DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology (Cancer: Principles & Practice (DeVita)(Single Vol.)) 10 Ed.

Malignant Tumors of the Breast

Monica Morrow, Harold J. Burstein, and Jay R. Harris

INTRODUCTION

Breast cancer is a major public health problem for women throughout the world. In the United States, breast cancer remains the most frequent cancer in women and the second most frequent cause of cancer death. In 2012, it was estimated there were 226,870 new cases of breast cancer, with 39,510 deaths.1 Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths, although there is a five-fold variation in incidence between high-incidence areas such as the United States and Western Europe, and low incidence areas such as Africa and Asia.2 Since 1990, the death rate from breast cancer has decreased in the United States by 24%, and similar reductions have been observed in other countries.3,4 The adoption of screening mammography, and the use of adjuvant therapy, have contributed approximately equally to this improvement.5 Although breast cancer has traditionally been less common in nonindustrialized nations, its incidence in these areas is increasing.6 This chapter examines the salient features of breast cancer, stressing practical information of importance to clinicians and the results of prospective randomized trials that guide therapeutic decisions.

ANATOMY OF THE BREAST

The adult female breast lies between the second and sixth ribs, and between the sternal edge and the midaxillary line. The breast is composed of skin, subcutaneous tissue, and breast tissue, with the breast tissue including both epithelial and stromal elements. Epithelial elements make up 10% to 15% of the breast mass, with the remainder being stroma. Each breast consists of 15 to 20 lobes of glandular tissue supported by fibrous connective tissue. The space between lobes is filled with adipose tissue, and differences in the amount of adipose tissue are responsible for variations in breast size. The blood supply of the breast is derived from the internal mammary and lateral thoracic arteries. The breast lymphatic drainage occurs through a superficial and deep lymphatic plexus, and >95% of the lymphatic drainage of the breast is through the axillary lymph nodes, with the remainder via the internal mammary nodes. The axillary nodes are variable in number and have traditionally been divided into three levels based on their relationship to the pectoralis minor muscle, as illustrated in Figure 37.1. The sentinel axillary node is almost always found in the level 1 axillary nodes. The internal mammary nodes are located in the first six intercostal spaces within 3 cm of the sternal edge, with the highest concentration of internal mammary nodes in the first three intercostal spaces.

RISK FACTORS FOR BREAST CANCER

Multiple factors are associated with an increased risk of developing breast cancer, but the majority of these factors convey a small to moderate increase in risk for any individual woman. It has been estimated that approximately 50% of women who develop breast cancer have no identifiable risk factor beyond increasing age and female gender. The importance of age as a breast cancer risk factor is sometimes overlooked. In 2009, it was estimated that 18,640 invasive breast cancers and 2,820 breast cancer deaths occurred in US women under age 45 compared with 173,730 cancers and 37,350 deaths in women aged 45 years and older.7

Familial Factors

A family history of breast cancer has long been recognized as a risk factor for the disease, but only 5% to 10% of women who develop breast cancer have a true hereditary predisposition. Many women with a family history overestimate their risk of developing breast cancer or harboring a predisposing genetic mutation. Overall, the risk of developing breast cancer is increased 1.5-fold to 3-fold if a woman has a mother or sister with breast cancer. Family history, however, is a heterogeneous risk factor with different implications depending on the number of relatives with breast cancer, the exact relationship, the age at diagnosis, and the number of unaffected relatives. Even in the absence of a known inherited predisposition, women with a family history of breast cancer face some level of increased risk, likely from some combination of shared environmental exposures, unexplained genetic factors, or both.

Inherited Predisposition to Breast Cancer

Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with a significant increase in the risk of breast and ovarian carcinoma, and account for 5% to 10% of all breast cancers. These mutations are inherited in an autosomal dominant fashion and have varying penetrance. As a result, the estimated lifetime risk of breast cancer development in mutation carriers ranges from 26% to 85%, and the risk of ovarian cancer from 16% to 63% and 10% to 27%, respectively, in carriers of BRCA1 and BRCA2.8 In a meta-analysis of 10 international studies, the cumulative risks to age 70 for breast cancer were 57% for BRCA1 and 40% for BRCA2 carriers.9 More than 700 different mutations of BRCA1 and 300 different mutations of BRCA2 have been described, and the position of the mutation within the gene has been shown to influence the risk of both breast and ovarian cancers.

Other cancers associated with BRCA1 or BRCA2 mutations include male breast cancer, fallopian tube cancer, and prostate cancer. Carriers of BRCA2 may also have an elevated risk of melanoma and gastric cancer. Management strategies available for risk reduction in BRCA1/2 mutation carriers include intensive surveillance, chemoprevention with selective estrogen receptor modulators (SERM), and prophylactic (breast and salpingo-ovarian) surgery, and these are discussed in a later section. There is a great interest in the role of environmental and lifestyle factors in the modification of cancer risk amongBRCA1 or BRCA2 carriers; at present, however, the available data are inconsistent. It is worth noting that women with a significant family history of breast cancer (i.e., two or more breast cancers under the age of 50 years, or three or more breast cancers at any age), but who test negative for BRCAmutations have approximately a four-fold risk of breast cancer.10 In contrast, women in families where a BRCAmutation is present who test negative for the mutation are not at increased risk for breast cancer development in the absence of other risk factors, and do not require special surveillance.11

Women with BRCA1 mutations have a higher incidence of triple-negative/basal-like breast cancers (see the following), and cancers are more likely to be grade 3 tumors and to lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 overexpression than sporadic cancers.12 The phenotype of BRCA2 cancers does not differ from that seen in sporadic cancers. The presence of a BRCA1 orBRCA2 mutation may be suggested by the family history on either the maternal or paternal side of the family. The features considered by the 2005 US Preventive Services Task Force13 are listed in Table 37.1. Less-rigorous criteria for referral for genetic counseling are used for individuals of Ashkenazi Jewish ancestry, because the carrier frequency of specific BRCA1 (187delAG, 5385 ins C) and BRCA2(6174delT) mutations in this group is 1:40, compared with 1:500 in the general population. These guidelines are particularly useful for individuals not affected with breast cancer. In the patient with newly diagnosed breast cancer, young age at diagnosis (≤40 years), bilateral breast cancer, Ashkenazi ancestry, or a malignancy consistent with the BRCA1 phenotype all constitute reasons for referral to a genetic counselor, particularly in the woman with a small number of female relatives. Models are available to estimate the likelihood of a BRCA1 or BRCA2 mutation based on family history. The implications of genetic testing for both individuals and their family members are considerable, and these issues should be discussed prior to undertaking genetic testing.

Other genetic mutations have been associated with breast cancer risk, although with a lower prevalence or penetrance than BRCA1 and BRCA2TP53 and PTEN each account for <1% of cases, while mutations in CDH1 are associated with an autosomal dominant predisposition to diffuse gastric cancer and lobular breast cancer.14 Young women with TP53 mutations (Li-Fraumeni syndrome) seem to have a greater propensity for HER2+ breast cancers.15Mutations in low-penetrance genes are thought to account for a significant number of non-BRCA1 or -BRCA2 breast cancers. A specific mutation of the checkpoint kinase 2 (CHEK2) gene was found in 11.4% of families with three or more cases of breast cancer diagnosed before age 60,16 but in a large study of 10,860 unselected breast cancer patients from five countries, the CHEK2 mutation was identified in only 1.9% of cases17 and 0.7% of controls (odds ratio, 2.34), and testing for CHEK2 is not routine. The increasing availability of next-generation sequencing has already resulted in commercially available panels of high and moderate penetrance genes, and is likely to change the approach to genetic screening in future years.

Hormonal Factors

The development of breast cancer in many women appears to be related to female reproductive hormones, particularly endogenous estrogens. Early age at menarche, nulliparity or late age at first full-term pregnancy, and late age at menopause increase the risk of developing breast cancer. In postmenopausal women, obesity and postmenopausal hormone replacement therapy (HRT), both of which are positively correlated with plasma estrogen levels and plasma estradiol levels, are associated with increased breast cancer risk. Most hormonal risk factors have a relative risk (RR) of ≤2 for breast cancer development.

The age-specific incidence of breast cancer increases steeply with age until menopause, and then plateaus. There is substantial evidence that estrogen deprivation via iatrogenic premature menopause can reduce breast cancer risk. Premenopausal women who undergo oophorectomy without hormone replacement have a markedly reduced risk of breast cancer later in life, with an increasing magnitude of risk reduction as the age at oophorectomy decreases.18Data from women with BRCA1 and BRCA2 mutations suggest that early oophorectomy has a substantial protective effect on breast cancer risk in this population also.19

Age at menarche and the establishment of regular ovulatory cycles are strongly linked to breast cancer risk; the total duration of exposure to endogenous estrogens seems important. There appears to be a 20% decrease in breast cancer risk for each year that menarche is delayed. Of note, hormone levels through the reproductive years in women who experience early menarche may be higher than in women who undergo a later menarche.20 Additionally, late onset of menarche results in a delay in the establishment of regular ovulatory cycles, which may contribute to protective effects.

The relationship between pregnancy and breast cancer risk appears more complicated. Women whose first full-term pregnancy occurs after age 30 have a two- to five-fold increase in breast cancer risk in comparison with women who have a first full-term pregnancy before approximately age 18.20,21 Nulliparous women are at greater risk for the development of breast cancer than parous women, with a RR of about 1.4. Breast cancer risk increases transiently for the 10 years after a pregnancy, but then declines.21 Abortion, whether spontaneous or induced, does not increase breast cancer risk.22 Breastfeeding, particularly for longer duration, lowers the risk of breast cancer diagnosis. The combined effects of reproductive history and breastfeeding may account for substantial fractions of the difference in breast cancer risk between developed and developing nations.

The use of combined estrogen and progestin HRT also increases breast cancer risk. In the Women’s Health Initiative, use of combined estrogen and progestin HRT was associated with a hazard ratio (HR) of 1.24 (p <0.001) for breast cancer development as compared to placebo.23 The effects of HRT were noted after a relatively short duration of use. An excess of abnormal mammograms was observed after 1 year of HRT use and persisted throughout the study, and an increase in breast cancer incidence was noted after 2 years. The cancers occurring in HRT users were larger and more likely to have nodal or distant metastases than those occurring in the placebo group (25.4% versus 16%; p = 0.04), although they were of similar histology and grade.23 The observational UK Million Women Study found that current use of HRT was associated with a RR of breast cancer development of 1.66 (p <0.001) and a RR of breast cancer death of 1.22 (p = 0.05).24

Dietary and Lifestyle Factors

Observational studies suggested that high-fat diets were associated with higher rates of breast cancer than low-fat diets. However, a meta-analysis of eight prospective epidemiologic studies failed to identify an association between fat intake and breast cancer risk in adult women in developed countries.25 Consistent with these findings, a randomized dietary modification in 48,835 women in the Women’s Health Initiative study did not result in a statistically significant reduction in breast cancer incidence after 8 years of follow-up.26 Breast cancer risk increases linearly with the amount of alcohol consumed.27Decreased intake of nutrients such as vitamin C, folate, and β-carotene may enhance the risk related to alcohol consumption.

Obesity is associated with both an increased risk of breast cancer development in postmenopausal women and increased breast cancer mortality. Women with a body mass index of ≥31.1 have a 2.5-fold greater risk of developing breast cancer than those with a body mass index of ≤22.6.23 Weight and weight gain appear to play an important but complex role in breast cancer risk. During childhood, rapid growth rates decrease the age of menarche, an established risk factor, and result in greater attained stature, which has been consistently associated with increased risk. During early adult life, obesity is associated with a lower incidence of breast cancer before menopause, but no reduction in breast mortality. Weight gain after age 18 is associated with a graded and substantial increase in postmenopausal breast cancer, particularly in the absence of HRT.28

Benign Breast Disease

Benign breast lesions are classified as proliferative or nonproliferative. Nonproliferative disease is not associated with an increased risk of breast cancer, whereas proliferative disease without atypia results in a small increase in risk (RR = 1.5 to 2.0). Proliferative disease with atypical hyperplasia is associated with a greater risk of cancer development (RR = 4.0 to 5.0).29 Dupont and Page30 found a marked interaction between atypia and a family history of a first-degree relative with breast cancer. This subgroup of patients had a risk 11-fold that of women with nonproliferative breast disease, and an absolute risk of breast cancer development of 20% at 15 years, compared with 8% in women with atypical hyperplasia and a negative family history of breast carcinoma. Proliferative breast disease appears to be more common in women with a significant family history of breast cancer than in controls, further supporting its significance as a risk factor. Of note, however, the majority of breast biopsies done for clinical indications demonstrate nonproliferative disease. In the study of 10,000 breast biopsies by Dupont and Page,30 69% had nonproliferative changes and only 3.6% demonstrated atypical hyperplasia.

Breast Density

Mammographic breast density has emerged as an important predictor of breast cancer risk, and makes detection of cancer more difficult. A significant component of breast density is genetically determined, although density has also been shown to vary with the initiation and discontinuation of postmenopausal HRT. Women with >75% breast density have 4.7-fold increase in the odds of breast cancer development compared with those with >10% breast density.31The risk was apparent even after adjustment for other risk factors.

Environmental Factors

Exposure to ionizing radiation increases breast cancer risk, and the increase is particularly marked for exposure at a young age. This pattern has been observed in survivors of the atomic bombings, those undergoing multiple diagnostic X-ray examinations, and in women receiving therapeutic irradiation. A markedly increased risk of breast cancer development has been reported in women who received mantle irradiation for the treatment of Hodgkin lymphoma before age 15 years.32 Additionally, in women with Hodgkin lymphoma who develop unilateral breast cancer, the risk of a contralateral cancer approximates the level of risk seen in BRCA mutation carriers.32 Well-conducted studies do not suggest that exposure to electromagnetic fields and organochlorine pesticides increase breast cancer risk. A summary of the magnitude of risk associated with known breast cancer risk factors is provided in Table 37.2.

