Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

105. Breast Cancer

Chad M. Barnett, Laura Boehnke Michaud, and Francisco J. Esteva


 Images Breast cancer is usually diagnosed in the early stages when it is a highly curable malignancy.

 Images Local therapy of early-stage breast cancer consists of modified radical mastectomy or lumpectomy plus external-beam radiation therapy. The surgical approach to the ipsilateral axilla may consist of a lymph node mapping procedure with sentinel lymph node biopsy or a full level I/II axillary lymph node dissection.

 Images Adjuvant endocrine therapy reduces the rates of relapse and death in patients with hormone receptor–positive early breast cancer. Adjuvant chemotherapy reduces the rates of relapse and death in all patients with early-stage breast cancer.

 Images The choice of the most appropriate chemotherapy, endocrine therapy, and anti-HER2 regimen is complex and rapidly changing as results from ongoing randomized clinical trials are reported.

 Images Neoadjuvant chemotherapy and biotherapy are appropriate for selected patients with early breast cancer and most patients with locally advanced breast cancer and inflammatory breast cancer followed by local therapy and further adjuvant systemic therapy as indicated.

 Images Whereas the goal of adjuvant and neoadjuvant chemotherapy is curative, the goal of chemotherapy in the metastatic setting is palliative.

 Images Initial therapy of metastatic breast cancer in most women with hormone receptor–positive tumors should include endocrine therapy.

 Images About 60% of women with metastatic breast cancer will respond to chemotherapy regimens; anthracycline- and taxane-containing regimens are the most active.

 Images Anti-HER2 therapies and other biologic or targeted agents (e.g., everolimus) in combination with chemotherapy or endocrine therapy have significantly improved outcomes for selected patients with metastatic breast cancer.

 Images Although controversial, regular screening mammography in women younger than 50 years of age is beneficial, and many national and international studies demonstrate a reduction in the breast cancer mortality rate from annual or biennial screening mammography in women ages 50 to 74 years.


Breast cancer is the most common site of cancer and is second only to lung cancer as a cause of cancer death in American women. It was estimated that 234,580 new cases of breast cancer will be diagnosed and that 40,030 people will die of breast cancer in 2013.1 In addition to invasive breast cancers, it is estimated that 64,640 cases of noninvasive, or in situ, cancer will be diagnosed among women in the United States in 2013.

Female breast cancer incidence rates vary considerably across racial and ethnic groups. The average annual age-adjusted incidence rate from 2004 to 2008 was 122.3 cases per 100,000 among whites, 116.1 cases among African Americans, 92.3 cases in Hispanics, 89.2 cases in American Indians and Alaska Natives, and 84.9 cases among Asian Americans and Pacific Islanders.2 Reasons for the higher incidence rates in whites than in other racial and ethnic groups may include differences in reproductive and lifestyle factors and access to and use of screening.

Female breast cancer incidence rates have increased for all women combined since 1980, although the rate of increase slowed in the 1990s and has decreased starting in 2000 after peaking in 1999. The decrease in breast cancer incidence of about 7% from 2002 to 2003 is thought to be related to decreased use of postmenopausal hormone replacement therapy (HRT).2 Incidence rates were stable from 2004 to 2008. The incidence of ductal carcinoma in situ (DCIS) also increased rapidly between the early and late 1980s and continues to increase. The increase in DCIS is largely attributed to an increased use of screening mammography because most cases of DCIS manifest solely as clustered microcalcifications seen on mammography.1

Images For all racial and ethnic groups, most breast cancers are diagnosed at an early stage when tumors are small and localized. However, a higher proportion of disease is diagnosed at more advanced stages in African American and other minority women than in white women. The death rate is also higher among African American women than white women despite the lower incidence. From 2004 to 2008, the breast cancer death rate was highest in African Americans (32.0 cases per 100,000 women) followed by whites (22.8), American Indians and Alaska Natives (17.2), Hispanics (15.1), and Asian Americans and Pacific Islanders (12.2).2 The cause of this disparity between white and African American women is widely debated and multifactorial, with possible explanations including access to care, socioeconomic status, cultural differences, higher stage at diagnosis, and more aggressive biologic features. Despite these differences, overall mortality rates from breast cancer in the United States have declined since 1990. These declines have been attributed to increased use of screening and effectiveness of adjuvant treatment.35 Figure 105-1 shows the temporal trends in incidence and mortality by race.


FIGURE 105-1 Breast cancer incidence and mortality rates by race, 1975 to 2009. (Data from Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2009 [Vintage 2009 Populations]. Bethesda, MD: National Cancer Institute. 2009,

The median age at diagnosis for breast cancer is between the ages of 60 and 65 years.2 Although lung cancer is the leading cause of cancer deaths for women regardless of age, breast cancer is the leading cause of cancer deaths for females between the ages of 20 and 59 years.1


The two variables most strongly associated with the occurrence of breast cancer are gender and age. Although one commonly thinks of breast cancer as a disease confined to women, about 2,240 cases of male breast cancer were estimated to be diagnosed in the United States in 2013.1 Male gender had been considered a poor prognostic factor in some investigations, but it is now believed that higher mortality rates in men are attributable to more advanced disease at the time of diagnosis. When stage and other known prognostic factors are controlled for, the clinical outcome for men with breast cancer is comparable to that of women.6 Treatment of breast cancer in men is similar to treatment of breast cancer in women.

The incidence of breast cancer increases with advancing age. A frequently quoted breast cancer statistic is that one in eight women will develop breast cancer during her lifetime. It should be emphasized that this is a cumulative lifetime risk of developing the disease from birth to death. The one-in-eight women figure is often misinterpreted by women who assume that it translates into one in eight women being diagnosed with breast cancer each year. A more useful method of presenting the risk data is based on age intervals.7 Table 105-1 shows that the risk of a woman developing breast cancer before the age of 40 years is about one in 203, and more than half the risk occurs after age 60 years.

TABLE 105-1 Risk of Developing Breast Cancer, Women, All Races, 2006 to 2008


An understanding of the relationship between age and the incidence of breast cancer is particularly relevant when one discusses “risk factors” or factors other than age that increase a woman’s probability of developing breast cancer. The relative risk (RR) of developing breast cancer for an individual woman in a defined risk group is usually multiplied by the probability of a woman developing breast cancer during her lifetime, and this figure is taken as the cumulative lifetime risk of that individual developing breast cancer. However, the risk of developing breast cancer depends on age. Therefore, a more meaningful way to counsel patients regarding their risk of developing breast cancer based on the presence of a known risk factor incorporates an age-specific incidence rate, not cumulative lifetime risk. For example, if a 40-year-old woman with a strong family history of breast cancer has a RR ratio of 2.0, her risk of developing breast cancer by the age of 50 years is only 7.6% (2 × 3.8), not 24.6% (2 × 12.3) (Table 105-1). It is also important to note that recognized risk factors are not additive in a simple mathematical sense. Finally, most women with breast cancer have no identifiable major risk factor, indicating that the search for the etiology of this disease is largely incomplete.

A number of calculators are available to estimate a patient’s risk of developing breast cancer. The National Cancer Institute has an online version of the Breast Cancer Risk Assessment Tool ( This tool is based on a statistical model known as the Gail model, derived from data from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s. The Breast Cancer Risk Assessment Tool was designed for healthcare professionals to project a woman’s individualized risk for invasive breast cancer over a 5-year period and over her lifetime. This model has been shown to provide accurate estimates in white women, but it has not been validated for other racial and ethnic groups and other subgroups, including those with genetic risk factors. Other risk assessment models also exist, each taking into account different risk factors. Gail and colleagues have developed a similar model for assessing the risk of developing breast cancer in African American women.8 These empiric models may not be as useful for women with a history suggestive of hereditary breast cancer. Thus, no one model is appropriate for every patient.

Endocrine Factors

A number of endocrine factors have been linked to the incidence of breast cancer.9,10 Many of these relate to the total duration of menstrual life. Early menarche, generally defined as menstruation beginning before age 12 years, increases the cumulative lifetime risk of breast cancer development. Similarly, a late age of natural menopause (age 55 years or later) increases the risk of breast cancer development, although to a lesser degree than early menarche.9Conversely, bilateral oophorectomy before age 40 years reduces the risk of developing breast cancer.

Nulliparity and a late age at first birth (≥30 years) are reported to increase the lifetime risk of developing breast cancer. It is suggested that the period between the onset of menses and the age of first pregnancy provides a “window of initiation” for the development of breast cancer. This is a time when an unbalanced hormonal environment reacts with the abundant and highly responsive breast tissue. Investigators postulate that international differences in age of menarche, age at menopause, and childbearing may account for a substantial part of the international differences in the incidence of breast cancer.

Many studies have evaluated the relationship between exogenous hormones and the development of breast cancer. Postmenopausal estrogen replacement therapy has been the subject of several epidemiologic studies and meta-analyses, with conflicting results. The National Cancer Institute (NCI)–funded Women’s Health Initiative (WHI) is a series of clinical trials designed to investigate the risks and benefits of treatment strategies that could affect women’s health issues, such as breast cancer. The estrogen plus progestin trial randomized more than 16,000 postmenopausal women to take conjugated equine estrogen combined with medroxyprogesterone or a placebo.11 This study reported an increased risk of breast cancer (38 vs. 30 cases per 10,000 person-years; RR ratio = 1.26; 95%; confidence interval [CI], 1.00–1.59) in women taking combined estrogen and progestin for an average of 5.2 years compared with those receiving placebo. Analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registries showed that the age-adjusted incidence rate of breast cancer in women in the United States in 2003 fell by 6.7% compared with 2002.12 This decrease in breast cancer incidence seems to be temporally associated with the first report of the WHI study and subsequent decrease in estrogen and progestin HRT use among postmenopausal women. Additional follow-up of patients in this trial confirms a decrease in breast cancer incidence after cessation of estrogen and progestin.13 In the estrogen alone trial, more than 10,000 women who had a hysterectomy and therefore did not require progestin therapy because of a decreased risk of endometrial carcinoma were randomized to estrogen alone or placebo.14 The risk of breast cancer was not increased in women who received estrogen alone compared with those who received placebo. With additional follow-up, the incidence of breast cancer in women in this study was actually lower in patients who received estrogen compared with those who received placebo.15However, the authors concluded that estrogen alone may not reduce the incidence of breast cancer in patients at increased risk and therefore should not be used specifically for breast cancer risk reduction. Unresolved issues remain as to whether lower doses or short-term use of estrogen or estrogen–progestin for menopausal symptoms can be safe and effective. A longer duration of HRT and concurrent use of progestins appear to contribute to breast cancer risk. The use of postmenopausal HRT in women with a history of breast cancer is generally contraindicated. Women who are considering HRT should carefully consider the risks versus benefits (see Chap. 65) for a detailed discussion of HRT).

Epidemiologic studies of oral contraceptives do not show a consistent relationship between use of birth control pills and breast cancer risk. Results are conflicting, and assessment of the studies should consider the particular oral contraceptive products involved, daily and cumulative doses of the hormones administered, and latency period for development of breast cancer. A meta-analysis of 13 prospective cohort studies conducted between the years of 1989 and 2010 reported a nonsignificant increase in breast cancer incidence for patients who used oral contraceptives compared with those who had never used oral contraceptives.16 Newer formulations of oral contraceptives contain lower hormone concentrations, and the authors of this meta-analysis were not able to differentiate breast cancer risk based on the formulations of oral contraceptives. It is also important to note that oral contraceptives are known to reduce the risk of ovarian and endometrial cancers. Most experts believe that the safety and benefits of low-dose oral contraceptives currently outweigh the potential risks.

Genetic Factors

Both personal and family histories influence a woman’s risk of developing breast cancer. A personal history of breast cancer is associated with an increased risk of developing contralateral breast cancer. Cancers of the uterus and ovary are also associated with an increased risk of developing breast cancer. A number of cancer family syndromes include breast cancer in association with other types of cancers.

Many women have “lumpy breasts” or have a clinical diagnosis of fibrocystic breast disease or benign breast disease. Nonproliferative lesions, such as cysts or simple fibroadenomas, do not increase the risk of breast cancer. Proliferative lesions without atypia, such as intraductal papillomatosis, are associated with a mildly elevated breast cancer risk of about 1.5 to 2.0 times that of the general population. Atypical hyperplasias are classified as either ductal or lobular units, and these lesions may increase a woman’s risk for breast cancer to about 4.5 to 5.0 times that of the general population.17

Dense breast tissue reduces the sensitivity of mammography in detecting breast cancer and is associated with an increased risk of breast cancer. The risk of breast cancer in women with dense breasts (defined by mammography) has been estimated to be between two and six times that of women of the same age with little density.18 Many variables, including age, weight, menopausal status, HRT, and parity, can influence mammographic breast density. Genetic factors may also play a role in this finding because mammographic breast density has been shown to have high heritability and is also strongly associated with a positive family history of breast cancer.

The percentage of all breast cancers in the U.S. population that can be attributed to family history is about 10%. Empirical estimates of the risks associated with particular patterns of family history of breast cancer indicate the following19:

   1. Having any first-degree relative with breast cancer increases a woman’s risk of breast cancer about 1.5- to 3-fold. Risk increases with increasing numbers of affected first-degree relatives.

   2. The risk is affected by both a woman’s own age and the age of the relative when diagnosed. A higher risk is seen when a woman and her relative at diagnosis are younger than 50 years.

   3. The risk associated with having any second-degree relative with breast cancer is complex and depends on other family history patterns. However, the risk is generally lower than that of first-degree relatives.

   4. Affected family members on both the maternal and the paternal sides are important to consider in evaluation of risk.

Although women with a family history of breast cancer are at increased risk for the disease, the diagnosis of breast cancer is still uncommon in young women even with a positive family history.

Germ-line mutations in either BRCA1 or BRCA2 are associated with an increased risk for breast and ovarian cancer. These genes function as tumor suppressor genes, maintaining genomic integrity and DNA repair. Compared with an average woman’s 13% lifetime risk of developing breast cancer, the probability of developing breast or ovarian cancer by the age of 70 years in women with a BRCA1 or BRCA2mutation is estimated to be 57% and 49% for breast cancer and 40% and 18% for ovarian cancer, respectively.20

The probability of being a BRCA gene mutation carrier is related to ethnicity and family history. Jewish people of Eastern European decent (Ashkenazi Jews) have an unusually high (2.5%) carrier rate of germ-line mutations in BRCA1 and BRCA2 compared with the rest of the U.S. population. Conversely, it is estimated that clinically significant BRCA mutations occur at a frequency of about one in 500 persons in the general, non-Jewish U.S. population.21Testing for BRCA1 and BRCA2 mutations is now widely available, but testing is generally recommended only when there is personal or family history suggestive of hereditary cancer, when the test results can be adequately interpreted, and when results will assist with diagnosis and management. The decision to test an individual for a genetic mutation related to breast cancer risk is complex, and several organizations have published recommendations on genetic susceptibility testing for individuals who meet the criteria for increased risk.2225

Although most genetic causes of breast cancer are attributed to BRCA1 and BRCA2, other genes that have been identified as being associated with hereditary breast cancer include TP53CHK2PTENATM, and others.26

Environmental and Lifestyle Factors

Breast cancer incidence rates vary considerably among countries, which suggests that environmental and lifestyle factors play an important role in the etiology. Compelling evidence is derived from studies of Asian women who migrated to the United States. Although the incidence of breast cancer in Asian women is quite low, the incidence of breast cancer in Asian women who were born in the United States or who migrated from Asia to the United States gradually increases over the individual’s lifetime to equal that of the white population in the same geographic area.27

Diet is an important and modifiable environmental risk factor. Possible relationships between fat intake and steroid hormone metabolism have led to an emphasis on dietary fat as a possible etiologic agent for breast cancer. Epidemiologic data show a positive correlation between higher dietary fat intake and breast cancer risk, which is stronger in postmenopausal than in premenopausal women. In a meta-analysis of 31 case-control and 14 cohort studies on dietary fat and breast cancer, Boyd et al. reported a small but significant RR ratio of 1.13 (95% CI, 1.03–1.25) when comparing the highest and lowest fat intake categories.28 To confirm this association prospectively, the hypothesis that low dietary fat intake reduces breast cancer risk was further tested in the WHI Randomized Controlled Dietary Modification Trial.29More than 48,000 postmenopausal women were randomized to a dietary intervention that consisted of reducing total fat intake to 20% of energy and consuming at least five servings of fruits and vegetables daily and six servings of grains daily versus a comparison group without any dietary interventions. Over an 8-year mean follow-up period, the incidence of invasive breast cancer was not significantly different between the two groups (annualized incidence rate, 0.42% vs. 0.45%; hazard ratio [HR], 0.91; 95% CI, 0.83–1.01). Although there is still much to be learned about the effects of diet on the risk of developing breast cancer, a low-fat diet seems to be a reasonable approach to potentially reduce the risk of breast cancer.

An additional dietary factor to be explored in the breast cancer population includes food-derived heterocyclic amines, which are known carcinogens found commonly in cooked red meat or processed meat. Studies of red or processed meat ingestion and breast cancer incidence are inconsistent, and no association was reported in one meta-analysis.30

Many studies have also examined the association between breast cancer and intake of dietary fiber and micronutrients, including β-carotene, and vitamins A, C, and E. The relationship between vitamins and breast cancer is unclear. No consistent benefit of fruits or vegetable consumption and the risk of breast cancer has been demonstrated.30

Another dietary factor that deserves mention is the possible effect of phytoestrogens on breast cancer risk. Phytoestrogens are natural plant estrogens found in soybean products, seeds, berries, and nuts. The two most studied classes of dietary phytoestrogens are isoflavones and lignans; isoflavones are richer in Asian diets, and lignans are the main source of phytoestrogens in the Western diet.31,32 Because these compounds exhibit weak estrogenic properties, some experts believe that they may function as relative antiestrogens by displacing natural estradiol. However, studies have also reported a potential stimulatory effect on breast tissue. A meta-analysis of observational studies that evaluated phytoestrogen use and the risk of breast cancer suggests that any potential associated risk reduction is modest and may be limited to postmenopausal patients.31 Nonetheless, the effect of phytoestrogens on breast cancer is very controversial, and further research is needed.

Both body weight and height are associated with the incidence of breast cancer. Most studies of premenopausal women show either no relationship with body weight or slightly declining breast cancer risks with increasing body weight. Most studies in postmenopausal women show increasing breast cancer risks with increasing body weight. Accordingly, a meta-analysis by Renehan et al. found that an increase in body mass index was associated with an increase in the risk of breast cancer for postmenopausal women (RR, 1.12; 95% CI, 1.08–1.16; P <0.0001) but had the opposite effect in premenopausal women (RR, 0.92; 95% CI, 0.88–0.97; P <0.001).33 An increase in circulating estrogen is postulated to be the most likely explanation for these results. Although height is not a modifiable risk factor, weight and body composition are modifiable and should be studied further. Maintaining a healthy weight and body composition appear to be beneficial and promote many different health benefits but requires further study in association with the incidence of breast cancer.

Many studies report an inverse association between physical activity and breast cancer risk.34 A review of 19 cohort and 29 case-control studies suggests that the association is stronger for postmenopausal breast cancer than for premenopausal breast cancer. Exercise may provide modest protection against breast cancer, but the relationship is complex. Possible explanations include the effects of physical activity on menstrual characteristics (in premenopausal women), body size, weight, and serum hormone levels. Estrogen-related pathways or other metabolic hormones such as insulin and insulin-like growth factors may influence this relationship. Making healthy choices appears to be the best health advice for women.

Many epidemiologic studies have evaluated the relationship between alcohol and breast cancer. Studies indicate both a modest positive association between alcohol and breast cancer and a dose–response relationship.35 The risk increases with consumption of alcohol in general regardless of the beverage type or woman’s menopausal status. Although the exact mechanism is unknown, the most plausible biologic hypothesis relates to increased levels of estrogen or other reproductive steroid hormones caused by impaired liver function. Although a causal relationship between alcohol consumption and breast cancer has not been proven in a prospective trial, the weight of the available evidence suggests that a relationship (direct or indirect) may exist. Because alcohol consumption is a modifiable risk factor, use in moderation appears to be a sensible approach.

Radiation to the breast tissue is associated with an increased risk of breast cancer, particularly with exposure at a young age (<20 years), again suggesting that a “window of initiation” for breast cancer occurs at a relatively early age. Much of the knowledge about radiation-related breast cancer comes from epidemiologic studies of patients exposed to diagnostic or therapeutic radiation and of Japanese survivors of the atomic bombs.36 Women treated with chest irradiation for Hodgkin lymphoma in childhood or adolescence and survivors of other childhood cancers (in which radiation is used as a mainstay of therapy) are among the populations at greater risk for secondary breast cancers. The risk increases linearly with radiation dose. Exposure to diagnostic x-rays, including annual screening mammography, does not impart a sufficient dose of radiation for clinical concern in the general population. However, the risk of breast cancer after radiation exposure even in low levels in those with genetic risk factors is unclear and is an ongoing area of research.

In conclusion, numerous studies have been performed to investigate potential causative factors in the etiology of breast cancer. Several endocrine, genetic, environmental, and lifestyle factors are associated with the development of breast cancer to varying degrees. Some factors are modifiable, but others are not. Additionally, the impact of individual risk factors may vary depending on other confounding variables such as age, family history, estrogen use, and menopausal status. Although epidemiologic studies provide a large body of the current evidence, they have their limitations, and results are varied. Meta-analyses summarize numerous study results, but heterogeneity of studies may limit the applicability of the evidence. Additional prospective, randomized controlled trials are needed to confirm the importance of factors that are associated with the risk of developing breast cancer.


