (hazard ratio= 0.84 [95% CI: 0.73, 0.99]).[225]

Exercise

A study by Winters-Stone et al found that a combined program of resistance and impact exercise reduced risk factors for fracture among postmenopausal breast cancer survivors and may be of particular benefit for those taking aromatase inhibitors. In this 1-year trial, women who participated in thrice-weekly progressive, moderate-intensity resistance plus impact exercise (n=52) maintained bone mineral density (BMD) at the lumbar spine, while women in the control group (n=54), who performed stretching exercises only, consistently lost BMD at the lumbar spine. In addition, women who were doing combined exercises and were on aromatase inhibitors had the greatest increase in lean mass, while those doing stretches who were not on aromatase inhibitors appeared to have a slight decrease in lean mass.[226]

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.

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 three 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.[169]

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.

The aromatase inhibitors exemestane and anastrozole are used off label for breast cancer risk reduction in postmenopausal women. In the Mammary Prevention.3 (MAP.3) trial, conducted in 4560 postmenopausal women with moderately increased breast cancer risk, exemestane decreased the incidence of invasive breast cancer by 65% and that of invasive plus in situ breast cancer by 53%, compared with placebo.[227] In the International Breast Cancer Intervention Study II (IBIS-II), conducted in 3864 postmenopausal women at increased risk of developing breast cancer, after a median follow-up of 131 months, anastrozole was associated with a 54% decrease in ER-positive invasive breast cancer, and a 59% decrease in DCIS.[228]

ASCO guidelines on endocrine therapy to reduce breast cancer risk recommend the following[229] :

The ASCO guidelines delineate the risk thresholds for use of individual agents, along with the benefits and risks that clinician and patient should discuss when considering endocrine therapy for primary breast cancer prevention. In particular, SERMs carry warnings about risk of thromboembolic events, and aromatase inhibitors carry warnings about bone mineral density (BMD) reduction. Hence, tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization.[229]

Anastrozole is relatively contraindicated in women with a history of osteoporosis and/or severe bone loss, and should be used only with caution in postmenopausal women with moderate BMD loss. If anastrozole is used, the addition of bone-protective agents such as bisphosphonates and RANKL inhibitors should be considered. Regular exercise and adequate calcium and vitamin D supplementation should be encouraged in all patients receiving aromatase inhibitors.[229]

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.[230]

Genetic factors that place a woman at very high risk of developing breast cancer include the following[230] :

The National Comprehensive Cancer Network (NCCN) recommends that in general, risk-reduction mastectomy should be considered in individuals with a gene mutation that confers a high risk for breast cancer, a compelling family history, or 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 (ie, endocrine therapy, healthy lifestyle) is currently the preferred approach for LCIS.[231]

A Cochrane review noted that 21 studies reported reductions in the incidence of breast cancer or disease-specific mortality, or both,  after bilateral risk-reducing mastectomy, particularly for women with BRCA1/2 mutations. Women who underwent bilateral risk-reducing mastectomy reported significantly less worry over breast cancer, compared with both their own baseline worry levels and with women who opted for surveillance rather than mastectomy; however, they also reported diminished satisfaction with body image and sexual feelings.[232]

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.[230, 231]

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.[233]

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:

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:

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

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 12 below).

Table 12. Follow-up Recommendations for Breast Cancer Survivors



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ASCO guidelines for monitoring bone density

Table 13.



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Postoperative imaging

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

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

Monitoring of metastatic disease

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

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

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

Standardized guidelines for imaging are not yet established; the choice and timing of imaging procedures should be tailored to each 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.

Monitoring of radiation-induced heart disease

According to a 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.[234]

Recommendations of the statement include the following[234] :

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[235] :

Psychedelic therapy

Evidence from early clinical trials of psychedelic-assisted psychotherapy suggests that the use of such drugs (eg, psilocybin) in this setting can benefit carefully screened patients with cancer who have persistent existential suffering; note that these trials have not specifically addressed breast cancer.[236, 237] Although these agents remain Schedule I controlled substances, National Cancer Institute–supported clinical trials are in progress, and more studies are planned or recruiting.

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[238] :

Guidelines Summary

Guidelines on the following aspects of breast cancer care have been published:

For more information, see Breast Cancer Guidelines.

