Breast Cancer

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Practice Essentials

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



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

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

Signs and symptoms

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

See Clinical Presentation for more detail.

Diagnosis

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

Evaluation of breast cancer includes the following:

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 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.

Biopsy

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

See Workup for more detail.

Management

Surgery and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are now considered primary treatment for breast cancer. Surgical therapy may consist of lumpectomy or total mastectomy. Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing recurrence rates. There are 2 general approaches for delivering radiation therapy:

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

Pharmacologic agents

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

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women.

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

In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass. These agents are given along with calcium and vitamin D supplementation.

See Treatment and Medication for more detail.

Background

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women. In many less-developed countries, it is the leading cause of cancer death in women; in developed countries, however, it has been surpassed by lung cancer as a cause of cancer death in women.[2] In the United States, breast cancer accounts for 30% of all cancers in women and is second only to lung cancer as a cause of cancer deaths.[3] (For discussion of male breast cancer, see Breast Cancer in Men.)

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

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

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

Adjuvant breast cancer therapies are designed to treat micrometastatic disease or breast cancer cells that have escaped the breast and regional lymph nodes but do not yet have an established identifiable metastasis. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the decrease in mortality.

Over the past 3 decades, extensive and advocate-driven breast cancer research has led to extraordinary progress in the understanding of the disease. This has resulted in the development of more targeted and less toxic treatments. (See Treatment and Medication.)

For patient education information, see Breast Cancer and the Breast Cancer Health Center.

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 4 main breast tumor subtypes, with distinct genetic and epigenetic aberrations[4] (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 cancer patients.[5]

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 being used in the practice setting.

Age and gender

Increasing age and female sex are established risk factors for breast cancer. Sporadic breast cancer is relatively uncommon among women younger than 40 years but increases significantly thereafter. The effect of age on risk is illustrated in the SEER (Surveillance, Epidemiology and End Results) data, where the incidence of invasive breast cancer for women younger than 50 years is 44.0 per 100,000 as compared with 345 per 100,000 for women aged 50 years or older.[6]

The total and age-specific incidence for breast cancer is bimodal, with the first peak occurring at about 50 years and the second occurring at about 70 years.[7] This bimodal pattern may reflect the influence of age within the different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier, whereas hormone-sensitive, slower-growing tumors tend to occur with advancing age.

Family history of breast cancer

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

Despite a history indicating increased risk, many of these families have normal results on genetic testing. However, identification of additional genetic variants associated with increased risk may prove valuable. Michailidou et al conducted a controlled genome-wide association study (GWAS) of breast cancer that included 122,977 cases of European ancestry and 14,068 cases of East Asian ancestry, and identified 65 new loci associated with overall breast cancer risk.[8] A GWAS by Milne et al identified 10 variants at 9 new loci that are associated with risk of estrogen receptor–negative breast cancer.[9]

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

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

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:

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

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

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

Direct-to-consumer genetic testing

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

Reproductive factors and steroid hormones

Late age at first pregnancy, nulliparity, early onset of menses, and late age of menopause have all been consistently associated with an increased risk of breast cancer.[13, 14, 15, 16, 17] Prolonged exposure to elevated levels of sex hormones has long been postulated as a risk factor for developing breast cancer, explaining the association between breast cancer and reproductive behaviors.[18, 19]

Clinical trials of secondary prevention in women with breast cancer have demonstrated the protective effect of selective estrogen receptor modulators (SERMs) and aromatase inhibitors on recurrence and the development of contralateral breast cancers.[20] Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers.[21, 22, 23] These data support estradiol and its receptor as a primary target for risk reduction but do not establish that circulating hormone levels predict increase risk.

A number of epidemiologic and pooled studies support an elevated risk of breast cancer among women with high estradiol levels.[24, 25] The Endogenous Hormones and Breast Cancer Collaborative Group (EHBCG) reported a relative risk of 2.58 among women in the top quintile of estradiol levels.[26]

Upon thorough review of the collective data, the Breast Cancer Prevention Collaborative Group (BCPCG) prioritized additional factors that might be included in the validation phase of a risk prediction model and gave a high priority score to free plasma estradiol levels.[25] At present, routine measurement of plasma hormone levels is not recommended in the assessment of breast cancer risk.

One of the most widely studied factors in breast cancer etiology is the use of exogenous hormones in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT).[27, 28] The overall evidence suggests an approximately 25% greater risk of breast cancer among current users of OCs. The risk appears to decrease with age and time since OC discontinuance. For OC users, risk returns to that of the average population risk about 10 years after cessation.

Data obtained from case-control and prospective cohort settings support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT.[29] Increased risk of breast cancer has been positively associated with length of exposure, with the greatest risk being observed for hormonally responsive lobular, mixed ductal-lobular, and tubular cancers.[29] Risk is greater among women taking combination HRT than among those taking estrogen-only formulations.[30, 31]

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[32] :

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%).[33] 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).[34]  

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

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

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

There are currently no formal guidelines for the use of HRT in women at high risk for breast cancer (ie, women with a family history of breast cancer, a personal history of breast cancer, or benign breast disease). Only a few studies have evaluated the effect of HRT after a diagnosis of breast cancer. The largest of these, the HABITS (Hormonal replacement therapy After Breast cancer—is IT Safe?) study was stopped early because unacceptable rates of breast cancer recurrence and contralateral disease with 2 years of HRT use (hazard ratio, 3.5).[35]

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.[36] 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.[37] 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.[38, 39, 40] 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.[41, 42]

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.[41, 42] 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.[43]

Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast disease or fibroadenoma, have not been associated with increased risk.[44]

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.[45, 46, 47, 48] 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.[49]

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.[50, 51]

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.[50, 51]

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).[56, 57, 58] 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[59, 60, 61, 62] :

Of these environmental exposures, only high doses of ionizing radiation to the chest area, particularly during puberty, have been unequivocally linked with an increased risk of breast cancer in adulthood.[62, 63] 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[64] ; evidence suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[65]

A meta-analysis by Yuan et al found an increased risk of breast cancer in women who do long-term night shift work.  In North America and Europe, working the night shift was associated with a 32% increased risk for breast cancer overall (odds ratio [OR], 1.316). Risk increased in a dose-response fashion, rising 3.3% (OR, 1.033) Risk was even higher for nurses (OR, 1.577).[66, 67]

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

Epidemiology

United States statistics

In the United States, approximately 268,600 new cases of female invasive breast cancer are predicted to occur in 2019, along with 2670 cases in men.[3] Among US women in 2019, in addition to invasive breast cancer, 62,930 new cases of in situ breast cancer are expected to occur; approximately 83% of these cases are expected to be DCIS, and 12% are expected to be LCIS.[3]

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

Incidence over this period of time varied dramatically by histologic type. Common ductal carcinomas increased modestly from 1987 to 1999, whereas invasive lobular and mixed ductal-lobular carcinomas increased dramatically during this time period.[68] For women under the age of 50, breast cancer rates have remained stable since the middle to late 1980s. Rates of DCIS have stabilized since 2000.[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.[68, 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.[6] 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.[2]

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

Age-related demographics

The incidence rate of breast cancer increases with age, from 1.5 cases per 100,000 in women 20-24 years of age to a peak of 421.3 cases per 100,000 in women 75-79 years of age; 95% of new cases occur in women aged 40 years or older. The median age of women at the time of breast cancer diagnosis is 62 years.[6]  Among women over the age of 50, breast cancer incidence rates were relatively stable from 2005-2014. In contrast, incidence rates, among women under age 50 have increased 0.2% per year since the mid-1990s.[69]

Rates of in situ breast cancer stabilized among women 50 years and older in the late 1990s; this is consistent with the proposed effects of screening saturation. However, the incidence of in situ breast cancer continues to increase in younger women.[69]

Race- and ethnicity-related demographics

In the United States, the incidence of breast cancer is higher in non-Hispanic whites than in women of other racial and ethnic groups. Among women younger than 40 years, African Americans have a higher incidence. In addition, a larger proportion of African-American women are diagnosed with larger, advanced-stage tumors (>5 cm) and are more likely to die of breast cancer at every age.[69]

According to the American Cancer Society (ACS), breast cancer rates per 100,000 among women from various racial and ethnic groups are as follows[69] :

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 2006 through 2015, breast cancer death rates declined annually by 2.6% in American Indians/Alaskan Natives, 1.8% in non-Hispanic whites, NHWs, 1.5% in non-Hispanic blacks, 1.4% in Hispanics, and 0.9% in Asians/Pacific islanders.  Breast cancer death rates in black women began to exceed those in white women in the early 1980s, and the disparity remains large; in 2015, breast cancer death rates were 39% higher in black women than white women.[69]

Prognosis

From 1990 through 2015, death rates from breast cancer in the United States decreased 39%. The decrease occurred in both younger and older women, but has slowed among women younger than 50 since 2007.[69]  

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

Prognostic and predictive factors

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

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.[77] (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. Preliminary data also suggest that HER2 positivity may predict response to and benefit from paclitaxel in the adjuvant setting.[78] (See Breast Cancer and HER2.)

Prognosis by cancer type

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

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

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

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

Overall, patients with mucinous carcinoma have an excellent prognosis, with better than 80% 10-year survival. Similarly, tubular carcinoma has a low incidence of lymph node involvement and a very high overall survival rate. Because of the favorable prognosis, these patients are often treated with only breast-conserving surgery and local radiation therapy.

Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype, even though approximately 70% of cases are ER-positive. A retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least one component of invasive micropapillary ductal carcinoma.[79]

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%.[80] In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[81] Nodal status does not appear to impact survival in metaplastic breast cancer.

Paget disease of the breast is associated with an underlying breast cancer in 75% of cases. Breast-conserving surgery can achieve satisfactory results, but at the risk of local recurrence. Poor prognostic factors include a palpable breast tumor, lymph node involvement, histologic type, and an age of less than 60 years. Paget disease with a palpable mass usually has an invasive component and a lower 5-year survival rate (20-60%). Those that do not have an underlying palpable mass have a higher 5-year survival rate (75-100%).[82, 83]

Cardiovascular disease

Cardiovascular disease (CVD) risk is increased in women with breast cancer. The increase is due in part to the cardiotoxic effects of some breast cancer treatments (eg, chemotherapy, radiotherapy, targeted therapy such as trastuzumab). In addition, breast cancer and CVD, share several risk factors, including smoking, obesity, and the typical Western diet.[84]

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. [84]

 

 

History

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

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

The US Preventive Services Task Force (USPSTF) has updated its 2005 guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows[85, 86] :

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:

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

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

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 in the past few years regarding the age at which to initiate, the modality to use, the interval between screenings, whether to screen older women, and even the impact on breast cancer−related deaths. It is widely believed that breast tumors that are smaller or nonpalpable and that present with a favorable tumor marker profile are more treatable when detected early.

A survival benefit of early detection with mammography screening has been demonstrated.[87, 88] 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%).[87] 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.[88]

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).[89]

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.[90]  

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.[91]

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]).[91] 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 is less successful treatment in older women.[92]

A number of screening modalities exist for breast cancer, including clinical breast examination, mammography, ultrasonography, and MRI. (See Breast Cancer Screening.)