A painless lump is the initial sign of breast cancer in most women. The typical malignant mass is solitary, unilateral, solid, hard, irregular, and nonmobile. In small numbers of cases, stabbing or aching pain is the first symptom. Less commonly, nipple discharge, retraction, or dimpling may herald the onset of the disease. In more advanced cases, prominent skin edema, redness, warmth, and induration of the underlying tissue may be observed.

The breast is a complex organ composed of skin, subcutaneous tissue, fatty tissue, and branching ductal and glandular structures (Fig. 105-2). Various diseases that affect these structures can produce a palpable mass. In addition, the physiologic changes associated with the menstrual cycle can cause normal breast changes. Common causes of breast masses in young women are fibroadenoma, fibrocystic disease, carcinoma, and fat necrosis.


FIGURE 105-2 Breast anatomy.

Many women detect some breast abnormality themselves, but in the United States, it is increasingly common for breast cancer to be detected during routine screening mammography in asymptomatic women. It is widely accepted that the smaller the mass, the higher the likelihood of cure. Thus, as the number of breast cancer cases found by screening mammography increases, overall survival (OS) of breast cancer patients has improved; however, this decreasing mortality rate is also related to improved systemic therapy.



    • The patient may not have any symptoms because breast cancer may be detected in asymptomatic patients through routine screening mammography.

Local Signs and Symptoms

    • A painless, palpable lump is most common.

    • Less common: pain; nipple discharge, retraction, or dimpling; skin edema, redness, or warmth

    • Palpable local–regional lymph nodes may also be present.

Signs and Symptoms of Systemic Metastases

    • Depend on the site of metastases, but may include bone pain, difficulty breathing, abdominal pain or enlargement, jaundice, or mental status changes

Laboratory Tests

    • Tumor markers such as cancer antigen (CA 27.29) or carcinoembryonic antigen (CEA) may be elevated.

    • Alkaline phosphatase or liver function test results may be elevated in patients with metastatic disease.

Other Diagnostic Tests

    • Mammography (with or without ultrasonography, breast MRI, or both).

    • Biopsy for pathology review and determination of tumor ER or PR status and HER2 status.

    • Systemic staging tests may include chest radiography, chest computed tomography (CT), bone scan, abdominal CT or ultrasonography, or MRI

Breast cancer that is confined to a localized breast lesion is often referred to as earlyprimarylocalized, or curable. Breast cancer that has spread to local–regional lymph nodes is still considered early stage (Fig. 105-3). Unfortunately, breast cancer cells often spread by contiguity, through lymph channels, and through the blood to distant sites. This often occurs early in breast cancer growth, and deposits of tumor cells form in distant sites that are undetected with current diagnostic methods and equipment (micro-metastases). When breast cancer cells can be detected clinically or radiologically in sites distant from the breast, the disease is referred to as advanced or metastaticbreast cancer. Tissues most commonly involved with distant metastases are lymph nodes (other than local–regional lymph nodes), skin, bone, liver, lungs, and brain. Symptoms of bone pain, difficulty breathing, abdominal enlargement, jaundice, and mental status changes may herald the clinical presentation of metastatic breast cancer. A small percentage of women have signs and symptoms of distant metastases when they first seek treatment. In virtually all of them, a neglected breast mass has been present for several months to years. In addition, about half of all patients who initially are treated for localized disease eventually develop signs and symptoms of metastatic breast cancer.


FIGURE 105-3 Lymph node anatomy.


The initial workup for a woman presenting with a breast mass or symptoms suggestive of breast cancer should include a careful history, physical examination of the breast, three-dimensional mammography, and possibly other breast imaging techniques such as ultrasonography or magnetic resonance imaging (MRI). Most breast cancers can be visualized on a mammogram as a mass, a cluster of calcifications, or a combination of these findings. Specific mammographic features associated with the highest risk of malignancy include masses with spiculated margins or an irregular shape and calcifications with a linear or segmental distribution.37 One major factor that affects the ability of mammography to detect cancer includes breast density (the fat-to-glandular tissue ratio of the breast), which may be affected by age, menopausal status, and HRT use. Ultrasonography, MRI, and digital mammography are alternate breast imaging methods that are being investigated for women with dense breasts or other specific subsets of patients with breast cancer (e.g., MRI in patients with inflammatory breast cancer).38 The technical quality of the examination and the expertise of the radiologist are also important factors.

The Breast Imaging Reporting and Data System (BI-RADS) was developed by the American College of Radiology to standardize mammographic reporting.39 There are seven assessment categories (0–6) with four possible recommendations: (a) additional imaging evaluation, (b) routine interval screening, (c) short-term follow-up, and (d) biopsy. The probability of a biopsy positive for malignancy increases from less than 2% for BI-RADS category 3 mammograms to 20% to 30% for category 4 mammograms, to greater than 95% for category 5 mammograms. Similar categories for reporting have also been developed for breast MRI and ultrasonography.

Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or for a palpable mass on physical examination. Three techniques are available: fine-needle aspiration, core-needle biopsy, and excisional biopsy.40 Excisional biopsy completely removes the abnormal tissue. Needle biopsies are performed percutaneously and include both core-needle biopsy (which removes a core of tissue) and fine-needle aspiration (which removes cells from the suspicious site). Core-needle biopsy is the preferred biopsy method for mammographically detected, nonpalpable abnormalities.38 Core-needle biopsy offers a more definitive histologic diagnosis, avoids inadequate samples, and can distinguish invasive from in situ breast cancer (which fine needle biopsy cannot). After confirmation of malignancy via core-needle biopsy, subsequent surgical procedures are performed (either before or after systemic therapy) to assure complete removal of the abnormal tissue.


Breast cancer stage is defined on the basis of the primary tumor extent and size (T1–4), presence and extent of lymph node involvement (N1–3), and presence or absence of distant metastases (M0–1) (Table 105-2 and Fig. 105-4). Although many possible combinations of T and N are possible within a given stage, simplistically, stage 0 represents carcinoma in situ (Tis) or disease that has not invaded the basement membrane of the breast tissue. Stage I represents a small primary invasive tumor without lymph node involvement or with micrometastatic nodal involvement, and stage II disease usually involves regional lymph nodes. Stages I and II are often referred to as early breast cancer. It is in these early stages that the disease is highly curable (99% 5-year survival in patients with disease confined to the breast, node negative). Stage III, also referred to as locally advanced disease, usually represents a large tumor with extensive nodal involvement in which either node or tumor is fixed to the chest wall. Stage IV disease is characterized by the presence of metastases to organs distant from the primary tumor and is often referred to as advanced or metastatic disease as described earlier (23% 5-year survival rate in patients with distant metastases). Most breast cancer today presents in early stages where the prognosis is favorable (93% of newly diagnosed patients have disease confined to the breast or local lymph nodes).2

TABLE 105-2 Tumor, Node, Metastasis Stage Grouping for Breast Cancer



FIGURE 105-4 TNM (tumor, node, metastasis) staging system for breast cancer. (Used with the permission of the American Joint Committee on Cancer [AJCC], Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 7th ed. [2010] published by Springer Science and Business Media LLC,

Staging for breast cancer is separated into two groups, clinical and pathologic. Clinical staging is assigned before surgery and is based on physical examination (assessment of tumor size and presence of axillary lymph nodes), imaging (mammography, ultrasonography, and so on), and pathologic examination of tissues (e.g., biopsy results). Pathologic staging occurs after surgery and uses information from clinical staging but adds data from surgical exploration and resection, such as tumor size at surgery and the involvement of micro- or macro-invasive tumor in the lymph nodes or other metastatic sites. Because of the advent of sentinel lymph node biopsy (SLNB; see the Treatment of Early Breast Cancer section), the assessment of lymph node status has become more complex. The American Joint Committee for Cancer (AJCC) publishes staging criteria for cancers, and the breast cancer criteria were most recently updated in January 2010.41 This staging system is widely accepted and used in all breast cancer patients to determine prognosis and assist with treatment decisions. It is also used to report and track breast cancer diagnoses in tumor registries and databases.


The pathologic evaluation of breast tissue serves to establish the histologic diagnosis and to confirm the presence or absence of other factors believed to influence prognosis.

Invasive Carcinoma

Invasive breast cancers are a histologically heterogeneous group of lesions. Most breast cancers are adenocarcinomas and are classified on the basis of their microscopic appearance as ductal or lobular, corresponding to the ducts and lobules of the normal breast (Fig. 105-2). The various histologic types of breast cancer have different prognoses, but it is unknown whether their response to therapy differs because patients in therapeutic trials are not typically stratified according to histologic type. The five most common types of invasive breast cancer are briefly described.42

Invasive or infiltrating ductal carcinoma is the most common histology, accounting for about 75% of all invasive breast cancers. These tumors commonly spread to the axillary lymph nodes, and their prognosis is poorer than for other histologic types (specifically tubular, medullary, and mucinous). Invasive or infiltrating lobular carcinoma accounts for 5% to 10% of breast tumors. Both clinical and radiologic findings for these tumors may be quite subtle. The typical presentation is an area of ill-defined thickening in the breast in contrast to a prominent lump characteristic of infiltrating ductal carcinoma. Infiltrating lobular carcinoma can also be more difficult to detect by mammography. Overall, infiltrating lobular carcinoma and infiltrating ductal carcinoma have similar likelihoods of axillary node involvement and disease recurrence and death, yet the sites of metastases may differ. Whereas Infiltrating ductal carcinoma more frequently metastasizes to the bone or to the liver, lung, or brain, infiltrating lobular carcinoma tends to metastasize to the leptomeninges, peritoneal surfaces, retroperitoneum, gastrointestinal tract, reproductive organs, and other unusual sites.

The three most common special types of invasive cancer are medullarymucinous, and tubular. The prognosis may be more favorable with these unusual histologies. Medullary carcinoma accounts for fewer than 7% of all breast carcinomas, mucinous (or colloid) carcinoma constitutes about 3%, and tubular carcinoma accounts for about 2% of all breast cancers. Histologies rarely reported include adenocystic carcinoma, carcinosarcomas, metaplastic, cribriform, and papillary carcinoma.

Special situations seen clinically and histologically include Paget’s disease of the breast, phyllodes tumors, and inflammatory breast cancer. Paget’s disease of the breast occurs in 1% to 4% of all patients with breast cancer and is characterized by neoplastic cells in the nipple areolar complex. The patient presents clinically with eczematous changes in the nipple with itching, burning, oozing, bleeding, or some combination of these. In most cases, the nipple changes are associated with an underlying carcinoma in the breast that is usually palpable.

Phyllodes tumors of the breast (also known as cystosarcoma phyllodes) are rare tumors with subtypes that range from benign to malignant. These tumors often enlarge rapidly, are painless, and can appear as fibroadenomas.43

Inflammatory breast cancer is characterized clinically by prominent skin edema, redness and warmth, and induration of the underlying tissue. Biopsies of the involved skin reveal cancer cells in the dermal lymphatics. Inflammatory breast cancer typically has a very rapid onset and is often mistaken for an infectious cellulitis or mastitis. Although it may look somewhat similar to a neglected mass, its presentation with rapid onset and progression of local symptoms distinguishes it from other cases of locally advanced breast cancer. The prognosis of patients with inflammatory breast cancer is poor even if the disease is apparently localized.44

Noninvasive Carcinoma

As with invasive carcinoma, the noninvasive lesions may be divided broadly into ductal and lobular categories. Evidence supports that the development of malignancy is a multistep process and that invasive breast cancer has a preinvasive, in situ phase. During the carcinoma in situ phase, normal epithelial cells undergo genetic alterations that result in malignant transformation. Transformed epithelial cells proliferate and pile up within lobules or ducts but lack the required genetic alterations that enable the cells to penetrate the basement membrane. Therefore, carcinoma in situ is diagnosed when malignant transformation of cells has occurred but the basement membrane is intact.

The widespread use of screening mammography with subsequent biopsy and greater recognition of noninvasive breast carcinoma by pathologists has resulted in a significant increase in the diagnosis of in situ breast cancer over the past decade. Assuming a consistent incidence and survival rates, researchers estimate that the prevalence of noninvasive (in situ) breast will exceed 1 million cases by 2016.45 The natural history of these disorders is not well described, and thus the debate continues regarding carcinoma in situ: Is carcinoma in situ preinvasive cancer or simply a marker of unstable epithelium that represents an increased risk for the development of subsequent aggressive cancer?46,47 Answering this question may change the way noninvasive breast cancers are treated.

Ductal carcinoma in situ is more frequently diagnosed than lobular carcinoma in situ (LCIS). Most cases of DCIS today are found by biopsies performed for clustered microcalcifications seen on screening mammography, a hallmark of this disorder.

The ultimate goal of treatment for noninvasive carcinomas is to prevent the development of invasive disease. If left untreated, it is estimated that 14% to 50% of DCIS lesions will progress to invasive breast cancer.46 Therefore, up to 50% of these tumors do not progress to invasive disease, but identifying this group of patients is not yet feasible, and all diagnoses should be treated. Locoregional treatment of DCIS depends on its location, size, and pathology.48 Treatment options include (a) local excision alone with negative margins, (b) local excision (with negative margins) followed by breast irradiation, and (c) traditional total mastectomy with or without reconstruction. Whole-breast irradiation is recommended after excision to significantly decrease the risk of local recurrence, although there is no evidence that survival differs between the previously mentioned options.48 Excision with negative margins alone without radiation may be considered in patients with small and low-grade DCIS. Mastectomy had been the standard treatment of DCIS for several decades, but long-term survival appears to be equivalent with mastectomy versus local excision and irradiation, and the latter option allows for breast conservation. If more than one area of the breast is involved with DCIS, a mastectomy is the preferred option. Axillary lymph node dissection (ALND) is generally not indicated, although sentinel lymph node biopsy (see the Early Breast Cancer section) may be considered in selected patients.48 Cytotoxic chemotherapy has no role in the treatment of patients with pure DCIS. It is important to determine hormone receptor status on the cancer cells. Tamoxifen treatment for 5 years may be considered in some women with hormone receptor–positive DCIS. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, which randomized women with DCIS to lumpectomy with radiation plus either tamoxifen or placebo, showed a benefit with tamoxifen in reducing ipsilateral breast cancer recurrence (44% reduction; P = 0.03).49 Further subgroup analyses of this trial suggest a benefit for patients with estrogen receptor (ER)–positive DCIS. Ongoing clinical trials are evaluating the role of aromatase inhibitors (AIs) in the treatment of postmenopausal hormone receptor–positive DCIS. These treatment decisions are often difficult to discuss with patients because these treatments have toxicities that are worrisome to most patients. Nonetheless, an open and honest conversation regarding the risks and benefits is warranted.

Lobular carcinoma in situ is a microscopic diagnosis. In these cases, there is generally no palpable mass, and no specific clinical abnormality is noted. Unlike DCIS, LCIS does not generally demonstrate calcifications on mammography and in fact is usually undetectable by mammography. Consequently, the diagnosis of LCIS is usually an incidental finding in biopsy specimens obtained because of symptoms or mammography findings consistent with benign lesions. It is unclear whether LCIS is a precursor lesion to invasive carcinoma or serves as a marker of risk for invasive carcinoma developing somewhere in the breast. The risk for developing invasive carcinoma is about 0.5% to 1% per year, and both invasive ductal carcinoma and invasive lobular carcinoma can occur. In about 30% to 50% of patients, there are multiple foci of LCIS in the ipsilateral breast, and the contralateral breast is also affected. Thus, the risk for the development of breast cancer is equally high in either breast, which makes the management of LCIS very controversial.47 Some experts favor a program of observation, with semiannual physical examination and annual mammography.48 In selected patients with high-risk genetic mutations or strong family history and in women who are particularly anxious about the development of cancer, bilateral mastectomies with or without reconstruction may be considered.50 Radiation and systemic chemotherapy have no role in the management of LCIS. The use of chemoprevention with tamoxifen in premenopausal women or tamoxifen, raloxifene, or exemestane in postmenopausal women may also be considered for risk reduction in these patients.50 See Prevention and Early Detection later for details.5153


The natural history of breast cancer varies among patients, with some having extremely aggressive disease that progresses rapidly and others following a more indolent course. The ability to predict prognosis is extremely important in designing treatment recommendations to maximize quantity and quality of life. A number of pathologic prognostic and predictive factors have been identified. Prognostic factors are characteristics or measurements available at diagnosis or time of surgery that in the absence of adjuvant systemic therapy are associated with recurrence rate, death rate, or other clinical outcomes. Predictive factors are measurements available at diagnosis that are associated with response to a specific therapy. Prognostic and predictive factors fall into three general categories: (a) patient characteristics that are independent of the disease such as age; (b) cancer characteristics such as tumor size or histologic type; and (c) other biomarkers that are measurable parameters in tissues, cells, or fluids, such as hormone receptor status. Ideally, the use of prognostic and predictive factors can limit a specific treatment to patients who are most likely to derive benefit, thus sparing unwanted toxicities in those who are unlikely to benefit.

Age at diagnosis and ethnicity are patient characteristics that may affect prognosis. Some younger patients, particularly those younger than 35 years of age, have more aggressive forms of breast cancer and a worse prognosis. Younger patients are more likely to present with poor prognostic features, such as affected lymph nodes, large tumor size, and tumors negative for hormone receptors. Race and ethnicity may also play a role in breast cancer prognosis. African American women have decreased survival periods compared with white women. The cause of this racial disparity is widely debated, with possible explanations including access to care, socioeconomic status, cultural differences, higher stage at diagnosis, and more aggressive biologic features.

Potentially modifiable prognostic factors include alcohol use, dietary factors, weight, and exercise. The association between breast cancer prognosis and alcohol consumption is not as strong as with alcohol and breast cancer risk. A review of seven observational studies showed that postdiagnosis alcohol consumption was not associated with breast cancer outcomes.54 Two randomized controlled studies examined the effects of diet on the risk of breast cancer with conflicting results, primarily focusing on lowering dietary fat.55,56 One study found an improvement in disease-free survival (DFS) with incorporation of a low-fat diet (less than 15% dietary fat per day versus no intervention),56but another study found no difference in recurrence rates between two dietary intervention approaches (both incorporating a low-fat, high-fiber approach).55 Although these studies asked different questions and had many confounding variables that potentially affected the results, most clinicians recommend that breast cancer survivors eat a low-fat, high-fiber diet and maintain a healthy weight. Obesity at the time of a breast cancer diagnosis has been shown to increase the risk of breast cancer–specific and overall mortality compared with nonobese breast cancer patients, although the impact of weight loss in this population is unclear.54 Observational studies have reported that exercise in women after a diagnosis of breast cancer may also decrease the likelihood of breast cancer recurrence and breast cancer–related death.54 Based on these data, agencies such as the American Cancer Society (ACS) have recognized that physical activity, weight control, and diet are potentially modifiable risk factors for reducing the risk of recurrent breast cancer and other comorbidities (e.g., heart disease, diabetes).57

Disease characteristics that have been shown to provide important prognostic information include lymph node status, tumor size, histologic subtype, nuclear or histologic grade, lymphatic and vascular invasion, and proliferation indices.

Tumor size and the presence and number of involved lymph nodes are established primary factors in assessing the risk for breast cancer recurrence and subsequent metastatic disease. Table 105-3 shows 5-year survival rates according to size of the primary tumor and axillary node involvement. The major factor that influences the likelihood of recurrence is the presence of positive lymph nodes. However, regardless of lymph node status, the size of the primary tumor remains an independent prognostic factor for disease recurrence.

TABLE 105-3 Five-Year Survival Rates (%) According to Tumor Size and Axillary Lymph Node Status


The number of affected lymph nodes is directly related to the risk of disease recurrence. The revised staging system for breast cancer recognizes the absolute number of positive nodes as a prognostic factor: N1 represents one to three positive nodes, N2 represents four to nine positive nodes, and N3 represents 10 or more positive nodes in its pathologic staging system.41 The relationship between tumor size and lymph node status is complex and not a simple grouping (see discussion below).

Certain histologic subtypes and clinical presentation of breast cancer have prognostic importance. As mentioned earlier, because women with pure tubular or mucinous tumors have more favorable outcomes than those with invasive ductal carcinomas, treatment recommendations may differ.48 Inflammatory breast cancer, although a clinical designation and not a distinct histologic subtype, is associated with a poor prognosis.44

Nuclear grade and tumor (histologic) differentiation are known independent prognostic indicators. Several histologic grading systems have been developed, most of which grade tumors with a score from 1 to 3: grade 1, well differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated. Higher grade tumors are associated with higher rates of distant metastasis and poorer survival. This factor aids in making treatment decisions, particularly for patients with small tumors and negative lymph nodes.

Lymphatic and vascular invasion (LVI), defined as evidence of tumor emboli in lymphatic or vascular spaces, is a poor prognostic factor likely representing ability of the cancer to spread via hematogenous routes. However, the utility of this as a prognostic factor is largely unknown and is not currently included in either staging or treatment guidelines.41,48

The rate of tumor cell proliferation also is associated with risk of breast cancer recurrence. Rate of cell proliferation can be evaluated with various techniques, including (1) mitotic index, which counts the number of mitotic bodies; (2) thymidine-labeling index or S-phase fraction with DNA flow cytometry, which determines the percentage of tumor cells actively dividing; or (3) the use of monoclonal antibodies (MoABs) to antigens present on proliferating cells, such as Ki-67. In a meta-analysis of 85 studies and nearly 33,000 patients, proliferation markers (including Ki-67, mitotic index, proliferating cell nuclear antigen, and thymidine or bromodeoxyuridine labeling index) were associated with significantly shorter disease-free and OS periods.58 These proliferation indices are additional factors that may be useful in decision making and may predict for responsiveness to chemotherapy, although this is still controversial.