MANAGEMENT OF THE HIGH-RISK PATIENT

There is no formal definition of what constitutes high risk. Without question, women who carry mutations in either BRCA1 or BRCA2, or who have a family history consistent with genetically transmitted breast cancer, are considered to be at higher risk than those in the general population. Other high-risk groups include women who have received mantle irradiation, usually for treatment of Hodgkin lymphoma, and those with lobular carcinoma in situ (LCIS) or atypical hyperplasia. Although a variety of hormonal factors (e.g., early menarche, late age at first full-term pregnancy) affect breast cancer risk on a population basis, these conditions have a relatively small effect on risk for any individual woman.

Many women overestimate their risk of developing breast cancer, so providing an accurate assessment of breast cancer risk will often allay anxiety and facilitate management decisions. It can be helpful to provide women who are concerned about their breast cancer risk with a numeric risk estimate. The Gail et al. model,33 which calculates a woman’s risk of developing breast cancer based on age at menarche, age at first live birth, number of previous breast biopsies, the presence or absence of atypical hyperplasia, and the number of first-degree female relatives with breast cancer, has been used in the National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention trials. Efforts to validate the Gail et al. model in different settings have produced variable results. It was highly accurate in the NSABP P1 prevention trial,34 with a ratio of observed to predicted cancers in study participants of 1.03. In general, the Gail et al.33 model is thought to underestimate risk in women with strong family histories, at least in part because it only incorporates a family history in first-degree relatives and does not include ovarian carcinoma. The Claus et al.35 model takes into account both first- and second-degree relatives, although it does not include other risk factors, and may be more useful for women at risk on the basis of family history.

Management strategies available for high-risk women include intensive surveillance, chemoprevention with endocrine agents, and prophylactic surgery. Surveillance, consisting of monthly breast self-examination, annual screening mammography, and clinical breast examinations once or twice yearly, did not clearly result in early detection in high-risk women in the placebo arm of the NSABP P1 prevention trial where 29% of the women who developed breast cancer had axillary node metastases at diagnosis.34 Women at risk as a result of known or suspected BRCA1 or BRCA2 mutations warrant screening with magnetic resonance imaging (MRI), which results in earlier detection of breast cancer than conventional surveillance strategies, and has a higher specificity and sensitivity among high-risk women.36 Because the cancers detected by MRI are smaller and less likely to be associated with nodal positivity, it is likely that a survival benefit is present. However, there is no benefit for MRI screening in women with atypical hyperplasia or LCIS.37 An expert panel convened by the American Cancer Society in 2007 to develop guidelines for MRI screening recommended the use of MRI in addition to mammography for a small group of women at very high risk of breast cancer development, either due to genetic factors or a history of prior thoracic irradiation (Table 37.3). It has been estimated that only 1% of the population would be eligible for MRI screening using these criteria.38 For women with a <15% risk of breast cancer development, the American Cancer Society recommended against the use of MRI screening.39 In the remainder, they thought that the evidence was insufficient to recommend for or against MRI screening. Chemoprevention is an option in addition to surveillance strategies. Two SERMs, tamoxifen and raloxifene, have been shown to reduce the incidence of ER+ breast cancer. Four prospective, randomized trials have examined the effect of tamoxifen on breast cancer incidence (Tables 37.4 and37.5).34,4042 There is considerable heterogeneity in outcome among the trials, much of which can be attributed to differences in the populations studied. In an overview of the four studies, tamoxifen produced a 38% reduction in breast cancer incidence (95% confidence interval [CI], 8 to 46; p <0.001), and a 48% reduction in the incidence of ER+ breast cancers.43 No effect on the incidence of ER cancers was seen in any of the trials, and the cancers occurring in women taking tamoxifen were not found to have had more positive nodes or to be larger in size than those in the placebo arm, providing reassurance that tamoxifen chemoprevention does not result in the occurrence of biologically more-aggressive cancers.

In the largest of these studies, the NSABP P1 trial, a 49% risk reduction was seen with tamoxifen, with 43.4 cancers per 1,000 women occurring in the placebo arm compared with 22.0 per 1,000 in the tamoxifen arm.34 The benefits of tamoxifen were observed for both invasive and noninvasive carcinoma, and were seen in women of all ages. A particular benefit was seen in those at risk because of atypical hyperplasia, with an 84% reduction in cancer incidence in this group. The risk reductions were similar in those at risk on the basis of a family history of breast cancer and those at risk from other factors. Controversy exists over the benefit of tamoxifen in BRCA mutation carriers,44,45 but it appears that it is the likelihood of expressing the ER that determines the efficacy of tamoxifen as a chemopreventive agent rather than the presence of a BRCA mutation.

The side effects of tamoxifen were well known from its use as a cancer treatment and were again observed in the prevention trials. In the combined analysis of the four studies, the RR of thromboembolic events in tamoxifen users was 1.9 (95% CI = 1.4 to 2.6; p <0.0001) and the RR of endometrial cancer was 2.4 (95% CI = 1.5 to 4.0; p = 0.0005).43 Significant elevation in endometrial cancer and thromboembolic events was limited to postmenopausal women. Thus, women most likely to have a favorable risk-benefit ratio for tamoxifen prevention include premenopausal women, younger postmenopausal women without a uterus, and those at risk on the basis of atypical hyperplasia or LCIS. Despite the proven efficacy, use of tamoxifen as chemoprevention has been limited because of concerns about side effects and the small absolute differences in outcomes.

Raloxifene is a SERM used for the treatment and prevention of osteoporosis that was noted to reduce the incidence of ER+ breast cancer in this population. The NSABP P2 trial, the Study of Tamoxifen and Raloxifene (STAR) trial, directly compared the chemopreventive actions and side effects of tamoxifen and raloxifene in 19,747 postmenopausal women at increased risk of breast cancer development.36 No difference in the incidence of invasive cancer was seen between women taking tamoxifen and those taking raloxifene (RR = 1.02; 95% CI = 0.82 to 1.28). More cases of noninvasive cancer were noted in the raloxifene group, with a cumulative incidence of 11.7 per 1,000 compared with 8.1 per 1,000 in the tamoxifen group at 6 years (RR = 1.4; p = 0.052). A more favorable side-effect profile was seen for raloxifene, with a reduction in the number of hysterectomies and endometrial cancers in the raloxifene group (RR = 0.62; 95% CI = 0.35 to 1.08), although the difference did not reach statistical significance. Significantly fewer thromboembolic events and cataracts occurred with raloxifene. Raloxifene is thus a viable alternative to tamoxifen for the chemoprevention of breast cancer in postmenopausal women at increased risk for the disease. In addition, the use of raloxifene in women with osteoporosis has the potential to lower breast cancer incidence in a group of women not considered at high risk.

Trials of aromatase inhibitors (AI) for breast cancer prevention suggest qualitatively similar results as seen with SERMs. The MAP.3 trial examined the use of the AI exemestane in postmenopausal women with a Gail risk score of 1.66, atypical hyperplasia, LCIS, or unilateral ductal carcinoma in situ (DCIS) treated with mastectomy. After a median follow-up of 3 years, a 65% reduction in invasive breast cancer was seen with exemestane (p = 0.002).46 The reduction in cancer incidence was also limited to ER+ cancers. At present, there are no chemopreventive agents that have been proven to be effective in reducing the incidence of ER breast cancer.

The 2013 American Society of Clinical Oncology (ASCO) guideline on pharmacologic agents for breast cancer risk reduction47 recommends discussion of tamoxifen for breast cancer risk reduction with premenopausal women age 35 and older at increased risk for breast cancer development, and discussion of tamoxifen, raloxifene, and exemestane with high-risk postmenopausal women. Histories of deep vein thrombosis, stroke, pulmonary embolism, or transient ischemic attacks are considered contraindications to the use of both tamoxifen and raloxifene.

Prophylactic surgery, in the form of bilateral mastectomy or bilateral salpingo-oophorectomy, is another option for breast cancer risk reduction. The efficacy of prophylactic mastectomy has never been studied in a prospective, randomized trial. In a retrospective study of 639 women who had bilateral prophylactic mastectomy due to a family history of breast cancer,48 a 90% to 94% reduction in breast cancer incidence (95% CI = 71% to 99%) and an 81% to 100% reduction in breast cancer mortality with prophylactic mastectomy compared to unaffected sisters or Gail model predictions was observed. Prospective studies in BRCA mutation carriers (Table 37.6) demonstrate similar levels of risk reduction.4850

Prophylactic bilateral salpingo-oophorectomy is an alternative risk-reduction strategy in women at risk on the basis of BRCA mutations, which has the added benefit of reducing the risk of ovarian carcinoma, a disease for which effective screening is not available. In a prospective study of the benefits of prophylactic salpingo-oophorectomy in 170 BRCA mutation carriers, Kauff et al.19 observed that the HR for breast cancer was reduced to 0.32 (95% CI = 0.08 to 1.20) and to 0.25 for gynecologic cancer (95% CI = 0.08 to 0.74) at a mean follow-up of 24 months. In a meta-analysis51 of risk-reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2mutation carriers, statistically significant reductions in breast cancer (HR = 0.49; 95% CI = 0.37 to 0.65 with similar risk reductions in BRCA1 and BRCA2 mutation carriers) and in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39) were observed. More recently, recognition that BRCA-associated cancers arise in the fallopian tube rather than the ovary has led some to propose bilateral salpingectomy, with ovarian preservation, as a risk-reducing strategy, but the efficacy of this approach is uncertain.

DIAGNOSIS AND BIOPSY

The presence or absence of carcinoma in a suspicious clinically or mammographically detected abnormality can only be reliably determined by tissue biopsy. An abnormal MRI does not reliably indicate the presence of cancer, and a nonworrisome MRI does not reliably exclude carcinoma.52 Available biopsy techniques include fine needle aspiration (FNA), core needle biopsy, and excisional biopsy. Needle biopsy techniques (FNA or core biopsy) are preferred because they are more cost-effective than surgical excision, and because most breast lesions are benign, they avoid a surgical scar and potential cosmetic deformity.

FNA is easily performed, but requires a trained cytopathologist for accurate specimen interpretation and does not reliably distinguish invasive cancer from DCIS, a particular drawback for nonpalpable abnormalities, which are often DCIS. Core-cutting needle biopsy has many of the advantages of FNA, but provides a histologic specimen suitable for interpretation by any pathologist, and facilitates ER, PR, and HER2 testing. False-negative results from sampling error may occur with both core-cutting needle biopsy and FNA. When concordance between the core biopsy or FNA diagnosis, and the clinical and imaging findings is not present, additional tissue should be obtained, usually by excisional biopsy. Concerns about the false-negative rate of image-guided core biopsy have been resolved with the availability of large, vacuum-assisted biopsy devices that increase the extent of lesion sampling, coupled with the development of clearly defined indications for follow-up surgical biopsy. False-negative rates of core biopsy are now reliably <1%. Indications for surgical biopsy following core biopsy are listed in Table 37.7. Although the finding of atypical ductal hyperplasia on a core biopsy is uniformly accepted as an indication for open surgical biopsy, the need for surgical excision of all lesions showing atypical lobular hyperplasia (ALH) or LCIS remains controversial (discussed in the section “Lobular Carcinoma in Situ”). Papillary carcinoma in situ cannot always be readily distinguished from benign papillary lesions on a core biopsy, and radial scar may be difficult to distinguish from tubular carcinoma without complete removal of the lesion.

The use of core biopsy for the diagnosis of mammographic abnormalities is cost-effective and increases the likelihood that the patient will be able to undergo a single surgical procedure for definitive cancer treatment.53 Excisional biopsy as a diagnostic technique should be reserved for patients with imaging abnormalities that cannot be targeted for core biopsy. A core biopsy diagnosis permits a complete discussion of treatment options prior to the placement of an incision on the breast and allows the breast procedure and the axillary surgery to take place at a single operation.

When excisional biopsy is performed for diagnosis, a small margin of grossly normal breast should be excised around the tumor, orienting sutures should be placed, and the specimen should be inked to allow margin evaluation.

LOBULAR CARCINOMA IN SITU

In 1941, Foote and Stewart54 published their landmark study of LCIS, describing a relatively uncommon entity characterized by an “alteration of lobular cytology.” They hypothesized that LCIS was a precursor lesion of invasive cancer, and, based on this, treatment with mastectomy was recommended. More recently, the term ALH has been introduced to describe morphologically similar, but less well-developed, lesions. Some centers use the term lobular neoplasia (LN) to cover both ALH and LCIS. Morphologically, LN is defined as “a proliferation of generally small and often loosely cohesive cells originating in the terminal duct-lobular unit, with or without pagetoid involvement of terminal ducts.”55

In the past, LCIS was most frequently diagnosed in women aged 40 to 50, a decade earlier than DCIS, but recent literature indicates that the incidence in postmenopausal women is increasing.56 Determining the true incidence of LCIS is difficult, as there are no specific clinical or mammographic abnormalities associated with the lesion and the diagnosis of LCIS is often made as an incidental, microscopic finding in a breast biopsy performed for other indications. The prevalence of LN in an otherwise benign breast biopsy has been reported as between 0.5% and 4.3%.57 LCIS is both multifocal and bilateral in a large percentage of cases.