In December 2013, the US Food and Drug Administration (FDA) issued a warning that nipple aspirate tests are not an effective screening tool for breast cancer or other breast diseases and should not be used in place of mammography, other imaging tests, or biopsy. The agency is concerned that the test, which involves analysis of fluid aspirated from a woman's breast with a pump device, could lead to false-positive or -negative results if fluid analysis alone is used as a screen.[93]

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.[88, 94, 95]

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

Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at less than 100 µm. Mammography often detects a lesion before it is palpable by clinical breast examination and, on average, 1 to 2 years before noted by breast self-examination.

Recent advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems.[96] CAD systems have been developed to help the radiologist identify mammographic abnormalities.

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

In a cohort study of women aged 50-74 years, which used data from the Ontario Breast Screening Program, computed radiography (CR) was 21% less effective than digital direct radiography (DR) for breast cancer detection; however, DR was equivalent to screen-film mammography (SFM).[97, 98]

The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in women aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged 40-49 years, the risk of death is decreased by 17%.[99]

Screening mammography

Although mammography guidelines have been in place for more than 30 years, 20-30% of women still do not undergo screening as indicated. The 2 most significant factors governing a woman’s decision to undergo mammography are physician recommendation and access to health insurance. Nonwhite women and those of lower socioeconomic status remain less likely to obtain mammography services and more likely to present with life-threatening, advanced stage disease.[100, 101]

At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS). In October 2015, the ACS updated its guidelines, which had previously recommended annual screening mammography, beginning at age 40 years for all women and continuing for as long as a woman is in good health, along with clinical breast examinations about every 3 years for women in their 20s and 30s and every year for women 40 and over, with monthly breast self-examination as an option for women starting in their 20s.[102]

The 2015 ACS recommendations for women at average risk of breast cancer are as follows[103] :

Since 2009 the USPSTF has recommended biennial screening mammography for women aged 50-74 years (grade B recommendation). The USPSTF recommends against routine screening mammography in women aged 40-49 years because of high rates of false-negative findings, perceived harm of unnecessary biopsy, and concern for the harm associated with overdiagnosis and overtreatment (grade C recommendation).[101]

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

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

Similarly, a 2015 review by the American College of Physicians (ACP) recommends the following strategies as the least intensive and having the highest value for asymptomatic women at average risk and in good health[104] :

For women of any age, the ACP does not recommend the following low-value screening strategies[104] :

In contrast to the ACP recommendation against the use of tomosynthesis (3D mammography) in breast cancer screening, the American College of Radiology (ACR) states that, “breast tomosynthesis has shown to be an advance over digital mammography, with higher cancer detection rates and fewer patient recalls for additional testing.” The ACR notes that further studies will be needed to determine which subgroups of women are likely to benefit most from tomosynthesis screening.[105]

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.[106] Thus, the benefit of significantly increased breast cancer detection with tomosynthesis screening must be weighed against the possible risk of overdiagnosis.

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

For women whose mammogram reveals dense breast tissue, 21 US states have laws requiring that the women be notified and be advised to discuss supplemental imaging with their provider. However, a prospective cohort study found that only a minority of women with dense breasts have high interval cancer rates. The authors concluded that supplemental imaging should not be justified on the basis of breast density alone .[107]

Kerlikowske et al reported that women at high risk can be identified by combining 5-year breast cancer risk, as determined with the Breast Cancer Surveillance Consortium (BCSC) risk calculator, with breast density as categorized with the Breast Imaging Reporting and Data System (BI-RADS).[107]

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.[107]

The highest rate of advanced-stage breast cancer, >0.4 case per 1000 examinations, was seen in women with 5-year BCSC risk of 2.50% or greater and heterogeneously or extremely dense breasts. Such patients comprised 21% of all women with dense breasts.[107]

Diagnostic mammography

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

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

Ultrasonography

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

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

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

Magnetic resonance imaging

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

In an observational study by Buist et al that included more than 2 million screenings in over 800,000 women, MRI screening for breast cancer was associated with higher rates of subsequent biopsy but a lower yield of cancer findings. In women with a breast cancer history, biopsy rates were more than twofold higher after MRI than after mammography alone; in women with no history of breast cancer, biopsy rates were more than fivefold higher.[108]

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.[108]

Indications for MRI

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

Contraindications for MRI

Conversely, in a number of situations, MRI is contraindicated, usually because of physical constraints that prevent adequate patient positioning. Additional contraindications include the following:

Relative contraindications also exist. These are essentially based on the high sensitivity but limited specificity of the technique. MRI may not be useful for the following:

Nuclear imaging

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

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

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

Positron Emission Tomography

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

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

Accuracy of Breast Imaging Modalities

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

Table 1. Accuracy of Breast Imaging Modalities



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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.

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:

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, currently standing at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.



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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% 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, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6.

Tubular carcinoma

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

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

Papillary carcinoma

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



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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).[110]

Metaplastic breast cancer

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

A wide variety of histologic patterns includes the following:

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

Mammary Paget disease

Mammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of the nipple-areola complex and is composed of the histologic hallmark Paget cells within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed between the keratinocytes singly or as a cluster of cells.

Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain. In situ or invasive breast cancer is found in approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast examination and mammographic evaluation, with additional imaging, including breast MRI, if the mammogram is negative.

Breast Cancer Staging

The American Joint Committee on Cancer (AJCC) provides two principal groups for breast cancer staging: anatomic, which is based on extent of cancer as defined by tumor size (T), lymph node status (N), and distant metastasis (M); and prognostic, which includes anatomic TNM plus tumor grade and the status of the biomarkers human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). The prognostic stage group is preferred for patient care and is to be used for reporting of all cancer patients in the United States.[111]

In turn, prognostic stages are divided into clinical and pathological groups. Pathological stage applies to patients who have undergone surgery as the initial treatment for breast cancer. It includes all information used for clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological prognostic stage does not apply to patients who received neoadjuvant therapy (systemic agents or radiation prior to surgical resection).[77]  

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 or axillary lymph node dissection (ALND) has also been considered necessary for staging and prognosis.

A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following patients[112] :

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

ASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy 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 SLN biopsy. In addition, the NCCN concluded that there is insufficient evidence to make recommendations for or against SLN biopsy in pregnant patients; the NCCN recommends that decisions regarding use of SLN biopsy in pregnancy be individualized. However, isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid appears to be safe.[77]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following cases[77] :

Also see Breast Cancer Staging for summarized information.

Additional Testing

The NCCN guidelines[77] 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:

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression.[113] (See Breast Cancer and HER2.)

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

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

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

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

Molecular profiling assays

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

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

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies, the Onco type Dx assay was shown retrospectively to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors.[114] Similarly, among women with 1- to 3-node-positive, hormone receptor-positive disease, the Onco type Dx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in RS.

Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In contrast, women with a high RS had a significant improvement in DFS with the addition of chemotherapy to hormonal therapy (tamoxifen).

The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still controversial. The Trial Assigning Individualized Options for Treatment [TAILORx], a large, prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is addressing this important question.

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

Approach Considerations

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

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

 In early-stage breast cancer, tumor gene-expression assays can be used to determine the likelihood of recurrence and thus the potential benefit of adjuvant chemotherapy. For example, with a commercially available 21-gene assay, a recurrence score of 0 to 10 is prognostic for a 2% rate of distant recurrence at 10 years that is unlikely to be improved by adjuvant chemotherapy. A high score, which has variably been defined as 26 or 31 or higher, is predictive of chemotherapy benefit.[115]

The prospective Trial Assigning Individualized Options for Treatment (TAILORx) studied the outcome in 9719 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer who had a midrange recurrence score of 11 to 25. At 9 years, patients treated with chemoendocrine therapy or endocrine therapy alone had similar rates of invasive disease–free survival, freedom from disease recurrence, and overall survival. Chemotherapy offered some benefit only in women 50 years of age or younger with a recurrence score of 16 to 25, who represented 46% of this age group.[115]

A secondary analysis of the TAILORx data confirmed that there is a cohort of these women who benefit from chemotherapy. In the women with a recurrence score of 26 to 100, who received adjuvant chemotherapy in addition to endocrine therapy, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93% at 5 years; in comparison, the expected rate in this population of women, if treated with endocrine therapy alone, is 79% at 5 years.[116]

See Breast Cancer Treatment Protocols for summarized information.

Treatment of Invasive Breast Cancer

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

In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axillae who were undergoing either breast conservation or mastectomy with SLN mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND) in women with a positive SLN.[117]

In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy.[117] 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.[118, 119]

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[120, 121] :

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.[77]

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

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

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

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

The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when patients are being considered for treatment with accelerated PBI[122] :

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.[123, 124, 125] However, the study data did not reflect use of the newest forms of brachytherapy, a limitation that may reduce the real-world applicability of these findings.

Single-dose radiotherapy

According to 2 major studies, single-dose radiotherapy delivered during or soon after surgery for breast cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local recurrence.[126]

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.[126]

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.[127, 128]

Postmastectomy radiation therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), along with several prospective, randomized clinical trials, recommend that postmastectomy radiation therapy be performed according to the following criteria[5] :

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%.[129, 130]

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.[131]

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.[132] 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.[133, 134]

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.[133, 134]

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.[135]

Adjuvant tamoxifen also reduces the risk of contralateral breast cancer.[136, 137] 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.[136, 137]

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).[136, 137]

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.[138]

Lobular carcinoma in situ

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

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS.[21] The researchers found a 55% risk reduction in women treated with tamoxifen.

Treatment of Locally Advanced and Inflammatory Breast Cancer

Originally, the reason for grouping locally advanced breast cancer (LABC) with inflammatory breast cancer (IBC) was the recognition that both diseases had little or no chance of cure from local therapy alone and were therefore considered inoperable. The definition of locally advanced disease has now broadened to include patients who are technically operable but who have large primary tumors (>5 cm).

It is important to recognize, however, that the reasons for using neoadjuvant therapy in women with large primary tumors, in whom the goal is to increase the possibility of breast-conserving surgery, are different from the reasons in women with disease that meets the original criteria of LABC or IBC, for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure.

In September 2013, the FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive). Approval was based on a randomized trial that compared a number of regimens with and without pertuzumab in women with HER2-positive breast cancer. In the trial, 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel (n = 107) achieved a pathologic complete response (pCR) compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery.[139] A confirmatory trial will provide long-term outcomes and is expected to be completed in 2016.

According to evidence-based guidelines from the American Society of Clinical Oncology (ASCO), the HER2 -targeted drugs trastuzumab, pertuzumab, and taxane should be used as first-line therapy for patients with advanced HER2 -positive breast cancer (except in patients with a contraindication to taxane).[140, 141] These guidelines provide indications not only for first-line HER2 -targeted therapy but also for second- and third-line treatment.

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

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

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

Inflammatory breast cancer

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

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

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

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

Locally advanced breast cancer

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

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

Evaluation of lymph nodes and response

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

Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-negative result, or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection.[142]

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

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

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

Hormone therapy

For patients who have hormone receptor (ER and/or PR)–positive disease without a life-threatening component (eg, massive liver metastases) or systemic symptoms requiring immediate palliation for comfort, in general, hormone manipulation is the initial treatment of choice. Response rates are higher with chemotherapy, but so is the incidence of potentially dangerous toxicity, and there is no evidence that patients live longer as a result of receiving initial chemotherapy.