Hormone receptors are not strong prognostic markers but are used clinically to predict response to endocrine therapy. Hormone receptors are nuclear transcription factors that, upon ligand binding, activate a variety of signal transduction pathways that result in cell growth and proliferation. Determination of both ER and progesterone receptor (PR) status is an established procedure that is important in the management of breast cancer. Immunohistochemistry is used to determine the level (i.e., quantity) of hormone receptors, which is important for predictive ability. Other methods of determining ER and PR status, such as mRNA expression, are under investigation but have not been validated as predictive markers. Hormone receptors are most valuable in predicting response to endocrine therapy. About 60% to 70% of patients with ER-positive and PR-positive tumors will respond to hormonal manipulation. More recently, the importance of PR has come under question because response to tamoxifen has been shown to be related to ER status independent of PR status.4 Guidelines for testing of ER and PR status are available and recommend standards for what tumors to test and methodologic guidelines for pathologists.59About 50% to 70% of patients with primary or metastatic breast cancer have hormone receptor–positive tumors. Hormone receptor positivity, more common in postmenopausal women, is associated with a higher response to endocrine therapy and a longer DFS.

The HER2/neu (HER2) gene is located on chromosome 17q21 and encodes a 185-kilodaton transmembrane tyrosine kinase growth factor receptor. The HER2 protein is normally expressed at low levels in the epithelial cells of normal breast tissue. HER2 is a member of the HER growth factor receptor family, and its overexpression is associated with transmission of growth signals that control aspects of normal cell growth and division. HER2overexpression occurs in about 20% to 30% of breast cancers and is associated with increased tumor aggressiveness, increased rates of recurrence, and increased mortality rates. In some studies, HER2 gene amplification and protein overexpression, measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively, correlates with factors associated with a poor prognosis. HER2-positive status clearly predicts response to trastuzumab, which is a MoAB directed against the extracellular domain of the HER2 receptor. Tumors that are either IHC 3+ or FISH positive for gene amplification are considered to be positive for HER2.60 For equivocal results of IHC (2+) or FISH, confirmatory testing with the alternate test is recommended. HER2 gene amplification or protein overexpression has traditionally been considered a poor prognostic factor. However, more recent data suggest that patients with HER2-positive metastatic breast cancer treated with trastuzumab have improved survival rates compared with patients with HER2-negative metastatic breast cancer or patients with HER2-positive metastatic breast cancer who do not receive trastuzumab.61 These results demonstrate the powerful impact trastuzumab therapy has made on improving patient outcomes.

Although there is a growing understanding of the prognostic significance of individual factors, it is not clear how each factor contributes to the overall prognosis for an individual patient. Computer-aided models, including Adjuvant! (, are available that combine patient- and tumor-related variables to estimate overall prognosis for individual patients with early stage breast cancer and aid in decisions regarding adjuvant systemic therapy.62 Such programs have limitations and should be used by healthcare professionals and not directly by patients because of the importance of accurate data entry, selection of different treatment options, and appropriate interpretation of results (see Systemic Adjuvant Therapy later).

Genetic profiling is also being used to provide prognostic and predictive information on clinical outcomes of breast cancer.62 The Oncotype DX assay uses a reverse-transcription polymerase chain reaction (RT-PCR) assay of 21 genes to predict the likelihood of distant recurrence in lymph node–negative and ER-positive breast cancer patients treated with tamoxifen. MammaPrint is another molecular prognostic test that uses DNA microarray analysis to measure the activity of a set of 70 genes to determine the likelihood of breast cancer recurrence in women with stage I or II breast cancer, tumor size 5 cm or smaller, and no lymph node involvement. Further details on these assays are available in the Systemic Adjuvant Therapy section later.

Novel molecular markers that have shown prognostic and predictive significance include urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1, cyclin E, and the presence of tumor cells in bone marrow or circulating blood.63 Prospective validation studies will determine whether these tests can be used to assist decision making in individual patients.

In summary, lymph node status and tumor size are two significant prognostic factors that assist clinicians in estimating prognosis and making treatment recommendations for most breast cancer patients (see also Systemic Adjuvant Therapy later). Although the risk of recurrence is clearly high in patients with large primary tumors or lymph node–positive disease, many patients with small primary tumors and lymph node–negative disease will still develop metastases, yet our ability to accurately identify these individual patients is limited. Evaluation of additional prognostic factors can help identify which patients will have a good outcome with local therapy alone and which patients with aggressive features who would benefit from more aggressive, multimodality treatment. Despite these markers, a large proportion of patients will likely be treated unnecessarily with systemic adjuvant therapy (see later discussion), and better prognostic and predictive tools are needed to better select patients to undergo these toxic and costly treatments and procedures.


Early Breast Cancer (Stage I and II)

Desired Outcomes

The desired therapeutic outcome of adjuvant therapy of breast cancer differs significantly from that of metastatic disease. Adjuvant therapy—chemotherapy, biologic therapy, and hormonal therapy—is administered with curative intent. The rationale for adjuvant therapy is that breast cancer, even when diagnosed in early stages when clinical evidence of distant spread is not apparent, is a systemic disease that spreads early to distant sites. Adjuvant therapy is intended to eradicate micrometastases and thus cure the patient of breast cancer. A predetermined number of cycles of adjuvant therapy or years of biologic or hormonal therapy (or both) are administered. The goals of neoadjuvant therapy are to eradicate micrometastatic disease, determine prognosis, and potentially conserve the breast tissue for a better cosmetic result. Adjuvant and neoadjuvant chemotherapy is often associated with significant toxicity. Clinicians and patients must weigh the short- and long-term risks of chemotherapy, biological therapy, and endocrine therapy with the benefits of lowering the risk of breast cancer recurrence.

Locoregional Therapy

Images Most patients presenting with breast cancer today have an in situ tumor, a small invasive tumor with negative lymph nodes (stage I), or a small invasive tumor with axillary lymph node involvement (stage II). Surgery alone can cure most, if not all, patients with in situ cancers; 70% to 80% of patients with stage I; and about half of all patients with stage II cancers. The choice of surgical procedures has changed drastically over the past 50 years. This is partly a result of changes in our understanding of the biology of breast cancer and is partly a result of a series of well-conducted clinical trials performed over this time period.

Over the years, many trials have investigated reducing the amount of surgery required to maintain acceptable cosmetic results and rates of local and distant recurrence and mortality. Breast-conserving therapy (BCT) includes removal of part of the breast, surgical evaluation of the axillary lymph node basin, and radiation therapy to the breast. The amount of breast tissue removed as a part of BCT varies from just removing the cancerous “lump” (a lumpectomy) with a small margin of adjacent normal-appearing tissue to removing the “lump” with a wider excision of adjacent normal-appearing tissue (a wide local excision) to removing the entire quadrant of the breast that includes the cancerous “lump” (a quadrantectomy). All of these techniques are referred to as a segmental or partial mastectomy. A meta-analysis of 18 clinical trials in almost 10,000 women found no difference in OS for patients who received BCT compared with mastectomy.64 However, this and other meta-analyses have suggested the potential for a small increase in the risk of locoregional recurrence with BCT.64,65

Most patients diagnosed today with breast cancer can be treated with BCT. Several factors should be considered in selecting patients for BCT, including any additional risk the remaining breast tissue poses despite the local effects of radiation therapy. The National Comprehensive Cancer Network (NCCN) recommends that women who carry a known BRCA1 or BRCA2 mutation undergo mastectomy and consider additional risk reduction strategies (e.g., bilateral mastectomies).48 Bilateral total mastectomy and oophorectomy reduce the risk of breast cancer occurrence in patients with BRCA1 or BRCA2mutations, but both breast and ovarian cancers have been reported in patients who have had prophylactic removal of these organs. Multiple sites of cancer within the breast and the inability to attain negative pathologic margins on the excised breast specimen are predictive for an increased risk of recurrence with BCT and are indications for mastectomy. Some preexisting collagen vascular diseases (e.g., scleroderma, systemic lupus erythematosus) are relative contraindications for the use of BCT because of an increased risk of radiation-related adverse effects. Although local recurrence after BCT has not been consistently associated with an increased mortality rate, it is distressing to the patient and requires surgical removal of the breast. In addition, reconstructive therapy is often not feasible in a breast that has previously received irradiation. Another major consideration in selecting patients for BCT is the expected cosmetic result. For some patients, preservation of a limited amount of breast tissue may not justify the inconvenience of radiation therapy. Another approach to therapy for these patients is primary (neoadjuvant) systemic therapy to potentially shrink the tumor and minimize surgery (see the Systemic Adjuvant Therapy and Locally Advanced Breast Cancer sections for further details). Aside from the probability of local recurrence and the ability to achieve a satisfactory cosmetic result, consideration must be given to the availability of an external-beam radiation facility and the patient’s willingness to comply with the prescribed course of radiotherapy. In most instances, external-beam radiation therapy used in conjunction with BCT involves 4 to 6 weeks of radiation therapy directed to the entire breast tissue (typically a total of 50 Gy [5000 Rad] administered in 25 daily doses Mondays through Fridays with an optional boost of radiation to the tumor bed) to eradicate residual disease. Complications associated with radiation therapy to the breast are generally minor and include reddening and erythema of the breast tissue and subsequent shrinkage of the total breast mass beyond that predicted on the basis of breast tissue removal. Clinical trials are investigating the use of accelerated partial breast irradiation, intraoperative radiotherapy, or no radiation after segmental mastectomy for certain patient populations with a very low risk of recurrence.66 Until the results of these studies are available, the standard approach to BCT includes full-breast radiation therapy.

Postmastectomy radiation therapy to the chest wall may also be required in certain situations when tumors are large or the number of positive axillary lymph nodes is high (see the Locally Advanced Breast Cancer section). However, these criteria are also widely debated and are the subject of several meta-analyses. Despite the controversy, it is clear that some women may benefit from local radiation therapy even after removal of the entire breast (i.e., total mastectomy). The NCCN Guidelines state that women with four or more positive axillary lymph nodes should undergo postmastectomy radiation therapy. Patients with one to three positive ipsilateral axillary lymph nodes should strongly consider postmastectomy radiation, although conflicting data exist in this patient population.48 Patients with (a) positive surgical margins, (b) a tumor larger than 5 cm, or (c) tumors less than 5 cm with close margins (<1 mm of normal adjacent tissue) should consider postmastectomy chest wall radiation therapy. Finally, patients with surgical margins of at least 1 mm, tumor size of 5 cm or less, and negative axillary lymph nodes do not require postmastectomy chest wall radiation therapy. The optimal sequence of radiation therapy and chemotherapy is somewhat controversial. Concurrent administration of chemotherapy and radiation therapy is usually avoided because of an increase in local adverse effects. Most clinicians administer systemic chemotherapy immediately after surgery (if chemotherapy was not administered before surgery) given the hypothetical presence of systemic micrometastases that cannot be eradicated by local radiation therapy. Radiation therapy is then administered after chemotherapy, leaving hormone therapy (which is given for many years) for the end (see the Adjuvant Biologic Therapy section for a discussion of sequencing trastuzumab).

Accurate assessment of the spread of breast cancer cells to the axillary lymph nodes is critical for prognosis and the determination of the utility of both local and systemic treatments. ALND with histopathologic study of the full axillary specimen, including level I and II lymph nodes, was the gold standard for detecting axillary nodal involvement and determining the number of lymph nodes containing tumor. The number of positive axillary lymph nodes remains the most powerful predictor of breast cancer recurrence and survival, but other benefits may include a therapeutic effect of removing the lymph nodes and obtaining information to guide treatment selection. However, axillary dissection is associated with significant morbidity, with an acute complication rate as high as 20% to 30% and rates of chronic lymphedema as high as 20% to 30%.67,68 Recent studies indicate that about 60% of patients with early stage breast cancer present with lymph node–negative disease, which indicates that many women would derive no therapeutic benefit but would be exposed to the complications from the procedure.

For these reasons, a procedure involving lymphatic mapping and SLNB is recommended at many centers across the United States, and guidelines regarding recommendations for this procedure are now available.69 The sentinel lymph node(s) is the first lymph node(s) that receives lymph drainage from the primary tumor. Injection of a vital blue dye, a radiocolloid, or both around the primary breast tumor identifies the sentinel lymph node(s) in most patients, and the status of this lymph node(s) may predict the status of the remaining nodes in the nodal basin. Patients with lymph nodes that are suspicious for cancer involvement either by physical examination or imaging should have a biopsy performed to exclude lymph node involvement. SLNB has become the standard of care for patients with clinically negative axillary lymph nodes.48 Patients with a positive sentinel node or in whom the sentinel node is not identified should proceed to a level I and II ALND, although ALND after a positive lymph node found with SLNB is also controversial in certain patient populations. Data from a single randomized trial suggest that ALND after SLNB in women with clinically node negative tumors smaller than 5 cm, fewer than three involved sentinel lymph nodes, and undergoing BCT with subsequent breast irradiation resulted in higher morbidity, no improvement in local recurrence, and no difference in DFS or OS with SLNB alone.70

Despite differences in the mapping technique, the experience of the surgeon, or the patient populations studied, recent studies show that this approach identified the sentinel lymph node(s) in more than 90% of patients.71 In studies that incorporated completion axillary dissections for comparison, the SLNB procedure accurately predicted the status of the remaining axillary nodes in more than 90% of patients. Considerable controversy exists over the use of this procedure in women with large tumors (>5 cm) or locally advanced disease, palpable axillary lymph nodes, a multifocal or multicentric breast tumor, prior neoadjuvant (preoperative) chemotherapy, or prior surgery involving the breast or axilla. Patients who are pregnant or lactating are generally not considered candidates for this procedure because of concerns regarding the effects of the blue dye or the radiocolloid on the fetus. The decision of whether to use the sentinel lymph node procedure or a full axillary dissection is complex, and readers are referred to an excellent review for further information.72

Simple or total mastectomy involves removal of the entire breast without dissection of the underlying muscle or axillary nodes. The major disadvantage of this procedure is that axillary nodal status is not determined, and therefore important prognostic information may be lost. This procedure is used in patients with carcinoma in situ, in whom there is a 1% incidence of axillary node involvement, or in cases of in-breast recurrences after BCT.

The early trials investigating less extensive surgical approaches to breast cancer are widely credited with the finding that BCT is an appropriate primary therapy for most women with stages I and II disease and is preferable because it arguably provides survival rates equivalent to those of modified radical mastectomy. These historical trials provided valuable information regarding the natural history of the disease and identified pathologic prognostic factors associated with early cancer spread. The preponderance of information available regarding selection of women most likely to benefit from systemic adjuvant therapy was derived from pathologic evaluation of tissues archived from these early trials. It is hoped that further investigation into less extensive local therapy (now focused on the surgical approach to the axilla and radiation therapy) will continue to provide valuable information for the future.

Systemic Adjuvant Therapy

Images Systemic adjuvant therapy is defined as the administration of systemic therapy after definitive local therapy (surgery, radiation, or a combination of these) when there is no evidence of metastatic disease but a high likelihood of disease recurrence. By the time breast cancers become clinically detectable, they have likely been present for a number of years and have had ample opportunity to establish distant micrometastases. Micrometastatic disease can travel from the primary breast tumor and spread to distant organs through several different routes (e.g., hematogenous spread through blood vessels, lymphangitic spread through lymph channels, local extension to surrounding structures). Because local therapies such as breast surgery and irradiation do not address distant micrometastases, systemic therapy may be required to target these tumor cells that have escaped the local area of the breast. The likelihood of micrometastatic disease presence is used to attempt to identify patients with a high risk of recurrence who would require systemic adjuvant therapy. Many collaborative research groups have conducted step-wise series of studies designed to identify appropriate candidates for systemic adjuvant therapy and the optimal regimens and duration of therapy. Several hundred randomized clinical trials evaluating various systemic adjuvant modalities have been reported. Most published results confirm that administration of chemotherapy, endocrine therapy, or both, results in improved DFS or OS for all treated patients or more commonly for patients in specific prognostic subgroups (e.g., nodal involvement, menopausal status, hormone receptor status, or HER2 status). The huge amounts of data generated by these trials have resulted in a great deal of controversy, with different conclusions being reached by various experts.

Images Interpretation of results of systemic adjuvant therapy is difficult because of differences in the patient populations studied, the variation in natural history of breast cancer, the absence of information regarding pathologic prognostic factors in many studies, and differences in treatment approach and methods of analysis. Several groups around the world have conducted meta-analyses of similar breast cancer trials in hopes of gaining more insight regarding adjuvant systemic therapy than a single study can provide. One such effort, organized by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), is based on a worldwide collaboration involving multiple randomized trials and is continually updated with results from new clinical trials. The EBCTCG’s overview analyses are updated periodically as new data become available. The most recent updates, published in 2011 and 2012, reflect the long-term effects on breast cancer recurrence and survival for adjuvant tamoxifen and chemotherapy, respectively.4,5Many important questions regarding the optimal way to administer adjuvant chemotherapy and endocrine therapy and the magnitude of benefit as measured by DFS or OS in clinically relevant subsets of patients have been answered by these overview analyses. Simply stated, the results of these analyses support the use of adjuvant endocrine therapy in all patients with positive hormone receptor status regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size.4 The results of these overview analyses also support the use of adjuvant chemotherapy in most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node negative and node positive).5 It is important to note that data from clinical trials incorporating modern AIs or trastuzumab into adjuvant regimens are not included in these analyses because sufficient long-term follow-up has not been reached. Results from these more recent clinical trials are discussed later (see the Adjuvant Biologic Therapy and Adjuvant Endocrine Therapy sections).

Clinicians need to understand the relative and absolute magnitude of benefit associated with adjuvant systemic therapy in breast cancer if they are to help patients understand their treatment options and make informed decisions regarding their care. A proportional reduction of 25% might equivalently be described as an odds ratio (OR), RR ratio, or HR of 0.75; a RR or odds reduction of 25%; or a 25% reduction in the risk of death or death rate. For a given proportional reduction in death rate, the absolute improvement in 15-year survival will depend on the baseline risk of death with no treatment, which varies based on prognostic factors that include patient characteristics, disease characteristics, and biomarkers identified earlier in this chapter. Table 105-4 shows the number of deaths avoided per 100 patients treated in several hypothetical subsets of patients with different estimated 15-year survivals without adjuvant therapy as a function of different estimates of treatment benefit shown as the proportional reductions in mortality if they did receive adjuvant therapy. About 15 of every 100 patients benefited at 15 years from adjuvant therapy when a 30% proportional reduction in mortality is observed in the highest risk subgroups (50% death rate with no adjuvant therapy). In contrast, the same 30% proportional reduction in mortality translated into a benefit for only three of 100 patients in the lowest risk subset (10% death rate with no adjuvant therapy). Thus, the absolute benefit of adjuvant therapy depends on both the proportional reduction in mortality and the risk of disease recurrence, with the greatest benefit observed in the highest risk treatment groups.

TABLE 105-4 Absolute Reduction in Mortality at 10 Years per 100 Patients Treated


Table 105-5 uses data from the overview analyses to show the absolute benefits of adjuvant chemotherapy in terms of age and nodal status. In the highest risk group, node-positive women younger than 50 years of age, only 44.8% were alive and disease free at 5 years with no polychemotherapy compared with 59.4% with polychemotherapy, which translates into an absolute DFS benefit of 14.6%. However, in the node-negative group, patients younger than 50 years old in whom DFS with no polychemotherapy was highest (i.e., 72.6%), the addition of polychemotherapy produced an absolute benefit of only 9.9%. It should be pointed out that all of these differences in DFS are clearly statistically significant and form the basis for national and international guidelines that recommend offering cytotoxic chemotherapy to most women with early stage breast cancer.48,73 However, the absolute survival benefit in node-positive women 50 to 69 years old is quite small (3%), and depending on other disease characteristics and comorbid conditions, patients may elect not to pursue treatment. Although a 3% absolute reduction in death attributable to polychemotherapy may appear small, at least two investigators report that most patients with breast cancer would accept severe toxicity from treatment to achieve as little as a 1% to 5% absolute improvement in survival.74,75

TABLE 105-5 Absolute Benefits of Adjuvant Chemotherapy by Age and Nodal Status


Several international and national groups have developed guidelines for treatment of early stage breast cancer based on specific patient and disease characteristics and the results of the overview analyses. The two most commonly referenced guidelines are the St. Gallen International Expert Consensus Conference and the NCCN guidelines.48,73 The St. Gallen guidelines are updated every 2 years by an international group of researchers that meets in St. Gallen, Switzerland to review available evidence and create consensus recommendations for selection of adjuvant systemic therapies in specific patient populations outside of the framework of clinical trials. The NCCN has also developed practice guidelines for the treatment of breast cancer that are updated annually or more often based on the available evidence. Recommendations from the NCCN for patients with tumors 1 cm or larger or positive lymph nodes are summarized in Figure 105-5. For patients with tumors smaller than 1 cm, micrometastatic lymph node involvement, or negative lymph nodes, treatment is highly individualized and based on multiple patient- and tumor-related factors, including hormone receptor status, HER2 status, comorbidities, and patient preferences. Specific treatment recommendations are complex, and readers are referred to the guidelines for further details.


FIGURE 105-5 Treatment of patients with breast cancers larger than 1 cm or with positive lymph nodes. Refer to the text for definitions of HR and HER2 positivity. Refer to the text for management of patients with tumors smaller than 1 cm, micrometastatic lymph node involvement, or negative lymph nodes.aOncotype DX may identify patients who derive little benefit from chemotherapy (lymph node–negative patients only) (see Systemic Adjuvant Therapy section for details). (HR, hormone receptor; HER2, human epidermal growth factor receptor-2.)