In an analysis of nine studies including 172 patients with LCIS who were treated by biopsy alone, 15% developed invasive carcinoma in the ipsilateral breast and 9.3% carcinoma in the contralateral breast after 10 years of follow-up.58 This corresponds to a risk of development of invasive carcinoma of about 1% to 2% per year, with a lifetime risk of 30% to 40%. In this study (conducted prior to effective breast imaging), 5.7% of the patients developed metastatic breast cancer. In a more recent study of 776 women with LCIS followed in a high-risk screening program at Memorial Sloan-Kettering Cancer Center, King et al.37 reported that 13% had developed cancer at a median follow-up of 58 months, a rate similar to that seen in older studies. Cancers were detected at a median size of 0.8 cm (0.1 cm to 3.5 cm), and 78% were node negative. MRI screening had no significant impact on cancer stage at diagnosis in this cohort. Subsequent cancers are more often invasive ductal carcinoma than invasive lobular carcinoma (ILC), but the incidence of subsequent ILC is substantially increased compared with women without LCIS. Although the risk for development of breast cancer is bilateral, subsequent ipsilateral carcinoma is more likely than contralateral breast cancer, supporting the view that ALH and LCIS act both as precursor lesions and as risk indicators. The RR for development of subsequent breast cancer is lower in women diagnosed with ALH compared with LCIS. Therefore, although LN is a helpful term for collectively describing this group of lesions, specific classification into ALH and LCIS is preferable in terms of risk assessment and management.

LCIS is typically positive for ER and PR staining and negative for HER2/neu staining. LN (and ILC) characteristically lacks expression of E-cadherin, an epithelial cell membrane molecule involved in cell-cell adhesion. E-cadherin negativity serves as a fairly reliable means of distinguishing ductal from lobular disease, both in situ and invasive. Pleomorphic LCIS is a relatively uncommon variant of LCIS characterized by medium-to-large pleomorphic cells containing eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm. As with classic LCIS, it is usually ER+ and negative for E-cadherin; it also tests positive by immunohistochemistry (IHC) for gross cystic disease fluid protein-15. Pleomorphic LCIS can be associated with central necrosis, may be associated with mammographic microcalcifications, and may be difficult to distinguish from DCIS. Although pleomorphic LCIS has a more aggressive histologic appearance than classic LCIS, the relative rarity of this lesion and the lack of uniform diagnostic criteria make it difficult to know if pleomorphic LCIS has a different natural history than classic LCIS.

Genetic changes in LN have been evaluated in a number of studies using comparative genomic hybridization. In both ALH and LCIS, there was loss at 16q21-q23.1, an altered region previously identified in invasive carcinoma.59This genomic signature, common to LN and ILC, further suggests that LN is a precursor lesion in some women.

Management of LN must address the bilateral risk, and options therefore include surveillance, chemoprevention, and prophylactic bilateral mastectomy. Surveillance is the strategy selected by most patients. Mammographic screening is the standard breast imaging technique for patients selecting surveillance. Breast MRI has been used, but, as noted previously, existing evidence does not support its routine use for patients with LCIS. Prophylactic mastectomy reduces breast cancer risk among high-risk women by approximately 90%. Chemoprevention with tamoxifen in patients with LCIS has been evaluated as part of the NSABP P1 study.34 Overall, tamoxifen reduced the incidence of breast cancer by 49% (p <0.00001), and a similar level of risk reduction was seen in the 826 participants with a history of LCIS. In the NSABP P2 (STAR) trial,36 893 participants gave a history of LCIS, and their rates of subsequent breast cancer were similar with tamoxifen and raloxifene. Benefit for exemestane in women with LCIS was also seen in the MAP.3 study.46

In the past, the finding of LN on a core needle biopsy usually led to a recommendation for surgical biopsy to rule out coexisting DCIS or invasive cancer. Recent studies have demonstrated that when the diagnosis of LN is concordant with the imaging findings, upgrade rates with surgical excision are ≤3%.60 Discordance between the pathology and imaging, and the presence of pleomorphic LCIS in a core biopsy remain indications for surgical excision. The recent recognition that, in some cases, LCIS may be a precursor lesion has led to confusion as to whether it should be treated like DCIS (i.e., excised to negative margins and irradiated). At this time, there are no data indicating that the incidence of subsequent cancer is reduced with this approach. When LCIS is seen on an excised tissue, it is not necessary to obtain negative margins of resection, and there is no established role for radiation therapy in patients with LN.

DUCTAL CARCINOMA IN SITU

DCIS is defined as the proliferation of malignant-appearing mammary ductal epithelial cells without evidence of invasion beyond the basement membrane. Prior to the widespread use of screening mammography, <5% of mammary cancers were DCIS. At present, 15% to 30% of the cancers detected in mammography screening programs are DCIS, and the greatest increase in the incidence of DCIS has been seen in women aged 49 to 69 years. DCIS can present as a palpable or nonpalpable mass, Paget disease of the nipple, an incidental finding at biopsy, or, most commonly, as mammographically detected calcifications.

A central problem in the management of DCIS is the lack of understanding of its natural history and the inability to determine which DCIS will progress to invasive carcinoma during a woman’s lifetime. The concordance between risk factors for DCIS and invasive carcinoma suggests that they are part of the same disease process.61 Attempts to better characterize the natural history of DCIS on the basis of pathologic features have not been particularly successful. The traditional morphologic classification into comedo, papillary, micropapillary, solid, and cribriform types is confounded by the observation that as many as 30% to 60% of DCIS lesions display more than one histologic pattern. To overcome this difficulty, a number of classifications based on nuclear grade and the presence or absence of necrosis have been developed. No single classification scheme has been widely adopted and, most importantly, none of the classification systems have been prospectively demonstrated to predict the risk of development of invasive carcinoma. Molecular profiling studies in DCIS have been limited by the need for histologic examination of the entire lesion to reliably exclude the presence of invasive carcinoma. The Oncotype DX (Genomic Health, Redwood City, CA) assay using paraffin-embedded tissue was modified for DCIS, and an initial study suggested usefulness in predicting the risk of invasive in-breast recurrence. This finding has not been validated in other populations, nor has this test been shown to predict the benefit of radiotherapy (RT).62 The available data indicate that DCIS lesions share many of the genetic alterations of invasive carcinoma, but predictors of progression to invasion remain to be identified.

Treatment of the Breast

Cancer-specific survival for the woman diagnosed with DCIS exceeds 95%, regardless of the type of local therapy employed.63,64 Mastectomy, excision and RT, and excision alone have all been proposed as management strategies for DCIS. The appropriate therapy for the woman with DCIS depends on the extent of the DCIS lesion, the risk of local recurrence (LR) with each form of treatment, and the patient’s attitude toward the risks and benefits of a particular therapy.

Total or simple mastectomy is curative in approximately 98% of patients regardless of age, DCIS presentation, size, or grade.65 The primary medical indication for mastectomy in DCIS is a lesion too large to be excised to negative margins with a cosmetically acceptable outcome.66 The extent of DCIS is most accurately estimated preoperatively with the use of magnification mammography.67 Studies indicate that MRI both overestimates and underestimates the size of DCIS lesions, does not improve surgical planning when compared with diagnostic mammography, and does not decrease the rate of ipsilateral breast tumor recurrence (IBTR).68

For women with localized DCIS, management by excision alone and excision plus RT have both been employed. Four published prospective, randomized trials have directly compared these two approaches in >4,500 patients.63,64,69,70 In all four trials, the majority of participants had mammographically detected DCIS, and in all but the Swedish trial,70 negative margins (no ink on tumor) were required. A dose of 50 Gy of radiation was delivered to the whole breast in 25 fractions, and a boost dose to the tumor bed was not required. The results of these trials are summarized in Table 37.8. No differences in overall survival (OS) were seen between treatment arms. In all four studies, the use of RT resulted in a highly significant reduction in the risk of an IBTR, with proportional risk reductions ranging from 47% to 63%.40,63Consistent with observations from many retrospective studies, approximately 50% of the recurrences in both groups were invasive carcinoma, and a benefit for RT was seen in the reduction of both invasive and noninvasive recurrences.

A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) provides a concise overview of RT effect following lumpectomy for DCIS.71 With a median follow-up of 8.9 years, RT approximately halved the rate of ipsilateral breast events (rate ratio = 0.46; standard error [SE] = 0.05; 2p <0.00001). RT was effective in all subgroups. There were 291 “low-risk” cases of DCIS that were low-grade, >20 mm in size, and with negative surgical margins identified. Among them, the 10-year risk of an ipsilateral event in those allocated to lumpectomy alone was substantial at 30.1%, and even with this relatively small number of women, the effect of RT was highly significant (rate ratio = 0.48; SE = 0.17; 2p =0.002), with a 10-year absolute gain of 18.0% (SE = 5.5%).

The Radiation Therapy Oncology Group (RTOG) study 9804 sought to determine RT benefit after lumpectomy for patients with low-risk DCIS.72 In comparison to the other randomized trials, RTOG 9804 enrolled patients with smaller lesions, all low- or intermediate-grade DCIS, and had a much higher rate of adjuvant tamoxifen use (62%). Recurrence rates were 6.7% in the observation arm, compared to 0.9% in the RT arm, after a median follow-up of 7.2 years (HR = 0.11; 95% CI = 0.03 to 0.47; p = 0.0003).72 This suggests that even in low-risk DCIS, RT can lower the risk of in-breast recurrence. LR rates after excision and RT have decreased over time due to improvements in imaging and pathologic analysis. In a retrospective review of 246 consecutive patients treated at Dana-Farber Cancer Institute and Brigham and Women’s Hospital from 2001 to 2007, there were no LRs with a median follow-up time of 58 months.73

Despite the clear benefit of RT seen in these five trials, there was considerable interest in identifying patients who could be spared RT for DCIS. The Dana-Farber/Harvard Cancer Center conducted a single-arm, prospective trial of wide excision alone from 1995 to 2002 among 158 patients.74 Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of no greater than 2.5 cm and final margin width of at least 1 cm. Tamoxifen was not permitted. The study was closed to further accrual because the number of LRs (n = 13) met the predefined stopping rules. The median patient age was 51 years, and 94% had mammographically detected DCIS. The median follow-up was 11 years, and 143 patients were followed for >8 years. Nineteen patients developed an LR. Fourteen recurrences were in the same quadrant as the initial DCIS, and five were elsewhere in the ipsilateral breast. A total of 32% recurred with invasive disease. No patient developed distant metastasis. The 10-year cumulative incidence of LR was 15.6%.

Similar results were seen in the Eastern Cooperative Oncology Group single-arm trial of excision alone for DCIS. Eligibility criteria for this study included DCIS at least 3 mm in size, excised with a margin width of ≥3 mm as determined by sequential sectioning, and complete embedding. The study enrolled patients with low- or intermediate-grade DCIS ≤2.5 cm in size and high-grade DCIS (defined as nuclear grade 3 with necrosis) up to 1 cm in size. A postexcision mammogram was required for all patients. At a median follow-up of 8.8 years, the 10-year LR rate was 19.0% for patients with high-grade DCIS, and 14.6% for those with low- or intermediate-grade DCIS.62 Taken together, these prospective studies indicate that even patients with small low- to immediate-grade DCIS treated with excision to widely negative margins of resection have about a 15% 10-year risk of a LR in the absence of RT. No reduction in recurrence was observed for patients excised to margins of ≥1 cm compared to those with margins of 3 to 9 mm.

The 2016 National Comprehensive Cancer Network (NCCN) Guidelines® endorse lumpectomy and whole breast radiation therapy or total mastectomy as category 1 recommendations, and lumpectomy without RT as a category 2B recommendation.66 Clearly, patients should be included in the treatment decision making to learn what magnitude of risk reduction is meaningful to them. A detailed discussion of the pros and cons of the various treatment options is needed to allow each woman with DCIS to make an informed treatment choice.

Treatment of the Axilla

In situ carcinoma by definition does not metastasize, so theoretically, axillary staging should be unnecessary for DCIS. Studies of axillary dissection (ALND) in DCIS have demonstrated axillary nodal metastases in only 1% to 2% of patients, presumably due to unrecognized microinvasion. Data from the NSABP B-17 and B-24 studies confirm that the risk of isolated axillary recurrence with no axillary surgery is <0.1%, regardless of whether RT and tamoxifen are administered.75 These low rates of axillary recurrence argue against routine use of sentinel lymph node biopsy in DCIS. Selective use of sentinel node biopsy in patients with DCIS who are at significant risk of having coexistent invasive carcinoma is appropriate. Approximately 15% of patients diagnosed as having DCIS with large vacuum-assisted biopsy devices are found to have invasive cancer after complete excision of the lesion. The diagnosis of DCIS in a palpable breast mass and pathologic interpretation of a core biopsy specimen as suspicious, but not diagnostic, of microinvasion are circumstances in which invasive cancer is frequently found when the lesion is completely examined and so sentinel node biopsy should be considered.

Because patients undergoing mastectomy forfeit the opportunity for sentinel node biopsy if not performed concurrently, patients receiving mastectomy for DCIS should undergo sentinel node biopsy.