For ER–positive metastatic breast cancer, the American Society of Clinical Oncology (ASCO) recommends using endocrine therapy rather than chemotherapy as first-line treatment, except in patients with immediately life-threatening disease or if there are concerns about endocrine resistance. The recommendation is part of an ASCO clinical practice guideline on the use of chemotherapy and targeted therapy for women with human epidermal growth factor 2 (HER2)-negative (or unknown) advanced breast cancer, with recommendations based on a systematic review of 79 studies.[143]

A trial of hormone manipulation alone can assess whether hormone therapy is effective, which is impossible to determine if it is given together with cytotoxic chemotherapy. This is especially important when the patient has relapsed disease, because the benefit of second-line hormone manipulation is nearly 50%, and failure to benefit from an initial trial with endocrine therapy correlates with second-line failure. Common hormone therapies and dosages are listed in Table 5, below.

Table 5. Hormone Agents Used in Breast Cancer



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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.[144]

In the international, double-blind phase III MONARCH 2 trial, 669 patients were randomized in a 2:1 ratio to abemaciclib (a CDK inhibitor) plus fulvestrant or fulvestrant plus placebo. Patients received 500 mg of fulvestrant plus placebo or 150 mg of abemaciclib twice daily. The median progression-free survival was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group. The overall response rates among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.[145]

Chemotherapy

Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single-agent regimens. Combination therapy is currently considered up front, depending on the patient's performance status, because of higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life.

When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit. Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single agent, but this practice has not been widely adopted, because the combination is more toxic and the study designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the other drug component of the initial therapy at the time of relapse.

A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is combined with a targeted agent other than hormone therapy. These targeted agents often have very low response rates when given as monotherapy, but they provide added benefit when given in combination with cytotoxic chemotherapy. A list of targeted chemotherapeutic agents is provided in Table 6, below, followed by Table 7, showing combination regimens for breast cancer.

Table 6. Targeted Chemotherapy for Metastatic Breast Cancer



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Table 7. Combination Regimens for Metastatic Breast Cancer



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The initial choice of chemotherapy is highly influenced by the patient's personal history of previous drug exposure. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a higher risk of developing resistance, and there is a relationship between cumulative lifetime total dose of doxorubicin and the risk of potentially fatal cardiomyopathy.

It is important to realize that if 1 year or more has elapsed since completion of adjuvant therapy, a patient's tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting.

Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further administration problematic. Substitution of one taxane for another is possible, depending on the nature of the chronic toxicity.

If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective. At least one third of breast cancer patients with taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is administered on a weekly schedule at a lower dose.

The Cancer and Leukemia Group B (CALGB) 9840 trial reported an improved overall response rate (ORR) in patients receiving weekly dosing of paclitaxel (40%) compared with every-3-week paclitaxel (28%), as well as improved median time to progression (9 mo vs 5 mo). However, care should be taken in watching for progression of adverse effects, especially neuropathy.

In addition to taxanes and anthracyclines, a variety of other chemotherapeutic agents can be used as single agents or in combination with taxanes. Capecitabine (Xeloda) is an oral agent that essentially represents a sustained-release formulation of the older antimetabolite fluorouracil (5-FU) and provides the convenience of self-administration.

Drugs such as capecitabine have very little associated myelosuppression, and they are often chosen when the patient's bone marrow has been damaged by previous therapy or when there is a desire to coadminister a myelosuppressive agent for more rapid effect. As a single agent, capecitabine has an ORR of 25-30%, with minimal toxicity. When combined with a taxane, an ORR of 40-50% has been observed, along with a median overall survival benefit of 3-15 months.

Another antimetabolite, gemcitabine (Gemzar), is typically given in combination with paclitaxel, based on results from a phase III trial comparing paclitaxel with the combination regimen in locally advanced breast cancer (LABC) and metastatic breast cancer. A total of 529 patients were randomized to receive paclitaxel 175 mg/m2 on day 1 plus gemcitabine 1250 mg/m2 on days 1 and 8, or receive the same dose of paclitaxel alone every 3 weeks. ORR (41% vs 26%) and overall survival (18.6 mo vs 15.8 mo) were significantly higher with the paclitaxel/gemcitabine arm than with paclitaxel alone.[160]

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

Palbociclib (Ibrance) is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 used for first-line treatment for ER-positive, HER2-negative metastatic breast cancer in postmenopausal women, in combination with the aromatase inhibitor letrozole.[161]  A phase II study in which progression-free survival (PFS) for women receiving palbociclib and letrozole was 20.2 months, versus 10.2 months for those on letrozole alone (P = 0.0004).[161, 162]

The CDK 4,6 inhibitor ribociclib (Kisqali) was approved by the FDA in March 2017 for postmenopausal HR+/HER- advanced or metastatic breast cancer in combination with letrozole. Approval was based on interim analysis results from the phase III MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer (n=668). Ribociclib plus letrozole yielded a PFS rate of 63% with a duration of 19.3 months, compared with a rate of 42.2% and a duration of 14.7 months with letrozole alone.[151]  

Since those data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone, according to a company statement.[163]

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

PARP Inhibitors

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. In January 2018, the FDA expanded approval of olaparib to include treatment of BRCA-mutated, HER2-negative metastatic breast cancer in patients who have been previously treated with chemotherapy. Olaparib (which had previously been approved for treatment of BRCA-mutated ovarian cancer) is the first PARP inhibitor approved to treat breast cancer, and the first drug of any kind approved to treat certain patients with BRCA-mutated metastatic breast cancer.[164]

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).[165]

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).[165]

In October 2018, talazoparib, another PARP inhibitor, was approved for patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Approval was based on the phase III EMBRACA trial (n=431), which talazoparib reduced the risk of disease progression or death by 46% compared with chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. Patients were randomized in a 2:1 ratio to receive talazoparib or physician’s choice of chemotherapy (PCT), which included eribulin, gemcitabine, vinorelbine, and/or capecitabine. [166]

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.[166]

Treatment of HER2-positive metastatic breast cancer

See HER2 Breast Cancer for more information on this topic.

Treatment of triple-negative metastatic breast cancer

Unresectable metastatic triple-negative breast cancer (ie, estrogen receptor–, progesterone receptor–, and HER2 receptor–negative) is aggressive and carries a poor prognosis. However, combination therapy with the programmed cell death ligand–1 (PDL1) inhibitor atezolizumab plus nanoparticle albumin-bound (nab)–paclitaxel has been shown to prolong PFS in these patients.[167]  In March 2019, FDA approved atezolizumab in combination with nab-paclitaxel for triple-negative breast cancer.[168]

Approval was based on the phase III IMpassion130 trial in patients with untreated metastatic triple-negative breast cancer, in which intention-to-treat analysis showed median PFS of 7.2 months with atezolizumab plus nab-paclitaxel versus 5.5 months with placebo plus nab-paclitaxel (hazard ratio [HR] for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); in patients with PDL1-positive tumors, median PFS was 7.5 months and 5.0 months, respectively (HR, 0.62; 95% CI, 0.49 to 0.78; P< 0.001).[167]

Antiangiogenic therapy in metastatic breast cancer

Angiogenesis is recognized as a key process in the progression and metastasis of breast cancer. Bevacizumab (Avastin) is a humanized mAb directed against vascular endothelial growth factor (VEGF), which exerts an independent effect on the process of new blood vessel formation in tumors (angiogenesis). Bevacizumab was approved by the FDA as a first-line therapy for HER2-negative metastatic breast cancer patients, based on results from the phase III ECOG 2100 trial.

However, on November 18, 2011, the FDA officially rescinded its approval of bevacizumab because the drug had not been shown to be safe and effective for this use. The decision is based on the totality of data, including 3 trials in first-line treatment of metastatic breast cancer (E2100, AVADO, and RIBBON-1), as well as the EVF 2119 trial for second-line treatment in this setting.

The bevacizumab data review found that patients treated with bevacizumab did not live any longer than patients who were not taking it, but they were at greater risk of adverse effects, including those unique to bevacizumab, such as gastrointestinal perforations, which can be life threatening. Other serious and potentially life-threatening effects include the risk of stroke, wound-healing complications, and organ damage or failure; bevacizumab has also been linked with the neurological condition reversible posterior leukoencephalopathy syndrome (RPLS).

Adjunctive bisphosphonate therapy in metastatic breast cancer

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

Surgical Treatment of Metastatic Breast Cancer

As modern systemic chemotherapy has become more effective, some patients with intact primary tumors and metastasis can have long-term stable distant disease or even no evidence of residual metastatic disease after treatment. There is increasing interest in the role of surgical intervention for the intact primary tumor of these metastatic breast cancer patients. Several single-institution cohort and retrospective studies have concluded that surgical resection of the intact primary tumor may provide a survival advantage.

It is still unknown whether a selection bias affects the findings of a survival advantage in favor of surgery. However, the dogmatic belief that one should never operate in the setting of metastatic disease has certainly been dispelled in favor of critical evaluation of whether surgically achieved local control can lead to improved survival as a part of multimodal treatment. An ongoing prospective randomized clinical trial, E2108, is addressing the role of surgery for the primary tumor in metastatic setting.

Pharmacologic Reduction of Breast Cancer Risk

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

ASCO has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, and aromatase inhibitors) for breast cancer risk reduction.[169] Some of the highlights of the expert panel’s literature review are as follows.

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

As noted earlier, in an analysis that used pooled observational cohort data from 3 studies and included 1583 BRCA1 and 881 BRCA2 mutation carriers, adjuvant tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry these mutations.[136, 137]

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

Exemestane, an aromatase inhibitor, has also been found to be effective at reducing the incidence of invasive breast cancers in postmenopausal women at moderately increased breast cancer risk. In the NCIC- led MAP.3 trial, exemestane decreased the incidence of invasive breast cancer by 65% and that of invasive plus in situ breast cancer by 53% as compared with placebo.[170] Arthritis and hot flashes were more common in women treated with the aromatase inhibitor.

ASCO guidelines recommend the following[169] :

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.[171]

Genetic factors that place a woman at very high risk of developing breast cancer include the following[171] :

The National Comprehensive Cancer Network (NCCN) recommends that in general, the only women who should consider risk-reduction mastectomy are those with a genetic mutation that confers a high risk for breast cancer, a compelling family history, or possibly a personal history of receiving thoracic radiation therapy before 30 years of age. The NCCN notes that while risk-reduction mastectomy had previously been considered for lobular carcinoma in situ (LCIS), risk-reduction therapy is currently the preferred approach for LCIS.[172]

In retrospective studies with median follow-up periods of 13-14 years, bilateral risk-reduction mastectomy decreased the risk of developing breast cancer by at least 90% in women at moderate to high risk and in those with known BRCA1/2 mutations. In women with deleterious mutations in other genes that are associated with a 2-fold or greater risk for breast cancer but without a compelling family history of breast cancer, the value of risk-reducing mastectomy is unknown.[172]

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.[171, 172]

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.[173]

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 5 below).

Table 5. Follow-up Recommendations for Breast Cancer Survivors



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ASCO guidelines for monitoring bone density

Table.