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 have not yet established an identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer−related morbidity and mortality. In patients with metastatic breast cancer, interventions include hormone therapy; chemotherapy; and biologic therapy targeted to the histologic and mutational characteristics of the tumor.

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.

Carboplatin

Clinical Context:  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)

Clinical Context:  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.

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.

Doxorubicin

Clinical Context:  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)

Clinical Context:  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.

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.

Pamidronate (Aredia)

Clinical Context:  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)

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

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.[81]

Capecitabine (Xeloda)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

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.

Vinorelbine (Navelbine)

Clinical Context:  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.

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.

ado-trastuzumab emtansine (Kadcyla)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Trastuzumab deruxtecan (Enhertu, fam-trastuzumab deruxtecan-nxki)

Clinical Context:  HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the topoisomerase I inhibitor, deruxtecan. It is indicated for unresectable or metastatic HER2-positive breast cancer in adults who have received 2 or more prior anti-HER2-based regimens in the metastatic setting.

Sacituzumab govitecan (Sacituzumab govitecan-hziy, Trodelvy)

Clinical Context:  Sacituzumab govitecan is an antibody-drug conjugate that is directed against Trop-2 and binds to Trop-2 and delivers the anti-cancer drug, SN-38, to kill cancer cells. FDA granted accelerated approval to the first antibody drug conjugate for metastatic TNBC in patients who received at least two prior therapies for metastatic disease.

Pertuzumab/trastuzumab/hyaluronidase (Pertuzumab-trastuzumab-hyaluronidase-zzxf, Phesgo)

Clinical Context:  Pertuzumab/trastuzumab/hyaluronidase is a fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase administered as a subcutaneous injection. It is indicated in combination with IV chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer.

Datopotamab deruxtecan (Datopotamab deruxtecan-dlnk, Datroway)

Clinical Context:  Datopotamab deruxtecan is an antibody-drug conjugate consisting of a humanized IgG1 antibody against trophoblast cell surface antigen 2 (Trop-2) attached via cleavable linker to deruxtecan, which is a small molecule topoisomerase I inhibitor. Binds to Trop-2 on tumor cells and undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, membrane-permeable deruxtecan causes DNA damage and apoptotic cell death. Indicated for second-line therapy of unresectable or metastatic, hormone receptor–positive, HER2-negative breast cancer.

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.

Lapatinib (Tykerb)

Clinical Context:  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)

Clinical Context:  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.

Tucatinib (Tukysa)

Clinical Context:  Tucatinib (tyrosine kinase inhibitor or HER2) inhibits phosphorylation of HER2 and HER3, ultimately inhibiting MAPK and AKT signaling and cell proliferation and antitumor activity in HER2 expressing tumor cells. It is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

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.

Eribulin (Halaven)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

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

Anastrozole (Arimidex)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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]

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.

Palbociclib (Ibrance)

Clinical Context:  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)

Clinical Context:  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 HR+/HER- stage II and III early breast cancer at high risk of recurrence and for HR+/HER- advanced or metastatic breast cancer in postmenopausal women.

Abemaciclib (Verzenio)

Clinical Context:  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.

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.

Olaparib (Lynparza)

Clinical Context:  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. It also indicated for adjuvant treatment of deleterious or suspected deleterious gBRCAm HER2-negative high-risk early breast cancer in adults previously treated with neoadjuvant or adjuvant chemotherapy.  

Talazoparib (Talzenna)

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

Class Summary

This class of agents is thought to augment cytotoxic therapy without increasing adverse 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.[207]

Tamoxifen (Soltamox)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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]

Elacestrant (Orserdu)

Clinical Context:  Indicated for men or postmenopausal women with estrogen receptor positive (ER+), HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. 

Class Summary

Selective estrogen receptor modulators (SERMs) stimulate or inhibit the estrogen receptors of various target tissues.

Atezolizumab (Tecentriq)

Clinical Context:  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.

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.

Alpelisib (Piqray)

Clinical Context:  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.

Capivasertib (Truqap)

Clinical Context:  Capivasertib is an adenosine triphosphate (ATP)-competitive inhibitor of all 3 AKT isoforms (AKT1/2/3). It is indicated in combination with fulvestrant for HR+/HER2- locally advanced or metastatic breast cancer with at least 1 PIK3CA/AKT1/PTEN-alteration, following progression on at 1 or more endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

Class Summary

AKT (protein kinase B [PKB]) is the collective name of a set of 3 serine/threonine-specific protein kinases. Inhibition of AKT prevents phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. 