Endocrine Therapy

The ER is present in about 80% of DCIS lesions and is more frequent in noncomedo than comedo DCIS.76 Endocrine therapy might reduce LR after breast-conserving therapy (BCT) and prevent development of new primary breast cancers in the contralateral breast. Two trials have examined the use of tamoxifen in women with DCIS. In the NSABP B-24 trial,64 patients with DCIS were treated with excision and RT and randomized to tamoxifen 20 mg daily or a placebo for 5 years. Patients in the tamoxifen arm had a 32% reduction in the risk of an invasive LR (p = 0.025), a 16% reduction in the risk of a DCIS LR (p= 0.33), and a 32% reduction in contralateral breast cancer (p = 0.023) compared to the patients in the placebo arm. In the subset of women with ER+ DCIS, tamoxifen reduced the risk of any breast cancer event by 51% (RR = 0.41; 95% CI = 0.25 to 0.65; p = 0.0002); there was no benefit seen if the DCIS lesion was ER.76 The United Kingdom/Australia New Zealand trial69 that randomized women to tamoxifen or to no tamoxifen and with a median follow-up of 12.7 years found that tamoxifen reduced ipsilateral events (HR = 0.78; 95% CI = 0.62 to 0.99), but more significantly, reduced contralateral events (HR = 0.44; 95% CI = 0.25 to 0.77) (In a subset analysis, the benefit of tamoxifen appeared restricted to patients who did not receive RT.) Taken together, these trials suggest that tamoxifen modestly reduces ipsilateral events with or without RT, and substantially reduce contralateral events. The addition of tamoxifen to RT is particularly attractive in young patients with ER+DCIS, in whom the risk of LR is higher and the toxicity of tamoxifen is less than in older patients.

Evidence that the AIs reduce the incidence of contralateral breast cancer to a greater extent than tamoxifen has led to interest in their use in DCIS. Ongoing trials (NSABP B53 and IBIS II) are comparing tamoxifen with an AI; however, at present, there are no data for use of AIs in management.

In summary, patients with localized DCIS have treatment options ranging from simple excision to mastectomy, all of which have high survival rates but different risks of LR. Patient preference plays a major role in treatment selection, but available evidence indicates that patients have limited understanding of the nature of DCIS. In one study, women with DCIS estimated their risk of breast cancer death to be 39%.77 Perhaps related to this, Katz et al.78found that although patients reported that their surgeon infrequently recommended mastectomy for DCIS, greater involvement of patients in the decision-making process was associated with higher rates of mastectomy.

STAGING

The staging system for breast cancer was last updated in 2010.79 The American Joint Committee on Cancer (AJCC) system is both a clinical and pathologic staging system, and is based on the TNM system in which “T” refers to tumor, “N” to nodes, and “M” to metastasis. The current version is the seventh edition of the system and is provided in the following.79

The major changes in this edition were the inclusion of a new classification system for patients after neoadjuvant therapy and the creation of a new M0(i+) category for patients found to have circulating tumor cells, tumor in the bone marrow, or incidentally detected tumor deposits in other tissues not exceeding 0.2 mm in size. Patients in this category are staged according to T and N, and are not classified as stage IV.

The AJCC staging system provides a strategy for grouping patients with respect to prognosis. However, TNM staging, while still important, has been superseded by rapidly evolving molecular characterizations of breast cancers, which more precisely define subgroups with different outcomes, both in terms of prognosis and response to specific treatments. Increasingly, multigene diagnostic tests, such as Oncotype DX and MammaPrint (Agendia Inc. USA, Irvine, CA), are employed as part of treatment decision making for invasive breast cancer.

Tumor, Node, and Metastases Definitions

Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). If other measurements are used, such as mammographic or pathologic measurements, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1 cm increment. The AJCC TNM staging system is illustrated in Table 37.9. Stage IIIC breast cancer includes patients with any T stage who have pN3 disease. Patients with pN3a and pN3b disease are considered operable and are managed as described in the section on stage I, II, IIIA, and operable IIIC breast cancer. Patients with pN3c disease, in which the ipsilateral supraclavicular nodes are affected by cancer, are considered inoperable and are managed as described in the section on inoperable stage IIIB or IIIC or inflammatory breast cancer (IBC).79 Pathologic stage after neoadjuvant therapy is designated with the prefix “yp.” Complete response is defined as the absence of invasive carcinoma in the breast and axillary nodes.

PATHOLOGY OF BREAST CANCER

Historically, classification of invasive breast cancers has been based on the morphologic appearance of the cancer as seen by light microscopy.80 The most widely used such classification is that of the World Health Organization (second edition),55 based on the growth pattern and cytologic features of the invasive tumor cells. Although the classification system recognizes invasive “ductal” and “lobular” carcinomas, this is not meant to indicate that the former originates in the ducts and the latter in the lobules of the breast. Most invasive breast cancers arise in the terminal duct lobular unit, regardless of histologic type.

The most common histologic type of breast cancer is invasive (infiltrating) ductal carcinoma, comprising 70% to 80% of cases. The diagnosis of invasive ductal carcinoma is a diagnosis by exclusion (i.e., this tumor type is defined as a type of cancer not classified into any of the other special categories of invasive mammary carcinoma, such as invasive lobular, tubular, mucinous, medullary, and other special types). To emphasize this point, most classification systems use the term infiltrating ductal carcinoma, not otherwise specified (NOS) or infiltrating carcinoma of no special type. In practice, the terms invasive ductal carcinoma, infiltrating ductal carcinoma, and infiltrating or invasive carcinoma of no special type are used interchangeably.

Special types of cancers comprise approximately 20% to 30% of invasive carcinomas. At least 90% of a tumor should demonstrate the defining histologic characteristics of a special type of cancer to be designated as that histologic type. Breast cancer histologic classifications recommended by the AJCC Staging Manual include NOS; ductal; inflammatory; medullary, NOS; medullary with lymphoid stroma; mucinous; papillary (predominantly micropapillary pattern); tubular; lobular; Paget disease and infiltrating; undifferentiated; squamous cell; adenoid cystic; secretory; and cribriform. Tumor subtypes that occur in the breast, but that are not considered to be typical breast cancers, include cystosarcoma phyllodes, angiosarcoma, and primary lymphoma.

Invasive breast cancers can be further subclassified based on microscopic features. The most common subclassification has been grading, based either solely on nuclear features (nuclear grading) or on a combination of architectural and nuclear characteristics (histologic grading). In nuclear grading, the appearance of the tumor cell nuclei is compared with those of normal breast epithelial cells, and the tumor nuclei are classified as well differentiated, intermediately differentiated, or poorly differentiated. In current practice, histologic grading is the most commonly used method of grading. In histologic grading, breast carcinomas are categorized based on the evaluation of (1) tubule formation, (2) nuclear pleomorphism, and (3) mitotic activity. The grading system by Elston and Ellis,81 a modification of the grading system proposed by Bloom and Richardson in 1957, is recommended as part of AJCC staging. Tubule formation (>75%, 10% to 75%, and <10%), nuclear pleomorphism (small and uniform, moderate variation in size and shape, and marked nuclear pleomorphism), and mitotic activity (per field area) are each scored on a scale of 1 to 3. The sum of the scores for these three parameters is the overall histologic grade. Tumors with a sum of the scores of 3 to 5 are designated grade 1 (well differentiated), those with sums of 6 and 7 are designated grade 2 (moderately differentiated), and those with sums of 8 and 9 are designated grade 3 (poorly differentiated). Histologic grading, particularly the distinction between grades 1 and 3, has prognostic significance as discussed in the section “Prognostic and Predictive Factors in Breast Cancer.” In addition, breast cancers with pure tubular, mucinous, papillary, or cribriform features are recognized to have a more favorable outcome than the more common types of breast cancer.80 Micropapillary tumors are a recently recognized entity with a high incidence of lymphatic and vascular invasion, and systemic recurrence.82

LOCAL MANAGEMENT OF INVASIVE CANCER

The evaluation of the patient newly diagnosed with breast cancer begins with a determination of operability. The presence of distant metastases at diagnosis has traditionally been considered a contraindication to surgery. Some retrospective studies have suggested a survival benefit for surgery of the primary tumor in the patient presenting with metastatic disease,83,84 but systemic therapy remains the initial therapeutic approach. Extensive evaluations to look for metastatic disease are not warranted in asymptomatic patients with stage I and II cancer because of the low likelihood of identifying metastatic disease.85In patients with stage III disease, occult metastases are more frequent, often estimated at 20% of cases, and staging studies are recommended.85

Patients with T4 tumors and those with N2 or N3 nodal disease are also not candidates for surgery as the first therapeutic approach and should be treated with systemic therapy initially (discussed in the section “Locally Advanced Breast Cancer and Inflammatory Breast Cancer” on page 477). In the patient with clinical stage I, II, and T3N1 disease, the initial management is usually surgical. In these patients, the evaluation consists of a determination of their suitability for BCT and a discussion of the options of mastectomy with and without reconstruction. Initial systemic therapy may be used to shrink the primary tumor to allow BCT in a woman who would otherwise require mastectomy, but is not mandatory, as it is for women with locally advanced and inflammatory carcinoma. The current status of management approaches for primary operable breast cancer is discussed in detail in the following sections.

Breast-Conserving Therapy

The goal of BCT using conservative surgery (CS) and RT is to provide survival equivalent to mastectomy with preservation of the cosmetic appearance and a low rate of recurrence in the treated breast. Because of the wide acceptance of the Halstedian dogma, a relatively large number of randomized clinical trials were conducted comparing mastectomy and BCT, and they demonstrated equivalent survival. The long-term stability of this equivalence was confirmed by the 20-year follow-up reports of the two largest studies, the NSABP B-06 and Milan I trials.86,87 An overview of all the trials has also demonstrated comparable survival,88 indicating that survival for most patients with breast cancer does not depend on the choice of mastectomy versus BCT.

Medical contraindications to BCT are infrequent. In a population-based study of 1984 patients with DCIS, stage I and II breast cancer, only 13.4% were advised by their surgeon that mastectomy was medically necessary.89 In the 1,459 women in whom BCT was attempted, conversion to mastectomy occurred in 12%, and re-excision was not attempted in the majority. Thus, the available data indicate that a minority of patients have contraindications to BCT, and these are readily identified with standard clinical tools. Patient participation in the surgical decision-making process is an important factor in mastectomy use. In a population-based study of patients diagnosed with breast cancer in 2002 in two large metropolitan areas (Los Angeles and Detroit), more patient involvement in decision making was associated with a greater likelihood of undergoing mastectomy.90,91 The incidence of LR after BCT has declined over time, from 10-year rates of 8% to 19% seen in retrospective studies and the initial randomized trials of BCT, to 2% to 7% in patients excised to negative margins in more recent studies. Table 37.10 shows the 10-year rates of LR in node-negative NSABP trials.92 This decrease in LR rates is the result of a combination of improved mammographic and pathologic evaluation, and the more frequent use of adjuvant systemic therapy (discussed in detail in the section “Risk Factors for Local Recurrence Following Conservative Surgery and Radiation Therapy” on page 459). In contrast, rates of LR after mastectomy have remained stable over the same time period.

Recurrences in the breast are typically classified by their location in relation to the original tumor. Recurrences at or near the primary site (presumably representing a recurrence of the original tumor) are classified as either a true recurrence (within the boosted region), a marginal miss (adjacent to the boosted region), or elsewhere in the breast (occurring at a distance from the original tumor and presumably representing a new primary). The time course to LR in the patient undergoing BCT is prolonged. In one study, the annual incidence rate for a true recurrence/marginal miss recurrence was between 1.3% and 1.8% for years 2 through 7 after treatment and then decreased to 0.4% by 10 years after treatment. The annual incidence rate for recurrence elsewhere in the breast increased slowly to a rate of approximately 0.7% per year at 8 years and remained stable. It also appears that just as the time to development of distant metastases is more rapid in patients with ER or HER2+ cancers than in those with ER+ and PR+cancers, the time to LR also varies with receptor status. (These results have been contrasted to those seen after mastectomy, in which most LRs occur in the first 3 to 5 years after surgery.) In the Milan I trial, after 20 years of follow-up, the risk of any type of recurrence in the treated breast was 0.63 per 100 woman-years compared with a risk of 0.66 per 100 woman-years for contralateral cancer.87 This suggests that although whole-breast irradiation (WBI) is effective at eradicating subclinical multicentric foci of breast carcinoma present at the time of diagnosis, it does not prevent the subsequent development of new cancers. Thus, patients who elect BCT require lifelong follow-up to screen for the development of new cancers in both the treated and the contralateral breast.

Risk Factors for Local Recurrence Following Conservative Surgery and Radiation Therapy

Risk factors for recurrence after CS and RT can be subdivided into patient, tumor, and treatment factors.

Patient Risk Factors

The most important patient risk factors for LR recurrence are age and inherited susceptibility. Age (<35 or 40) is associated with an increased risk of LR after BCT. Young patient age is associated with an increased frequency of various adverse pathologic features, such as lymphatic vessel invasion, grade 3 histology, absence of ER/presence of HER2, and the presence of an extensive intraductal component (EIC). However, even when correction is done for the differing incidence of the pathologic features of the primary tumor between the age groups, young age is still associated with an increased likelihood of recurrence in the breast.93 However, young age is also a risk factor for LR after mastectomy and should not be considered a contraindication to BCT.

An inherited susceptibility to breast and ovarian cancer, and other cancers has been mainly linked to germline mutations in BRCA1 and BRCA2. Patients with breast cancer with a mutation have a substantial risk of contralateral and late ipsilateral breast cancers. In a retrospective study, outcome following CS and RT was compared for 302 stage I-III patients with breast cancer with germline BRCA1 or BRCA2mutations and 353 stage I-III patients treated with mastectomy.94 With a follow-up time of 8.2 and 8.9 years for BCT and mastectomy patients, respectively, LR was significantly more likely in those treated with BCT compared to mastectomy, with a cumulative estimated risk of 23.5% versus 5.5%, respectively, at 15 years (p <0.0001); the 15-year estimate in carriers treated with BCT and chemotherapy was 11.9% (p = 0.08 when compared to mastectomy). Most LR events appeared to be second primary cancers. The risk of contralateral breast cancer was high in all groups, exceeding 40%. It is important to consider genetic testing in a patient with newly diagnosed breast cancer with a personal and family history suggestive of a BRCA1 or BRCA2 germline mutation. In patients with a mutation, the option of bilateral mastectomy should be strongly considered to avoid the long-term risk of a second breast cancer in either breast. Patients with breast cancer most likely to benefit from bilateral mastectomy are those who are young and have early-stage disease. Given the high risk of a contralateral breast cancer, unilateral mastectomy is generally not performed in a patient who is a candidate for BCT.