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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 new consensus statement from the European Association of Cardiovascular Imaging and the American Society of Echocardiography, patients treated with radiotherapy to the chest for Hodgkin's disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10 years to detect radiation-induced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times higher in patients treated with radiation for breast cancer.[174, 175]

Recommendations of the statement include the following[174, 175] :

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[176] :

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[177] :

Guidelines Summary

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

Breast Cancer Screening

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

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

American Cancer Society screening guidelines

The ACS updated its guidelines for breast cancer screening in average-risk women in October 2015.[178] At this time, the ACS is in the process of updating the breast cancer screening guidelines for women at high risk, which were last updated in 2007.[179]

Breast examination

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

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

Mammography

ACS recommendations are as follows[178] :

Breast MRI Screening as an Adjunct to Mammography

The ACS recommends annual MRI screening along with mammography, based on evidence from nonrandomized screening trials and observational studies, in women with the following risk factors[180] :

The ACS recommends annual MRI screening, based on expert consensus opinion that considers evidence of lifetime risk for breast cancer, in women with the following risk factors[180] :

The ACS found insufficient evidence to recommend for or against MRI screening in women with the following risk factors[180] :

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

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

USPSTF screening guidelines

In 2016, the USPSTF released updated recommendations on breast cancer screening, but did not update its 2009 recommendations for breast examination. In its 2016 statement, the USPSTF encouraged patients to be aware of changes in their bodies and discussing these changes with clinicians.[181]

The 2009 breast examination recommendations are as follows[101] :

The 2016 screening mammography recommendations are as follows[181] :

BCRA-related cancer

In 2013, the USPSTF issued updated guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows[182] :

ACOG screening guidelines

The ACOG released guidelines for breast cancer risk assessment and screening in average-risk women in 2017.[183] For women at average risk, ACOG categorizes its recommendations as follows:

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

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

Breast examination

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

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

Mammography

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

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

ECIBC screening guidelines

The European Commission Initiative on Breast Cancer (ECIBC) screening guidelines include the following recommendations for women age 40-74 years who are at average risk of breast cancer[184] :

In addition, for asymptomatic women with an average risk for breast cancer, screening with digital mammography is recommended over DBT for breast cancer screening. The guidelines also suggest that screening with digital mammography alone is preferred over screening with both DBT and digital mammography.[184]

For women with dense breast tissue and negative mammography findings, ECIBC suggests not implementing tailored screening with automated breast ultrasound system (ABUS), hand-held ultrasound (HHUS), or MRI.[184]

 

 

Pharmacologic Interventions for Breast Cancer Risk Reduction

Guidelines for pharmacologic intervention in women who are at increased risk for breast cancer, but do not have a personal history of breast cancer, have been issued by the American Society of Clinical Oncology (ASCO)[185] and the U.S. Preventive Services Task Force (USPSTF).[186] The guidelines differ in their classification of increased risk and in their inclusion of women with lobular carcinoma in situ (LCIS).

American Society of Clinical Oncology

ASCO has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, and aromatase inhibitors) for breast cancer risk reduction.[185]

ASCO guidelines recommend the following[185] :

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

Tamoxifen

ASCO guidelines recommend that use of tamoxifen, 20 mg per day orally for 5 years, should be discussed as an option to reduce the risk of invasive breast cancer (BC), specifically ER-positive BC, in women 35 years of age or older who are premenopausal or postmenopausal and have a 5-year projected absolute breast cancer risk ≥ 1.66% or with LCIS. Risk reduction benefit continues for at least 10 years.[185]

ASCO guidelines advise that tamoxifen not be used in the following cases[185] :

Raloxifene

ASCO guidelines recommend that raloxifene should be discussed as an option to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women who are age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS. Raloxifene is given in a dosage of 60 mg/ day orally for 5 years; it can be used for longer than 5 years in women with osteoporosis, in whom BC risk reduction is a secondary benefit.[185]

ASCO guidelines advise that raloxifene not be used in the following cases[185] :

Exemestane

Exemestane is not FDA approved for breast cancer risk reduction. However, ASCO guidelines recommend that it should be discussed as an alternative to tamoxifen and/or raloxifene to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS or atypical hyperplasia. It should not be used for BC risk reduction in premenopausal women. Exemestane is given in a dosage of 25 mg per day orally for 5 years.[185]

USPSTF guidelines

The USPSTF updated its guidelines for primary breast cancer risk reduction in 2019.[186]  The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors.

The USPSTF recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (eg, atypical ductal or lobular hyperplasia and lobular carcinoma in situ). The recommendation does not apply to women with a current or previous diagnosis of breast cancer or ductal carcinoma in situ..[186]

Lymph Node Biopsy and Dissection

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

American Society of Clinical Oncology

A 2014 update on SLNB for patients with early-stage breast cancer by ASCO advises that SLNB may be offered to the following patients[187] :

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

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

National Comprehensive Cancer Network

The 2017 NCCN guidelines recommend that SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate candidate for SLNB.[77] Candidates include patients with clinical stage I, IIA, IIB, and IIIA T3, N1, M0 who are clinically node negative at the time of diagnosis, as well as those who are clinically node positive but have negative results on fine needle aspiration or core biopsy.

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

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

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

In contrast with ASCO, the NCCN concluded that insufficient data exist on which to base recommendations regarding the use of SLNB in pregnant women. The NCCN advises that whether to use SLNB in pregnancy should be an individualized decision, but cites a review recommending that SLNB should not be offered to pregnant women under 30 weeks' gestation. If SLNB is used, the NCCN advises that isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy, but radiolabeled sulfur colloid appears to be safe.[77]

 

Hormone Receptor Testing

Updated guidelines from the American Society of Clinical Oncology and the College of American Pathologists contain the following recommendations on estrogen receptor (ER) and progesterone receptor (PR) testing in breast cancer[188] : 

Lumpectomy Margins

In 2016, the Society of Surgical Oncology, American Society for Radiation Oncology and American Society of Clinical Oncology released a consensus guideline that addresses margins for breast-conserving surgery with whole-breast radiation therapy (WBRT) in ductal carcinoma in situ (DCIS). Key recommendations include[189] :

The following consensus guideline, released in 2014 by the Society of Surgical Oncology and the American Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer.[190] :

Radical Mastectomy

According to National Comprehensive Cancer Network (NCCN) guidelines, mastectomy with level I/II axillary lymph node dissection is the recommended procedure in patients who respond to neoadjuvant chemotherapy. Other NCCN indications for mastectomy include the following[77] :

Relative indications for mastectomy include the following:

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

Postmastectomy Radiation Therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), recommend that postmastectomy radiation therapy be performed according to the following criteria[191] :

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

For women with invasive breast cancer who receive whole-breast irradiation (WBI), updated guidelines from the American Society of Radiation Oncology (ASTRO) recommend the use of hypofractionated WBI regardless of patient age, chemotherapy history, or tumor stage. The 2018 update expands the indications for WBI; previous guidelines, from 2011, recommended the treatment for patients aged 50 and older whose disease was less advanced (T1–2, N0) and who had not undergone chemotherapy. For WBI with or without inclusion of the low axilla, the preferred scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions.[192]

Treatment of HER2-Positive Breast Cancer

Evidence-based guidelines from the American Society of Clinical Oncology (ASCO) for treatment of HER2 -positive breast cancer, which are largely adapted from the 2015 Cancer Care Ontario (CCO) clinical practice guidelines, are as follows[193, 194, 195] :

Hormonal Adjuvant Therapy

In 2016, the American Society of Clinical Oncology (ASCO) issued an updated clinical practice guideline on adjuvant endocrine therapy for premenopausal women with hormone receptor–positive breast cancer.  ASCO recommends high-risk women receive adjuvant endocrine therapy with ovarian suppression but lower-risk patients should not.[196]

Specific recommendations include [196] : 

In its 2014 practice guidelines, ASCO addressed postmenopausal women and recommended they be offered adjuvant endocrine therapy with one of the following treatments[197, 198] :

Postmenopausal patients should be offered adjuvant endocrine therapy with one of the following treatments[197, 198] :

Postmenopausal patients who are intolerant of either tamoxifen or an aromatase inhibitor should be offered an alternative adjuvant endocrine therapy. Patients who have received an aromatase inhibitor but discontinued treatment at less than 5 years may be offered tamoxifen for a total of 5 years. Patients who have received tamoxifen for 2-3 years should be offered an aromatase inhibitor for up to 5 years, for a total duration of up to 7-8 years of adjuvant endocrine therapy.[197, 198]

Breast Cancer in Young Women

Guidelines on the management of breast cancer in young women from the European School of Oncology (ESO) and the European Society of Medical Oncologists (ESMO), and endorsed by the European Society of Breast Specialists (EUSOMA), include 75 statements.[199] Among them are the following recommendations:

Follow-up for Breast Cancer Survivors

The National Comprehensive Cancer Network (NCCN)[77]  and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO)[200]  have issued guidelines on followup care for breast cancer survivors. The guidelines differ principally in the timing of care. See the table below.

Table Follow-up Recommendations for Breast Cancer Survivors



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Use of Biomarkers to Guide Adjuvant Systemic Therapy

A guideline from the American Society of Clinical Oncology (ASCO) advises that the only biomarkers that can guide choices of specific treatment regimens in breast cancer are as follows[201] :

ASCO recommendations regarding further biomarker use include the following[201] :

Medication Summary

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

In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass. These agents are given along with calcium and vitamin D supplementation.

Bevacizumab, a humanized monoclonal antibody that inhibits angiogenesis, had been approved for use in combination therapy for metastatic breast cancer. In November 2011, however, the US Food and Drug Administration (FDA) revoked its approval for this indication, after concluding that bevacizumab had not been shown to be safe and effective for that use.[77]  

In December 2013, Hoffmann-La Roche, manufacturer of capecitabine (Xeloda), an oral agent for the treatment of breast and colorectal cancers, reported that in rare cases, patients using the drug may develop potentially fatal cutaneous disease, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Signs and symptoms of severe skin reactions may include flu-like symptoms, fever, itching, mouth sores, and burning eyes, as well as a painful, red or purplish rash that causes the skin to shed.[202]

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

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

Data from FALCON showed that fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole. Overall response rate and clinical benefit rate did not differ significantly between groups. Fulvestrant resulted in a median duration of response of 20 months as compared with 13.2 months with anastrozole. Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole. Expected duration of response also favored fulvestrant, as did expected duration of clinical benefit.[203]

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

Approval for alpelisib was supported by the SOLAR-1 trial (n=572). Results demonstrated that adding alpelisib to fulvestrant significantly prolonged median PFS (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation.[204]

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

Approval of palbociclib for initial endocrine-based therapy in postmenopausal women was based on the phase II trial (PALOMA-1) which measured median progression-free survival (PFS) duration. The mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group.[150]

The approval of palbociclib for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy was based on the PALOMA-3 trial (n=521). PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo. vs 3.8 mo.).[205]

Approval of ribociclib was based on interim analysis results from the pivotal phase 3 MONALEESA-2 trial in postmenopausal women who received no prior systemic therapy for their advanced breast cancer. The trial demonstrated that ribociclib plus the aromatase inhibitor letrozole reduced the risk for progression or death compared with letrozole alone. The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63% with a duration of 19.3 months in the ribociclib group and 42.2% with a duration of 14.7 months in the letrozole alone group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively.[151]  Since these data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination vs 16 months with letrozole alone, according to a company statement.