Ribociclib/letrozole (Kisqali/Femara Copack)

Clinical Context:  Copackaged CDK inhibitor (ribociclib) and aromatase inhibitor (letrozole) for treatment of HR-positive, HER2-negative early, advanced, or metastatic breast cancer.

Inavolisib (Itovebi)

Clinical Context:  Indicated in combination with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine therapy

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 are basic facts about 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 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?What is the association between breast cancer and cardiovascular disease (CVD)?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?Which conditions should be included in the differential diagnosis of breast cancer?What are the differential diagnoses for Breast Cancer?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 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 prognostic stages 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?What is the role of PET scanning in the workup of breast cancer?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 of 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?Which organizations have issued guidelines on breast cancer screening?What are the ACS guidelines for breast self-exam (BSE)?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?What are European Commission Initiative on Breast Cancer (ECIBC) screening guidelines?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 fine needle aspiration (FNA) and core biopsy 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?What were the ASCO/CAP guidelines for hormone receptor testing in patients with breast cancer?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 Antineoplastics, Antimicrotubular 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 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?

Author

Pavani Chalasani, MD, MPH, Professor of Medicine, Director, Division of Hematology and Oncology, Leader, Breast Cancer Clinical Research Team, Co-Program Leader, Clinical and Translational Oncology Program, George Washington Cancer Center, George Washington University School of Medicine and Health Sciences

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bayer, Heron, Amgen, Athenex, Novartis, Eisai, Eli Lilly, Zentalis <br/>Received research grant from: Pfizer.

Coauthor(s)

Abigail Camenisch, BS, MPH, MD Candidate, University of Arizona College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Amy Hemstreet, PharmD,

Disclosure: Nothing to disclose.

Chief Editor

John V Kiluk, MD, FACS, Associate Professor, Department of Oncologic Sciences, Department of Surgery (Joint Appointment), University of South Florida Morsani College of Medicine; Clinical Director, Breast Surgical Oncology, Associate Member, Comprehensive Breast Program, Department of Women's Oncology, H Lee Moffitt Cancer Center and Research Institute

Disclosure: Nothing to disclose.

Additional Contributors

Alison T Stopeck, MD, Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from AstraZeneca for speaking and teaching; Received grant/research funds from AstraZeneca for other.

Patricia A Thompson, PhD, Assistant Professor, Department of Pathology, University of Arizona College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Leona Downey, MD Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center

Leona Downey, MD is a member of the following medical societies: American Geriatrics Society, American Society of Clinical Oncology, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Manjit Singh Gohel, MD, MRCS, MB, ChB Specialist Registrar, Division of Breast and Endocrine Surgery, Northwick Park Hospital

Disclosure: Nothing to disclose.

Harold Harvey, MD Professor, Department of Medicine, Pennsylvania State University

Disclosure: Nothing to disclose.

Kanchan Kaur, MBBS, MS (General Surgery), MRCS (Ed) Consulting Breast and Oncoplastic Surgeon, Medanta, The Medicity, India

Disclosure: Nothing to disclose.

Julie Lang, MD Assistant Professor of Surgery and the BIO5 Institute, Director of Breast Surgical Oncology, University of Arizona College of Medicine

Julie Lang, MD is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology

Disclosure: Genomic Health Grant/research funds Speaking and teaching; Agendia Grant/research funds Speaking and teaching; Surgical Tools Grant/research funds Research; Sysmex Grant/research funds Research

Robert B Livingston, MD Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center

Robert B Livingston, MD is a member of the following medical societies: American Association for Cancer Research, American Federation for Clinical Research, and American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Hanan Makhoul, MD Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine

Disclosure: Nothing to disclose.

Issam Makhoul, MD Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences

Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology

Disclosure: Nothing to disclose.

Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy

Disclosure: Nothing to disclose.

Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) Senior Lecturer, Director of Breast Service, Department of Surgery, Imperial College School of Medicine; Consultant Surgeon, Northwick Park and St Marks Hospitals, UK

Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada and Royal College of Surgeons of Edinburgh

Disclosure: Nothing to disclose.