Tumor-Based Risk Factors

An important tumor risk factor is the margin of resection. A negative margin is defined by absence of cancer cells at inked surfaces, but there is no standard definition of a close margin. Margins need to be interpreted in conjunction with the operative findings. A close deep margin is not significant if the breast resection was carried down to the pectoral fascia; the same is true for a close anterior margin if the resection extended to the deep dermal surface. Patients with negative margins of excision have low rates of LR after treatment with CS and RT. The impact of close margins of resection on LR has been more controversial, resulting in the frequent use of re-excision to obtain margins more widely clear than no ink on tumor. A 2013 multidisciplinary consensus panel considered a meta-analysis of margin width and IBTR from a systematic review of 33 studies including 28,162 patients. The results of randomized trials, reproducibility of margin assessment, and current patterns of multimodality care were also considered. The panel concluded that positive margins (ink on invasive carcinoma or DCIS) were associated with a two-fold increase in the risk of IBTR compared to negative margins. This increased risk was not mitigated by favorable biology, endocrine therapy, or a radiation boost. The panel also concluded that more widely clear margins beyond “no ink on tumor” do not significantly decrease the rate of IBTR. There is no evidence that more widely clear margins reduce IBTR for young patients, unfavorable biology, lobular cancers, or cancers with an EIC. (When an EIC is present, young age and multiple close margins are associated with an increased risk of IBTR and can be used to select patients who might benefit from re-excision). Therefore, the use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health-care costs.95

The underlying molecular subtype of the tumor is the most significant determinant of the likelihood of LR after BCT (and mastectomy), particularly among those treated in the modern era with surgery to achieve negative margins.9698 Higher risks of LR are observed in patients with triple-negative breast cancer than in those with other subtypes, regardless of whether they are treated with BCT or mastectomy.99

There is interest in identifying molecular predictors of the risk of LR. The 21-gene recurrence score (Oncotype DX) predicts local-regional recurrence (LRR) in node-negative, ER+ breast cancer, regardless of type of surgery.100The 10-year LR rate was 4.3% for patients with a low recurrence score (<18), 7.2% with an intermediate recurrence score (18 to 30), and 15.8% with a high recurrence score (>30).

Treatment-Based Risk Factors

Other important treatment risk factors are the use of a boost and the use of adjuvant systemic therapy. A boost or supplementary irradiation to the area of the primary site is generally used. It is standard in RT after lumpectomy for patients to receive 45 to 50 Gy of WBI followed by a 10 to 16 Gy boost to the region of the tumor bed (Fig. 37.2). The use of a boost is supported by the large European Organisation for Research and Treatment of Cancer (EORTC) trial in which 5,318 patients with negative margins were randomized to a boost of 16 Gy or no boost following 50 Gy to the whole breast.101 With a median follow-up of 10.8 years, the cumulative incidence of ipsilateral breast recurrence was 10.2% without a boost and 6.2% with a boost (p <0.0001). This 41% proportional reduction in LR was similar in all age groups; however, the absolute benefit of the boost was greatest in young patients aged 40 years or less (24% decreased to 14%) and was smallest in patients over age 60 (7% decreased to 4%). Severe fibrosis was increased from 2% to 4% with the boost. Survival at 10 years was the same in both arms. A clinicopathologic study was performed on 1,616 patients in the EORTC trial. In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of LR (HR = 1.67; p = 0.026), and the boost was effective in reducing LR in this subgroup.102

The use of adjuvant systemic therapy is a very important factor associated with recurrence in the treated breast in conjunction with CS and RT. This effect is clearly demonstrated in three randomized clinical trials. In the NSABP B-14 trial, node-negative, ER+ patients were randomized to receive tamoxifen or to a placebo. The 10-year rate of recurrence in the ipsilateral breast was 14.7% without tamoxifen and only 4.3% with tamoxifen.103 A similar result was seen in the Stockholm Breast Cancer Study Group among node-negative patients randomized to receive tamoxifen or a placebo.104 In the NSABP B-21 trial, patients with node-negative breast cancer measuring ≤1 cm treated with lumpectomy were randomized to tamoxifen alone, RT, or RT and tamoxifen. With a mean follow-up of 87 months, the 8-year rate of ipsilateral LR was 9.3% in the patients treated with RT and 2.8% in the patients treated with RT and tamoxifen.105 Similar results are seen with adjuvant chemotherapy. In the NSABP B-13 trial, node-negative, ER patients were randomized to chemotherapy or to a no-treatment control group. Among the 235 patients treated with CS and RT, the 8-year rate of recurrence in the ipsilateral breast was 13.4% without chemotherapy and only 2.6% with chemotherapy given concurrently with the RT.106 The net result of the benefit of systemic therapy on local control is that between 1990 and 2011, LRR decreased from 30% to 15% of all recurrences seen in a population of 86,598 women enrolled in 53 randomized phase 3 trials.107

The standard approach is to use sequential chemotherapy and RT. Given the primary importance of preventing systemic relapse, it has been the standard to use initial chemotherapy followed by RT. Although concerns have been expressed about an increased rate of LR with this approach, the results of clinical trials in patients with negative margins have not shown this to be a problem even following 6 months of chemotherapy as with four cycles of doxorubicin and cyclophosphamide followed by four cycles of taxol, both given every 3 weeks.108

Preservation of a Cosmetically Acceptable Breast

A major goal of BCT is the preservation of a cosmetically acceptable breast. When modern treatment techniques are used, an acceptable cosmetic outcome can be achieved in almost all patients (without compromise of local tumor control) (Fig. 37.3). Treatment-related changes in the breast stabilize at around 3 years. Evolution of the untreated breast, such as change in size because of weight gain and the normal ptosis seen with aging, continue to affect the symmetry. The major factor determining the cosmetic result is the extent of surgical resection.109 A variety of factors must be considered together (the size of the patient’s breast, the size of the tumor, the depth of the tumor within the breast, and the quadrant of the breast in which the tumor is located) to judge the feasibility of a cosmetically acceptable resection. For example, although the removal of a large tumor in the lower portion of the breast often results in distortion of the breast contour, this is only apparent with the arms raised and is acceptable to most women. A similar distortion in the upper inner quadrant of the breast, which is visible in most types of clothing, might not be as acceptable.

Guidelines for Patient Selection

Because of the potential options for treatment of early-stage breast cancer, careful patient selection and a multidisciplinary approach are necessary. Critical elements in patient selection for BCT are (1) history and physical examination, (2) mammographic evaluation, (3) histologic assessment of the resected breast specimen, and (4) assessment of the patient’s needs and expectations.

Recent (i.e., usually within 3 months) preoperative mammographic evaluation is necessary to determine a patient’s eligibility for BCT by defining the extent of a patient’s disease, the presence or absence of multicentricity, and other factors that might influence the treatment decision. If the mass is associated with microcalcifications, an assessment of the extent of the calcifications within and outside the mass should be made using magnification views. Mammography of the contralateral breast is also standard at the time of diagnosis to exclude synchronous lesions.

There is controversy regarding the role of additional imaging studies, particularly MRI of the breast, in selecting patients for BCT. A meta-analysis of 3,112 patients in nine studies with comparison cohorts treated with and without MRI found no difference in the need for re-excision or unexpected conversion to mastectomy, after age adjustment, in patients managed with and without MRI.110 The age-adjusted rate of initial mastectomy was increased three-fold in patients having MRI. Several other studies have shown an association between MRI use and greater, but unwarranted, use of mastectomy.111,112 MRI frequently identifies additional areas of involvement in the breast, but long-term clinical experience has demonstrated that the majority of this disease is controlled with RT. In addition, MRI has a substantial false-positive rate. Ideally, prospective trials demonstrating a clinical benefit in patients selected for BCT with MRI are needed before these examinations are routinely used for patient selection.

The patient and her physician must discuss the benefits and risks of mastectomy compared with those of BCT in her individual case. The following factors should be discussed:

1.  The absence of a long-term survival difference between treatments

2.  The possibility and consequences of LR with both approaches

3.  Psychological adjustment (including the fear of cancer recurrence), cosmetic outcome, sexual adaptation, and functional competence

Psychological research comparing patient adaptation after mastectomy with that after BCT shows no significant differences in global measures of emotional distress. However, women whose breasts are preserved have more positive attitudes about their body image and experience fewer changes in their frequency of breast stimulation and feelings of sexual desirability. In addition, patients treated with BCT have better physical functioning compared with patients treated with mastectomy at the end of primary treatment.113

Absolute and Relative Contraindications to Breast-Conserving Therapy (National Comprehensive Cancer Network 2014)

Contraindications for BCT requiring radiation therapy include the following:

Absolute:

 Radiation therapy during pregnancy

 Diffuse suspicious or malignant-appearing microcalcifications

 Widespread disease that cannot be incorporated by local excision through a single incision that achieves negative margins with a satisfactory cosmetic result

 Positive pathologic margin

Relative:

 Active connective tissue disease involving the skin (especially scleroderma and lupus)

 Tumors >5 cm

 Focally positive margin

 Women with a known or suspected genetic predisposition to breast cancer:

 May have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with BCT

 Prophylactic bilateral mastectomy for risk reduction may be considered

Preoperative Systemic Therapy for Operable Cancer

Women who desire BCT but are not candidates for the procedure because of a large tumor relative to the size of the breast should be considered for preoperative or neoadjuvant therapy. This approach does not allow BCT for patients with multicentric carcinoma or those with an EIC that precludes a cosmetic resection. Patients most likely to be converted to BCT with neoadjuvant chemotherapy are those with unicentric, higher-grade, HER2+ or triple-negative cancers, as such cancers often respond dramatically to chemotherapy.

Pathologic complete response (pCR)—defined as the absence of residual invasive cancer in the breast and axilla following preoperative therapy—is a common endpoint for clinical trials of preoperative treatment. Multiple studies have shown that patients who experience pCR with neoadjuvant treatment have, on average, better long-term outcomes, with lower risk of cancer recurrence, than women with residual cancer following neoadjuvant chemotherapy. The US Food and Drug Administration has recently indicated that pCR may be a surrogate for accelerated drug approval in neoadjuvant treatment of operable breast cancer.114

Prospective, randomized trials of patients with operable breast cancer have demonstrated that clinical response rates to neoadjuvant chemotherapy are high, ranging from 50% to 85% in many studies. pCRs in the breast range from 15% to 40%. Despite these high response rates, only 25% to 30% of patients who were not candidates for BCT at presentation were able to undergo the procedure after preoperative therapy.115,116 This is a reflection of both the difficulty of assessing the extent of residual viable tumor after preoperative chemotherapy and the often patchy nature of cancer cell death in response to chemotherapy. This type of response significantly decreases the total number of viable tumor cells, but viable tumor remains scattered throughout the same volume of breast tissue, precluding BCT. MRI is better than mammography or ultrasonography in evaluating the extent of viable tumor and its distribution, but may both underestimate and overestimate the extent of residual disease.

In patients who overexpress HER2, the preoperative administration of anti-HER2 therapy in combination with chemotherapy has been associated with high rates of pCR. Clinical trials have confirmed that adding trastuzumab to chemotherapy improves the pCR rate among women with HER2+ breast cancer receiving neoadjuvant therapy and improves long-term survival,117 consistent with the survival benefit observed for trastuzumab when given with chemotherapy in the adjuvant setting.

In 2013, the US Food and Drug Administration approved concurrent use of a second anti-HER2 antibody, pertuzumab, for use in combination with trastuzumab and chemotherapy in women receiving neoadjuvant therapy for HER2+ breast cancer, after it was shown that pertuzumab enhanced the rates of pCR.118

A meta-analysis of nine randomized trials of preoperative chemotherapy demonstrated no increase, or decrease, in survival with preoperative compared with postoperative treatment,119 but an elevated risk of LRR (RR = 1.22; 95% CI = 1.04 to 1.45) was noted. Some of the increase in LR was due to the inclusion of studies in the meta-analysis in which patients who had a clinical complete response did not have surgery. Even in patients undergoing surgery, an elevated risk of LR has been observed. In the NSABP B-18 study,115 LR rates were 15% in patients who required chemotherapy to undergo BCT compared with only 7% in those who were initially candidates for BCT. The increased rates of LR after neoadjuvant therapy likely reflect that in this setting, a negative margin may still be associated with a clinically significant residual tumor burden that is unlikely to be controlled by RT. Thus, an evaluation of both surgical margins and the extent of viable tumor elsewhere in the specimen is essential and may dictate resection of additional breast tissue even when margins are apparently tumor-free. Among women who have mastectomy after neoadjuvant chemotherapy, a pCR is a favorable prognostic finding, associated with a far lower risk of LRR than seen in women with residual cancer.120 Percutaneous placement of marker clips within the primary tumor prior to the initiation of chemotherapy will provide a landmark for localization and excision should a clinical and radiographic complete response occur. The lack of a survival benefit for neoadjuvant therapy and the increased complexity in determining the appropriate extent of resection suggest that for women who are candidates for breast conservation at presentation, neoadjuvant therapy outside the context of a clinical trial offers little benefit.