A third inhibitor, abemaciclib was FDA approved in September 2017. Approval was based on results from the MONARCH 1 and 2 trial. The Monarch 1 trial studied the safety and efficacy of abemaciclib as a stand-alone treatment in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. Abemaciclib was administered at 200 mg orally twice daily until disease progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.The investigator-assessed, confirmed ORR was 19.7%, which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months.[206]

In February 2018, the FDA also approved this CDK inhibitor for use in combination with an aromatase inhibitor for frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Approval was based on data from the MONARCH 3 trial; a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor (NSAI) in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. The addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the NSAI alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer. In the study, the median progression-free survival was 28.2 months in the abemaciclib arm versus 14.8 months with the NSAI alone. In those with measurable disease, the ORR was 55.4% with the CDK4/6 inhibitor and 40.2% in the control arm. The median duration of response was 27.4 months for the abemaciclib arm compared with 17.5 months in the control arm.[207]

 

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.

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.[77]

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.

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.

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.

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 postmenopausal women with HR+/HER- advanced or metastatic breast cancer.

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.

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 side effects and to kill cancer cells with DNA repair defects as a single agent. The genomic instability of some tumor cells allows poly (ADP-ribose) polymerase (PARP) inhibitors to have selectivity for the tumor cells over normal cells.

Olaparib was the first PARP inhibitor approved for breast cancer. Its approval was based on the first phase 3 randomized trial that demonstrated PARP inhibitors were superior to chemotherapy for patients with HER2-negative metastatic breast cancer with a BRCA mutation.[165]

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]

Class Summary

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

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.

What is breast cancer?What are the signs and symptoms of breast cancer?What is included in the evaluation of breast cancer?Which physical findings suggest breast cancer?What features of a palpable lump suggest breast cancer?How is breast cancer screening performed?What is the role of biopsy in the workup of breast cancer?How is breast cancer treated?What are the chemotherapy regimens used to treat breast cancer?What is the role of drug treatment for breast cancer?What is breast cancer?What is the anatomy relevant to breast cancer?What is the pathophysiology of breast cancer?How is breast cancer categorized?What are the types of breast cancer?What causes breast cancer?What is the role of age in the etiology of breast cancer?What is the role of family history in the etiology of breast cancer?Which family history factors increase the risk for breast cancer?How is family history–based risk for breast cancer assessed?What is the role of reproductive factors in the etiology of breast cancer?What is the role of estradiol in the etiology of breast cancer?What is the role of oral contraceptives (OCs) in the etiology of breast cancer?What is the role of hormone replacement therapy (HRT) in the etiology of breast cancer?What are guidelines for HRT in women at high risk of breast cancer?How should menopausal symptoms be treated in women at high risk of breast cancer?Which history findings increase the risk for a second primary breast cancer occurrence?What is the role of lifestyle factors in the etiology of breast cancer?What is the role of obesity in the etiology of breast cancer?Which Western lifestyle factors increase the risk for breast cancer?Which environmental factors increase the risk for breast cancer?What is the prevalence of breast cancer in the US?What are the historical trends in the incidence of breast cancer in the US?What is the role of HRT in the incidence of breast cancer in the US?What is the global prevalence of breast cancer?Which age groups have the highest prevalence of breast cancer?What are the racial predilections of breast cancer?How do the mortality rates for breast cancer vary among racial and ethnic groups?What is the association between breast cancer and cardiovascular disease (CVD)?What is the prognosis of breast cancer?What are the prognostic and predictive factors for breast cancer?What are the survival rates for breast cancer?What is the prognosis of breast cancer following HER2-targeted therapies?What is the prognosis of DCIS breast cancer?What is the prognosis of LCIS breast cancer?What is the prognosis of infiltrating ductal carcinoma breast cancer?What is the prognosis of medullary carcinoma breast cancer?What is the prognosis of mucinous carcinoma breast cancer?What is the prognosis of cystic papillary carcinoma breast cancer?What is the prognosis of metaplastic breast cancer?What is the prognosis of mammary Paget disease?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 role of PET scanning in the workup of breast cancer?What is the accuracy of breast imaging modalities for the diagnosis of breast cancer?What is the role of breast biopsy in the diagnosis of breast cancer?What are the histologic findings of lobular carcinoma in situ breast cancer?What are the histologic findings of infiltrating ductal carcinoma breast cancer?What are the histologic findings of medullary carcinoma breast cancer?Which tumor features affect treatment selection for breast cancer?What are the histologic grades for breast cancer?What are the histologic characteristics of DCIS breast cancer?What are the histologic findings of infiltrating lobular carcinoma breast cancer?What are the histologic findings of mucinous carcinoma breast cancer?What are the histologic findings of tubular carcinoma breast cancer?What are the histologic findings of papillary carcinoma breast cancer?What are histologic findings of metaplastic breast cancer?What are the histologic findings of mammary Paget disease?What is the AJCC staging system for breast cancer?How is the primary tumor (T) in breast cancer staged?How are regional lymph nodes (N) in breast cancer staged?How is distant breast cancer metastasis staged?What are the 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?How is breast cancer treated?How is invasive breast cancer treated?What are the guidelines for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer?What is the role of post lumpectomy radiation therapy in the treatment of breast cancer?What are the ASBrS selection criteria for treatment of breast cancer with accelerated partial breast irradiation (PBI)?What are the potential complications of partial breast irradiation (PBI) in the treatment of breast cancer?What is the efficacy of external-beam radiotherapy (EBRT) in the treatment of breast cancer?What is the role of single-dose radiotherapy in the treatment of breast cancer?What are the ASCO criteria for postmastectomy radiation therapy in the treatment of breast cancer?What is the efficacy of radiation therapy for the treatment of invasive breast cancer?What is the role of systemic adjuvant therapy in the treatment of breast cancer?How is DCIS breast cancer treated?What is the role of WBRT in the treatment of DCIS breast cancer?What is the role of tamoxifen in the treatment of DCIS breast cancer?How is LCIS breast cancer treated?How is locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) treated?What is the prognosis of locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) following treatment?What is inflammatory breast cancer (IBC)?What is locally advanced breast cancer (LABC)?How are lymph nodes evaluated in locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC)?What are the systemic treatments for metastatic breast cancer?What is the role of hormone therapy in the treatment of metastatic breast cancer?What is the role of chemotherapy in the treatment of metastatic breast cancer?Which chemotherapy agents are used in the treatment of metastatic breast cancer?What is the role of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of metastatic breast cancer?What is the efficacy of combination therapy in the treatment of triple-negative breast cancer?What is the role of antiangiogenic therapy in the treatment of metastatic breast cancer?What is the role of surgery for the treatment of metastatic breast cancer?What is the role of tamoxifen and raloxifene for the reduction of breast cancer risk?What are the ASCO guidelines for the pharmacologic reduction of breast cancer risk?What is the role mastectomy in the prevention of breast cancer?What are the ASBrS recommendations for contralateral prophylactic mastectomy (CPM) in the treatment of breast cancer?What are the differences between the NCCN and ASCO guidelines for the long-term monitoring of breast cancer survivors?What are ASCO guidelines for monitoring bone density following the treatment for breast cancer?What is the role of postoperative imaging in the long-term monitoring of breast cancer?What is the role of postoperative imaging in the monitoring of metastatic breast cancer?How is radiation-induced heart disease monitored in patients with breast cancer?What are Society for Integrative Oncology guidelines for use of integrative therapy in breast cancer?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 axillary lymph node dissection (ALND) in the treatment of breast cancer?What are the NCCN guidelines for use of sentinel lymph node biopsy (SLNB) in the treatment of breast cancer during pregnancy?What are the guidelines for breast-conserving surgery with whole-breast radiation therapy (WBRT) in ductal carcinoma in situ (DCIS) breast cancer?What are the guidelines for breast-conserving surgery with whole-breast radiation therapy (WBRT) in stages I and II invasive breast cancer?What are the NCCN guidelines for radical mastectomy in the treatment of breast cancer?What are the ASCO guidelines for postmastectomy radiation therapy in the treatment of breast cancer?What are the ASCO treatment guidelines for HER2-positive breast cancer?What are the ASCO guidelines for the use of hormonal adjuvant therapy in the treatment of premenopausal women with breast cancer?What are the ASCO guidelines for adjuvant endocrine therapy in the treatment of postmenopausal women with breast cancer?What are guidelines on the treatment of breast cancer in young women?Which organizations issued guidelines on follow-up care for breast cancer survivors?What are ASCO guidelines for use of biomarkers in the treatment of breast cancer?What is the role of adjuvant therapies in the treatment of breast cancer?Which medications are used in the adjuvant treatment of breast cancer?Which medications in the drug class Antineoplastics, Estrogen Receptor Antagonist are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, PARP Inhibitors are used in the treatment of Breast Cancer?Which medications in the drug class CDK Inhibitors are used in the treatment of Breast Cancer?Which medications in the drug class Aromatase Inhibitors are used in the treatment of Breast Cancer?Which medications in the drug class Tyrosine Kinase Inhibitors are used in the treatment of Breast Cancer?Which medications in the drug class Monoclonal Antibodies are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, Vinca Alkaloid are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Breast Cancer?Which medications in the drug class Calcium Metabolism Modifiers are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, Anthracycline are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Breast Cancer?Which medications in the drug class Antineoplastics, Antimicrotubular are used in the treatment of Breast Cancer?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Breast Cancer?Which medications in the drug class PI3K Inhibitors are used in the treatment of Breast Cancer?

Author

Pavani Chalasani, MD, MPH, Assistant Professor of Medicine, Section of Hematology/Oncology, Department of Medicine, Arizona Health Sciences Center, University of Arizona College of Medicine

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

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.

Kathy D Miller, MD, Professor of Medicine, Indiana University School of Medicine; Co-Director, Breast Cancer Program, Indiana University Simon Cancer Center

Disclosure: Nothing to disclose.

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.