Carl V Smith, MD The Distinguished Chris J and Marie A Olson Chair of Obstetrics and Gynecology, Professor, Department of Obstetrics and Gynecology, Senior Associate Dean for Clinical Affairs, University of Nebraska Medical Center

Carl V Smith, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Council of University Chairs of Obstetrics and Gynecology, Nebraska Medical Association, and Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Wiley Souba, MD Chairman, Professor, Department of General Surgery, Pennsylvania State College of Medicine; Chief Surgeon, The Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Rachel Swart, MD, PhD Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona

Rachel Swart, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Arizona Medical Association, and Southwest Oncology Group

Disclosure: Roche Grant/research funds Other

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Simon Thomson, MB, BCh, MD, FRCS Specialist Registrar, Department of Breast and Endocrine Surgery, Northwick Park Hospital, UK

Simon Thomson, MB, BCh, MD, FRCS is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

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

Anatomy of the breast.

Intrinsic subtypes of breast cancer.

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

Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.

Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.

Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.

Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.

Anatomy of the breast.

Intrinsic subtypes of breast cancer.

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

Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.

Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.

Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.

Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.

Anatomy of the breast. Courtesy of Wikimedia Commons (Patrick J Lynch, medical illustrator).

Modality Sensitivity Specificity PPV Indications
Mammography63-95% (>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
Ultrasonography68-97% palpable74-94% palpable92% (palpable)Initial investigation for palpable lesions in women younger than 35 y
MRI86-100%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
Scintigraphy76-95% palpable, 52-91% impalpable62-94% (94% impalpable)70-83% (83% palpable, 79% impalpable)Lesions >1 cm and axilla assessment; may help predict drug resistance
PET96% (90% axillary metastases)100% Axilla assessment, scarred breast, and multifocal lesions
MRI = magnetic resonance imaging; PET = positron emission tomography; PPV = positive predictive value.
  Score
  1 > 2 > 3
A. Tubule formation>75%10-75%< 10%
B. Mitotic count/HPF (microscope- and field-dependent)< 77-12>12
C. Nuclear size and pleomorphismNear normal; little variationSlightly enlarged; moderate variationMarkedly 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.
DCIS Characteristic Comedo Noncomedo
Nuclear gradeHighLow
Estrogen receptorOften negativePositive
DistributionContinuousMultifocal
NecrosisPresentAbsent
Local recurrenceHighLow
PrognosisWorseBetter
DCIS = ductal carcinoma in situ.
Primary tumor (T)
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma 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
T1Tumor ≤ 20 mm in greatest dimension
T1miTumor ≤ 1 mm in greatest dimension
T1aTumor > 1 mm but ≤ 5 mm in greatest dimension (round any measurement >1.0-1.9 mm to 2 mm)
T1bTumor > 5 mm but ≤ 10 mm in greatest dimension
T1cTumor > 10 mm but ≤ 20 mm in greatest dimension
T2Tumor > 20 mm but ≤ 50 mm in greatest dimension
T3Tumor > 50 mm in greatest dimension
T4Tumor 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
T4aExtension to chest wall, not including only pectoralis muscle adherence/invasion
T4bUlceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma
T4cBoth T4a and T4b
T4dInflammatory carcinoma
Regional lymph nodes (N)
Clinical
cNXRegional lymph nodes cannot be assessed (eg, previously removed)
cN0No regional lymph node metastasis (on imaging or clinical examination)
cN1Metastasis to movable ipsilateral level I, II axillary lymph node(s)
cN1miMicrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
cN2Metastases 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
cN2aMetastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
cN2bMetastases only in ipsilateral internal mammary nodes and in the absence of axillary lymph node metastases
cN3Metastases 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
cN3aMetastasis in ipsilateral infraclavicular lymph node(s)
cN3bMetastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
cN3cMetastasis 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)
pNXRegional lymph nodes cannot be assessed (for example, previously removed, or not removed for pathologic study)
pN0No 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 
pN1Micrometastases; 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
pN1miMicrometastases (200 cells, > 0.2 mm but none > 2.0 mm)
pN1aMetastases in 1-3 axillary lymph nodes (at least 1 metastasis > 2.0 mm)
pN1bMetastases in ipsilateral internal mammary lymph nodes, excluding ITCs, detected by sentinel lymph node biopsy
pN1cMetastases in 1-3 axillary lymph nodes and in internal mammary sentinel nodes (ie, pN1a and pN1b combined)
pN2Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases
pN2aMetastases in 4-9 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm)
pN2bClinically detected* metastases in internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary lymph nodes
pN3Metastases 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 
pN3aMetastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes
pN3bpN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging) or pN2a in the presence of pN1b
pN3cMetastases 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)
M0No 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
cM1Distant metastases detected by clinical and radiographic means 
pM1Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases > 0.2 mm 
Histologic grade (G)
GXGrade cannot be assessed
G1Low combined histologic grade (favorable)
G2Intermediate combined histologic grade (moderately favorable)
G3High combined histologic grade (unfavorable)
Stage T N M
0TisN0M0
IAT1N0M0
IBT0N1miM0
 T1N1miM0
IIAT0N1M0
 T1N1M0
 T2N0M0
IIBT2N1M0
 T3N0M0
IIIAT0N2M0
 T1N2M0
 T2N2M0
 T3N1M0
 T3N2M0
IIIBT4N0M0
 T4N1M0
 T4N2M0
IIICAny TN3M0
IVAny TAny NM1
TNM Grade HER2 ER PR Stage
Tis N0 M0AnyAnyAnyAny0
T1 N0 M0