Neoadjuvant endocrine therapy has also been used to increase rates of BCT. In trials of postmenopausal women with ER+ cancers who were not considered candidates for BCT at presentation, roughly 30% to 40% of those who received 4 months of endocrine therapy were able to undergo BCT.121,122 These studies indicate that in postmenopausal women with hormone receptor-positive tumors, the preoperative use of an AI or tamoxifen significantly increases the likelihood of breast conservation. However, despite the proven survival benefit seen with adjuvant endocrine therapy, pCR is rare with the short duration of treatment used in the neoadjuvant setting. Patients who experience substantial tumor shrinkage with endocrine therapy, even short of pCR, may also have a more favorable prognosis.123 For women with ER+breast cancer, a small randomized trial has suggested that either endocrine or chemotherapy can be equally effective.124 In clinical practice, neoadjuvant endocrine therapy is typically reserved for women not considered to be candidates for neoadjuvant chemotherapy.

Conservative Surgery Without Radiation Therapy

An unresolved question is whether RT is necessary in all patients with invasive breast cancer after CS. It is well known that RT after CS reduces LR by about 70%, but there has been uncertainty about whether this improvement in LR is important to survival and whether there is a subgroup of patients with a low risk of LR following CS alone. The impact of improving local control on overall long-term survival was greatly clarified with the findings of the EBCTCG meta-analysis125 first published in 2005, and updated in 2011.125 In this updated analysis, 17 trials including 10,801 women, 3,143 deaths, and 9.5 median woman-years at risk were included. Importantly, the EBCTCG moved from assessing the effect of RT on LR to its effect on first failure (or first recurrence, either LR or distant metastasis). (Although commonly employed in studies on the local treatment of breast cancer, actuarial calculation of time to LR is, strictly, not statistically valid.) RT proportionally reduced the annual rate of any failure (LR or distant metastases) over the first 10 years by about half (RR = 0.52) and proportionally reduced the annual rate of breast cancer death by about one-sixth. The absolute benefit of RT was greater in patients with the greater risk of recurrence. In node-negative patients, the absolute benefit was strongly correlated with age (inversely), tumor grade and size, and ER status, with very small absolute benefit seen in some subgroups. The updated EBCTCG analysis still demonstrates that RT after CS is not only important for local control, but also for maximizing long-term survival.

Attempts to identify a subgroup of patients (based on various clinical and histologic features) within the available clinical trials who have a low risk of LR after CS alone have been unsuccessful. LR rates are generally lower in trials that use more extensive surgery than in those using lumpectomy, and in older patients than in younger patients. The Joint Center for Radiation Therapy in Boston conducted a prospective single-arm trial of wide excision alone for patients with a tumor size of ≤2 cm, histologically negative axillary nodes, absence of either lymphatic vessel invasion or an EIC in the cancer, and no cancer cells within 1 cm of inked margins.126 The median age of patients in this trial was 66 years, 75% of cancers were detected by mammography alone, and the median pathologic size of the cancers was 9 mm. None of the patients received adjuvant endocrine therapy or chemotherapy. This trial was stopped shortly before it reached its accrual goal of 90 patients because of stopping rules ensuring against an excessively high LR rate. With a median follow-up time of 86 months among the 81 eligible patients, the crude rate of LR was 23%. The average LR rate was 2.8% per year. Of note, of the six patients with a tubular cancer, three had an LR. Examination of subsets of patients by age and tumor size did not find any statistically significant differences. Similar results were seen in a small randomized clinical trial from Finland. Based on the results of these prospective studies, it was concluded that even highly selected patients with breast cancer (based on patient and tumor characteristics) have a substantial risk of early LR after treatment with wide excision alone. Newer markers are needed to more reliably identify patients who can be safely treated with wide excision alone.

More recently, there have been five trials that have compared tamoxifen with and without RT after breast-conserving surgery (BCS; largely in ER+ patients), and their details are shown in Table 37.11.105,127130The LRR rates for these trials are shown in Table 37.12. The 5-year results seem reasonable, but the rate of LR appears increased after 5 years. In the Canadian trial,128 LR was 7.7% at 5 years, but 17.6% at 8 years. This raises the question of whether tamoxifen is merely delaying LR. As previously discussed, the combination of tamoxifen and RT provides a very low rate of LR. Tamoxifen alone has its greatest appeal in older patients (older than 70 years)129 where competing risks of other illnesses are substantial. In a prospective randomized trial of 636 patients age 70 and above with stage 1, ER+ breast cancers treated by lumpectomy and randomized to tamoxifen or tamoxifen plus WBI, no differences in OS or rates of breast preservation were observed at 10 years. WBI reduced the incidence of LRR from 10% to 2% in this population.129 In elderly patients, it is critical for the clinician to assess the patient’s particular cancer characteristics (especially tumor grade) as well as her comorbid illnesses and individual value system in determining the advisability of adding RT. (The website ePrognosis.com is useful is estimating life expectancy in older patients.)

Hypofractionated Whole-Breast and Accelerated Partial-Breast Irradiation

There have been a growing number of studies attempting to decrease the overall treatment time for RT after lumpectomy through the administration of fewer, but larger daily doses (hypofractionation) of RT delivered to the whole breast or only to the portion of the breast containing the primary tumor, typically given twice a day (accelerated).

Hypofractionated WBI was studied131 among women with invasive breast cancer who had undergone BCS and in whom resection margins were clear and axillary lymph nodes were negative. Women were randomly assigned to receive WBI either at a standard dose of 50 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). The risk of LR at 10 years was 6.7% with standard irradiation as compared to 6.2% in the hypofractionated regimen (95% CI = −2.5 to 3.5). At 10 years, 71.3% of women in the control group compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome. In a subset analysis, conventional fractionation had better results in patients with high-grade cancers. This trial was initiated before the value of a boost was established, and it is not clear how best to give a boost in patients treated with hypofractionated WBI. As noted previously, the value of a boost is very small in patients aged 60 years and greater, so at a minimum, it seems reasonable to treat patients aged 60 and greater with grade 1 or 2 node-negative breast cancer with accelerated WBI without a boost. A task force of the American Society for Radiation Oncology (ASTRO) developed guidelines for the use of hypofractionated WBI in 2011.132 The task force favored a dose schedule of 42.5 Gy in 16 fractions (“Canadian”) and its use in patients aged 50 years or older with pT1-2N0 cancer treated with BCS, and not treated with adjuvant chemotherapy where the dose homogeneity is within ±7% and the heart can be excluded from direct irradiation. There was no agreement on the use of a boost.

Ten-year results are now available from the similar START-B trial fully corroborating the results of the Canadian trial.133 In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. START-B enrolled 2,215 women. A boost dose was allowed in this trial. Median follow-up was 9.9 years, after which 95 LRRs had occurred. The proportion of patients with LRR at 10 years did not differ significantly between the 40 Gy group (4.3%; 95% CI = 3.2 to 5.9) and the 50 Gy group (5.5%; 95% CI = 4.2 to 7.2; HR = 0.77; 95% CI = 0.51 to 1.16; p = 0.21). In START-B, breast shrinkage, telangiectasia, and breast edema were significantly less-common normal tissue effects in the 40 Gy group than in the 50 Gy group. It is anticipated that the use of hypofractionated WBI will increase.

There are several potential benefits for accelerated partial-breast irradiation (APBI), including the following: (1) the quality of life of patients could be improved by relieving patients of the necessity of daily treatments for 5 to 6 weeks, (2) the underutilization of BCT could be reduced by making it more feasible for patients to receive RT, (3) the integration of local and systemic therapies could be simplified, and (4) long-term complications of RT could be decreased by limiting the volume of critical structures irradiated to high dose. The rationale for APBI is based on studies of the patterns of recurrence after standard whole-breast RT and after excision alone that demonstrate that the large majority of recurrences are in the immediate vicinity of the tumor bed.134 In addition, pathologic studies on the distribution of tumor cells in relation to the primary tumor demonstrate in most cases that the vast majority of tumor cells in the breast are found near the primary tumor.

These are a number of different APBI techniques, including interstitial brachytherapy, (three-dimensional conformal) external-beam irradiation, intracavitary brachytherapy, and intraoperative limited RT. At present, there are few long-term data, especially from randomized clinical trials, for APBI, and appropriate patient selection remains controversial. Successful application of this approach requires technical expertise. Two cooperative group studies—the recently completed NSABP/RTOG phase 3 trial comparing conventional RT versus APBI (allowing implant or external-beam techniques) and the National Cancer Institute of Canada RAPID study, which permitted external beam technique—will answer important questions about APBI. To provide some direction during this time of uncertainty, an ASTRO expert panel has defined a “suitable” group, for whom APBI outside a clinical trial was acceptable, as being patients135 meeting all of the following criteria: age 60 years or greater, BRCA1/2 mutation not present, unicentric invasive ductal carcinoma measuring ≤2 cm, margins negative by at least 2 mm, without lymphatic vessel invasion or an EIC, ERs present, and node-negative on pathologic examination. The panel also identified “cautionary” and “unsuitable” groups.

The most widely used form of APBI is with external beam irradiation. There is controversy whether cosmetic results are compromised relative to conventional whole breast external beam treatment. An interim cosmetic and toxicity analysis from the RAPID trial was published in 2013.136 Between 2006 and 2011, 2,135 women had been randomly assigned to APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% versus 17%; p <0.001), by patients (26% versus 18%; p = 0.0022), and by physicians reviewing digital photographs (35% versus 17%; p<0.001). Grade 3 toxicities were rare in both treatment arms (1.4% versus 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (p <0.001). The authors concluded that external beam APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI.

The first results of a trial from the European Institute of Oncology in Milan testing APBI using intraoperative radiation with electron beam versus conventional whole-breast radiation were published in 2013. A total of 1,305 patients were randomized, and after a median follow-up of 5.8 years, the 5-year rate of LR (IBTR) was 4.4% in the APBI arm and only 0.4% in the conventional whole breast arm (HR = 9.3; 95% CI = 3.3 to 26.3). OS did not differ.137

Toxicities of Breast Radiotherapy

Breast RT is generally very well tolerated with very few long-term toxicities. Evidence has long been accumulating that RT involving the heart can result in premature ischemic heart disease, but interest peaked in 2013 when a case-control study found an increased risk for cardiac-related deaths in patients with breast cancer who received RT.138 This was a population-based case-control study involving 2,168 Scandinavian women treated between 1958 and 2001. It found that rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy (p <0.001), with no apparent threshold. The increase started within the first 5 years after RT and continued into the third decade after RT. The proportional increase in the rate of major coronary events per Gy was similar in women with and without cardiac risk factors at the time of RT, but the absolute increase was greater in patients with cardiac risk factors. The overall average of the mean doses to the whole heart in this study was 4.9 Gy.

It is important to note the major limitations of the study; mainly, it is a case-control study and as such, it does not provide the highest level of evidence. Also, there were limitations in design. The investigators developed virtual simulations of RT dose based on CT scans of patients with “typical anatomy,” which they used to construct idealized radiation fields and with which they estimated the doses to the heart.

It is also important to emphasize that despite the proportional relationship between RT dose to the heart and heart disease, the absolute increase was very small. For 50-year-old women without cardiac risk factors, the lifetime increased risk was 0.5% after 0.5 Gy, 0.2% after 1 Gy, and just 0.5% after 3 Gy delivered as a mean heart dose. Today, for most node-negative women having BCT, the mean heart dose is only about 1 Gy, although higher doses (still only about 2 Gy) are more common for women with left-sided postmastectomy RT.

It should also be noted that any cardiac mortality risk in current practice is small compared to the survival benefit from RT both in the setting of BCT and PMRT. The survival benefit seen for RT in these older trials includes the deleterious effects on the heart seen with doses as high as 10 Gy. This means that using current techniques that spare the heart, RT will provide even greater survival benefit. The issue of cardiac irradiation, however, has more importance in patients with DCIS, where the survival impact of RT is small at best.

Notwithstanding these study limitations and improvements in technique, radiation oncologists should operate on the principle that there is no totally safe radiation dose to the heart, and that the heart dose should be kept as low as possible. A number of maneuvers, such as using cardiac blocks, prone techniques, and deep inspiration breath holds, make radiation delivery much safer in current practice.