Images The use of preoperative systemic therapy is gaining favor in both early stage and locally advanced breast cancers. This approach to therapy, referred to as neoadjuvant or primary systemic therapy, usually consists of chemotherapy but in special circumstances may also include endocrine therapy (e.g., in inoperable patients with significant comorbidities or in patients with high sensitivity to endocrine therapy). Advantages of preoperative systemic therapy include (a) a decrease in the size of the tumor to minimize surgery, (b) determination of the response to chemotherapy or hormone therapy in vivo (an important prognostic indicator), and (c) other theoretical advantages (e.g., delivery of chemotherapy through an intact vascular system). In a pivotal study conducted by the NSABP (Trial B18), preoperative chemotherapy was compared with traditional chemotherapy given after surgery (the same chemotherapy and the same number of cycles).76,77 Although no difference was found in DFS or OS, rates of BCT were higher in the group receiving preoperative chemotherapy (67.8% vs. 59.8%).77 This study also identified a small subset of patients (13%) who had a pathologic complete response (pCR; no tumor left at surgery) after chemotherapy. These patients went on to have a significantly longer DFS compared with patients who did not achieve a pCR (P <0.0001).77 Importantly, even after 16 years of follow-up, patients who achieved a pCR continued to have superior DFS and OS compared with patients who did not achieve a pCR.78 Although this approach to therapy was historically reserved for patients with inoperable tumors (locally advanced), the use of preoperative systemic therapy in patients with early stage breast cancer is increasing in popularity because of the ability to assess the response to therapy in vivo as well as the potential to decrease the size of the tumor, allowing for less radical surgery and better cosmetic results.

Intensive research efforts are directed toward identifying characteristics of the primary tumor (e.g., pathologic or molecular prognostic factors) that may predict for a higher or lower likelihood of distant metastases and death in node-negative patients. Although many prognostic factors are being investigated, no single factor or combination of factors sufficiently identifies those at risk of metastases or is sufficiently standardized to be reproducibly applicable to all patients. Currently, two commercially available genetic tests are being prospectively validated as decision-support tools for adjuvant chemotherapy. Oncotype DX® is one of these tests that screens for expression of 21 genes using RT-PCR and results in a recurrence score that can be used to determine the risk of distant recurrence or death from breast cancer in women with ER-positive, node-negative, invasive breast cancer.62 The tumor tissue used for this test is paraffin-embedded tumor from archived samples. A low recurrence score (<18) indicates a low risk of recurrence with endocrine therapy alone indicating that perhaps adjuvant chemotherapy could be avoided. A high recurrence score (≥31) indicates a high risk of recurrence despite endocrine therapy, suggesting a need for adjuvant chemotherapy followed by endocrine therapy. The utility of chemotherapy in patients with an intermediate score (18–30) is unclear, and ongoing clinical trials hope to further elucidate the role of Oncotype DX in this patient population and in patients with one to three positive lymph nodes after surgery. A second test, MammaPrint, was approved to estimate prognosis in breast cancer patients with early-stage disease, regardless of hormone receptor status. MammaPrint screens the tumor for 70 genes using microarray technology. The assay requires fresh-frozen tissue and reports the predicted rates of recurrence as high or low. This information has been shown to accurately predict for recurrence in a subset of patients not receiving systemic adjuvant therapy. The MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) trial, ongoing in Europe, will compare the predictive capabilities of MammaPrint against the standard prognostic factors to assess which patients with node-negative, ER-positive breast cancer will benefit from adjuvant chemotherapy. Although many clinicians use these tools for individual patients, we await further information to guide the appropriate use of these novel pharmacogenomic tools.

A clinical tool that has been widely adopted for clinical use is an Internet-based tool called Adjuvant! (, which helps clinicians and patients make informed decisions regarding adjuvant therapy for breast, colon, and lung cancers. The tool allows healthcare professionals to estimate the risks of negative outcomes (e.g., cancer recurrence, death), and the potential benefits of therapy (e.g., reductions in risks of recurrence and death). This is a validated, evidence-based tool that incorporates multiple prognostic and predictive factors into a mathematical model in which each factor is weighted based on established evidence from clinical trials and is placed in the background of the SEER database for patients living in the United States.62 By entering the patient’s age, comorbidities, ER status, tumor grade, tumor size, and nodal status, the clinician can use the tool to estimate the breast cancer mortality and recurrence risk at 10 years and determine the impact of chemotherapy, hormone therapy, or both on these risks. The results are then projected in a graphic format that is easy to understand and explain to patients. Some of the limitations of Adjuvant! include the limited information regarding outcome in patients with tumors that are smaller than 1 cm and no axillary lymph node involvement; it does not incorporate proliferation markers or HER2 status of the primary tumor; and it does not consider potential adverse effects of therapy for individual patients. Estimates of outcome with the Adjuvant! program may also vary in specific subgroups of patients, such as women who are diagnosed with breast cancer at a younger age.

Adjuvant Chemotherapy Cytotoxic drugs that have been used alone and in combination as adjuvant therapy for breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, melphalan, prednisone, vinorelbine, and vincristine. Table 105-6 lists some of the most common combination chemotherapy regimens used in the adjuvant setting.

TABLE 105-6 Selected Adjuvant Chemotherapy Regimens for Breast Cancer


The basic principle of adjuvant therapy for any cancer type is that the regimen with the highest response rate in advanced disease should be the optimal regimen for use in the adjuvant setting. However, results from individual clinical trials investigating specific regimens in the adjuvant setting are required to identify the benefits and risks in a specific patient population. Early administration of effective combination chemotherapy at a time when the tumor burden is low should increase the likelihood of cure and minimize the emergence of drug-resistant tumor cell clones. Historically, combination chemotherapy regimens (polychemotherapy) have been more effective than single-agent chemotherapy. Anthracyclines (doxorubicin and epirubicin) and more recently taxanes (paclitaxel and docetaxel) have become the cornerstones of modern chemotherapy for the adjuvant treatment of breast cancer. The overview analysis of adjuvant chemotherapy (discussed previously) analyzed the use of CMF- (cyclophosphamide, methotrexate, fluorouracil) or anthracycline-based chemotherapy regimens (polychemotherapy) compared with no chemotherapy. Patients who received polychemotherapy had a 23% ± 2% reduction in annual odds of recurrence and a 14% ± 2% reduction in annual odds of death compared with patients who did not receive chemotherapy, establishing adjuvant chemotherapy as a powerful option for reducing breast cancer recurrence. The authors also analyzed results from 20 trials that directly compared an anthracycline-containing regimen with a CMF-type regimen and demonstrated a significant advantage with the anthracycline regimens.5 In that meta-analysis, anthracycline-containing regimens were modestly superior in reducing recurrence and death compared with regimens without anthracyclines. A 7% ± 3% reduction in annual odds of recurrence and a 9% ± 3% reduction in annual odds of death were reported in the 2012 update with the anthracycline-containing regimens. It should be noted that regimens with higher cumulative doses of anthracycline (at least 240 mg/m2 of doxorubicin and at least 360 mg/m2 of epirubicin) were associated with improvements in the relative risk of recurrence (11% ± 4%) and overall survival (16% ± 4%) compared with standard CMF regimens. Until the 2012 update, adjuvant chemotherapy regimens with taxanes did not have sufficient follow-up to be included in the EBCTCG analyses. This meta-analysis reported data from 33 clinical trials and discovered that incorporation of a taxane reduced the risk of distant recurrence (13% ± 3%), any recurrence (14% ± 2%), and overall mortality (11% ± 3%) compared with a nontaxane regimen.5 These trials included both sequential and concurrent taxane therapy (paclitaxel or docetaxel) in conjunction with anthracyclines (with or without cyclophosphamide, fluorouracil, or methotrexate). Proportional reductions in recurrence and breast cancer mortality were largely independent of age, nodal status, tumor size, tumor differentiation, or ER status. Most of these trials enrolled node-positive patients only, but some high-risk node-negative patients were also included. There is no apparent biologic reason why patients with node-negative disease should respond differently to the taxanes than those with node-positive disease. However, the absolute benefits for this population may not be large enough to require that all patients with node-negative disease receive an anthracycline- and taxane-based chemotherapy regimen. Because the addition of a taxane may predispose patients to peripheral neuropathy, myelosuppression, and alopecia, adverse events should also be considered. Taxane-containing, non-anthracycline regimens were not included in the meta-analysis but may be appropriate for some patients with a low risk of disease recurrence based on the results from a single randomized clinical trial.79 However, this subject remains widely debated, and no single adjuvant chemotherapy regimen is preferred.

Cytotoxic chemotherapy is a particularly important treatment modality for patients with tumors that do not express ER or PR and do not overexpress HER2 (so called triple-negative breast cancers [TNBCs]).80 Patients with TNBC treated with anthracycline- and taxane-based chemotherapy have significantly decreased survival compared with patients with other breast cancer subtypes. Ironically, this subgroup of patients is more likely to respond to neoadjuvant chemotherapy. Therefore, patients with TNBC who achieve a pCR have an excellent long-term survival, but those who have residual disease at the time of surgery have a worse prognosis than non-TNBC patients. The optimal type and duration of chemotherapy for patients with TNBC is unknown. Because none of the previously identified molecular targets are present in TNBC, incorporation of nontraditional chemotherapy (e.g., platinum agents) into these regimens is under investigation. Identification of meaningful molecular targets is much needed and is where most research is ongoing. Molecular targets of interest include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly-ADP ribose polymerase (PARP).

Although the optimal duration of adjuvant chemotherapy administration is unknown, it appears to be on the order of 12 to 24 weeks and depends on the regimen being used. Optimally, chemotherapy should be initiated within 12 weeks of surgical removal of the primary tumor.81 “Dose intensity” and “dose density” appear to be critical factors in achieving optimal outcomes in adjuvant breast cancer therapy. Dose intensity is defined as the amount of drug administered per unit of time and is typically reported in milligrams per square meter of body surface area per week (mg/m2/wk). Increasing dose, decreasing time between doses, or both can increase dose intensity. Dose density is one way of achieving dose intensity but not by increasing the amount of drug given, as occurs with dose escalation, but instead by decreasing the time between treatment cycles. The importance of dose intensity first received wide attention in 1981 when the Milan group reported in a retrospective analysis of their original CMF adjuvant study that only patients who received at least 85% of their planned CMF dose benefited significantly from adjuvant therapy, and those receiving less than 65% of the planned dose had the same DFS and OS as the group of control patients treated with surgery alone.82 Therefore, dose reductions for standard treatment regimens should be avoided unless necessitated by severe toxicity. But increasing doses beyond those contained in standard treatment regimens does not appear to be beneficial and may be harmful.

Several studies investigating the impact of dose density have now been reported. Interest in this approach to adjuvant therapy was stimulated when the Cancer and Leukemia Group B (CALGB) reported results from their trial 9741, which tested not only dose density but also the question of using sequential versus combination chemotherapy regimens. Using a 2 × 2 factorial design, investigators randomized node-positive breast cancer patients after surgery to compare sequential versus concurrent chemotherapy and standard dose versus dose density.83 The arms of the study were group 1, sequential doxorubicin (A) for 4 cycles followed by paclitaxel (P) for 4 cycles followed by cyclophosphamide (C) for 4 cycles, with all cycles given every 3 weeks; group 2, sequential A for 4 cycles followed by P for 4 cycles followed by C for cycles with all cycles given every 2 weeks with filgrastim; group 3, concurrent AC for 4 cycles followed by P for 4 cycles with all cycles given every 3 weeks; and group 4, concurrent AC for 4 cycles followed by P for 4 cycles with all cycles given every 2 weeks with filgrastim. After a median follow-up period of 36 months, the patients receiving chemotherapy every 2 weeks had a significantly prolonged DFS (at 3 years: 85% vs. 81%; RR, 0.74; P = 0.01) and OS (92% vs. 90%; RR, 0.69; P = 0.013) compared with chemotherapy every 3 weeks.83 The use of sequential versus concurrent chemotherapy did not show a benefit for one over the other in terms of DFS or OS, but sequential therapy did appear to be less toxic. Patients in the concurrent every 2 week group (group 4) had significantly more regimen-related toxicity, including a very high rate of red blood cell transfusions for anemia (13% of cycles).83 Red blood cell transfusions are rarely required with most other standard adjuvant chemotherapy regimens used for breast cancer.

Dose intensity appears to be important for some drugs but not for others. Many studies with anthracyclines (without taxanes) appear to indicate no benefit from a dose-dense approach to drug administration. These data seem to contradict the CALGB 9741 data. However, data with the taxanes, especially paclitaxel, appear to support a dose-dense (not intense) approach, with weekly therapy producing optimal outcomes.84 Data with paclitaxel given weekly versus every 3 weeks indicate that this drug is more effective when given weekly in the adjuvant, neoadjuvant, and metastatic settings.8486 Thus, some speculate that the different paclitaxel schedule is the primary reason for the success with this approach to therapy. A direct comparison between taxane dosing intervals was evaluated in the North American Breast Cancer Intergroup Trial E1199, which randomized patients to receive doxorubicin and cyclophosphamide for 4 cycles every 3 weeks followed by either weekly or every 3 week paclitaxel or docetaxel.84Although this study does not directly address the question of dose density because of the lower doses given in the weekly arms, it appears to support the pharmacologic advantage of a taxane given more frequently as the essential factor driving the beneficial outcomes seen with “dose density” in the CALGB 9741 trial. Although no differences in DFS or OS were observed between the weekly or every 3 week schedule or the different taxanes in the E1199 trial, a subgroup analysis indicated that the weekly paclitaxel arm resulted in improved DFS (OR, 1.27; 95% CI, 1.03–1.57; P = 0.006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = 0.01) compared with paclitaxel administered every 3 weeks. Docetaxel, when administered every 3 weeks, resulted in improved DFS (OR, 1.23; 95% CI, 1.00–1.52; P = 0.02) but not OS (OR, 1.13; 95% CI, 0.88–1.46; P = 0.25) compared with paclitaxel administered every 3 weeks. DFS and OS with weekly docetaxel were not significantly different from paclitaxel administered every 3 weeks. Although other trials have attempted to investigate dose-dense regimens, they also have other variables that were altered that could potentially impact the outcomes. A meta-analysis by Bonilla et al. evaluated four trials of chemotherapy given in a dose-dense fashion compared with conventional administration.87 In these studies, patients who received dose-dense chemotherapy had statistically improved DFS and OS compared with patients who received conventionally administered chemotherapy. Unfortunately, none of the trials, with the exception of the CALGB 9741 study, adequately evaluated the true impact of dose density.88 This remains an area of continued research.

A major focus of clinical investigations in the past was the use of high-dose chemotherapy regimens as adjuvant therapy. Because bone marrow suppression is the dose-limiting toxicity for most chemotherapeutic agents, high-dose chemotherapy regimens followed by colony-stimulating factors or reinfusion of autologous hematopoietic stem cells were developed. Several cooperative groups have conducted trials of high-dose chemotherapy with stem cell support versus conventional adjuvant therapy. In an evaluation of 15 clinical trials, the use of high-dose chemotherapy significantly reduced the risk of disease recurrence compared with standard chemotherapy, but no difference in OS was observed.89 Based on the available evidence, this approach to therapy is currently not recommended outside the context of a clinical trial.

The short-term toxic effects of chemotherapy used in the adjuvant setting are generally well tolerated. Although a number of investigators have demonstrated a reduction in quality of life, most patients are able to maintain a reasonable level of function and emotional and social well-being during treatment.90,91 Supportive therapy of patients receiving systemic adjuvant chemotherapy has improved over the past decades. Increased attention to the impact of symptoms on quality of life may account for some of this improvement. In addition, more effective antiemetics have become available to assist in managing chemotherapy-induced nausea and vomiting, and myeloid growth factors are often helpful in preventing febrile neutropenia, particularly in elderly patients and patients receiving dose-dense chemotherapy regimens. Despite the use of newer antiemetics for prevention of nausea and vomiting, many women still have difficulty with this side effect, and delayed nausea and vomiting remains problematic in some patients. Aprepitant, a novel neurokinin-1 antagonist, may be considered in addition to serotonin receptor antagonists and dexamethasone to improve outcomes for some patients receiving anthracycline-based chemotherapy, but clinicians should be aware of the potential for clinically significant drug–drug interactions between aprepitant and other drugs, including some chemotherapy. The use of myeloid growth factors to support some adjuvant chemotherapy regimens may be required (e.g., with dose-dense regimens), but these are not routinely used for all adjuvant chemotherapy regimens. Because erythropoiesis-stimulating agents have potential effects on cancer cells and the cellular environment that may negatively impact the antitumor effects of chemotherapy or enhance adverse effects related to the chemotherapy, they should be avoided in patients receiving chemotherapy with a curative intent.92

Many other side effects are common with the chemotherapy regimens used for the treatment of early stage breast cancer, and patients should be appropriately counseled regarding the likelihood of alopecia, weight gain, and fatigue. Patients who are menstruating often experience a cessation of menses that may not return; cessation of menses may be accompanied by signs and symptoms of menopause. Deep-vein thrombosis (DVT) has been reported in women receiving combination chemotherapy regimens.93 Leukemia and other hematologic disorders have long been associated with the alkylating agents (e.g., cyclophosphamide) and the topoisomerase II inhibitors (e.g., doxorubicin and epirubicin). Several studies have estimated a 0% to 1.5% cumulative incidence of leukemia or myelodysplasia after adjuvant chemotherapy with median follow-up period of 3 to 11 years.94 To date, the dose-dense regimens have not been associated with an excess rate of leukemias, but the follow-up period for these trials is relatively short.

Cardiomyopathy induced by doxorubicin occurs in fewer than 1% of women whose total dose of doxorubicin is less than 320 mg/m2.95 This risk may be further decreased by use of continuous infusion or weekly doxorubicin. It should be noted that epirubicin in the adjuvant setting is usually given at a dose of 100 to 120 mg/m2.48 At this dose, epirubicin has an equal chance of causing cardiomyopathy as standard doxorubicin doses when both agents are given as bolus or short infusions. Taxanes are often associated with hypersensitivity reactions, peripheral neuropathy, or myalgias and arthralgias for a few days after the infusion.

It is important to note that the magnitude of survival benefit for adjuvant chemotherapy in stages I and II breast cancer is modest, with an absolute reduction in mortality rate of only 5% at 10 years for patients with negative axillary lymph nodes and 10% for patients with positive axillary lymph nodes. In addition, it is currently not possible to accurately predict who will attain this survival benefit. The advent of genetic prognostic tools, such as Oncotype DX, can help to identify patients who may derive little or no benefit from chemotherapy. However, these tests are only appropriate in specific subsets of patients. Studies have reported that most breast cancer patients would accept severe toxicity from treatment to achieve as little as a 1% to 5% improvement in survival.74,75 Thus, in the absence of the ability to predict who will benefit, it is likely that most patients with stage I and stage II breast cancer would choose adjuvant chemotherapy.

The optimal chemotherapy regimen for use in the adjuvant setting has yet to be identified, and the choice of chemotherapy regimen for a specific patient is complex. Many adjuvant chemotherapy regimens are available, and most of these regimens have not been directly compared in randomized clinical trials. In some cases, the choice of chemotherapy regimen may be geographic, particularly if a regimen has been developed and studied by a particular institution. Based on data from clinical trials and the previously mentioned pooled analysis, the concomitant or sequential addition of a taxane to an anthracycline-based chemotherapy regimen has become the standard of care for women with node-positive breast cancer. The use of taxanes in combination with anthracyclines is more controversial in patients with node-negative disease, although data from meta-analyses and a single trial specifically in patients with high-risk node negative disease support the use of anthracycline- and taxane-based chemotherapy regimens in this patient population.5,96 Results from a single trial that evaluated a taxane-containing (non-anthracycline) regimen are available, and this regimen may be an appropriate treatment in a subset of patients at low risk of disease recurrence. NCCN recommendations are purposefully vague, and they do not differentiate between patients with node-positive or -negative breast cancer. The NCCN has designated preferred chemotherapy regimens, as listed in Table 105-6, although detailed information is not provided regarding the rationale behind these designations.

Adjuvant Biologic Therapy As biologic agents continue to demonstrate significant activity against metastatic breast cancer, they are subsequently tested in the adjuvant or neoadjuvant setting. Trastuzumab is a MoAB targeted against the HER2-receptor protein. It has demonstrated significant survival benefits when administered with chemotherapy in women with metastatic, HER2-positive breast cancer. Several published trials support the use of trastuzumab in combination with or sequentially after adjuvant chemotherapy for patients with early stage, HER2-positive breast cancer (Table 105-7).97 Results from these trials report up to a 50% reduction in the risk of recurrence with the addition of trastuzumab to an adjuvant chemotherapy regimen. A meta-analysis of the six available clinical trials investigating the addition of trastuzumab to chemotherapy involving almost 14,000 women revealed superior DFS (OR, 0.69; 95% CI, 0.59–0.80; P <0.001) and OS (OR, 0.78; 95% CI, 0.69–0.88; P <0.001) in patients with HER2-positive breast cancer who received trastuzumab with chemotherapy compared with those that received chemotherapy alone.98 This difference in DFS translated into a 31% overall lower relative risk for disease progression or death from any cause for patients who received trastuzumab. Although clearly the benefit of adding trastuzumab to these regimens is obvious, the type of chemotherapy, sequence of administration, and duration of trastuzumab differed among the trials, making the optimal trastuzumab-based regimen less obvious.