References

  1. Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar. 17 (3):367-77. [View Abstract]
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov. 68 (6):394-424. [View Abstract]
  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan. 69 (1):7-34. [View Abstract]
  4. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4. 490(7418):61-70. [View Abstract]
  5. [Guideline] Recht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001 Mar 1. 19(5):1539-69. [View Abstract]
  6. Surveillance Epidemiology and End Results (SEER). Cancer Stat Facts: Female Breast Cancer. National Cancer Institute. Available at http://seer.cancer.gov/statfacts/html/breast.html#incidence-mortality. Accessed: January 17, 2019.
  7. Jatoi I, Anderson WF, Rosenberg PS. Qualitative age-interactions in breast cancer: a tale of two diseases? doi: 10.1097/COC.0b013e3181844d1c. Am J Clin Oncol. 2008 Oct. 31(5):504-6. [View Abstract]
  8. Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017 Oct 23. [View Abstract]
  9. Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet. 2017 Oct 23. [View Abstract]
  10. Parmigiani G, Chen S, Iversen ES Jr, Friebel TM, Finkelstein DM, Anton-Culver H, et al. Validity of models for predicting BRCA1 and BRCA2 mutations. Ann Intern Med. 2007 Oct 2. 147(7):441-50. [View Abstract]
  11. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005 Dec 15. 104(12):2807-16. [View Abstract]
  12. FDA authorizes, with special controls, direct-to-consumer test that reports three mutations in the BRCA breast cancer genes. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm599560.htm?utm_campaign=03062018_PR_23andme_BRCA&utm_medium=email&utm_source=Eloqua. March 6, 2018; Accessed: March 8, 2018.
  13. Kelsey JL, Bernstein L. Epidemiology and prevention of breast cancer. Annu Rev Public Health. 1996. 17:47-67. [View Abstract]
  14. Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol. 2000 Nov 15. 152(10):950-64. [View Abstract]
  15. Deligeoroglou E, Michailidis E, Creatsas G. Oral contraceptives and reproductive system cancer. Ann N Y Acad Sci. 2003 Nov. 997:199-208. [View Abstract]
  16. Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst. 2004 Feb 4. 96(3):218-28. [View Abstract]
  17. Pike MC, Pearce CL, Peters R, Cozen W, Wan P, Wu AH. Hormonal factors and the risk of invasive ovarian cancer: a population-based case-control study. Fertil Steril. 2004 Jul. 82(1):186-95. [View Abstract]
  18. Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst. 2006 Oct 4. 98(19):1406-15. [View Abstract]
  19. Hankinson SE, Eliassen AH. Circulating sex steroids and breast cancer risk in premenopausal women. Horm Cancer. 2010 Feb. 1(1):2-10. [View Abstract]
  20. Cuzick J, DeCensi A, Arun B, Brown PH, Castiglione M, Dunn B, et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol. 2011 May. 12(5):496-503. [View Abstract]
  21. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005 Nov 16. 97(22):1652-62. [View Abstract]
  22. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998 Sep 16. 90(18):1371-88. [View Abstract]
  23. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21. 295(23):2727-41. [View Abstract]
  24. Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002 Apr 17. 94(8):606-16. [View Abstract]
  25. Santen RJ, Boyd NF, Chlebowski RT, Cummings S, Cuzick J, Dowsett M, et al. Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocr Relat Cancer. 2007 Jun. 14(2):169-87. [View Abstract]
  26. Endogenous Hormones and Breast Cancer Collaborative Group. Free estradiol and breast cancer risk in postmenopausal women: comparison of measured and calculated values. Cancer Epidemiol Biomarkers Prev. 2003 Dec. 12(12):1457-61. [View Abstract]
  27. Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002 Jun 27. 346(26):2025-32. [View Abstract]
  28. Garbe E, Levesque L, Suissa S. Variability of breast cancer risk in observational studies of hormone replacement therapy: a meta-regression analysis. Maturitas. 2004 Mar 15. 47(3):175-83. [View Abstract]
  29. Reeves GK, Beral V, Green J, Gathani T, Bull D. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol. 2006 Nov. 7(11):910-8. [View Abstract]
  30. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000 Jan 26. 283(4):485-91. [View Abstract]
  31. Speroff L. The Million Women Study and breast cancer. Maturitas. 2003 Sep 25. 46(1):1-6. [View Abstract]
  32. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28. 394 (10204):1159-1168. [View Abstract]
  33. Anderson GL, Chlebowski RT, Aragaki AK, Kuller LH, Manson JE, Gass M, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012 May. 13(5):476-86. [View Abstract]
  34. Ingram I. HRT Has 20-Year Impact on Breast Cancer Risks. MedPage Today. Available at https://www.medpagetoday.com/meetingcoverage/sabcs/83882. December 13, 2019; Accessed: December 16, 2019.
  35. Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004 Feb 7. 363(9407):453-5. [View Abstract]
  36. Loprinzi CL, Michalak JC, Quella SK, O'Fallon JR, Hatfield AK, Nelimark RA, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med. 1994 Aug 11. 331(6):347-52. [View Abstract]
  37. Bordeleau L, Pritchard K, Goodwin P, Loprinzi C. Therapeutic options for the management of hot flashes in breast cancer survivors: an evidence-based review. Clin Ther. 2007 Feb. 29(2):230-41. [View Abstract]
  38. Page DL, Jensen RA. Evaluation and management of high risk and premalignant lesions of the breast. World J Surg. 1994 Jan-Feb. 18(1):32-8. [View Abstract]
  39. Kollias J, Ellis IO, Elston CW, Blamey RW. Clinical and histological predictors of contralateral breast cancer. Eur J Surg Oncol. 1999 Dec. 25(6):584-9. [View Abstract]
  40. Page DL, Schuyler PA, Dupont WD, Jensen RA, Plummer WD Jr, Simpson JF. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet. 2003 Jan 11. 361(9352):125-9. [View Abstract]
  41. Page DL. Breast lesions, pathology and cancer risk. Breast J. 2004 Jan-Feb. 10 Suppl 1:S3-4. [View Abstract]
  42. Ashbeck EL, Rosenberg RD, Stauber PM, Key CR. Benign breast biopsy diagnosis and subsequent risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2007 Mar. 16(3):467-72. [View Abstract]
  43. Degnim AC, Visscher DW, Berman HK, Frost MH, Sellers TA, Vierkant RA, et al. Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol. 2007 Jul 1. 25(19):2671-7. [View Abstract]
  44. Dupont WD, Page DL, Parl FF, Vnencak-Jones CL, Plummer WD Jr, Rados MS, et al. Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med. 1994 Jul 7. 331(1):10-5. [View Abstract]
  45. Henderson BE, Bernstein L. The international variation in breast cancer rates: an epidemiological assessment. Breast Cancer Res Treat. 1991 May. 18 Suppl 1:S11-7. [View Abstract]
  46. Kaaks R. Nutrition, hormones, and breast cancer: is insulin the missing link?. Cancer Causes Control. 1996 Nov. 7(6):605-25. [View Abstract]
  47. Stoll BA. Breast cancer and the western diet: role of fatty acids and antioxidant vitamins. Eur J Cancer. 1998 Nov. 34(12):1852-6. [View Abstract]
  48. Holmes MD, Liu S, Hankinson SE, Colditz GA, Hunter DJ, Willett WC. Dietary carbohydrates, fiber, and breast cancer risk. Am J Epidemiol. 2004 Apr 15. 159(8):732-9. [View Abstract]
  49. Holmes MD, Willett WC. Does diet affect breast cancer risk?. Breast Cancer Res. 2004. 6(4):170-8. [View Abstract]
  50. Mediterranean Diet Cuts Some Breast Cancer Risk by 40%. Medscape Medical News. Available at http://www.medscape.com/viewarticle/876981. March 08, 2017; Accessed: March 13, 2017.
  51. van den Brandt PA, Schulpen M. Mediterranean diet adherence and risk of postmenopausal breast cancer: results of a cohort study and meta-analysis. Int J Cancer. 2017 Mar 5. [View Abstract]
  52. Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006 Jul 12. 296(2):193-201. [View Abstract]
  53. Han D, Nie J, Bonner MR, McCann SE, Muti P, Trevisan M, et al. Lifetime adult weight gain, central adiposity, and the risk of pre- and postmenopausal breast cancer in the Western New York exposures and breast cancer study. Int J Cancer. 2006 Dec 15. 119(12):2931-7. [View Abstract]
  54. Kaaks R. Nutrition, insulin, IGF-1 metabolism and cancer risk: a summary of epidemiological evidence. Novartis Found Symp. 2004. 262:247-60; discussion 260-68. [View Abstract]
  55. Lukanova A, Lundin E, Zeleniuch-Jacquotte A, Muti P, Mure A, Rinaldi S, et al. Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Endocrinol. 2004 Feb. 150(2):161-71. [View Abstract]
  56. Baer HJ, Colditz GA, Rosner B, Michels KB, Rich-Edwards JW, Hunter DJ, et al. Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study. Breast Cancer Res. 2005. 7(3):R314-25. [View Abstract]
  57. Ruder EH, Dorgan JF, Kranz S, Kris-Etherton PM, Hartman TJ. Examining breast cancer growth and lifestyle risk factors: early life, childhood, and adolescence. Clin Breast Cancer. 2008 Aug. 8(4):334-42. [View Abstract]
  58. Fuemmeler BF, Pendzich MK, Tercyak KP. Weight, dietary behavior, and physical activity in childhood and adolescence: implications for adult cancer risk. Obes Facts. 2009. 2(3):179-86. [View Abstract]
  59. Laden F, Hunter DJ. Environmental risk factors and female breast cancer. Annu Rev Public Health. 1998. 19:101-23. [View Abstract]
  60. Coyle YM. The effect of environment on breast cancer risk. Breast Cancer Res Treat. 2004 Apr. 84(3):273-88. [View Abstract]
  61. Gammon MD, Eng SM, Teitelbaum SL, Britton JA, Kabat GC, Hatch M, et al. Environmental tobacco smoke and breast cancer incidence. Environ Res. 2004 Oct. 96(2):176-85. [View Abstract]
  62. Smith-Bindman R. Environmental causes of breast cancer and radiation from medical imaging: findings from the Institute of Medicine report. Arch Intern Med. 2012 Jul 9. 172(13):1023-7. [View Abstract]
  63. Carmichael A, Sami AS, Dixon JM. Breast cancer risk among the survivors of atomic bomb and patients exposed to therapeutic ionising radiation. Eur J Surg Oncol. 2003 Jun. 29(5):475-9. [View Abstract]
  64. Clemons M, Loijens L, Goss P. Breast cancer risk following irradiation for Hodgkin's disease. Cancer Treat Rev. 2000 Aug. 26(4):291-302. [View Abstract]
  65. Hill DA, Gilbert E, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, et al. Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. Blood. 2005 Nov 15. 106(10):3358-65. [View Abstract]
  66. Jenkins K. Night Shifts Increase Breast Cancer Risk, Especially for Nurses. Medscape Medical News. Available at https://www.medscape.com/viewarticle/891048. January 08, 2018; Accessed: February 13, 2018.
  67. Yuan X, Zhu C, Wang M, Mo F, Du W, Ma X. Night Shift Work Increases the Risks of Multiple Primary Cancers in Women: A Systematic Review and Meta-analysis of 61 Articles. Cancer Epidemiol Biomarkers Prev. 2018 Jan. 27 (1):25-40. [View Abstract]
  68. Li CI, Daling JR. Changes in breast cancer incidence rates in the United States by histologic subtype and race/ethnicity, 1995 to 2004. Cancer Epidemiol Biomarkers Prev. 2007 Dec. 16(12):2773-80. [View Abstract]
  69. American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed: January 17, 2019.
  70. Glass AG, Lacey JV Jr, Carreon JD, Hoover RN. Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst. 2007 Aug 1. 99(15):1152-61. [View Abstract]
  71. Jemal A, Ward E, Thun MJ. Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women. Breast Cancer Res. 2007. 9(3):R28. [View Abstract]
  72. Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19. 356(16):1670-4. [View Abstract]
  73. Katalinic A, Rawal R. Decline in breast cancer incidence after decrease in utilisation of hormone replacement therapy. Breast Cancer Res Treat. 2008 Feb. 107(3):427-30. [View Abstract]
  74. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9. 362(9382):419-27. [View Abstract]
  75. Anderson WF, Reiner AS, Matsuno RK, Pfeiffer RM. Shifting breast cancer trends in the United States. J Clin Oncol. 2007 Sep 1. 25(25):3923-9. [View Abstract]
  76. Evidence-based assessment of the impact of the WHI on women’s health. doi: 10.3109/13697137.2012.655564. Burger HG, MacLennan AH, Huang KE, Castelo-Branco C. Climacteric. 2012 Jun. 15(3):281-7.
  77. [Guideline] NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Version 1.2019 — March 14, 2019; Accessed: June 7, 2019.
  78. Baselga J, Seidman AD, Rosen PP, Norton L. HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications. Oncology (Williston Park). 1997 Mar. 11(3 Suppl 2):43-8. [View Abstract]
  79. Nassar H, Wallis T, Andea A, Dey J, Adsay V, Visscher D. Clinicopathologic analysis of invasive micropapillary differentiation in breast carcinoma. Mod Pathol. 2001 Sep. 14(9):836-41. [View Abstract]
  80. Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN. Metaplastic breast cancer: prognosis and response to systemic therapy. Ann Oncol. 1999 Apr. 10(4):413-9. [View Abstract]
  81. Chao TC, Wang CS, Chen SC, Chen MF. Metaplastic carcinomas of the breast. J Surg Oncol. 1999 Aug. 71(4):220-5. [View Abstract]
  82. Chaudary MA, Millis RR, Lane EB, Miller NA. Paget's disease of the nipple: a ten year review including clinical, pathological, and immunohistochemical findings. Breast Cancer Res Treat. 1986. 8(2):139-46. [View Abstract]
  83. Kollmorgen DR, Varanasi JS, Edge SB, Carson WE 3rd. Paget’s disease of the breast: a 33-year experience. J Am Coll Surg. 1998 Aug. 187(2):171-7.
  84. American Heart Association. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect. Available at http://circ.ahajournals.org/content/circulationaha/early/2018/01/31/CIR.0000000000000556.full.pdf. Accessed: January 17, 2019.
  85. Brooks M. BRCA Testing Update: 'Do This, Don't Do That.'. Medscape Medical News. Available at http://www.medscape.com/viewarticle/818267. December 23, 2013; Accessed: February 2, 2018.
  86. [Guideline] Moyer VA. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013 Dec 24. [View Abstract]
  87. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005 Oct 27. 353(17):1784-92. [View Abstract]
  88. Elmore JG, Armstrong K, Lehman CD, Fletcher SW. Screening for breast cancer. JAMA. 2005 Mar 9. 293(10):1245-56. [View Abstract]
  89. Moss SM, Wale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. Lancet Oncol. 2015 Jul 20. [View Abstract]
  90. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014 Feb 11. 348:g366. [View Abstract]
  91. García-Albéniz X, Hernán MA, Logan RW, Price M, Armstrong K, Hsu J. Continuation of Annual Screening Mammography and Breast Cancer Mortality in Women Older Than 70 Years. Ann Intern Med. 2020 Feb 25. [View Abstract]
  92. Brawley OW. On Mammography Screening for Women Older Than 70 Years. Ann Intern Med. 2020 Feb 25. [View Abstract]
  93. Chustecka Z. FDA Warning on Nipple Aspirate Test as Breast Cancer Screen. Medscape Medical News. Dec 13 2013.
  94. Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002 Mar 16. 359(9310):909-19. [View Abstract]
  95. Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003 Apr 26. 361(9367):1405-10. [View Abstract]
  96. Noble M, Bruening W, Uhl S, Schoelles K. Computer-aided detection mammography for breast cancer screening: systematic review and meta-analysis. Arch Gynecol Obstet. 2009 Jun. 279(6):881-90. [View Abstract]
  97. Barclay L. Digital mammography: direct outperforms computed radiography. Medscape Medical News. May 14, 2013.
  98. Chiarelli AM, Edwards SA, Prummel MV, Muradali D, Majpruz V, Done SJ, et al. Digital compared with screen-film mammography: performance measures in concurrent cohorts within an organized breast screening program. Radiology. 2013 May 14. [View Abstract]
  99. Humphrey LL, Helfand M, Chan BK, Woolf SH. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002 Sep 3. 137(5 Part 1):347-60. [View Abstract]
  100. Ward E, Jemal A, Thun M. Regarding "Increase in breast cancer incidence in middle-aged women during the 1990s". Ann Epidemiol. 2005 Jul. 15(6):424-5; author reply 426-7. [View Abstract]
  101. US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 Nov 17. 151 (10):716-26, W-236. [View Abstract]
  102. Smith RA, Saslow D, Sawyer KA, Burke W, Costanza ME, Evans WP 3rd, et al. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin. 2003 May-Jun. 53(3):141-69. [View Abstract]
  103. [Guideline] Oeffinger KC, Fontham ETH, Etzioni R, et al. Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. JAMA. October 20, 2015. 314:
  104. [Guideline] Wilt TJ, Harris RP, Qaseem A, et al. Screening for Cancer: Advice for High-Value Care From the American College of Physicians. Ann Intern Med. 2015. 162:718-725.
  105. American College of Radiology. ACR Statement on Breast Tomosynthesis. Available at https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Breast-Tomosynthesis. November 24, 2014; Accessed: January 17, 2019.