Mastectomy

Mastectomy, with or without immediate breast reconstruction, is the surgical approach for the patient with breast cancer who has contraindications to BCT or who prefers treatment with mastectomy. The mastectomy used today is a total or complete mastectomy, with removal of the breast tissue from the clavicle to the rectus abdominous and between the sternal edge and the latissimus dorsi muscles. A total mastectomy also removes the nipple-areolar complex (NAC), the excess skin of the breast, and the fascia of the pectoralis major muscle. When accompanied by an ALND, the procedure is termed a modified radical mastectomy. Mastectomy is an extremely safe operation. The 30-day mortality is approximately 0.25%, and the 30-day incidence of major complications is about 5%, the majority of which are related to wound healing. In contemporary American practice, roughly 30% of women underwent mastectomy for breast cancer owing to either contraindications to BCT or patient choice.90

Advances in plastic surgical technique have made immediate reconstruction an option for most patients who undergo mastectomy. There have been no prospective trials comparing mastectomy alone with mastectomy with immediate reconstruction, but the available retrospective data do not support concerns about the incidence or detection of LR in the reconstructed patient. The majority of postmastectomy recurrences occur in the skin or subcutaneous fat of the chest wall and present as palpable masses in the skin flap, so detection is not affected by the presence of the reconstruction.139 Skin-sparing mastectomy in which skin excision is limited to the NAC and the excisional biopsy scar (if present) is now routinely used to preserve the skin envelope of the breast and facilitate reconstruction. The reported rates of LR after skin-sparing mastectomy are comparable to those of patients treated with conventional mastectomy. This finding is consistent with prior observations that the extent of skin removal in patients treated with mastectomy alone is not a major determinant of the risk of chest wall recurrence. Traditionally, skin-sparing mastectomy has included resection of the NAC due to the need to leave breast tissue on the NAC to provide a blood supply and the risk of leaving behind malignancy within the ducts of the nipple. Nipple sparing mastectomy (NSM) preserves the NAC and is being used with increasing frequency due to the excellent cosmetic results that can be obtained with this technique. Intraoperative frozen section of the tissue beneath the nipple is often used to minimize the risk of residual cancer. To date, most studies of this procedure have consisted of highly selected patients who had relatively short follow-up periods, making the long-term safety of NSM, particularly in high-risk women such as those with BRCAmutations, difficult to ascertain. The reported incidence of occult involvement of the NAC in patients with known breast cancer ranges from 0% to 58%.140 Despite this, a review of 10 studies including 1,148 NSMs reported a 2.8% rate of LRR after a median follow-up of only 2 years.141 In a large series from the European Institute of Oncology, including 772 patients with invasive cancer, and 162 with DCIS treated with NSM and intraoperative RT to the NAC, at a median follow-up of 50 months, the 5-year rate of LR was 4.4% in the invasive cancer group and 7.8% in patients with DCIS.142 The majority of recurrences were at a distance from the NAC, suggesting that the more difficult exposure with this operation may result in retained breast tissue on the skin flaps. These studies indicate that NSM may be a viable option in highly selected women, specifically, patients with small, peripherally located, node-negative tumors with favorable histologic features. Most women in this category, however, are candidates for conventional BCT. The eligible population for NSM is further limited by the requirement that the nipple be in the appropriate position on the reconstructed breast. This is rarely the case for women with large, ptotic breasts, further limiting the application of this procedure.

In summary, immediate reconstruction with preservation of the skin envelope of the breast has not been shown to alter the outcome of mastectomy or to delay the administration of systemic therapy. Immediate reconstruction has the advantages of avoiding the need for a second major operative procedure and the psychological morbidity of the loss of the breast. The two major reconstructive techniques involve the use of implants and/or tissue expanders or the use of myocutaneous tissue flaps to create a new breast mound. The advantages and disadvantages of the techniques are summarized in Table 37.13. Implant reconstructions are best suited for women with small- to moderate-sized breasts with minimal ptosis, while flap reconstructions allow more flexibility in the size and shape of the reconstructed breast (Fig. 37.4). In the past, most breast implants were filled with silicone gel. However, after reports from uncontrolled studies suggested an increased incidence of connective tissue disease in women with silicone implants, the US Food and Drug Administration declared a moratorium on their use. Since that time, several epidemiologic studies have failed to demonstrate an increased incidence of connective tissue disorders in women with implants compared with matched control populations. Silicone implants are again available for use in patients with breast cancer, but many patients opt for saline implants or flap reconstructions as a result of the adverse publicity surrounding silicone implants.

Reconstructive choices may be influenced by the possible need for postmastectomy RT. As indications for postmastectomy RT have expanded, the impact of RT on reconstruction has also become an issue. Immediate reconstruction can negatively impact the technical delivery of RT, possibly resulting in greater irradiation of the heart (in left-sided cancers) and lung, and undercoverage of the chest wall.143 There are a variety of strategies that have been proposed for selecting the type of reconstruction for a patient with a significant likelihood of requiring postmastectomy RT. There is considerable variability in outcome reported in the medical literature for the same approaches, and there are no prospective studies reported to date. The use of RT in patients who have been reconstructed with implants is associated with a higher risk of encapsulation and implant loss than in nonirradiated patients. In one study, however, Cordeiro et al.144 reported that after a mean follow-up of 34 months in 68 patients reconstructed with tissue expanders or implants who received RT, 80% had good to excellent aesthetic results and 72% would have chosen the same form of reconstruction again. The figures for nonirradiated patients were 88% (p = not significant) and 85%, respectively. Implant loss occurred in 11% of patients with irradiated implants and 6% of nonirradiated patients. The finding that the majority of patients who require RT after implant reconstruction have good cosmesis and are satisfied with their reconstruction choice has led some to advocate insertion of an expander at the time of mastectomy, which is inflated during chemotherapy and exchanged for a permanent implant prior to RT. In patients who are satisfied with the cosmetic outcome after RT, no further surgery is required. In patients with significant cosmetic deformity, a secondary flap reconstruction is performed. This approach has the advantage of allowing preservation of the breast skin and providing the patient with a breast mound during what may be a prolonged course of postoperative cancer therapy. However, additional favorable experience with irradiation of expanders or implants at other institutions is needed.

A primary flap reconstruction is another alternative for the patient who may require postmastectomy RT. Variable outcomes have been reported for patients who receive RT after transverse rectus myocutaneous flap or latissimus dorsi flap reconstruction. Complete flap loss is rare, but fat necrosis, fibrosis, and volume loss can occur. As in the native breast, the full cosmetic impact may not be evident until 3 years posttreatment. In one study, the 5-year incidence of major complications after transverse rectus myocutaneous reconstruction was 0% (n = 35) and 5% after tissue expander/implant (n = 50) reconstruction followed by RT.145 In contrast, 4 of 47 (9%) patients reconstructed with flaps and 6 of 15 (40%) implant patients underwent major corrective surgery a median of 8 months after RT in another series.146 An alternative approach is to perform sentinel node biopsy prior to mastectomy to identify patients with nodal involvement at highest risk for requiring postmastectomy RT and delay reconstruction in this subset of women until after the completion of oncologic therapy. This is an area that continues to evolve, and multidisciplinary consultation between the oncologic surgeon, reconstructive surgeon, and radiation oncologist will help to ensure optimal patient outcomes.

MANAGEMENT OF THE AXILLA

For many years, standard management of the axilla for patients with invasive breast carcinoma consisted of a complete ALND. Initially, this was thought to be a critical component of the surgical cure of breast cancer. This changed when studies such as the NSABP B-04 trial, in which clinically node-negative patients were randomized to radical mastectomy, total mastectomy with RT to the regional lymphatics, or total mastectomy with observation of the axillary nodes and delayed ALND if nodal metastases developed, showed no survival benefit for the axillary surgery.147 ALND came to be regarded as a staging procedure that provided prognostic information and maintained local control in the axilla. However, the observation that 25% to 30% of long-term survivors treated with radical mastectomy alone had positive nodes,148 coupled with the decreased survival observed after inadequate axillary treatment in the Guys Hospital trial,149 suggested that ALND was therapeutic for some patients with axillary nodal metastases.

Lymphatic mapping and sentinel node biopsy has replaced ALND as the staging procedure of choice in clinically node-negative women. A sentinel node can be identified in 97% of women.150,151 In the American College of Surgeons Oncology Group (ACOSOG) Z10 trial, participating surgeons chose the method of lymphatic mapping, and no significant differences were seen in the rate of sentinel node identification with the use of blue dye alone, radiocolloid alone, or the combination of the two.150 Increasing body mass index, increasing age, and <50 patients accrued to the trial were all associated with a significant decrease in sentinel node identification rate, but a sentinel node was successfully identified in >95% of patients in all groups. Complications of sentinel node biopsy are infrequent, with anaphylaxis to lymphazurin blue dye observed in 0.1% of patients in the ACOSOG Z10 trial152 and axillary paresthesias 6 months postoperatively in 8.6%. Lymphedema can occur after sentinel node biopsy, but at a much lower rate than after ALND. In the randomized Axillary Lymphatic Mapping Against Nodal Axillary Clearance trial, the absolute incidence of lymphedema in the sentinel node biopsy group was 5% at 12 months, with an RR of 0.37 (95% CI = 0.23 to 0.60) compared with the axillary clearance group in an intention-to-treat analysis.153

The majority of patients with stage I and II cancer are candidates for sentinel node biopsy. Contraindications to the procedure include pregnancy, lactation, and locally advanced breast cancer (LABC). Care should be taken to excise any palpably abnormal nodes intraoperatively because lymph nodes that contain a heavy tumor burden may not take up the mapping agent. In the patient with clinically positive nodes, confirmation of metastases preoperatively with needle biopsy allows an immediate ALND. Caution should be used in proceeding directly to dissection without pathologic confirmation because the false-positive rate of physical examination is approximately 20%. Multicentric cancers and T3 primary tumors were initially thought to be contraindications to lymphatic mapping, but studies have shown that sentinel node biopsy is accurate in these circumstances.154 Early in the experience with sentinel node biopsy, the false-negative rates of approximately 10%, determined by completing an ALND after the sentinel node(s) were removed, were a source of concern. However, three randomized studies directly comparing the identification of axillary metastases with ALND and sentinel node biopsy found no difference in the likelihood of identifying nodal disease.151,153,155 Follow-up studies of patients treated by sentinel node biopsy alone demonstrate that the rate of LR in the axilla is extremely low if the sentinel node does not contain metastases, despite the 10% false-negative rate. In one study with a median follow-up of 31 months, isolated axillary first failure was seen in only 3 of 4,008 patients (0.07%) who had a sentinel node biopsy.156

In clinically node-negative patients receiving neoadjuvant chemotherapy, sentinel node biopsy after chemotherapy offers the patient the potential benefit of axillary downstaging and avoidance of ALND. A meta-analysis of 27 studies involving 2,148 patients undergoing sentinel node biopsy after chemotherapy reported a sentinel node identification rate of 90.5% (95% CI = 88% to 92%) and a false-negative rate of 10.5% (8% to 14%), comparable to what is seen in the primary surgical setting,157 and in the NSABP B18 trial,158 the rate of nodal positivity was reduced from 57 to 41% with neoadjuvant chemotherapy (p<0.001). The accuracy of sentinel node biopsy in patients with clinically evident axillary nodal metastases at presentation who receive neoadjuvant therapy with resolution of clinically apparent adenopathy has been addressed in two multi-institutional prospective studies, as summarized in Table 37.14.159,160 These studies demonstrate false-negative rates <10% only when three or more sentinel nodes are identified, a circumstance present in only 28% of patients in the German multi-institutional Sentinel Neoadjuvant trial.160These findings suggest that ALND should remain the standard approach for patients presenting with clinically evident nodal involvement unless three or more sentinel nodes are identified. Ongoing trials are examining whether nodal irradiation could replace ALND in this setting.

The ability to perform a more detailed examination of the sentinel node has significantly increased the identification of small tumor deposits in the axillary nodes. The presence of isolated tumor cells (<0.2 mm deposits) and micrometastases (>0.2 mm, <2.0 mm) was initially thought to identify patients at increased risk for distant metastases. However, prospective trials in the modern era, including systemic therapy, have failed to identify an OS difference associated with micrometastases.161,162 A prospective randomized trial addressing the need for completion ALND in patients with sentinel node micrometastases163 found no significant difference in local, regional, or distant recurrence rates among patients with sentinel node micrometastases treated with sentinel node biopsy alone versus completion ALND, despite the finding of additional nodal metastases in 13% of the ALND group. Based on these findings, the routine use of serial sections and IHC to detect micrometastases is not warranted.

ALND has been the standard approach to patients with axillary nodal metastases. Studies comparing sentinel node biopsy with ALND have provided important information on the morbidity of the procedure. In the Axillary Lymphatic Mapping Against Nodal Axillary Clearance trial, moderate to severe lymphedema was reported by 13% of patients 12 months after ALND as well as sensory loss in 31%.153Decreases in shoulder flexion and abduction were present 1 month after surgery but resolved rapidly after that time. ALND provides excellent long-term local control, with only 1.4% of patients treated by radical mastectomy in the NSABP B-04 trial147 having an isolated axillary recurrence at 10-year follow-up. The use of axillary irradiation as an alternative to ALND was studied in the presentinel node era in a randomized trial in clinically node-negative patients performed at the Institute Curie. After 15 years of follow-up, the axillary failure rate was 3% in the radiated group and 1% in the surgical group (p = 0.03),164 indicating that this is an acceptable alternative in patients with contraindications to axillary surgery or those who refuse the procedure. The recognition that patients in the modern era who are eligible for BCT often have smaller cancers with lower nodal disease burdens, coupled with the recognition that systemic therapy significantly reduces LR,165 led to the ACOSOG Z0011 trial, a prospective randomized study to address the need for ALND in clinically node-negative women found to have macrometastases in less than three sentinel nodes. The study was designed to identify a 5% difference in survival between patients undergoing a completion ALND and those treated with sentinel node biopsy alone. It closed prematurely because of a low event rate, but 891 patients were randomized. After a median follow-up of 6.2 years, the 5-year nodal recurrence rate was 0.5% in the dissection arm and 0.9% in the sentinel node biopsy alone arm (p = 0.11). No difference in 5-year DFS or OS was seen between groups, and no evidence of a trend toward a survival benefit for dissection, which might have been evident with a larger sample size, was observed. Morbidity, including wound infection, paresthesia, and patient-reported lymphedema, was significantly lower in the sentinel node group. All patients in this study were treated with BCT, 97% received some type of systemic therapy, and irradiation of an axillary field was not permitted, but it is likely that the low rate of axillary failure in the sentinel node biopsy alone group is at least in part related to irradiation of the low axilla with the breast tangents.166 These findings do not apply to women with clinically positive nodes or extensive nodal involvement, or those undergoing partial breast irradiation or treatment with mastectomy. Investigators from Memorial Sloan-Kettering Cancer Center applied the ACOSOG Z0011 eligibility criteria to a consecutive series of 287 women, and ALND was avoided in 84%.167 Patient age, hormone receptor status, and HER2 status did not differ between patients requiring ALND and those who did not.