TABLE 105-7 Selected Trastuzumab-Based Regimens for Early-Stage Breast Cancer


Most of the regimens investigated in these adjuvant trials included an anthracycline and a taxane given concurrently with trastuzumab or sequentially before trastuzumab. From the available evidence, it appears that administration of a taxane with trastuzumab may be more effective than trastuzumab administered after chemotherapy. In the previously mentioned meta-analysis, sequential and concomitant use of trastuzumab with chemotherapy both prolonged DFS compared with chemotherapy alone; whereas concomitant trastuzumab also improved OS, sequential trastuzumab did not.98 The adjuvant use of trastuzumab without an anthracycline has been reported in one trial (Breast Cancer International Research Group 006) and appears to provide similar benefit with diminished cardiac adverse effects as compared with traditional anthracycline-containing adjuvant trastuzumab regimens.99 The duration of trastuzumab therapy in these adjuvant trials ranges from 9 to 104 weeks in the published studies. The optimal duration of trastuzumab therapy is unknown, although the most current data support the use of trastuzumab for a total of 52 weeks. The most commonly used trastuzumab-based adjuvant chemotherapy regimens are listed in Table 105-7.

The incidence of adverse cardiac effects associated with the addition of trastuzumab appears to increase when an anthracycline is included in the regimen before administration of trastuzumab. The incidence of symptomatic heart failure with adjuvant trastuzumab ranges from 0.5% to 4% in highly selected patients who participated in the clinical trials.99,100 The higher risk of cardiac complications may be acceptable in many patients given the significant reductions in breast cancer recurrence and death rates. Sequential administration of trastuzumab after chemotherapy (as in the HERA trial) appears to produce a lower incidence of cardiac toxicity (symptomatic congestive heart failure = 2% with trastuzumab). Also, the use of a non–anthracycline-based regimen in the BCIRG 006 trial (Table 105-7) was associated with a low incidence (0.4%) of symptomatic heart failure compared with other regimens.99However, cross-trial comparisons are challenging because the definition of cardiac events in each trial was different. Therefore, application of these results to individual patients is fraught with difficulties, and many different regimens may be appropriate for a given patient. Concurrent administration of trastuzumab with an anthracycline is very controversial because of potentially higher rates of cardiac dysfunction (see the Anti-HER2 Agents of Metastatic Breast Cancer section). Concurrent administration of an anthracycline and trastuzumab in the neoadjuvant setting has been reported with extremely promising rates of pCR and limited cardiac complications.101 This combination should be administered with caution, and patients should be carefully monitored for signs and symptoms of cardiac dysfunction. Similar to many MoABs, trastuzumab is associated with infusion-related reactions such as fever, chills, and rigors temporally associated with trastuzumab infusions. Postmarketing surveillance data have identified “pulmonary toxicity” and “anaphylaxis” as rare but potentially life-threatening reactions associated with trastuzumab. Chemotherapy-related adverse effects, including neutropenia, infection, and diarrhea, are slightly more frequent with the addition of concurrent trastuzumab therapy, but these toxicities are easily managed and do not preclude the use of trastuzumab in patients with early stage breast cancer.

All of these adjuvant trials continued trastuzumab administration during adjuvant radiation therapy and endocrine therapy. The administration of trastuzumab during radiation therapy was evaluated in patients that participated in the N9831 clinical trial. Patients that received concurrent radiation therapy with adjuvant trastuzumab did not experience a significant increase in cardiac events or acute radiation-related adverse events with the exception of transient leukopenia.102 Therefore, if radiation therapy is clinically indicated, trastuzumab is typically administered concomitantly with radiation.

Many questions remain regarding the optimal use of trastuzumab in the adjuvant or neoadjuvant therapy of early stage breast cancer. The use of trastuzumab with chemotherapy in the adjuvant or neoadjuvant setting is now considered to be the standard of care for patients with node-positive and high-risk node-negative HER2-positive breast cancer.48 Several retrospective analyses of patients with HER2-positive tumors smaller than 1 cm who did not receive trastuzumab appear to indicate a poor prognosis, suggesting that these patients may also benefit from trastuzumab-based adjuvant chemotherapy.103 Although controversial, treatment with trastuzumab in patients with small, HER2-positive, node-negative tumors may be considered. A similar approach has been used in the neoadjuvant treatment of HER2-positive breast cancer as well (see the Locally Advanced Breast Cancer section). Clinical trials involving other novel anti-HER2 therapies, such as lapatinib and pertuzumab, in the adjuvant and neoadjuvant settings are ongoing.

Clinical Controversy…

Trastuzumab clearly has improved the outcomes for women with lymph node–positive and high-risk lymph node–negative early-stage, HER2-positive breast cancer. However, patients with small (<1 cm) tumors with negative lymph nodes were not included in prospective clinical trials with trastuzumab. Retrospective data suggest that patients with small HER2-positive tumors who did not receive trastuzumab-based chemotherapy have a poor prognosis. Questions remain regarding optimal use of trastuzumab in this patient population, and each patient must weigh the risks versus benefits for his or her individual circumstance.

Adjuvant Endocrine Therapy Endocrine therapies that have been studied in the treatment of primary or early-stage breast cancer include tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone–releasing hormone (LHRH) agonists, and AIs. The choice of agent(s) depends on menopausal status and is based on a multitude of clinical trials completed in this setting that establish different roles for different therapies.

Tamoxifen was traditionally the gold standard adjuvant endocrine therapy and has been used in the adjuvant setting for more than 3 decades. Tamoxifen is antiestrogenic in breast cancer cells, but it appears to have estrogenic properties in other tissues and organs.104,105 More recent studies show that tamoxifen and other similar drugs have many estrogenic and antiestrogenic effects that depend on the tissue and the gene in question, and they are more appropriately called selective estrogen receptor modulators (SERMs). Women receiving adjuvant tamoxifen therapy have reduced risk of recurrence and mortality compared with women not receiving adjuvant tamoxifen therapy.4This observation, coupled with evidence supporting tolerability of tamoxifen, including beneficial estrogenic effects on the lipid profile and bone density, led to tamoxifen’s being the endocrine agent of choice for both pre- and postmenopausal women compared with older, more toxic therapies (e.g., megestrol acetate). In the United States, tamoxifen is generally considered the adjuvant endocrine therapy of choice for premenopausal women. However, many ongoing clinical trials are investigating the use of the LHRH agonists or oophorectomy instead of tamoxifen or in addition to tamoxifen or AIs in this group of women.

The optimal dose of tamoxifen is widely debated. The EBCTCG overview showed that the reduction in recurrence was greater in studies that used higher tamoxifen doses (P = 0.02 for the trend between 20, 30, or 40 mg/day).4However, a dose effect did not exist for tamoxifen and breast cancer mortality. Therefore the current recommended dose for tamoxifen in the adjuvant, metastatic, and risk reduction settings is 20 mg/day. If chemotherapy and radiation therapy are not required, adjuvant tamoxifen therapy is generally initiated shortly after surgery or as soon as pathology results are known and the decision to administer tamoxifen as adjuvant therapy is made.

When adjuvant chemotherapy is also required, tamoxifen should be administered after chemotherapy is completed. This recommendation is based on laboratory and clinical evidence from a phase III trial suggesting tamoxifen administered concurrently with chemotherapy may antagonize the beneficial effect of chemotherapy.106 In the phase III clinical trial, administration of sequential tamoxifen resulted in a marginally superior DFS compared with concurrent use of tamoxifen with chemotherapy (HR, 0.84; 95% CI, 0.70–1.01; P = 0.061).106 Some clinicians also advocate the initiation of tamoxifen after completion of radiation therapy, but this subject is very controversial, and few trials have addressed the issue of concurrent versus sequential endocrine therapy and radiation therapy.

The optimal duration of tamoxifen therapy in the adjuvant setting is currently 5 years. Studies of prolonged administration (e.g., 10 years) have produced mixed results. In the ATLAS trial, patients with ER-positive breast cancer who had 10 years of tamoxifen had improved DFS and OS compared with those with 5 years of treatment.107 Previous randomized trials comparing 5 years of tamoxifen treatment with longer than 5 years of tamoxifen treatment have shown opposite results and, in fact, were stopped early because of these detrimental outcomes.108 Also, patients in the ATLAS trial who received 10 years of tamoxifen had increased risk of developing endometrial cancer and pulmonary embolism compared with those receiving tamoxifen for 5 years (a consistent finding in other randomized trials as well).107 With these conflicting data regarding efficacy and the possibility of increased toxicity related to a longer duration of tamoxifen therapy, the optimal dose appears to remain 5 years until data from other clinical trials investigating this question become available and either confirm or refute the benefits of the 5-year duration.

Clinical Controversy…

For premenopausal women with early-stage or locally advanced hormone-receptor-positive breast cancer, the optimal duration of tamoxifen therapy is currently under scrutiny. Clinical trials investigating 5 versus 10 years of tamoxifen therapy have reported conflicting results, with one demonstrating benefit and the other a detriment to prolonged use. Clinical trials further investigating this question are ongoing. Providers should discuss the risks and benefits of extended tamoxifen therapy individually with each patient.

The most reliable information regarding the side effects of tamoxifen comes from the NSABP Breast Cancer Prevention Trial (P1).51 This trial randomized 13,388 women 35 years of age or older who were at increased risk for breast cancer to placebo (n = 6,707) or to 20 mg/day of tamoxifen (n = 6,681) for 5 years. Although the primary finding of this study is that tamoxifen reduces the risk of invasive breast cancer by 49%, this study also provides an excellent opportunity to determine the risk of side effects associated with tamoxifen. Information was prospectively collected with regard to the occurrence of hot flashes, vaginal discharge, irregular menses, fluid retention, nausea, skin changes, diarrhea, and weight gain or loss. The self-administered depression scale and a global quality-of-life and a sexual function scale were administered at each follow-up visit. The only symptomatic differences noted between the placebo and tamoxifen group were related to hot flashes and vaginal discharge, both of which occurred more often in the tamoxifen group. No important differences between the two groups were observed in the various self-reporting instruments. Tamoxifen did not increase the risk of ischemic heart disease but did reduce the risk of hip radius and spine fractures. Of note, the rates of stroke, pulmonary embolism, and DVT were elevated in the tamoxifen group (stroke: RR, 1.59; pulmonary embolism: RR, 3.01; and DVT: RR, 1.60), particularly in women age 50 years or older. The rate of endometrial cancer was increased in the tamoxifen group (RR, 2.53), and this increased risk occurred predominantly in women age 50 years or older. The increased risk of endometrial carcinoma is similar in magnitude to that associated with postmenopausal estrogen replacement therapy and is likely a consequence of an estrogenic effect of tamoxifen on the endometrium. Some experts argue that this risk is acceptable because the endometrial cancer induced by tamoxifen is low stage, low grade, and easily treated with surgery or other means and does not pose a life-threatening risk to women. Tamoxifen was also associated with an increased risk of uterine sarcomas (a more aggressive form of endometrial cancer), but this risk appears to be lower than the more common endometrial cancers identified in the NSABP P-1 study. Routine endometrial biopsy is not currently recommended for women receiving tamoxifen therapy. However, women receiving tamoxifen therapy should be counseled to have regular gynecologic examinations and immediately report unusual vaginal bleeding to their primary clinicians for further evaluation.

In premenopausal women, the use of LHRH agonists (ovarian suppression) or ovarian ablation provides benefit in the adjuvant setting. In the EBCTCG overview analysis published in 2005, the overall benefit of ovarian ablation or suppression was significant compared with no treatment but was smaller than previously reported in 1996 (reduction in annual odds of recurrence = 25% ± 12% in women younger than 40 years old and 29% ± 6% in women 40–49 years old).109 Many of the ongoing trials with the LHRH agonists were not yet included in this analysis, and most of the clinical trials analyzed included patients with hormone receptor–positive, –negative, and unknown tumor status. In an update of this analysis, study inclusion was restricted to patients treated with ovarian suppression with LHRH agonists (not ovarian oblation or oophorectomy) and patients with tumors known to be hormone receptor positive.110 The addition of a LHRH agonist reduced the rates of recurrence by 25%, deaths after recurrence by 28%, and all deaths by 27% in women younger than 40 years; no significant reductions in recurrence or death were noted in patients older than 40 years. Also, a similar benefit was observed with goserelin as compared with CMF chemotherapy in hormone-sensitive premenopausal breast cancer patients but not in patients with hormone receptor–negative tumors.110 It is not clear whether the benefit of chemotherapy in this population is a result of the actual effects of chemotherapy or a result of the endocrine effects of chemotherapy-induced amenorrhea. Consequently, some studies have investigated the benefits of adding ovarian ablation or suppression to chemotherapy either with or without tamoxifen. Results from these studies clearly indicate a benefit from ceasing menses regardless of whether this is caused by chemotherapy or ovarian ablation or suppression.110 It is not clear whether the addition of an LHRH agonist to tamoxifen is advantageous in women with hormone receptor–positive tumors who continue to menstruate after chemotherapy. The optimal duration of adjuvant LHRH agonist use is unknown, with trials ranging from 18 months to 5 years of treatment. Multiple ongoing trials are evaluating whether an LHRH agonist alone with tamoxifen or with an AI is the most effective therapy for premenopausal women. Currently, the only trial with available results is a study by the Austrian Breast and Colorectal Cancer Study Group (ABCSG-12), which randomized premenopausal patients with hormone receptor–positive early-stage breast cancer to 3 years of tamoxifen or anastrozole, both concomitantly with goserelin for ovarian suppression.111 After a median follow-up period of 62 months, there was no significant difference in DFS between the two groups (HR, 1.08; P = 0.591). However, in a retrospective analysis of patients with disease recurrence, the relative risk of death was significantly higher in patients who received anastrozole than in patients who received tamoxifen (HR, 2.0; 95% CI, 1.23–3.24; P = 0.005). Until additional data are available, ovarian suppression in combination with an AI should not be considered as an appropriate adjuvant therapy for premenopausal women outside of a clinical trial. It should also be noted that a tamoxifen-only arm was not included in this trial, which makes comparison to the current standard of care for premenopausal women (tamoxifen alone) impossible.

In postmenopausal women, incorporation of AIs is the standard of care in the adjuvant setting. Four different approaches to therapy have been undertaken with these agents: (a) direct comparison with tamoxifen for adjuvant endocrine therapy; (b) sequential use after 5 years of adjuvant tamoxifen therapy; (c) sequential use after 2 to 3 years of adjuvant tamoxifen; and (d) 2 years of treatment with an AI followed by 3 years of adjuvant tamoxifen. Anastrozole and letrozole have been individually, directly compared with tamoxifen as initial therapy in postmenopausal women with hormone receptor–positive, early-stage breast cancer (ATAC [Arimidex, Tamoxifen, Alone or in Combination] Trial and BIG [Breast International Group] 1–98 Trial).112 These comparisons show an advantage with the AIs over tamoxifen in terms of DFS. Other approaches to adjuvant endocrine therapy with AIs include sequential use of newer agents after either 5 years or 2 to 3 years of tamoxifen. In the MA-17 study, 5 additional years of letrozole was compared with placebo in postmenopausal breast cancer patients who had completed 5 years of tamoxifen therapy.113 After a median follow-up period of 2.4 years, letrozole was associated with superior estimated 4-year DFS compared with placebo (93% vs. 87%; P <0.001). In a pooled analysis of trials investigating a switch to an AI, 9,015 patients who had completed 2 to 3 years of adjuvant tamoxifen therapy were randomized to continue tamoxifen or crossover to anastrozole or exemestane for the remainder of 5 years.112 The results of this analysis show a decreased risk of recurrence at 6 years after randomization in patients who switched to an AI compared with those who continued with tamoxifen alone (12.6% vs. 16.0%; P <0.00001). The BIG 1–98 trial, which compared letrozole with tamoxifen, also included two separate arms that investigated the value of switching from tamoxifen to an AI or vice versa. With 71 months of follow-up period, the sequential arms did not improve estimated 5-year DFS compared with letrozole alone in either comparison.114 Clinical trials are also investigating longer durations of AI use to assess the benefits and harms of continued estrogen deprivation, the results of which are greatly anticipated.

Most national and international guidelines currently recommend incorporation of an AI into the adjuvant endocrine therapy regimen for all postmenopausal, hormone-sensitive breast cancers.48 The current NCCN guidelines for breast cancer management state that any of the following are acceptable endocrine therapy regimens for these women: (a) an AI for 5 years (or longer based on expert opinion); (b) tamoxifen for 2 to 3 years followed by an AI for a total of 5 years of endocrine therapy, or (c) tamoxifen for 5 years followed by an AI for another 5 years (total of 10 years of endocrine therapy).48 The NCCN panel believes that the three available AIs (anastrozole, letrozole, and exemestane) have similar antitumor efficacy and toxicity profiles, and many other clinicians agree. Therefore, the optimal endocrine therapy regimen in the adjuvant setting has yet to be determined, and incorporation of biologic therapies into these regimens is also being examined. Results from ongoing trials are eagerly awaited to more clearly define a treatment strategy for women facing this clinical dilemma.

Aromatase inhibitors are generally well tolerated. Adverse effects include bone loss or osteoporosis, hot flashes, myalgia or arthralgia, vaginal dryness or atrophy, mild headaches, and diarrhea. Although concerns surrounding loss of bone density and an increased risk of osteoporosis are evident in these adjuvant trials, the overall impact on quality of life and long-term survival are still being evaluated. Bisphosphonates are coadministered with the AI in many patients in the metastatic setting and may also be beneficial in the adjuvant setting. Other adverse events that are worrisome include questionable effects on the cardiovascular system (e.g., hypercholesterolemia), cognitive functioning, and joint health. Longer follow-up from these trials will continue to provide valuable information to guide treatment decisions and management of adverse effects.

In summary, tamoxifen has been used in the adjuvant setting for nearly 30 years and has a very well-defined safety and efficacy profile in this setting. The roles of other agents such as AIs in postmenopausal women and LHRH agonists in premenopausal women have changed the landscape of adjuvant endocrine therapy, and incorporation of other biologic therapies may further impact outcomes.

The pharmacologic disposition of tamoxifen in humans is very complex and has only recently been elucidated (Fig. 105-6). Tamoxifen is now considered to be a prodrug. Although the parent compound has significant clinical activity, tamoxifen is metabolized through multiple enzymes, including CYP3A4, CYP2C19, CYP2D6, and others, to metabolites that appear to be more active than the parent compound.115The active metabolites 4-hydroxytamoxifen (4OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen) have nearly a 100-fold higher affinity for the ER compared with tamoxifen. Endoxifen is present in the serum at a six- to 12-fold higher concentrations compared with 4OH-TAM; hence, endoxifen is thought to be the most important metabolite for the clinical activity of tamoxifen. The formation of endoxifen is highly dependent on the enzymatic activity of CYP2D6. However, multiple other pathways may also be important for determining activity, including deactivation pathways (e.g., SULT-1-A1, UGT). Polymorphisms in CYP2D6 can lead to increased or decreased formation of endoxifen and may be related to improved or diminished clinical outcomes, respectively. Although clinical data suggest that certain polymorphisms in CYP2D6 may result in poorer DFS or relapse-free survival in patients receiving tamoxifen, other studies show either no relationship or the opposite effect between clinical outcomes and CYP2D6 polymorphisms. Multiple commercially available assays for CYP2D6 are available, but widespread testing for patients receiving tamoxifen is not currently recommended based on available evidence.48,73 Excellent reviews on this subject are available).115 Potent inhibitors of CYP2D6, such as paroxetine and fluoxetine, may decrease levels of endoxifen in patients receiving tamoxifen.116 The clinical outcomes related to such drug–drug interactions in an individual patient are largely unknown and may depend on their underlying CYP2D6 genetic status (e.g., poor metabolizer, extensive metabolizer). In one population-based cohort study, concomitant use of tamoxifen and paroxetine (but not other antidepressants) resulted in increased risk of breast cancer death.117 Even though high-quality data on strong CYP2D6 inhibitors and breast cancer outcomes in patients receiving tamoxifen are limited, common sense would dictate avoiding known strong inhibitors of CYP2D6, if possible, in patients receiving tamoxifen.


FIGURE 105-6 Tamoxifen metabolism. Widths of the arrows approximate allocation of parent compound to various metabolites. See text for further explanation.

Locally Advanced Breast Cancer (Stage III)

Images Locally advanced breast cancer generally refers to breast carcinomas with significant primary tumor and nodal disease but in which distant metastases cannot be documented. A wide variety of clinical scenarios can be seen within this group of patients, including neglected tumors that have spread locally, to inflammatory breast cancers that are a unique clinical entity. Inflammatory breast cancer is associated with similar clinical findings compared with neglected, locally advanced breast tumors (e.g., erythema representing skin involvement). The distinction between the two diagnoses lies in the rapidity of onset of symptoms. Many locally advanced breast cancers are diagnosed in patients who have had symptoms for months to years and have neglected to seek medical attention. Although these women have a poor prognosis because of the delay in diagnosis, they are not classified as inflammatory breast cancer. The hallmark of inflammatory breast cancers is the rapid onset of symptoms within weeks to months, including erythema of the skin with or without a detectable underlying breast mass. These patients are often inappropriately treated for cellulitis with antibiotics for several weeks to months. Because of the aggressive nature of this disease, a delay in diagnosis can be fatal for some of these women.