  106. Bernardi D, Macaskill P, Pellegrini M, Valentini M, Fantò C, Ostillio L, et al. Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study. Lancet Oncol. 2016 Aug. 17 (8):1105-13. [View Abstract]
  107. Kerlikowske K, Zhu W, Tosteson A, et al. Identifying Women With Dense Breasts at High Risk for Interval Cancer: A Cohort Study. Ann Intern Med. 2015. 162:673-681.
  108. Buist DSM, Abraham L, Lee CI, Lee JM, Lehman C, O'Meara ES, et al. Breast Biopsy Intensity and Findings Following Breast Cancer Screening in Women With and Without a Personal History of Breast Cancer. JAMA Intern Med. 2018 Feb 12. [View Abstract]
  109. Taillefer R. Clinical applications of 99mTc-sestamibi scintimammography. Semin Nucl Med. 2005 Apr. 35(2):100-15. [View Abstract]
  110. Chen AC, Paulino AC, Schwartz MR, Rodriguez AA, Bass BL, Chang JC, et al. Prognostic markers for invasive micropapillary carcinoma of the breast: a population-based analysis. Clin Breast Cancer. 2013 Apr. 13(2):133-9. [View Abstract]
  111. Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017 Mar 14. [View Abstract]
  112. [Guideline] Lyman GH, Temin S, Edge SB, Newman LA, Turner RR, Weaver DL, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2014 May 1. 32(13):1365-83. [View Abstract]
  113. [Guideline] Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007 Jan 1. 25(1):118-45. [View Abstract]
  114. Tang G, Cuzick J, Costantino JP, Dowsett M, Forbes JF, Crager M, et al. Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors. J Clin Oncol. 2011 Nov 20. 29(33):4365-72. [View Abstract]
  115. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. June 3, 2018.
  116. Sparano JA, Gray RJ, Makower DF, et al. Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial. JAMA Oncol. 2019 Sep 30. [View Abstract]
  117. Johnson K. For node-positive breast cancer, axillary radiation is best. Medscape Medical News. June 6, 2013.
  118. Haviland JS, Owen JR, Dewar JA, et al, on behalf of the START Trialists' Group. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013 Sep 18. [View Abstract]
  119. Mulcahy N. Ten-year data confirm shorter radiotherapy best for breast cancer. Medscape Medical News. September 19, 2013.
  120. Chustecka Z. New guideline on lumpectomy margins should reduce re-excision. Medscape Medical News. February 11, 2014.
  121. [Guideline] Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer. Int J Radiat Oncol Biol Phys. 2014 Mar 1. 88(3):553-64. [View Abstract]
  122. [Guideline] American Society of Breast Surgeons. Consensus Guideline on Accelerated Partial Breast Irradiation. Available at https://www.breastsurgeons.org/about/statements/PDF_Statements/APBI.pdf. June 5, 2018; Accessed: January 17, 2019.
  123. Mulcahy N. Is whole-breast radiation better in older women?. Medscape Medical News. February 6, 2014.
  124. Smith GL, Jiang J, Buchholz TA, Xu Y, Hoffman KE, Giordano SH, et al. Benefit of adjuvant brachytherapy versus external beam radiation for early breast cancer: impact of patient stratification on breast preservation. Int J Radiat Oncol Biol Phys. 2014 Feb 1. 88(2):274-84. [View Abstract]
  125. Kuske RR, Young SS. Breast brachytherapy versus whole-breast irradiation: reported differences may be statistically significant but clinically trivial. Int J Radiat Oncol Biol Phys. 2014 Feb 1. 88(2):266-8. [View Abstract]
  126. Mulcahy N. One-Stop' Radiotherapy Saves Time With Breast Cancer. Medscape Medical News. Available at http://www.medscape.com/viewarticle/814157. Accessed: April 5, 2017.
  127. Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2013 Nov 8. [View Abstract]
  128. Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Nov 8. [View Abstract]
  129. Ebctcg Early Breast Cancer Trialists' Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014 Mar 19. [View Abstract]
  130. Chustecka Z. Radiotherapy for Early Breast Cancer and 1 to 3 Positive Nodes. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/822213. Accessed: March 24, 2014.
  131. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015 Jul 23. [View Abstract]
  132. Narod SA, Iqbal J, Giannakeas V, Sopik V, Sun P. Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma In Situ. JAMA Oncol. 2015 Aug 20. [View Abstract]
  133. Mulcahy N. Large DCIS Study Is 'Compelling Case' for Change. Medscape Medical News. Available at http://www.medscape.com/viewarticle/849878. August 20, 2015; Accessed: February 2, 2018.
  134. Esserman L, Yau C. Rethinking the Standard for Ductal Carcinoma In Situ Treatment. JAMA Oncol. 2015 Aug 20. [View Abstract]
  135. Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012 Apr 20. 30(12):1268-73. [View Abstract]
  136. Phillips KA, Milne RL, Rookus MA, Daly MB, Antoniou AC, Peock S, et al. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. J Clin Oncol. 2013 Sep 1. 31(25):3091-3099. [View Abstract]
  137. Nelson R. Tamoxifen Cuts Risk for Breast Cancer in BRCA Carriers. Medscape Medical News. Available at http://www.medscape.com/viewarticle/809174. August 8, 2013; Accessed: April 6, 2017.
  138. Margolese RG, Cecchini RS, Julian TB, Ganz PA, Costantino JP, Vallow LA, et al. Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet. 2016 Feb 27. 387 (10021):849-56. [View Abstract]
  139. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan. 13(1):25-32. [View Abstract]
  140. Barclay L. New ASCO Guidelines Address HER2-Positive Breast Cancer. Medscape Medical News. Available at http://www.medscape.com/viewarticle/824751. May 7 2014; Accessed: April 6, 2017.
  141. [Guideline] Giordano SH, Temin S, Kirshner JJ, et al. Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014 May 5. [View Abstract]
  142. Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1. 24(13):2019-27. [View Abstract]
  143. [Guideline] Partridge AH, Rumble RB, Carey LA, Come SE, Davidson NE, Di Leo A, et al. Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2-Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014 Sep 2. [View Abstract]
  144. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2. 367(5):435-44. [View Abstract]
  145. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017 Sep 1. 35 (25):2875-2884. [View Abstract]
  146. Modi S, Saura C, Yamashita T, and the, DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019 Dec 11. [View Abstract]
  147. O'Shaughnessy J. Gemcitabine combination chemotherapy in metastatic breast cancer: phase II experience. Oncology (Williston Park). 2003 Dec. 17(12 Suppl 14):15-21. [View Abstract]
  148. Perez EA, Hillman DW, Stella PJ, Krook JE, Hartmann LC, Fitch TR, et al. A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer. 2000 Jan 1. 88(1):124-31. [View Abstract]
  149. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1. 24(34):5381-7. [View Abstract]
  150. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan. 16(1):25-35. [View Abstract]
  151. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016 Nov 3. 375 (18):1738-1748. [View Abstract]
  152. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27. 357(26):2666-76. [View Abstract]
  153. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20. 36 (24):2465-2472. [View Abstract]
  154. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15. 20(12):2812-23. [View Abstract]
  155. Biganzoli L, Martin M, Twelves C. Moving forward with capecitabine: a glimpse of the future. Oncologist. 2002. 7 Suppl 6:29-35. [View Abstract]
  156. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15. 344(11):783-92. [View Abstract]
  157. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1. 23(19):4265-74. [View Abstract]
  158. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2001 May 15. 19(10):2722-30. [View Abstract]
  159. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28. 355(26):2733-43. [View Abstract]
  160. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20. 26(24):3950-7. [View Abstract]
  161. Chustecka Z. Novel Drug Approved for Breast Cancer: Palbociclib (Ibrance). Medscape Medical News. Available at http://www.medscape.com/viewarticle/839171. February 3, 2015; Accessed: April 6, 2017.
  162. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan. 16(1):25-35. [View Abstract]
  163. Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor. Novartis. Available at https://www.novartis.com/news/media-releases/novartis-kisqalir-ribociclib-lee011-receives-fda-approval-first-line-treatment. March 13, 2017; Accessed: March 17, 2017.
  164. FDA approves first treatment for breast cancer with a certain inherited genetic mutation. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm592347.htm. January 12, 2018; Accessed: January 15, 2018.
  165. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug 10. 377 (6):523-533. [View Abstract]
  166. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23. 379 (8):753-763. [View Abstract]
  167. Schmid P, et al, for the IMpassion130 Trial Investigators. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. October 20, 2018.
  168. Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech, Inc. March 2019. Available at
  169. [Guideline] Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, et al. Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2013 Jul 8. [View Abstract]
  170. Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23. 364(25):2381-91. [View Abstract]
  171. Surgery to Reduce the Risk of Breast Cancer. National Cancer Institute. Available at https://www.cancer.gov/types/breast/risk-reducing-surgery-fact-sheet. August 12, 2013; Accessed: April 6, 2017.
  172. [Guideline] NCCN Clinical Practice Guidelines in Oncology. Breast Cancer Risk Reduction. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Version 1.2018 — February 2, 2018; Accessed: February 2, 2018.
  173. Boughey JC, Attai DJ, Chen SL, Cody HS, Dietz JR, Feldman SM, et al. Contralateral Prophylactic Mastectomy (CPM) Consensus Statement from the American Society of Breast Surgeons: Data on CPM Outcomes and Risks. Ann Surg Oncol. 2016 Oct. 23 (10):3100-5. [View Abstract]
  174. Busko M. Regular Echo Exams Warranted to Detect Radiation-Induced Heart Disease. Medscape Medical News. Available at http://www.medscape.com/viewarticle/808213. Accessed: July 30, 2013.
  175. Lancellotti P, Nkomo VT, Badano LP, Bergler J, Bogaert J, Davin L, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2013 Aug. 14(8):721-40. [View Abstract]
  176. [Guideline] Greenlee H, Balneaves L, Carlson M, et al. Clinical Practice Guidelines on the Use of Integrative Therapies as Supportive Care in Patients Treated for Breast Cancer. J Natl Cancer Inst. 2014. 50:346-358.
  177. Olsson Möller U, Beck I, Rydén L, Malmström M. A comprehensive approach to rehabilitation interventions following breast cancer treatment - a systematic review of systematic reviews. BMC Cancer. 2019 May 20. 19 (1):472. [View Abstract]
  178. Oeffinger KC, Fontham ET, Etzioni R, et al. Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. JAMA. 2015 Oct 20. 314 (15):1599-614. [View Abstract]
  179. Smith RA, Andrews K, Brooks D, DeSantis CE, Fedewa SA, Lortet-Tieulent J, et al. Cancer screening in the United States, 2016: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2016 Mar. 66 (2):95-114. [View Abstract]
  180. Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007 Mar-Apr. 57 (2):75-89. [View Abstract]
  181. [Guideline] Siu AL, U.S. Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016 Feb 16. 164 (4):279-96. [View Abstract]
  182. Moyer VA, U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Feb 18. 160 (4):271-81. [View Abstract]
  183. [Guideline] Practice Bulletin Number 179: Breast Cancer Risk Assessment and Screening in Average-Risk Women. Obstet Gynecol. 2017 Jul. 130 (1):e1-e16. [View Abstract]
  184. [Guideline] Schünemann HJ, Lerda D, Quinn C, et al, European Commission Initiative on Breast Cancer (ECIBC) Contributor Group. Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines. Ann Intern Med. 2019 Nov 26. [View Abstract]
  185. Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Aug 10. 31 (23):2942-62. [View Abstract]
  186. [Guideline] US Preventive Services Task Force., Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, et al. Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019 Sep 3. 322 (9):857-867. [View Abstract]
  187. Lyman GH, Temin S, Edge SB, Newman LA, Turner RR, Weaver DL, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2014 May 1. 32 (13):1365-83. [View Abstract]
  188. [Guideline] Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol. 2020 Jan 13. JCO1902309. [View Abstract]
  189. [Guideline] Morrow M, Van Zee KJ, Solin LJ, Houssami N, Chavez-MacGregor M, Harris JR, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma in Situ. Pract Radiat Oncol. 2016 Sep-Oct. 6 (5):287-95. [View Abstract]
  190. Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Int J Radiat Oncol Biol Phys. 2014 Mar 1. 88 (3):553-64. [View Abstract]
  191. Recht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001 Mar 1. 19 (5):1539-69. [View Abstract]
  192. [Guideline] Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Practical Radiation Oncology. 2018.
  193. Hackethal V. New ASCO Guide for Adjuvant Therapy in Early Breast Cancer. Medscape Medical News [serial online]. Available at http://www.medscape.com/viewarticle/862372. April 22, 2016; Accessed: May 16, 2016.
  194. [Guideline] Giordano SH, Temin S, Kirshner JJ, Chandarlapaty S, Crews JR, Davidson NE, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jul 1. 32 (19):2078-99. [View Abstract]
  195. [Guideline] Denduluri N, Somerfield MR, Eisen A, Holloway JN, Hurria A, King TA, et al. Selection of Optimal Adjuvant Chemotherapy Regimens for Early Breast Cancer and Adjuvant Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. 2016 Apr 18. [View Abstract]
  196. [Guideline] Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol. 2016 May 10. 34 (14):1689-701. [View Abstract]
  197. Brooks M. Tamoxifen for 10 Years an Option: ASCO Guideline Update. Medscape Medical News. Available at http://www.medscape.com/viewarticle/825727. May 27, 2014; Accessed: April 6, 2017.
  198. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol. 2014 Jul 20. 32 (21):2255-69. [View Abstract]
  199. [Guideline] Paluch-Shimon S, Pagani O, Partridge AH, Abulkhair O, Cardoso MJ, Dent RA, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017 Oct. 35:203-217. [View Abstract]
  200. [Guideline] Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J Clin. 2016 Jan-Feb. 66 (1):43-73. [View Abstract]
  201. [Guideline] Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016 Apr 1. 34 (10):1134-50. [View Abstract]
  202. Nelson R. Capecitabine Linked to Potentially Fatal Skin Reactions. Medscape Medical News. Dec 3 2012.
  203. Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17. 388 (10063):2997-3005. [View Abstract]
  204. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16. 380 (20):1929-1940. [View Abstract]
  205. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16. 373 (3):209-19. [View Abstract]
  206. Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2017 Sep 1. 23 (17):5218-5224. [View Abstract]
  207. Goetz MP, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017 Nov 10. 35 (32):3638-3646. [View Abstract]
  208. US Food & Drug Administration. FDA Commissioner announces Avastin decision: Drug not shown to be safe and effective in breast cancer patients. Available at https://wayback.archive-it.org/7993/20170111165229/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279485.htm. Accessed: April 6, 2017.
  209. Iwata H, Im SA, Masuda N, Im YH, Inoue K, Rai Y, et al. PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy-Safety and Efficacy in Asian Patients. J Glob Oncol. 2017 Aug. 3 (4):289-303. [View Abstract]
  210. Summaries for patients. Using medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med. 2013 Nov 19. 159 (10):I-28. [View Abstract]
  211. Ellence [package insert]. New York, NY: Pfizer. Feb 2007.
  212. Xeloda [package insert]. South San Francisco, Calif: Genentech. November 2009.
  213. Herceptin [package insert]. South San Francisco, Calif: Genentech. October 2010.
  214. Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline. January 2010.
  215. Femara [package insert]. East Hanover, NJ: Novartis. April 2010.
  216. Ruiter R, Bijl MJ, van Schaik RH, Berns EM, Hofman A, Coebergh JW, et al. CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen. Pharmacogenomics. 2010 Oct. 11(10):1367-75. [View Abstract]
  217. Fareston [package insert]. Memphis, Tenn: GTX. December 2004.
  218. Chustecka Z. New Guidelines on Chemoprevention for Breast Cancer. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/811553. Accessed: January 30, 2017.
  219. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20. 33 (3):244-50. [View Abstract]