T0 N1mi M0



T1 N1mi M0



G1PositivePositivePositiveIA
Negative
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIB
G2PositivePositivePositiveIA
Negative
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIB
G3PositivePositivePositiveIA
Negative
NegativePositive
Negative
NegativePositivePositive
NegativeIB
NegativePositive
Negative
T0 N1 M0



T1 N1 M0



T2 N0 M0



G1PositivePositivePositiveIB
NegativeIIA
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIA
NegativePositive
Negative
G2PositivePositivePositiveIB
NegativeIIA
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIA
NegativePositive
NegativeIIB
G3PositivePositivePositiveIB



IIA



Negative
NegativePositive
Negative
NegativePositivePositive
NegativeIIB
NegativePositive
Negative
T2 N1 M0



T3 N0 M0



G1PositivePositivePositiveIB
NegativeIIA
NegativePositive
NegativeIIB
NegativePositivePositiveIIA
NegativeIIB
NegativePositive
Negative
G2PositivePositivePositiveIB
NegativeIIA
NegativePositive
NegativeIIB
NegativePositivePositiveIIA
NegativeIIB
NegativePositive
NegativeIIIB
G3PositivePositivePositiveIB
NegativeIIB
NegativePositive
Negative
NegativePositivePositive
NegativeIIIA
NegativePositive
NegativeIIIB
T0 N2 M0



T1 N2 M0



T2 N2 M0



T3 N1 M0



T3 N2 M0



G1PositivePositivePositiveIIA
NegativeIIIA
NegativePositive
Negative
NegativePositivePositiveIIA
NegativeIIIA
NegativePositive
NegativeIIIB
G2PositivePositivePositiveIIA
NegativeIIIA
NegativePositive
Negative
NegativePositivePositiveIIA
NegativeIIIA
NegativePositive
NegativeIIIB
G3PositivePositivePositiveIIB
NegativeIIIA
NegativePositive
Negative
NegativePositivePositive
NegativeIIIB
NegativePositive
NegativeIIIC
T4 N0 M0



T4 N1 M0



T4 N2 M0



Any T N3 M0



G1PositivePositivePositiveIIIA
NegativeIIIB
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIIIC
G2PositivePositivePositiveIIIA
NegativeIIIB
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIIIC
G3PositivePositivePositiveIIIB
Negative
NegativePositive
Negative
NegativePositivePositive
NegativeIIIC
NegativePositive
Negative
Any T Any N M1AnyAnyAnyAnyIV
ER=estrogen receptor; PR=progesterone receptor
TNM Grade HER2 ER PR Stage
Tis N0 M0AnyAnyAnyAny0
T1 N0 M0



T0 N1mi M0



T1 N1mi M0



G1PositivePositivePositiveIA
Negative
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
Negative
G2PositivePositivePositive
Negative
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIB
G3PositivePositivePositiveIA
Negative
NegativePositive
Negative
NegativePositivePositive
Negative
NegativePositive
NegativeIB
T0 N1 M0