The natural history of locally advanced breast cancer shows that even when local–regional control is accomplished, systemic relapse and death from breast cancer eventually occur in most patients if systemic therapy is not used.118 That observation led to interest in the use of neoadjuvant or primary chemotherapy in locally advanced breast cancer, which renders inoperable tumors resectable and can increase rates of BCT. Other potential benefits related to early initiation of systemic therapy include delivery of drugs through an intact vasculature, in vivo assessment of response to therapy, and the opportunity to study the biologic effects of the systemic treatment. For patients with inoperable breast cancer, including inflammatory breast cancer, the initial approach to therapy should be chemotherapy with the goal of achieving resectability. The NCCN guidelines addressing the management of locally advanced disease recommend primary chemotherapy with an anthracycline- and taxane-containing regimen.48

After neoadjuvant chemotherapy, most tumors respond with more than a 50% decrease in tumor size; about 70% of patients experience a reduction in their stage of disease. The chemotherapy regimens used in this setting are similar to those used in the adjuvant setting, but the regimens usually include an anthracycline, incorporate a taxane in some manner, and may have a higher dose density or dose intensity. For patients with HER2-positive tumors, the incorporation of trastuzumab with chemotherapy is appropriate.119 For more detailed information regarding the specific regimen-related information, readers are referred to the referenced review.120 Neoadjuvant endocrine therapy may be an option for patients who have unresectable hormone receptor–positive tumors who are unable to receive chemotherapy (e.g., multiple comorbid conditions).121 However, this approach to therapy is not common.

Local therapy usually follows chemotherapy, and the extent of surgery is determined by response to chemotherapy, the wishes of the patient, and the cosmetic results likely to be achieved. However, many patients may be able to have BCT if an acceptable response to chemotherapy is accomplished. Adjuvant radiation therapy should be administered to all locally advanced breast cancer patients to minimize local recurrences regardless of the type of surgery used for that individual patient (e.g., mastectomy or segmental mastectomy). Inoperable tumors that are unresponsive to systemic chemotherapy may require radiation therapy for local management and may not be eligible for surgical resection after radiation. These patients are not commonly encountered but have a very poor prognosis. For most patients with locally advanced breast cancer, cure is still the primary goal of therapy and can be achieved in a large number of patients when all treatment modalities are used.

Metastatic Breast Cancer (Stage IV)

Images Treatment of metastatic breast cancer (MBC) with cytotoxic, biologic, or endocrine therapy often results in regression of disease and improvements in quality of life. The choice of therapy for metastatic disease is based on the presence or absence or certain tumor characteristics and site of disease involvement. The most important factors predicting response to therapy are the presence of estrogen, progesterone, and HER2 receptors in the primary tumor tissue. Tumors expressing high levels of ER, PR, or both are more likely to respond to endocrine therapy. Tumors overexpressing HER2 receptor protein are more likely to benefit from anti-HER2 therapy. The site of disease is also an important factor to consider. Endocrine therapy is the treatment of choice for patients with hormone receptor–positive tumors who exhibit the first sign of metastatic disease in soft tissue, bone, or pleura because of the equal probability of response to endocrine therapy compared with chemotherapy and a preferable toxicity profile with endocrine therapy. Patients with symptomatic visceral or central nervous system (CNS) involvement generally have more rapidly growing cancers that require up-front chemotherapy. This is true for tumors that are hormone receptor positive and HER2-positive, requiring endocrine therapy in combination with anti-HER2 therapy in this clinical scenario.

Patients who respond to initial endocrine therapy often respond to a second (or even third) hormonal manipulation. But the response rate is lower, and the duration of response is shorter with second (and third) hormonal manipulations. Patients are sequentially treated with endocrine therapy until their tumors cease to respond or the patient ceases to benefit from endocrine therapy, at which time cytotoxic chemotherapy can be administered. Concurrent administration of more than one endocrine therapy or combining chemotherapy plus endocrine therapy is generally avoided in the setting of MBC because of increased toxicity and no substantial improvement in efficacy. Women with hormone receptor–negative tumors; with rapidly progressive or symptomatic lung, liver, or bone marrow involvement (a visceral crisis); and with progressive disease while on initial endocrine therapy are usually treated initially with cytotoxic chemotherapy. All breast cancer patients with metastases to the bone should be considered for treatment with a bone-modifying agent (e.g., pamidronate, zoledronic acid, or denosumab) because these agents have been shown to decrease the rates of skeletal-related events, such as fractures, spinal cord compression, and pain, and the need for radiation to the bones or surgery.122 These agents do not act as anticancer agents and should be coadministered with chemotherapy, endocrine therapy, or anti-HER2therapy.

Desired Outcomes

After breast cancer has advanced beyond local–regional disease, breast cancer is currently incurable. However, some patients live for many years with metastatic disease, making this a chronic disease requiring long-term management strategies that incorporate improvements or maintenance of quality of life. Palliation is the desired therapeutic outcome in the treatment of MBC. Optimizing benefits and minimizing toxicity are general therapeutic goals of any therapy administered in this setting. Therefore, sequential single-agent chemotherapy is often chosen over combination regimens, but individual circumstances may call for more rapid responses in which combination therapy may be indicated. Endocrine therapy is generally less toxic than chemotherapy and may be a more appropriate option for patients with hormone receptor–positive breast cancer. Tumor response to a particular treatment regimen may be measured by changes in laboratory tests, diagnostic imaging, and physical signs and symptoms. If a patient is tolerating therapy well, clear evidence of disease progression on imaging or physical examination is required to warrant changing therapy. Unless the patient clearly cannot tolerate the regimen or the cancer is clearly progressing at a rate that will quickly cause symptoms (or is causing symptoms already), there is not a sound reason to change therapy. Optimizing quality of life is an important therapeutic end point in the treatment of patients with MBC and eventually requires discontinuation of active cancer therapy and a shift to supportive care with hospice services. Balancing between quantity and quality of life is a frequent battle waged by many oncology clinicians with their patients, and difficult decisions are faced during this time.

Endocrine Therapy

Images The pharmacologic goal of endocrine therapy for breast cancer is to either (a) decrease circulating levels of estrogen or (b) prevent the effects of estrogen at the breast cancer cell (targeted therapy) by blocking the hormone receptors or downregulating the presence of these receptors. Achievement of the first goal depends on the menopausal status of the patient, but achievement of the second goal is independent of menopausal status. Many endocrine therapies are available to target either goal of therapy, and combinations of drugs with differing mechanisms of action have also been investigated. Unfortunately, most combinations have not demonstrated significant benefits over single-agent hormone therapy but have increased toxicity. Therefore, combinations of endocrine agents for MBC are generally not recommended outside the context of a clinical trial. A few exceptions to this statement exist, and individual clinical decisions should carefully weigh the risks and benefits of combination therapy versus single-agent therapy. These approaches will be discussed further with each class of endocrine therapy. Sequential use of endocrine agents is common in the metastatic setting when a patient is progressing on one agent after experiencing an initial response. Responsive patients are often treated with a series of endocrine agents, usually over several years, before chemotherapy is considered.

There is little evidence that the survival benefit from one endocrine therapy is clearly superior to that achieved with other therapies in women with MBC. Randomized controlled trials have shown that antiestrogens, AIs, progestins, estrogens, and androgens as well as surgical procedures, including oophorectomy, adrenalectomy, and hypophysectomy, are associated with similar OS in patients with MBC. Consequently, the choice of a particular endocrine therapy is based primarily on the mechanism of action, toxicity, and patient preference (Tables 105-8 and 105-9). Based on these criteria, tamoxifen is the preferred initial agent when metastases are present in a premenopausal woman except when the patient’s cancer recurs at the same time or within 1 year of occurrence of adjuvant tamoxifen therapy. In these cases, other agents are generally used. For post-menopausal women, the AIs are generally used first followed by other endocrine therapies upon progression.48,123

TABLE 105-8 Endocrine Therapies Used for Metastatic Breast Cancer


TABLE 105-9 Drug Monitoring for Endocrine Therapies


In postmenopausal and castrated women, the main source of estrogen is derived from the peripheral conversion of androstenedione, produced by the adrenal gland, into estrone and estradiol. This conversion requires the enzyme aromatase. Aromatase also catalyzes the conversion of androgens to estrogens in the ovary in premenopausal women and in extraglandular tissue, including the breast and breast cancer cells, in postmenopausal women. Therefore, AIs effectively reduce the levels of circulating estrogens and estrogens in the target organ. Aminoglutethimide was the prototype AI but was a nonspecific, weak enzyme inhibitor associated with much toxicity and is no longer available in the United States. Several analogs and derivatives of aminoglutethimide, as well as novel endocrine compounds, have been tested over the years to try and improve on the therapeutic ratio of this agent. Third-generation AIs available in the United States include anastrozole, letrozole, and exemestane. These agents have far greater selectivity and higher potency for the aromatase enzyme than aminoglutethimide. A major advantage of these specific compounds is their preferable toxicity profile, which consists mainly of bone loss or osteoporosis, mild nausea, hot flashes, arthralgias or myalgias, and mild fatigue. Anastrozole and letrozole are nonsteroidal compounds that exhibit reversible, competitive inhibition of aromatase. These are triazole compounds and have no intrinsic hormonal activity. Exemestane is a steroidal compound that binds irreversibly to aromatase, forming a covalent bond. Although this mechanism may have theoretical advantages to the reversible binding seen with the nonsteroidal agents, there is no clinical evidence that this drug is superior to other agents in this class. Exemestane does possess some androgenic properties at doses that are much higher than those used clinically and may have unique toxicities in some patients.123

Third-generation AIs have been compared with several other endocrine therapies since their approval. Although results are somewhat mixed, there appears to be at least equivalent activity seen with all three of the AIs compared with tamoxifen as first-line therapy and megestrol acetate as second-line therapy after progression on tamoxifen in postmenopausal women with positive or unknown hormone receptor status.123 Compared with tamoxifen, there appears to be a lower incidence of thromboembolic events and vaginal bleeding in patients who received selective AIs. As second-line therapy after tamoxifen, more nausea, vomiting, and hot flashes are seen with the AIs and more weight gain, fluid retention, and thromboembolism with megestrol acetate. Although generally considered therapeutically equivalent, the use of a steroidal AI (exemestane) after a patient progresses on a nonsteroidal inhibitor (anastrozole or letrozole) may provide some benefit and is a common practice based on limited data. The opposite sequence also has shown some benefit; thus, patients may receive two AIs (first-line and second-line) sequentially, especially patients who progress while on adjuvant tamoxifen therapy.48

The AIs should only be used in postmenopausal women. Based on the available evidence, pre- or perimenopausal women, whose ovaries are functioning, are inappropriate candidates for these therapies. Use of the AIs in addition to ovarian ablation (e.g., oophorectomy or LHRH agonists) is under investigation. Interestingly, the use of AIs in men with advanced breast cancer is controversial due to concerns that the pituitary feedback loop may be activated, increasing the levels of follicle-stimulating hormone, luteinizing hormone (LH), and possibly testosterone. Therefore, although objective responses are seen with single-agent AI therapy in men with breast cancer, consensus has yet to be reached regarding the clinical utility of these agents in men, and some clinicians are investigating the combination of an LHRH agonist with an AI in this population.124 Until further clinical trials are completed, the efficacy and safety of this treatment approach are unknown.

Antiestrogens bind to ERs, which inhibit receptor-mediated gene transcription and therefore block the effect of estrogen on the end target. This class of agents is now subdivided into two pharmacologic categories, SERMs and pure antiestrogens. SERMs include tamoxifen and toremifene (and raloxifene for breast cancer risk reduction in high-risk women) and demonstrate tissue-specific activity, both estrogenic and antiestrogenic, as described previously. The agonistic activity is thought to be responsible for many of the adverse reactions seen with these agents, including the increased risk of endometrial cancer, and has led to the development of pure ER antagonists that lack estrogen agonist activity. Pure antiestrogens are also referred to as selective estrogen receptor downregulators (SERDs). These molecules bind to the ER, inhibit estrogen binding, and degrade the drug–ER complex, thus decreasing the amount of ER on the tumor cell surface. Fulvestrant is currently the only pure antiestrogen commercially available in the United States.

Tamoxifen is generally considered to be the antiestrogen of choice in premenopausal women with MBC who have hormone receptor–positive tumors. The toxicities of tamoxifen are described in the Adjuvant Endocrine Therapy section earlier. The only additional toxicity that may be observed in the setting of MBC (specifically bone metastases) is a tumor flare or hypercalcemia, which occurs in about 5% of patients after the initiation of any SERM therapy and is not an indication to discontinue SERM therapy. It is generally accepted that this reaction is associated with response to endocrine therapy, but patients who do not experience such a reaction may still respond. This reaction is seen less frequently with the concurrent use of bisphosphonates as a result of their inhibition of osteoclasts, subsequently preventing the release of calcium from the bone.

Toremifene is another commercially available SERM for the treatment of breast cancer. It exhibits similar efficacy and tolerability compared with tamoxifen in the metastatic setting. Cross-resistance to toremifene has been demonstrated in patients with tamoxifen-refractory disease.125 Thus, at the current time, toremifene appears to be an alternative to tamoxifen in postmenopausal patients with positive or unknown hormone receptor status with MBC. Raloxifene, another SERM, was originally approval for prevention of osteoporosis in postmenopausal women. Available data with raloxifene as a treatment for breast cancer show very low response rates and no significant clinical benefit. Consequently, use of this agent for breast cancer treatment should be discouraged. The use of raloxifene for breast cancer risk reduction in high-risk women has been reported (see Prevention and Early Detection).

Fulvestrant is approved for the second-line therapy of postmenopausal MBC patients with hormone receptor–positive tumors. It is unique in that it is given as an intramuscular injection. The dosing of fulvestrant has been controversial, and many comparative studies used what is now thought to be an insufficient dose; therefore, its place in therapy is also not clearly defined. Studies have compared this agent with anastrozole, exemestane, and tamoxifen in the treatment of postmenopausal women with MBC. Biologically, fulvestrant should produce similar outcomes in premenopausal women, but no data exist to confirm the safety or efficacy in premenopausal women. In the comparative trials with fulvestrant and an AI (anastrozole or exemestane), similar efficacy and safety were demonstrated with both agents when given after patients progressed on tamoxifen therapy.123 When compared directly with tamoxifen, time to progression was slightly shorter in the fulvestrant arm, but the difference did not reach statistical significance. That trial failed to confirm statistical noninferiority, which indicates that the trial could not show that fulvestrant was equivalent to tamoxifen.123 Subsequent pharmacokinetic data confirming a dose–response relationship with fulvestrant led investigators to design a dose comparison study of fulvestrant 250 mg versus 500 mg.126Results from this trial confirm that the appropriate dose of fulvestrant for MBC should be 500 mg intramuscularly administered every 2 weeks for 3 doses (days 1, 15, and 29) followed by administration every 28 days. This loading approach to dosing facilitates reaching steady-state plasma levels more rapidly, allowing for a response to be seen within a clinically relevant time frame. To accomplish this dosing, two injections of 5 mL each are administered simultaneously. Although cumbersome and slightly more uncomfortable, patients appear to tolerate this higher dose relatively well, exhibiting similar toxicity profiles regardless of the dose administered.

A subsequent randomized, phase II study comparing this dosing strategy with anastrozole in postmenopausal women with hormone receptor–positive MBC demonstrated superior time to progression with fulvestrant with similar objective responses seen with subsequent hormone therapy administered to both groups.127 Although the power of this phase II study is limited and survival data are not yet available, it is encouraging to better understand how dosing may impact response with this novel endocrine agent. Combining therapy with anastrozole and fulvestrant has been investigated in two randomized phase III trials with conflicting results.128,129 Although the combination does appear to be well tolerated, the overall benefits (if any) appear to be modest, and sequential single agents are most commonly administered in the palliative setting of metastatic disease. Adverse events related to fulvestrant include injection-site reactions, hot flashes, asthenia, and headaches. Based on the results of the comparative trial, the dose of fulvestrant approved by the Food and Drug Administration (FDA) was changed to 500 mg given intramuscularly every 28 days with an extra dose administered on day 14. This choice of therapy is covered by Medicare Part B and is a good option for patients who are unable to take an oral medication.

Another goal of endocrine therapy in premenopausal women is to reduce estrogen production with surgery, irradiation, or medication. Ovarian ablation (surgically or chemically) is still commonly used in some parts of the United States and is considered by many specialists to be the endocrine therapy of choice in premenopausal women. The mortality rate with surgical oophorectomy is low, usually less than 3% in appropriately selected patients. Irradiation of the ovaries was a means of castration many years ago but was associated with multiple complications and is no longer performed for these purposes. Chemical castration with LHRH analogs is increasingly used instead of oophorectomy in premenopausal women.

Medical castration with LHRH analogs induces responses in about one third of unselected premenopausal MBC cases. This is accomplished through downregulation of LHRH receptors in the pituitary, decreasing levels of LH, which subsequently lead to a decrease in circulating estrogen to castrated levels. Thus, the effect of LHRH analogs on circulating estrogen levels in premenopausal breast cancer simulates oophorectomy. The three agents available and used in the United States are leuprolide, goserelin, and triptorelin, but only goserelin is FDA approved for the treatment of MBC. These agents are administered as an injection every 4 weeks (all products have extended formulations, lasting 3 months to 1 year, but they are not recommended for the treatment of breast cancer) and are associated with minimal side effects, including amenorrhea, bone loss or osteoporosis, hot flashes, and occasional nausea (Table 105-9). LHRH agonists may also produce a flare response because of an initial surge in LH and estrogen production lasting 2 to 4 weeks. This flare response is similar to that seen with tamoxifen, and patients with high-volume, bulky disease should be monitored for increasing pain and hypercalcemia during the initiation period. A meta-analysis was conducted of several trials that combined tamoxifen and LHRH agonists versus LHRH agonists alone in premenopausal patients with MBC.130 With a median follow-up period of 6.8 years, there was a significant survival benefit and progression-free survival (PFS) benefit in favor of the combined treatment. The overall response rate was significantly higher with combined endocrine treatment. However, this analysis did not compare tamoxifen alone with the combination of an LHRH agonist with tamoxifen. Therefore, if an LHRH agonist is used as first-line therapy for MBC, it should be used in combination with tamoxifen. But if tamoxifen is used as first-line therapy for MBC, the addition of a LHRH agonist is controversial because of the lack of clinical data to support any additional benefit.48

Progestins such as megestrol acetate and medroxyprogesterone acetate have been compared with tamoxifen in randomized trials and have been found to yield equivalent response rates. Whereas medroxyprogesterone acetate is more frequently used in Europe, megestrol acetate is more frequently used in the United States. Based on efficacy and tolerability, these agents are generally reserved as third-line therapy after patients have failed an AI and an antiestrogen (tamoxifen, toremifene, or fulvestrant). The most common side effect of megestrol acetate is weight gain, occurring in 20% to 50% of patients. Patients experiencing weight gain may also have fluid retention, but fluid retention is not totally responsible for the weight gain. In cachectic cancer patients, the weight gain may be desirable, but this is not uniformly true of all patients with MBC. Other side effects associated with progestins include vaginal bleeding in 5% to 10% of patients, either while taking the progestational agent or when it is discontinued, and less than a 10% incidence of hot flashes. Thromboembolic complications are also associated with these agents.131

High-dose estrogens and androgens are rarely used today because of their side effect profile and the availability of better tolerated alternatives (e.g., AIs). About one-third of patients placed on high-dose estrogens will discontinue them because of side effects, the most important of which are thromboembolic events, vomiting, and fluid retention. Less common side effects include areolar hyperpigmentation, breast tenderness and engorgement, vaginal discharge, incontinence, hot flashes, and phlebitis. All of the effective androgens cause masculinizing effects, including hirsutism and acne, in more than 50% of patients. The mechanism by which these agents exert a therapeutic effect in breast cancer is unknown. However, these agents may inhibit aromatase, among other pharmacologic effects that antagonize estrogen.

Other agents recently approved for the treatment of metastatic prostate cancer are under investigation for the treatment of MBC. Abiraterone is an analog of ketoconazole that is administered with prednisone for metastatic prostate cancer and affects androgen biosynthesis. Because androgens are converted to estrogens in the presence of aromatase, the impact of abiraterone on estrogen synthesis is also being investigated. Ongoing clinical trials in women and men with MBC may yield positive results, but use of this agent for management of MBC is not currently recommended. Investigation into mechanisms of endocrine resistance have met with some success, leading to the FDA approval of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in combination with exemestane for patients with MBC progressing on a nonsteroidal AI. This combination is discussed further in the Biologic or Targeted Therapy section.

Cytotoxic Therapy

Images Cytotoxic chemotherapy is eventually required in most patients with MBC. Patients with hormone receptor–negative tumors require chemotherapy as initial therapy of metastases. Hormone-sensitive tumors that fail to respond to endocrine therapy or that initially respond to endocrine therapy, eventually ceasing to respond, require chemotherapy when endocrine options have been exhausted. Combination chemotherapy results in an objective response in about 60% of patients previously unexposed to chemotherapy. Combination chemotherapy regimens are associated with higher response rates than are single-agent therapies in the treatment of MBC, but the higher response rates have not usually translated into clinically significant differences in time to progression and OS in individual clinical trials.132Combination regimens are associated with greater toxicity. In the palliative metastatic setting, the least toxic approach is preferred when efficacy is considered equal. In clinical practice, patients who require a rapid response to chemotherapy (e.g., those with symptomatic bulky metastases) often receive combination therapy despite the added toxicity. This decision is complex and should be made on an individual patient basis.