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
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
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
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
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[146] Monoclonal antibody conjugate5.4 mg/kg IV q3weeks60.3%Interstitial lung disease and pneumonitis; neutropenia; LVEF
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[147]



Paclitaxel



1250 mg/m² days 1 and 8



175 mg/m² day 1



Repeat cycle every 21 days
Carboplatin[148]



Paclitaxel



AUC of 6 day 1



200 mg/m² day 1



Repeat cycle every 21 days
Carboplatin[149]



Docetaxel



AUC of 6 day 1



75 mg/m² day 1



Repeat cycle every 21 days
Palbociclib[150]



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[151]



Letrozole



600 mg PO once daily days 1-21



2.5 mg PO once daily days 1-28



Repeat cycle every 28 days
Paclitaxel[152] 90 mg/m² day 1, 8, and 15Repeat cycle every 28 days
Abemaciclib



Fulvestrant[145]



150 mg PO BID



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



Repeat cycle every 28 days
Ribociclib[153]



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
Trastuzumab



Vinorelbine



4 mg/kg loading dose then



2 mg/kg weekly



25 mg/m² day 1 weekly



 
Lapatinib



Capecitabine



1250 mg PO daily



2000 mg/m² daily days 1-14



Repeat cycle every 21 days
Paclitaxel



Lapatinib



175 mg/m2



1500 mg/d



Repeat cycle every 3 weeks
AUC = area under the curve (systemic exposure)



References for chemotherapy regimens: XT,[154] XP,[155] XN,[155] HER2-positive metastatic breast cancer regimens[156, 157, 158, 159]



  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
  NCCN ACS/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



Signs of recurranceNo recommendationEducated and counseled about signs and symptoms 
Mammography6 mo after post-BCS radiation therapy



Annually thereafter



Annually 
MRINo recommendationNot recommended for routine screening unless patient



meets high-risk criteria for increased surveillance



Pelvic examinationAnnually, for women on tamoxifen



Annual exam if uterus present



No recommendation
Routine blood testsNot recommendedNot recommended
Imaging studiesNot recommendedNot recommended
Tumor marker testingNot recommendedNo recommendation