T1 N1 M0



T2 N0 M0



G1PositivePositivePositiveIA
NegativeIB
NegativePositive
NegativeIIA
NegativePositivePositiveIA
NegativeIB
NegativePositive
NegativeIIA
G2PositivePositivePositiveIA
NegativeIB
NegativePositive
NegativeIIA
NegativePositivePositiveIA
NegativeIIA
NegativePositive
Negative
G3PositivePositivePositiveIA



IIA



Negative
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIA
NegativePositive
Negative
T2 N1 M0



T3 N0 M0



G1PositivePositivePositiveIA
NegativeIIB
NegativePositive
Negative
NegativePositivePositiveIA
NegativeIIB
NegativePositive
Negative
G2PositivePositivePositiveIB
NegativeIIB
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIB
NegativePositive
Negative
G3PositivePositivePositiveIB
NegativeIIB
NegativePositive
Negative
NegativePositivePositiveIIA
NegativeIIB
NegativePositive
NegativeIIIA
T0 N2 M0



T1 N2 M0



T2 N2 M0



T3 N1 M0



T3 N2 M0



G1PositivePositivePositiveIB
NegativeIIIA
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIIA
NegativePositive
Negative
G2PositivePositivePositiveIB
NegativeIIIA
NegativePositive
Negative
NegativePositivePositiveIB
NegativeIIIA
NegativePositive
NegativeIIIB
G3PositivePositivePositiveIIA
NegativeIIIA
NegativePositive
Negative
NegativePositivePositiveIIA
NegativeIIIA
NegativePositive
NegativeIIIC
T4 N0 M0



T4 N1 M0



T4 N2 M0



Any T N3 M0



G1PositivePositivePositiveIIIA
NegativeIIIB
NegativePositive
Negative
NegativePositivePositiveIIIA
NegativeIIIB
NegativePositive
Negative
G2PositivePositivePositiveIIIA
NegativeIIIB
NegativePositive
Negative
NegativePositivePositiveIIIA
NegativeIIIB
NegativePositive
NegativeIIIC
G3PositivePositivePositiveIIIB
Negative
NegativePositive
Negative
NegativePositivePositive
NegativeIIIC
NegativePositive
Negative
Any T Any N M1AnyAnyAnyAnyIV
ER=estrogen receptor; PR=progesterone receptor
Agent Dose and Schedule
Postmenopausal
Tamoxifen20 mg PO every day
Elacestrant345 mg PO every day
Or
Aromatase inhibitor
Anastrozole1 mg PO every day
Letrozole2.5 mg PO every day
Exemestane25 mg PO every day
Or
Fulvestrant500 mg IM on days 1, 15, 29, and once monthly thereafter
Or
Megestrol40 mg PO 4 times a day
Premenopausal
Tamoxifen20 mg PO every day
Or
Aromatase inhibitor + LHRH*
Leuprolide7.5 mg IM depot q28d



22.5 mg IM q3mo



30 mg IM q4mo



Goserelin3.6 mg SC depot q28d



10.8 mg SC q3mo



Megestrol40 mg PO 4 times a day
*LHRH = luteinizing hormone–releasing hormone.
Drug Class Dose/Schedule Overall Response Rate (ORR) Toxicity
AbemaciclibCDK inhibitor200 mg PO BID continue until disease progression19.7%Diarrhea, fatigue, neutropenia and nausea
AlpelisibPI3K inhibitor300 mg PO qDay continue until disease progression26.6%Hypersensitivity, diarrhea, cutaneous adverse reactions, hyperglycemia
CapecitabineOral fluoro-pyrimidine1250 mg/m²/d PO for 2 weeks with 1 wk off30%Rash, hand-foot syndrome,



diarrhea, mucositis



DocetaxelAntimicrotubule75-100 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



DoxorubicinAnthracycline



(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)



Anthracycline20 mg/m² IV q2wk



or



35-40 mg/m² IV q4wk



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



syndrome



EpirubicinAnthracycline90 mg/m² IV q3wk (not



to exceed cumulative dose



of 900 mg/m²)