Most patients experience partial responses, but complete disappearance of disease occurs in fewer than 10% of patients treated. The median duration of response is 5 to 12 months, but some patients have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. The median survival period of patients after treatment with commonly used drug combinations for MBC ranges between 14 and 33 months. The median time to response ranges from 2 to 3 months in most studies, but this period depends on the site of measurable disease and can range from 3 weeks (skin and lymph node metastases) to 18 weeks (bone metastases). After a chemotherapy regimen has been initiated, it is usually continued until there is unequivocal evidence of progressive disease or intolerable side effects. Table 105-10 lists some selected chemotherapy agents used in the metastatic setting.132

TABLE 105-10 Selected Chemotherapy Regimens for Metastatic Breast Cancer


Factors associated with an increased likelihood of response to chemotherapy include a good performance status, a limited number (one to two) of disease sites (or involved organ systems), and a prolonged previous response to chemotherapy or hormonal therapy (i.e., long disease-free interval). Patients who have progressive disease during chemotherapy have a lower likelihood of response to a subsequent chemotherapy. However, this is not necessarily true for patients who are given chemotherapy after a treatment-free interval of substantial duration (e.g., more than 1 year). Treatments may be repeated if some time has passed between therapies, but this is rarely done because of the large number of agents now available to treat breast cancer. Hormone receptor–positive tumors that are resistant to endocrine therapy are as likely to respond to chemotherapy as patients who receive upfront chemotherapy. Age, menopausal status, and receptor status do not appear to be directly associated with response to chemotherapy. However, there continues to be much debate surrounding the potential association between hormone receptor status and response to chemotherapy (e.g., ER status and anthracyclines). Most clinical decisions regarding chemotherapy are not currently influenced by hormone-receptor status.

A number of chemotherapeutic agents have demonstrated activity in the treatment of breast cancer, including doxorubicin, epirubicin, paclitaxel (conventional and protein bound), docetaxel, capecitabine, fluorouracil, cyclophosphamide, methotrexate, vinblastine, vinorelbine, gemcitabine, ixabepilone, eribulin, mitoxantrone, mitomycin C, thiotepa, and melphalan. The most active classes of chemotherapy in MBC are the anthracyclines and the taxanes, producing response rates as high as 50% to 60% in patients who have not received prior chemotherapy for metastatic disease.132 Doxorubicin (conventional and liposomal) and epirubicin have demonstrated significant efficacy in the metastatic setting and are generally considered therapeutically equivalent when dosed appropriately. Administration of these agents is limited by their cumulative cardiotoxicity. Paclitaxel, docetaxel, and protein-bound paclitaxel are also FDA approved for the treatment of MBC and are generally considered therapeutically equivalent. Taxane administration is limited by cumulative peripheral neuropathy.132 Most patients will receive each of these agents at some point in the course of their MBC because cross-resistance is incomplete.

An increasing number of patients diagnosed with MBC have been exposed to adjuvant chemotherapy consisting of an anthracycline and a taxane. If metastases are found within 6 to 12 months of completing treatment with these agents, many clinicians will choose treatment from a different chemotherapy class. If it has been longer since their adjuvant therapy, then retreating with the same agents may be considered. However, given the cardiotoxicity associated with the anthracyclines, the use of these agents in the metastatic setting has been generally avoided until the availability of liposomal anthracycline. Pegylated liposomal doxorubicin is associated with less cardiotoxicity and similar efficacy compared with conventional doxorubicin and is a viable option for women who recur more than 1 year after their adjuvant anthracycline regimen.

Weekly administration of paclitaxel and protein-bound paclitaxel results in higher response rates, time to progression, and survival in addition to a more favorable side effect profile compared with administration every 3 weeks.132 The most useful weekly dose of conventional paclitaxel in the metastatic setting appears to be 80 mg/m2/week with no breaks in therapy. With this approach, the toxicity profile of paclitaxel changes with less myelosuppression and delayed onset of peripheral neuropathy but slightly more fluid retention and skin and nail changes. Although the incidence of hypersensitivity reactions is also slightly less at these lower doses (requiring fewer premedications), it remains at about 3% despite incorporation of all available preventive measures. There is currently debate regarding the most appropriate weekly dose of protein-bound paclitaxel in the metastatic setting. Doses of 100 to 150 mg/m2/week administered on days 1, 8, and 15 of a 28-day cycle have been investigated, demonstrating some evidence of a dose–response relationship. In the metastatic palliative setting, a lower dose is generally chosen, minimizing toxicity while not significantly compromising efficacy.132 Docetaxel is most appropriately dosed on an every-3-week schedule for MBC. Weekly dosing did not produce improvements in disease response and was associated with significantly more toxicities than the every-3-week dosing strategy.132

After patients have been treated with an anthracycline and a taxane, single-agent capecitabine, vinorelbine, or gemcitabine have resulted in response rates of 20% to 25%.132 Of these agents, only capecitabine is FDA approved as a single agent for MBC. Gemcitabine is only FDA approved in combination with paclitaxel for MBC. However, all of these are included in most national and international guidelines as appropriate therapy for MBC. Decisions regarding which agent to choose are based on patient characteristics, expected toxicities, and previous exposure to chemotherapy.

Other antimicrotubule agents have also been approved for the management of MBC, demonstrating significant benefits in patients who have had prior exposure to multiple other chemotherapy agents. Ixabepilone is an epothilone compound with a similar but distinct mechanism of action from the taxanes, binding to β-microtubulin in a unique manner but ultimately leading to microtubule stabilization and cell death in a similar manner compared with the taxanes. It is approved for use in combination with capecitabine and as a single agent for the management of MBC.132 Eribulin is another antimicrotubule agent with a unique mechanism of action. The first synthetic analogue of halochondrin B, eribulin effectively inhibits polymerization of tubulin into microtubules and suppresses the microtubule growth phase similar to the vinca alkaloids. The mechanism of eribulin’s antitumor efficacy differs from the vinca alkaloids in that eribulin does not appear to have any effect on the microtubule shortening phase. These subtle differences are thought to be important for eribulin’s efficacy in patients who have been exposed to multiple therapies, including other antimicrotubule agents. It is approved for use as a single agent for the management of MBC patients who have received at least two prior chemotherapies for their metastatic disease.132

Both of these agents are associated with similar toxicities compared with the taxanes and vinca alkaloids, respectively (e.g., myelosuppression, neuropathy, myalgias or arthralgias, alopecia, and skin and nail changes with ixabepilone and myelosuppression and neuropathy with eribulin). Hypersensitivity is occasionally seen with ixabepilone because it is also solubilized in Cremophor-EL, the likely causative agent in paclitaxel-associated hypersensitivity. However, eribulin has not been associated with hypersensitivity reactions and is not formulated in a complex solvent system that may predispose patients to allergic-type reactions. Neuropathy may become problematic in patients who have received numerous sequential neurotoxic chemotherapy agents; therefore, careful monitoring of the impact on quality of life is imperative because these therapies are administered in a palliative setting. Ongoing clinical trials are investigating these agents in other combinations and in earlier stages of the disease, and these results are eagerly awaited.132

Biologic or Targeted Therapy

Therapies that focus on molecular targets through novel mechanisms are often referred to as biologic or targeted therapy. These agents, while using the biologic knowledge gained from decades of research, are designed to specifically target cancer cells while generally sparing normal tissues. For breast cancer, several agents are available that focus on a myriad of targets that are differentially expressed in breast cancer cells and play a critical role in their proliferation and survival.

Images Anti-HER2 Agents HER2, in selected breast cancers, is a very important protein for maintenance of breast cancer cell proliferation and survival. Currently, three anti-HER2 agents are available in the United States (trastuzumab, lapatinib, and pertuzumab), and a fourth is nearing approval (trastuzumab emtansine).

As mentioned previously, trastuzumab is a MoAB targeted against the HER2-receptor protein. Pertuzumab is also a MoAB but binds to a different epitope on HER2 and prevents protein dimerization and subsequent cell signaling. Lapatinib is a small-molecule tyrosine kinase inhibitor (TKI) targeted against the HER2 protein and the HER1 (EGFR) protein, leading to dual signaling blockade.

Evidence supporting the use of these agents differs greatly, with the majority of data focusing on trastuzumab administered in different combination regimens with chemotherapy, endocrine therapy, or other biologic therapies. Trastuzumab also has significant clinical activity as a single agent, albeit less than trastuzumab-combination regimens. Lapatinib has a fair amount of evidence to support its use in MBC in combination with chemotherapy, endocrine therapy, and other biologics. To date, single-agent lapatinib therapy has a limited role in the management of breast cancer. Pertuzumab was recently approved in the United States for first-line therapy of HER2-positive MBC in combination with trastuzumab and docetaxel. This limited role is likely to expand rapidly as many ongoing clinical trial results mature.

Single-agent treatment with trastuzumab yields a response rate of 15% to 20% and a clinical benefit rate of nearly 40% in patients with HER2- overexpressing MBCs.133 Moreover, the results of a large randomized trial demonstrated that trastuzumab has at least additive, and perhaps synergistic, activity with other chemotherapeutic agents.134 In this pivotal trial comparing chemotherapy in combination with trastuzumab versus chemotherapy alone, the addition of trastuzumab increased response rates, time to progression, and OS compared with chemotherapy alone. Patients who were anthracycline naive were treated with an anthracycline (mostly doxorubicin; some epirubicin) plus cyclophosphamide and patients who had received an adjuvant anthracycline regimen were treated with paclitaxel. During this trial, patients who received the anthracycline–trastuzumab combination had a very high incidence of cardiotoxicity (27%), leading to discontinuation of this arm of the study and a black box warning regarding this contraindication in the product information for trastuzumab. Many investigators are attempting to circumvent this toxicity while giving these two classes of agents together (e.g., liposomal doxorubicin, continuous-infusion doxorubicin, lower dose epirubicin). However, until further information regarding the safety of these approaches becomes available, anthracyclines administered concurrently with trastuzumab should not be given outside the context of a clinical trial in patients with MBC.134

Many other chemotherapy agents have successfully been administered with trastuzumab, including docetaxel, protein-bound paclitaxel, vinorelbine, gemcitabine, capecitabine, and the platinum agents (carboplatin and cisplatin). In phase III trials, single-agent docetaxel or capecitabine was found to be inferior to the same chemotherapy plus trastuzumab in terms of response rates, time to progression and OS (survival benefit only demonstrated with docetaxel–trastuzumab). In phase II trials, vinorelbine in combination with trastuzumab has shown very high response rates even in heavily pretreated patients.134 In another phase III trial, the triplet combination of paclitaxel, carboplatin, and trastuzumab was compared with paclitaxel and trastuzumab as dual therapy. This study demonstrated superior response rates and time to progression with the triplet regimen versus the doublet regimen.134 A similar trial designed to confirm this data using docetaxel instead of paclitaxel failed to demonstrate any advantage with the addition of carboplatin to a taxane–trastuzumab regimen. These conflicting results indicate that the benefit of adding a platinum compound to these regimens remains questionable. Toxicities with the addition of carboplatin are significantly greater in terms of myelosuppression and nausea, which should be considered when making treatment decisions in the setting of MBC in which quality of life is paramount.134

Significant cross-talk exists between the growth factor pathways (e.g., HER2) and hormone receptor pathways (e.g., ER). This has generated a hypothesis that combining endocrine therapies with anti-HER2therapies may be synergistic or at least additive in their anticancer effects. The TAnDEM trial randomized patients with HER2-positive MBC to anastrozole with or without trastuzumab. The addition of trastuzumab improved PFS from 2.4 months to 4.8 months (P = 0.0016), and overall response rate and clinical benefit rate were also significantly improved.134 Many other trials are seeking to confirm this information. Although confirming information is awaited, these combinations are frequently used in current clinical practice for patients with hormone receptor–positive, HER2-positive MBC.

Upon disease progression, trastuzumab is generally continued while the chemotherapy agent is switched. This clinical practice of continuing trastuzumab beyond progression is well accepted and supported by clinical evidence. von Minckwitz et al. randomized patients who were progressing on front-line trastuzumab-containing regimens to receive either capecitabine alone or capecitabine with continued trastuzumab therapy.134 Median time to progression was 5.6 months with capecitabine alone and 8.2 months with capecitabine plus trastuzumab (HR, 0.69; 95% CI, 0.48–0.97; P = 0.034). Although there were methodological problems with this trial (e.g., slow accrual led to early closure, open-label design), results support the decade-long clinical practice of continuing trastuzumab beyond progression but raise other questions as to the comparative benefit with this approach versus a lapatinib-based regimen (see later discussion).

Lapatinib is a TKI that dually targets HER2 and the epidermal growth factor receptor (EGFR or HER1). This small molecule works intracellularly to actively shut down the signaling pathway from these two receptors and thus inhibit cell growth and division. Lapatinib is an oral agent with modest activity against breast cancer as a single agent. In combination with capecitabine in women with HER2-positive MBC who were previously treated with an anthracycline, a taxane, and trastuzumab, lapatinib improved response rates and time to progression as compared to capecitabine alone.135 Based on this evidence, the FDA approved lapatinib in this setting. In combination with paclitaxel as first-line therapy for MBC (HER2-positive and -negative), the addition of lapatinib did not appear to improve outcomes for patients with HER2-negative disease. However, for patients with HER2-positive MBC, the addition of lapatinib significantly improved time to progression, event-free survival, objective response rates, and clinical benefit rate, although the HER2-positive patients on the paclitaxel–placebo arm did not receive any HER2-directed therapy.136

Lapatinib has also been combined with endocrine therapy in hopes of taking advantage of the cross-talk between the growth factor receptor and the hormone receptor pathways as mentioned previously. In a large randomized phase III study, letrozole was administered with either lapatinib or placebo in hormone receptor–positive patients with MBC (HER2 negative and positive).137 The addition of lapatinib in HER2-positive patients improved PFS from 3 months to 8.2 months (HR, 0.71; 95% CI, 0.53–0.96; P = 0.019). In HER2-negative patients, no significant benefit was observed with the addition of lapatinib. Another interesting approach to HER2-positive MBC has been to combine HER2-targeted agents with differing mechanisms of action. Blackwell and colleagues compared lapatinib alone with lapatinib plus trastuzumab in patients with MBC progressing on trastuzumab therapy. PFS was significantly improved with the combination (12 vs. 8.4 weeks; P = 0.029).138 However, the clinical significance of this small difference (less than 1 month) is debatable, and the expense of this regimen is obvious. Nonetheless, this regimen is well tolerated and commonly used. Treatment beyond progression with lapatinib is not generally considered.

Because lapatinib is a small molecule and can readily cross the blood–brain barrier, investigation has ensued to ascertain its effects on brain metastases. Trastuzumab does not cross the blood–brain barrier, and the CNS is often a sanctuary site for progressive metastases, representing the first site of recurrence in a relatively large number of patients. Phase II trials investigating the efficacy of lapatinib in patients with treated brain metastases failed to demonstrate any significant response. However, in the large randomized trial with capecitabine ± lapatinib, the addition of lapatinib was associated with a lower rate of the CNS as a site of first progression (2% with lapatinib vs. 6% with capecitabine alone; P = 0.045).135 Ongoing adjuvant trials with lapatinib will continue to evaluate this relationship and determine the value of lapatinib for prevention of CNS metastases.

Resistance to trastuzumab and lapatinib naturally develops, and patients eventually progress on trastuzumab- or lapatinib-based regimens. Pertuzumab, another MoAB targeted against HER2, binds to a different epitope of the HER2 receptor extracellular domain compared with trastuzumab. Similar to trastuzumab, pertuzumab receptor binding stimulates antibody-dependent cellular-mediated cytotoxicity, but pertuzumab also prevents HER2 from dimerizing with other HER receptors (most notably HER3), leading to more comprehensive signal blockade. Therefore, the mechanisms of trastuzumab and pertuzumab are thought to be complementary, and regimens that combine these MoABs have shown activity in HER2-positive MBC. Phase II trials combining the MoABs alone (without chemotherapy) have shown significant clinical benefit rates of 50% after progression on previous trastuzumab-based therapy.139 Single-agent therapy with pertuzumab alone in a similar cohort of patients resulted in a clinical benefit rate of only 10%, with an increased clinical benefit rate (up to 40%) when trastuzumab was introduced upon progression on pertuzumab.139 Although it is confusing as to why pertuzumab is largely ineffective as a single agent, it is interesting that reintroduction of HER2 blockade is effective in some patients. Therefore, it is likely that single agent pertuzumab will not be used. However, further clinical evidence will be forthcoming guiding the use of this and other new biologic therapies targeting HER2 and other molecular pathways.

Clinical Controversy…

Many options now exist for treatment of HER2-positive MBC, with multiple new agents approved with potential to significantly impact this disease. Determining the optimal treatment and sequence of therapies for trastuzumab-treated patients is extremely difficult. Many ongoing trials are attempting to better define the role of (a) continuing trastuzumab with different chemotherapies; (b) switching or adding pertuzumab, lapatinib, or TDM1; (c) multiple targeted therapies with or without chemotherapy/endocrine therapy; or (d) some combination of all of these approaches.

In the pivotal, registration trial for pertuzumab, combination therapy with trastuzumab and chemotherapy (docetaxel) demonstrated significant improvements in PFS compared with trastuzumab and chemotherapy alone with manageable increases in the rates of clinically significant toxicity (e.g., febrile neutropenia and grade 3 diarrhea greater with pertuzumab; cardiotoxicity similar).140 Similar data were reported in abstract form with dual HER2 therapy plus weekly paclitaxel, leading to addition of this agent (in combination with trastuzumab plus a taxane) to the NCCN guidelines for management of breast cancer.48 Developments of other anti-HER2 therapies are well underway, with a fourth agent expected to reach the market in the United States within the next few months. Trastuzumab emtansine is an antibody–drug conjugate consisting of trastuzumab with a potent cytotoxic agent (mertansine) being investigated alone and in combination with other anti-HER2 agents and chemotherapy. Promising results from early clinical trials with this agent will hopefully lead to FDA approval. The rapidity of available information and new drugs makes treatment decisions difficult in patients with HER2-positive MBC. Incorporation of new agents into treatment algorithms will likely become increasingly clear as more data become available to guide clinicians in the optimal use of these combinations and single agents. Until that time, individual treatment approaches become increasingly complex, but the hope these new agents bring to patients progressing on existing therapy is immense. Investigations into the use of these agents in early-stage breast cancer are also underway and may change the landscape for management of HER2-positive breast cancer in all stages of the disease. Adverse effects of the anti-HER2therapies have been identified and are primarily related to the heart. Therefore, all therapies in this class, regardless of their exact mechanism of receptor blockade, have some degree of cardiotoxicity that should be acknowledge and monitored for. The type of cardiotoxicity differs depending on the agent in question. Trastuzumab and likely pertuzumab are associated with myocardial damage leading to heart failure clinically similar to anthracycline-associated cardiomyopathy. As mentioned earlier, the incidence of heart failure is approximately 5% with single-agent trastuzumab, and the risk is unacceptably high when trastuzumab is given concurrently with an anthracycline.141Fortunately, heart failure seen with trastuzumab is somewhat reversible with pharmacologic management, and some patients have continued therapy with trastuzumab after their left ventricular ejection fraction has returned to normal with medical management. Although there are no guidelines for cardiac monitoring with trastuzumab, close monitoring for clinical signs and symptoms of heart failure is recommended in order to intervene with appropriate cardiac treatments. The incidence of cardiotoxicity with pertuzumab administered in combination with trastuzumab is largely unknown. One early study with pertuzumab was stopped early because of cardiotoxicity that surpassed 50% at the time of study discontinuation. Subsequent studies have not demonstrated an increased rate of cardiotoxicity beyond that seen with trastuzumab alone.139 This discrepancy is likely to be better characterized as further clinical evidence and experience is gained with this new agent. Nonetheless, careful clinical monitoring is required.

Because of concerns regarding the role of HER2 in normal cardiac functioning, lapatinib may also increase the risk for cardiac dysfunction. However, in a review of more than 3,689 patients who received lapatinib in phase I to III trials, cardiotoxicity occurred in only 1.6% of patients.142 Although these data are reassuring, it does not rule out the possibility of expanded toxicity when this agent is used in patients not included in the clinical trials such as those with underlying cardiac risks. Rare QT prolongation has also been reported with lapatinib, but the exact clinical significance of this effect is widely debated. Drug interactions that increase systemic exposure to lapatinib may predispose patients to this rare complication (see below).

Adverse events associated with MoABs are seen with trastuzumab and pertuzumab and include infusion-related reactions (primarily fever and chills). These occur in about 40% of patients receiving trastuzumab during the initial infusion and generally go unrecognized by patients. Other infusion-related reactions with trastuzumab include mild nausea, pain at tumor sites, rigors, headaches, dizziness, hypotension, rash, and asthenia, which are much less common.141 A rare but more severe reaction consisting of severe hypersensitivity or pulmonary reactions has been reported in post-marketing surveillance with trastuzumab. It is important to educate patients regarding the pulmonary reactions because these may occur up to 24 hours after the infusion and can be fatal if not promptly treated. Trastuzumab may increase the incidence of infection, diarrhea, and other adverse events slightly when given with chemotherapy, but most of these increases are not clinically significant for an individual patient. The adverse effects of pertuzumab appear to be similar, with increases in febrile neutropenia and grade 3 diarrhea evident in the phase III trial with docetaxel.139 As clinicians gain more experience with this agent outside the context of clinical trials, the true incidence and severity of these adverse events will become more evident.

Other adverse events associated with lapatinib include primarily rash and diarrhea. These adverse effects appear to be more significant when combined with chemotherapy (e.g., capecitabine, paclitaxel) but are generally manageable with aggressive antidiarrheal therapy or dose reductions. Other rare effects have been reported (QT prolongation, hepatotoxicity, and interstitial lung disease), and patients should be counseled regarding these effects. Drug–drug and drug–food interactions are particularly important with lapatinib because of its metabolism through the cytochrome P450 system (3A4) and other pharmacokinetic and pharmacodynamic issues.143 Many of the adverse effects listed previously may be exacerbated caused by drug or food interactions, and careful review of patients’ medication lists and education regarding these issues are extremely important.