35-50%Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity
EverolimusmTor kinase inhibitor10 mg PO qDay continue until disease progression12.6%Stomatitis, constipation, infection, asthenia, fatigue, cough
GemcitabineAntimetabolite725 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-paclitaxelAntimicrotubule80-100 mg/m²/wk IV X 3 then 1 wk off



or



260 mg/m² IV q3wk



58-62%



33%



Less neuropathy, and allergic reaction
OlaparibPARP inhibitor300 mg PO BID59.9%Anemia, fatigue, nausea, and vomiting
PaclitaxelAntimicrotubule80 mg/m²/wk IV



or



175 mg/m² IV over 3 hours q3wk



25-50%Myelosuppression, alopecia,



neuropathy, allergic reaction



PertuzumabMonoclonal antibody840 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



PalbociclibCDK inhibitor125 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
RibociclibCDK inhibitor600 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 ribociclibQT prolongation, hepatobiliary toxicity, neutropenia, alopecia, diarrhea, vomiting, constipation, fatigue, anorexia
Sacituzumab  govitecanMonoclonal antibody conjugate10 mg/kg IV on Days 1 and 8 with 2 wk off33.3%Nausea, neutropenia, diarrhea, fatigue, anemia, vomiting
TalazoparibPARP inhibitor1 mg PO qDay62.6%Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite
Trastuzumabor biosimilars of trastuzumabMonoclonal antibodyCombination therapy: 4 mg/kg IV once, then 2 mg/kg weekly for 12-18 weeks, then 6 mg/kg q3weeks to total 52 weeksSingle agent: 8 mg/kg IV once, then 6 mg/kg q3weeks to total 52 weeks10-15%Fever, allergic reaction, cardiotoxicity/congestive heart failure
Trastuzumab deruxtecan[190] Monoclonal antibody conjugate5.4 mg/kg IV q3weeks60.3%Interstitial lung disease and pneumonitis; neutropenia; left ventricular dysfunction
Tucatinib[191] Tyrosine kinase inhibitor of HER2300 mg PO BID40.6%Diarrhea, hand-foot syndrome, nausea, fatigue, hepatotoxicity
VinorelbineVinca alkaloid20 mg/m²/wk IV35-45%Myelosuppression, nausea/



vomiting, constipation, fatigue,



stomatitis, anorexia



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[192]



Paclitaxel



1250 mg/m² days 1 and 8



175 mg/m² day 1



Repeat cycle every 21 days
Carboplatin[193]



Paclitaxel



AUC of 6 day 1



200 mg/m² day 1



Repeat cycle every 21 days
Carboplatin[194]



Docetaxel



AUC of 6 day 1



75 mg/m² day 1



Repeat cycle every 21 days
Palbociclib[181]



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[184]



Letrozole



600 mg PO once daily days 1-21



2.5 mg PO once daily days 1-28



Repeat cycle every 28 days
Paclitaxel[195] 90 mg/m² day 1, 8, and 15Repeat cycle every 28 days
Abemaciclib



Fulvestrant[189]



150 mg PO BID



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



Repeat cycle every 28 days
Ribociclib[196]



Fulvestrant



600 mg PO once daily days 1-21500 mg IM on Days 1, 15 and 29 and once monthly thereafterRepeat 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
Pertuzumab/trastuzumab/hyaluronidaseDocetaxelLoading dose of 1,200 mg pertuzumab/600 mg trastuzumab SC x 1 dose followed by 600 mg pertuzumab/600 mg trastuzumab SC



Docetaxel is 75 mg/m2 IV, may escalate to 100 mg/m2



Repeat cycle every 3 week; continue until disease recurrence or unmanageable toxicity, whichever occurs first
Trastuzumab



Vinorelbine



4 mg/kg loading dose then



2 mg/kg weekly



25 mg/m² day 1 weekly



 
Trastuzumab



Capecitabine



Tucatinib[191] 		8 mg/kg loading dose then



6 mg/kg weekly



1000 mg/m2 PO BID days 1-14



300 mg PO BID		Repeat cycle every 21 days
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,[197] XP,[198] XN,[198] HER2-positive metastatic breast cancer regimens[199, 200, 201, 202]



  NCCN ASCO
History and physical examinationYear 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-examinationNo recommendationCounseled to perform monthly breast self-examination
Mammography6 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 examinationAnnually, 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 testsNot recommendedNot recommended
Imaging studiesNot recommendedNot recommended
Tumor marker testingNot recommendedNot recommended
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