It should be noted that only 20% to 30% of patients with MBC overexpress HER2, and commercially available IHC tests that are reported as 2+ for HER2 are often negative by the more sensitive and specific FISH technique. To date, there is no benefit associated with the administration of trastuzumab to patients with HER2- negative tumors (IHC score of 0 to 1+, or FISH negative) and a very questionable benefit associated with administration of trastuzumab to women with tumors that are 2+ for HER2 by IHC staining alone. The patients who benefit most from trastuzumab therapy include those whose tumors express HER2 protein at the 3+ level or who clearly demonstrate gene amplification by FISH testing. Further analyses investigating what other predictive markers may be clinically useful are currently ongoing.144

Other Targeted Agents As previously mentioned, treatments for MBC rarely eliminate all cancer cells, and cures are rarely seen after the cancer has spread beyond the local area of the breast and axilla. Acquired drug resistance develops in nearly all patients. Alterations in cell signaling, cell cycle control, and apoptotic signaling are among the common mechanisms of resistance with chemotherapy, endocrine therapy, and anti-HER2 therapy. The phosphatidylinositol 3-kinase (PI3K)/protein kinase-B (also called Akt) pathway includes many different proteins, one of the most important being the mTOR tyrosine kinase. mTOR is an important mediator for cell proliferation and regulation of apoptosis, angiogenesis, and cellular metabolism. Use of mTOR inhibitors to treat MBC has resulted in conflicting results. Temsirolimus, an IV mTOR inhibitor, was administered with letrozole as first-line therapy for MBC in a large randomized phase III trial, resulting in no improvement in PFS.145 Everolimus, an oral mTOR inhibitor, was administered with exemestane as second-line therapy for MBC after an AI and produced significant improvements in PFS.146 In combination with tamoxifen, everolimus demonstrated superior clinical benefit rate and time to progression in a randomized phase II trial. Preliminary results from this trial also appear to indicate a survival advantage.147 Further investigation of this combination is eagerly awaited.

Targeting mTOR also appears to be important for HER2-positive MBC patients progressing on trastuzumab, limited data have explored the use of everolimus with trastuzumab–taxane combinations that appear to be promising, but added toxicities and cost are important factors to consider when adding an mTOR inhibitor to a patient’s regimen.147 The most common adverse events experienced in the everolimus–exemestane trial were mucositis, fatigue or asthenia, cough, pyrexia, and hyperglycemia.146 As more patients receive this combination outside the context of a clinical trial, adverse effects related to metabolic effects (hypercholesterolemia, hypertriglyceridemia, hyperglycemia) and pneumonitis may become more prevalent because these are evident in patients receiving everolimus for other cancer types (e.g., renal cell carcinoma).

Targeting tumor blood vessels is another strategy to fight breast cancer and potentially reverse drug resistance. One of the most important growth factors that regulates the development of new blood vessels (angiogenesis) is VEGF. Bevacizumab is a MoAB targeted against VEGF and is FDA approved for use with chemotherapy for the management of a variety of malignancies. Bevacizumab has also been tested in clinical trials with capecitabine and paclitaxel in patients with MBC. Conflicting results have been reported with the use of bevacizumab in combination with chemotherapy in patients with MBC, and in 2012, the FDA withdrew the approval for bevacizumab in combination with paclitaxel for management of newly diagnosed MBC. Nonetheless, NCCN guidelines for management of breast cancer continue to list bevacizumab–paclitaxel as one option for the management of HER2-negative MBC. Continuing controversy exists regarding this agent in the management of MBC.148,149 Many other biologic or targeted agents are being investigated and may end up changing the overall management of breast cancer for both early and metastatic disease.

Radiation Therapy

Radiation is an important modality in the treatment of symptomatic metastatic disease. The most common indication for treatment with radiation therapy is painful bone metastases or other localized sites of disease refractory to systemic therapy. Radiation therapy provides significant pain relief to about 90% of patients who are treated for painful bone metastases. Radiation is also an important modality in the palliative treatment of metastatic brain lesions and spinal cord lesions, which respond poorly to systemic therapy, as well as eye or orbit lesions and other sites where significant accumulation of tumor cells occurs. Skin and lymph node metastases confined to the chest wall area may also be treated with radiation therapy for palliation (e.g., open wounds or painful lesions). Chemotherapy may also be added to radiation for sensitization purposes.


Current efforts at breast cancer prevention are directed toward the identification and removal of risk factors often referred to as risk reduction strategies. Unfortunately, a number of risk factors associated with development of breast cancer, such as family history of breast cancer or personal history of breast or other gynecologic malignancies, cannot be modified. Isolation and cloning of breast cancer susceptibility genes now allow screening of women with histories suggestive of “breast cancer families” and identification of appropriate candidates for prophylactic bilateral mastectomies or bilateral salpingo-oophorectomy. These surgeries are considered for women who are at very high risk for the development of breast or ovarian cancer, particularly if the women’s breasts are difficult to evaluate by both physical examination and mammography and if the women have persistent disabling fears that they will be diagnosed with cancer. Guidelines for the incorporation of surgical risk reduction strategies are largely based on genetics and other known risk factors for the development of breast (or ovarian) cancer.

In the last 20 years, there has been increasing interest in pharmacologic risk reduction for breast cancer. Two important classes of agents being studied in this setting are the SERMs and AIs.

The drugs with the most clinical information as risk reduction agents for breast cancer are the SERMs, tamoxifen and raloxifene. As previously described, tamoxifen is useful as an adjunct after treatment of primary breast cancer. In randomized trials of tamoxifen as an adjuvant treatment for breast cancer, women who received tamoxifen were also found to have a reduced incidence of contralateral primary breast carcinomas.109 In a large, randomized, placebo-controlled study, the NSABP demonstrated significant reductions in risk of invasive and noninvasive breast cancers with 5 years of tamoxifen therapy (20 mg/day) in women at high risk for developing the disease.51Although this study is controversial, other studies from around the world also have been reported that investigated the role of tamoxifen as a risk reduction strategy. A meta-analysis of these trials indicates a consistent benefit with tamoxifen in reducing the incidence of ER-positive breast cancers (48% reduction; 95% CI, 36%–58%; P <0.0001).150Tamoxifen has been repeatedly shown to be a relatively safe drug with an acceptable toxicity profile when used to treat patients with breast cancer. However, its estrogenic effects on the uterus and the coagulation system increase the risk of serious adverse effects that may be critical for patients taking this agent as a risk reduction strategy. Toxicities associated with tamoxifen were previously described in the Adjuvant Endocrine Therapy section. Any decision to use tamoxifen for risk reduction should be made after a thorough discussion of the woman’s risk of breast cancer, the potential benefits of tamoxifen, and the potential serious adverse events associated with tamoxifen.

A second trial has been reported that compared tamoxifen with raloxifene in a similar population of high-risk women. The Study of Tamoxifen and Raloxifene (STAR or P2) was published in 2006 and demonstrated a similar rate of invasive breast cancers with the two drugs.52 However, the rates of noninvasive breast cancer were numerically higher in the raloxifene arm of the trial, although this difference did not reach statistical significance. In 2010, an updated analysis was published, reporting that raloxifene retained 76% of tamoxifen’s effectiveness in preventing invasive breast cancer.151 Rates of endometrial cancer and DVT were more frequent in the tamoxifen arm, but overall quality of life was similar between the two agents.52 Based on these results, the FDA maintains raloxifene’s approval for breast cancer risk reduction in women at high risk of the disease.

A similar reduction in the incidence of contralateral primary breast cancers was demonstrated in the adjuvant clinical trials with the AIs, leading to the premise that AIs may also play a role in risk reduction of breast cancer.152Goss and colleagues published the first results of a randomized, placebo-controlled, phase III trial comparing exemestane with placebo for 5 years in high-risk women.153 Eligibility criteria were similar to the P-1 and STAR trials, and this report represented a median follow-up period of only 34 months. Nonetheless, significant reductions were seen in the rates of invasive breast cancers with exemestane (HR, 0.35; 95% CI, 0.18–0.70; P = 0.002) with tolerable adverse events. The authors suggest that adherence was poor, which is common in studies of drugs taken for a long duration in relatively well women. Despite this nonadherence, the benefits appear to be quite large. Ongoing clinical trials with the available AIs are underway, and results from these trials should further elucidate the role of these agents in breast cancer risk reduction strategies.152

The NCCN has established guidelines for risk reduction strategies, including mastectomy, oophorectomy, and pharmacologic agents.50 These guidelines are based on risk assessment tools such as the Gail, BRCAPRO, or Claus models as well as other established risk factors. Much of the guideline depends on a woman’s wishes for intervention. The American Society of Clinical Oncology also has published recommendations guiding the use of the pharmacologic agents for breast cancer risk reduction.154 These guidelines are similar to the NCCN’s guidelines in that they recommend the use of tamoxifen or raloxifene for postmenopausal women at high risk (as defined by the Gail or other models) and tamoxifen for premenopausal women at high risk based on the woman’s wishes.

The rationale for early detection of breast cancer is based on the relationship between stage of breast cancer at diagnosis and the probability for cure. If all breast cancer cases could be detected at a very early stage of the disease (i.e., small primary tumor and negative lymph nodes), then more patients theoretically could be cured of their disease. Screening guidelines for early detection of breast cancer in women at average risk have been developed by several organizations, including but not limited to the ACS, the United States Preventive Services Task Force (USPSTF), and the NCCN.38,155,156 The ACS guidelines are most commonly cited. However, it is important to note that the expert panels developing these guidelines often differ in their approach and analysis of the available data, as is evident in the controversies that currently exist.

The ACS currently recommends that all women 20 years and older be informed of the benefits and limitations of breast self-examinations (BSEs).155 Several studies have investigated the benefits of BSE. These trials were primarily conducted before the routine use of mammographic screening and demonstrated an inferential benefit in diagnosis of earlier stages of breast cancer. One trial, the Shanghai trial, appeared to indicate no benefit, but there was a higher rate of biopsies in women who were taught BSE than in women who were not taught BSE.157 The investigators from this trial caution that this was a study of BSE instruction and not BSE performance. Compliance and competency with the BSE were neither guaranteed nor evaluated in this trial. Because of the lack of direct evidence to support or refute a benefit with BSE and the apparent associated increase in biopsy rates, the ACS has taken the position that it is optional, but women of all ages should be encouraged to be aware of their breasts in order to recognize any changes and promptly report them to a health professional.155 Other organizations have taken a similar approach to their recommendations regarding BSE or simply state that there are insufficient evidence to recommend this practice.38,156

Recommendations for breast examination by a healthcare professional (clinical breast examination) vary among the screening guidelines most often cited. The rate of breast cancer detection using clinical breast examination (CBE) alone is low, with even lower rates in younger women and women with higher body weight.155 Randomized clinical trials have reported inconsistent results and often evaluated CBE in conjunction with mammograms. The ACS recommends CBE in conjunction with mammography for women ages 40 years and older.155 For younger patients (in their 20s and 30s), it is recommended as part of a periodic health examination every 3 years, but this recommendation is based on weak evidence. The USPSTF concluded that there is insufficient evidence to assess the benefits and risks of CBE beyond screening mammography in women older than the age of 40 years.156

Images The most controversial screening recommendation for breast cancer is related to annual mammography. It is clear that screening mammography decreases mortality from breast cancer. The controversies surround the balance of benefits and harms associated with a less than perfect screening test in women at average risk of developing breast cancer but of differing ages. Multiple clinical trials have been completed over the years, and multiple meta-analyses of these trials have been conducted as well. Most of the trials included women 50 to 74 years of age, and the interval between testing ranged from 12 to 33 months. The most recent meta-analysis of these data estimated a “number needed to invite for screening to extend one woman’s life” (NNI) as 1,339 for women aged 50 to 59 years.158 Some trials also included women aged 40 to 49 years, albeit significantly fewer women in this age group were included in the meta-analyses. The estimated NNI for women aged 40 to 49 years was reported as 1,904. The largest benefit was found in women ages 60 to 69 years with an estimated NNI of 377. None of the trials included women 75 years of age or older; therefore, there are no data to support or refute the benefit of screening mammography in this population.158

Incorporation of this new information into national guidelines differs with each organization. The ACS continues to recommend annual screening mammography for women ages 40 years and older (as long as they are in good health).155 This recommendation allows for individualized decisions to be made based on the overall health of the woman but does not limit access to younger or older women who may benefit from screening. The USPSTF took a different approach, stating that “the decision to start regular, biennial screening mammography before the age of 50 years should be an individualized one and take patient context into account, including the patient’s values regarding specific benefits and harms.”159 For women 50 to 74 years of age, the USPSTF recommends biennial screening mammography. This interval recommendation was based on assumptions of risks and benefits based on the available studies. Although the upper limit for screening varies among guidelines, most experts agree that mammograms in women older than the age of 74 are not supported by the current body of evidence, but some women may benefit if they are otherwise in good health and have a life expectancy of 10 years or more. There are also many other debates within this controversial area, and readers are referred to these references for further details.38,155,156,158,159

Other radiologic methods of breast imaging are also being investigated (e.g., digital mammography, ultrasonography, and MRI), and minimal data exist to support these methods in some high-risk populations. Recommendations for women with a high risk of breast cancer are not fully established, and definitions of “high risk” vary among different guidelines. The ACS include breast screening MRI as an adjunct to mammography for the following groups of high-risk women: (a) known BRCA mutation carriers; (b) untested individuals with a first-degree relative with a BRCA mutation; (c) women with a 20% or greater lifetime risk of breast cancer based on models that largely depend on family history; (d) women who had radiation to the chest between the ages of 10 and 30 years of age; (f) women with LiFraumeni’s syndrome, Cowden’s syndrome, or Bannayan-Riley-Ruvalcaba’s syndrome or who have a first-degree relative with one of these syndromes.155,160 The NCCN also has adopted consensus guidelines for women at high risk of breast cancer, incorporating breast MRI with other established screening tools for women as young as 25 years old (Table 105-11).25

TABLE 105-11 Breast Cancer Screening Guidelines


It should also be noted that there are risks associated with any screening procedure, and they should be discussed with all patients so they are able to make an informed decision regarding these procedures. The risks involved with screening mammograms include false-negative results, false-positive results, overdiagnosis (true positives that will not become clinically significant), and radiation risk. The rate of false-negative results with the current technology is about 20%, which explains why CBE is an important adjunct to screening for many women. Although the specificity of mammography is quite high (90%), most abnormal examinations are false–positive results, leading to additional biopsies and psychological distress. The issue of overdiagnosis refers primarily to the growth in detection of DCIS from screening mammography. The biologic significance of these tumors is unknown because only some of them would become invasive if left in place. So the question remains: Are we treating women who do not require treatment? Experts in the field continue to debate this issue. Radiation exposure also has been discussed in the context of screening mammography, but the small doses of radiation exposure with mammograms (2–4 mGy [0.2–0.4 Rad] per standard two-view examination) appears to be overshadowed by other benefits in terms of reduction in mortality as a consequence of early cancer detection.156

Significant advances in the safety and efficacy of screening mammography have occurred during the last 2 decades. These advances have enabled superior visualization of breast and breast tissue with a lower dose of radiation being delivered. Despite these advances, about 10% of all palpable masses are not detected by mammography. This is most commonly observed in premenopausal women and may be directly related to the increased density of breast tissue in this estrogen-rich environment.

Although the safety and efficacy of screening mammography in terms of image quality and dosimetry are very acceptable, the need for greater quality control in mammography was recognized for some time. The Mammography Quality Standards Act (MQSA) of 1992 ensures that all mammographic facilities achieve a common high standard of quality assurance. Responsibility for operation of the act was given to the FDA, and all facilities that offer mammography must be FDA certified to remain open. The MQSA has now been updated to include full-field digital mammography as well, although the use of this new technology has not yet been incorporated into national screening guidelines. Passage of this landmark legislation, as well as provision of appropriate levels of funding to conduct this program, represents an important contribution to the health of women. Similar quality assurance measures will need to be implemented for breast MRIs and ultrasonography, given the recommendations to use these imaging methods for early detection and diagnosis, respectively, in high-risk women and those with suspicious masses. All women should be aware that breast MRIs and ultrasonography are not currently regulated and should choose to have these tests performed at a reputable facility to ensure quality. The American College of Radiology has developed reporting guidelines to standardize the way these images are interpreted. These are referred to as the BI-RADS and are available for mammography, breast ultrasonography, and breast MRIs.39 This reporting method allows for uniformity among facilities and better comparisons over time. Nonetheless, differences remain between breast imaging quality and interpretation, and it is best to have imaging conducted at the same facility over time if possible.


Personalized pharmacotherapy is a very broad term that includes many old and new scientific approaches to predict which patients should be treated, how they should be treated, and their likelihood of response or toxicity to treatment. These approaches may be focused on the tumor(s) itself or on patient or host factors. Breast cancer clinicians have been using these approaches to therapeutic decisions for decades and continue to search for novel characteristics to further individualize the choice of therapies.

Most scientific studies in breast cancer focus on tumor-specific markers either individually or as a panel of markers. Since the mid 1970s, clinicians have been using biomarkers to individualize therapy for patients with breast cancer. Initially, the tumor’s ER or PR status was used to determine whether endocrine therapy (starting with tamoxifen) would benefit patients with MBC. Although these data have been widely available for many years, ER and PR testing in all breast cancers worldwide has been a relatively new phenomenon. Other biomarkers have been developed over the decades, with HER2 being the most widely accepted alternate marker for breast cancer. HER2 was initially studied as a prognostic biomarker in an attempt to ascertain an individual patient’s risk of breast cancer recurrence and chemotherapy sensitivity or resistance. Although these applications of HER2 testing remain controversial, the use of HER2 testing to establish the likelihood of response or benefit to anti-HER2 therapies is well established and required for all breast tumors at diagnosis. (See the Adjuvant Systemic Therapy section.)

It is clear from these individual biomarker studies that breast cancers are very heterogeneous, and interaction among markers is also important. Incorporation of multiple markers into biomathematical formulas that predict the likelihood of recurrence of cancer have been developed and are used across the United States to assist clinicians and patients in making informed decisions regarding adjuvant systemic therapy (e.g., Adjuvant! Online). These predictive formulas are useful but do not incorporate several markers that have since been validated individually (e.g., HER2, Ki-67, LVI). Genetic panels such as Oncotype DX were developed to screen for and quantify multiple genetic markers in tumor cells and are used as prognostic biomarkers to determine the risk of recurrence in early-stage breast cancer patients. The exact role these genetic panels will play in treatment decisions in the future is uncertain, but scientists and clinicians have embraced the technology, and the copious amounts of data collected from these analyses are being analyzed and incorporated into clinical trials and new standards every day.

Although these are all examples of tools that are used to individualize or personalize pharmacotherapy, very few markers are currently used clinically to represent host or patient differences. One promising area of research is in pharmacogenomics related to drug pharmacokinetics or pharmacodynamics. Results from studies with tamoxifen and CYP2D6 genotyping have been mixed, which is probably related to the complex metabolism of tamoxifen and large number of other prognostic factors (see the Adjuvant Endocrine Therapy section). Throughout this chapter are examples of characteristics that are used to individualize therapy. As more research is done in this field, the amount of tools available to clinicians to assist with treatment decisions will expand greatly.


The desired therapeutic outcome of adjuvant therapy of breast cancer differs significantly from that of metastatic disease. Adjuvant therapy—chemotherapy, biologic therapy, and hormonal therapy—is administered with curative intent. The rationale for adjuvant therapy is that breast cancer, even when diagnosed in early stages when clinical evidence of distant spread is not apparent, is a systemic disease that spreads early to distant sites. Adjuvant therapy is intended to eradicate micrometastases and thus cure the patient of breast cancer. Therefore, the overall goal of adjuvant therapy is to cure the disease, which is something that cannot be fully evaluated for years after initial diagnosis and treatment. In addition, because disease cannot be detected at the time adjuvant therapy is started, assessment of disease response is not possible. Instead, a predetermined number of cycles of adjuvant therapy or years of biologic or hormonal therapy are administered. Adjuvant chemotherapy is often associated with significant toxicity. Maintaining dose intensity has been demonstrated to be important in the cure of disease, and therefore optimizing supportive care measures such as antiemetics and growth factors is highly recommended. The concept of dose density, using growth factors to maintain blood counts while decreasing the interval between chemotherapy administrations, is very controversial in the management of early-stage breast cancer. Multiple studies investigating this approach to adjuvant chemotherapy have been conducted with conflicting results and many more trials continue to be analyzed in hopes of determining the long-term outcomes related to this approach to therapy. The goals of therapy with neoadjuvant chemotherapy are slightly different. These goals focus on earlier end points of tumor response so as to minimize surgery, determine prognosis, and potentially conserve the breast tissue for a better cosmetic result. The other outcomes discussed with adjuvant therapy also apply to this scenario in terms of improving survival and decreasing recurrences compared with no systemic therapy.

Palliation is the therapeutic outcome in treatment of MBC. Optimizing benefits and minimizing toxicity are general therapeutic goals of any therapy administered in this setting. Therefore, sequential single agents are often chosen over combination regimens, but individual circumstances may call for more rapid responses in which combination therapy may be indicated. Tumor response to a particular treatment regimen may be measured by changes in laboratory tests, diagnostic imaging, or physical signs or symptoms. Periodic testing is clinical useful in some circumstances, but careful interpretation of results is required. If a patient is tolerating therapy well, clear evidence of disease progression on imaging or physical examination is required to warrant changing therapy. Unless the patient clearly cannot tolerate the regimen or the cancer is clearly progressing at a rate that will quickly cause symptoms (or is causing symptoms already), there is not a sound reason to change therapy. Optimizing quality of life is an important therapeutic end point in the treatment of patients with MBC. A number of valid and reliable tools are available for objective assessment of quality of life in patients with breast cancer.






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