The After Mapping of the Axilla: Radiotherapy or Surgery trial examined alternative management approaches for the patient with a positive sentinel node, in this case, irradiation of the axillary and supraclavicular fields instead of dissection.168 At 5 years, axillary recurrence was seen in 0.54% of patients undergoing ALND and 1.03% of those having RT, without significant differences in 5-year DFS. There was a lower risk of lymphedema among women treated with axillary RT instead of surgery (14% versus 28%, p <0.0001). This study indicates that RT is an alternative to dissection, but does not prove that all patients with metastases to one or two sentinel nodes require nodal irradiation as similar rates of local control were observed in ACOSOG Z0011 after sentinel node biopsy alone. In marked contrast to these two studies are the results of the MA.20 trial, a study randomizing patients with T1 and T2 tumors undergoing WBI to ALND or ALND plus nodal RT. The majority of patients included in the study (85%) had involvement of one to three axillary nodes. The 5-year LR-free survival was improved from 94.5% to 96.8% (p = 0.02) with the addition of nodal RT, the distant DFS was improved from 87% to 92.4% (p = 0.002), and OS from 90.7% to 92.3% (p = 0.07).169 These trials are summarized in Table 37.15. At present, the optimal approach to the patient with positive sentinel nodes treated with BCS and whole-breast RT is a matter of debate, but ALND should no longer be considered the standard approach for all patients. Future research to clarify which subsets of patients are best managed with sentinel node biopsy alone versus sentinel node biopsy and axillary RT, and which high-risk groups require dissection and nodal RT, is needed.

POSTMASTECTOMY RADIATION THERAPY

The use of postmastectomy radiation therapy (PMRT) is in evolution based on emerging data from clinical trials. The 2005 publication from the EBCTCG suggested a 4:1 ratio between reduction in LRR at 5 years and improved mortality at 15 years with RT both after BCS and after mastectomy, and confirmed that LRR was reduced by 70% with RT after either BCS or mastectomy.88 This established LRR as a convenient intermediate endpoint for the survival benefit of PMRT.

ASTRO170 and ASCO171 have endorsed the routine use of PMRT in women with four or more involved nodes and node-positive women with tumors >5 cm, who have a high (>20% to 25%) risk of LRR without RT. There is uncertain benefit of PMRT in patients with T1/T2 primaries and one to three positive nodes (stage II) in whom the risk of LRR is intermediate (around 10% to 20%). Current NCCN guidelines give a category 1 recommendation for PMRT for patients with four or more positive nodes and a category 2A recommendation for PMRT for patients with one to three positive nodes.

However, in more recent analyses, the EBCTCG has focused on first recurrence of any type (LRR or distant) rather than LRR as a first event.125 This difference was partly because it is now clear that RT after BCT or mastectomy reduces breast cancer death, so it must also reduce distant recurrence. In addition, it is because women with a higher risk of LRR also have a higher risk of distant recurrence (i.e., the probabilities of LRR and of distant recurrence are not statistically independent), so valid estimates of the separate effects of RT on LRR and distant recurrence cannot be obtained.172 As a practical matter, this means that LRR is not an intermediate endpoint for the survival benefit of RT and that the survival benefit can only be learned in long-term follow-up of clinical trials testing RT.

This interplay between LRR and distant recurrence and its effect on survival was illustrated in a post hoc analysis of the Danish PMRT trials.173 Patients were assigned to one of three prognostic groups based on number of positive axillary nodes, tumor size, histologic grade, and receptor status. The 5-year LRR rates and the 15-year breast cancer mortality rates were analyzed in the three groups for patients randomly assigned to PMRT or not (Table 37.16). It is noteworthy that the “poor” group had the biggest absolute reduction in LRR with RT (36%), but had no improvement in 15-year breast cancer mortality. In contrast, the “good” group had the smallest absolute reduction in LRR with RT (11%), but the biggest absolute reduction in 15-year breast cancer mortality (11%). The EBCTCG data on trials of PMRT was updated in 2007.174 Although the data are still preliminary, they demonstrate that the benefit of PMRT was greater in the patients with one to three positive nodes than in patients with four or more positive nodes. In the subgroup of patients with one to three positive lymph nodes, the 15-year gain in breast cancer mortality was 10.2% (51.3 versus 41.1%, 2p <0.0001), and the 15-year gain in all-cause mortality was 7.3% (57.2% versus 49.9%, 2p = 0.004) with PMRT. The reduction in the rate of any first recurrence in the one to three positive node group at 10 years was 13.5% (2p <0.0001). In contrast, the reduction in the rate of any first recurrence in the four or more positive node group at 10 years was 11.5% (2p <0.0001). Thus, these and other data demonstrated that reduction in LRR is not a valid intermediate endpoint for the benefit in long-term survival and that the biggest benefit for PMRT might be in intermediate-risk, not high-risk, patients.

A critically important but unresolved issue is whether the use of effective adjuvant systemic therapy makes PMRT more or less useful. It is clear that effective adjuvant systemic therapy reduces the risk of LRR, but if this is no longer an important endpoint, then this does not provide a justification for less PMRT. We and others have argued that it is in context of effective systemic therapy that eradicates micrometastatic disease that improved local therapy might be most beneficial.175

A number of preliminary findings support the use of regional RT in intermediate-risk patients. The MA.20 trial169 randomized high-risk node-negative or node-positive patients to WBI alone or WBI plus regional RT including internal mammary node and medial supraclavicular (IM-MS) fields after BCS. Most patients had one to three positive nodes. With a median follow-up of 62 months, the addition of IM-MS RT improved LR DFS (LR DFS, 96.8% versus 94.8%), distant DFS (distant DFS, 92.4% versus 87%; p = 0.002), and overall DFS (DFS, 89.7% versus 84.0%), and had a borderline effect on OS (91.9% versus 89.5%). The HR reduction with RT for DFS was 0.67 (p = 0.003) and the HR reduction with RT for survival was 0.76 (p = 0.07).

The EORTC randomized patients to WBI plus IM-MS RT versus WBI alone.176 The patients in this trial were more heterogeneous than in the Canadian trial: 76% had BCT and 24% had mastectomy, and 44% were pN0, 43% were pN1, and 10% were pN2. With a median follow-up of 10.9 years, IM-MS RT improved DFS and distant DFS, and had a borderline effect on OS, the primary endpoint; but the magnitude of benefit in this larger study with longer follow-up was less than that seen in the MA.20 trial. The HR reduction with RT for DFS was 0.89 (p = 0.04) and the HR reduction with RT for survival was 0.87 (p = 0.056).

It will be important to examine the data in published manuscripts, but the evolving evidence suggests that a serious discussion of PMRT is warranted in the majority of women with intermediate-risk breast cancer treated with mastectomy, including those with one to three positive lymph nodes. There are a number of points about PMRT worth stressing. One is that, similar to the previous discussion on BCT, minimizing cardiac irradiation is critical but can be more difficult in PMRT, because unlike in BCT, the target volume includes the whole chest wall. The use of the deep inspiration breath hold technique is encouraged for left-sided patients. The other point relates to the multidisciplinary collaboration needed when reconstruction, particularly immediate reconstruction, is planned.

PROGNOSTIC AND PREDICTIVE FACTORS IN BREAST CANCER

The AJCC staging system reviewed elsewhere in this chapter79 is based on established clinical and pathologic prognostic factors, and stage—particularly the extent of axillary lymph node involvement by breast cancer—is the most established and reliable prognostic factor for subsequent metastatic disease and survival. Tumor size and histologic grading also have established prognostic significance. Tumor size is typically given as the microscopic size of the invasive cancer. Histologic grade is best determined by an established methodology, such as the Nottingham combined histologic grading system. However, persistent challenges in interpretation of grade either under the microscope or in genomic assays, especially intermediate grade, tend to diminish some of its prognostic impact.177

Estrogen and progesterone receptor expression are important and useful predictive factors. Patients with invasive breast cancer whose tumors are totally lacking in ER and PR do not derive benefit from hormonal treatment. Assays for ER and PR are performed using IHC techniques. Laboratories need to adhere to well-described techniques to ensure accurate determination of ER and PR as a centerpiece for quality care in breast cancer.178 Using tumor size and grade, ER status, and the number of involved axillary nodes, online services such as Adjuvant Online (www.adjuvantonline.com) can give accurate estimates of recurrence risk and treatment benefit.179

Patient age has also consistently been shown to be a prognostic factor. Very young breast cancer patients (≤35 years) have a poorer prognosis than older patients. The cancers in these patients tend to be higher grade, less often ER/PR+, and more likely to have lymphovascular invasion than cancers in older patients—differences that likely explain much of the worse outcomes in very young patients.180,181 A retrospective review of patients in clinical trials examining prognosis based on age, ER, PR, and HER2 status found that patients <35 years of age with ER/PR+HER2 tumors had no different risk of local or distant relapse than their older counterparts, but differences in LRR and survival persisted among other subgroups.182

Approximately 20% of patients with breast cancer have HER2/neu gene amplification, which results in glycoprotein overexpression. Approximately 5% of patients have overexpression without gene amplification, but otherwise, gene amplification and expression are highly correlated. HER2 amplification or overexpression has been associated with higher tumor grade, lower expression or lack of hormone receptors, higher levels of tumor proliferation, heavier nodal tumor burden, and poorer prognosis. HER2 status is the major predictive factor for benefit from anti-HER2 targeted therapies, which is discussed later in this chapter. There is some evidence that suggests that HER2status is predictive for benefit from anthracycline-based chemotherapy, although this relationship is not certain, particularly with the availability of trastuzumab.183 Measurements of HER2 can be performed by either IHC or fluorescent in situ hybridization. Similar to ER, laboratories need to adhere to well-described techniques to ensure accurate determination of HER2. In clinical practice, tumors that are considered HER2 3+ by IHC, or show evidence of HER2 gene amplification with ratios ≥2, warrant treatment with anti-HER2 therapies.184

Involvement of lymphovascular spaces is associated with a greater likelihood of lymph node metastases and is an independent adverse prognostic factor in both node-negative and node-positive patients. Rigid pathologic criteria are required for this factor to be reliable.

Other Factors

Numerous other prognostic and predictive factors have been evaluated, but have not been widely adopted in routine clinical use in the United States and include (1) markers of proliferation, such as S-phase fraction, the percentage of cells labeling with thymidine or bromodeoxyuridine or cellular expression of Ki-67 or MIB-1 (which measure the percentage of cells in the G1 phase of the cell cycle), and mitotic index; (2) measures of the plasminogen activator system, such as the concentrations of urokinase plasminogen activator and its inhibitor, plasminogen activator inhibitor-1; and (3) the detection of occult micrometastases in the bone marrow using IHC techniques.185 Sources are available for a more detailed discussion of these and other factors.186

Molecular and Genomic Factors

Breast cancer is a heterogeneous disease, and it has long been appreciated that tumors with different biologic features have different clinical outcomes and responses to therapy. At present, prognosis and treatment selection in breast cancer are based on characterization of tumor growth factor receptor status—ER, PR, and HER2. These markers can be used to define four functional groups of tumors: hormone receptor-positive, HER2, hormone receptor-negative, HER2 (“triple-negative” tumors), and HER2-overexpressing tumors with or without hormone receptor expression.

Recent advances in molecular biology have resulted in further refinement of these breast cancer subsets. Sorlie et al.187 and Perou et al.188 were able to classify breast cancers into tumor subtypes that had different prognoses using complementary DNA microarrays. These studies used hierarchical clustering analysis to identify tumor subtypes with distinct gene expression patterns. The differences in gene expression patterns among these subtypes reflect basic differences in the cell biology of the tumors and are manifest in differences in clinical outcome; clinicians are increasingly viewing these molecular subtypes as separable diseases. The subtypes are luminal A, luminal B, HER2/neu, and basal-like (or basaloid, or triple-negative). The subtypes are commonly approximated using routine tumor markers, such as luminal A: ER and/or PR+/HER2; luminal B: ER and/or PR+/HER2+HER2+: ER/PR/HER2+; and basal-like ER/PR/HER2 and/or CK5/6+ and/or epidermal growth factor-positive. Differences in gene expression pattern affecting hundreds of genes are found between the various subgroups; these differences appear to persist through the natural life history of the breast cancer,189 and neoadjuvant treatment of breast tumors appears to have little bearing on the gene expression patterns that contribute to the intrinsic tumor subtype.188,190 Subgroup affects both the likelihood and timing of cancer recurrence.191 Triple-negative/basal-like, HER2-associated, and luminal B breast cancers are at greater risk for early recurrence relative to luminal A cancers, which have a longer latency period of possible recurrence.

Complete genetic sequencing of human breast cancers has reinforced the idea that discrete subtypes of breast cancer exist.192 There is strong correlation between histologic subtypes of breast cancers, genomic profiles, and mutations identified by genomic sequencing. This information is beginning to influence clinical practice in breast cancer management.

In addition to defining biologic tumor subsets, gene expression profiling has been used to stratify tumors as having good-risk or poor-risk prognostic signatures.193,194 Several of these assays are now commercially available. MammaPrint is a 70-gene signature developed in the Netherlands.193 Prosigna (NanoString Technologies, Seattle, WA) is a 50-gene intrinsic subtype classifier that categories cancers into luminal A, luminal B, HER2, or basal-like subtypes.195 Retrospective analyses suggest that these gene signatures contribute independent prognostic information above and beyond that achieved with use of traditional pathologic markers, such as stage, grade, lymphovascular invasion, and ER/PR/HER2 status.

One molecular test that is of use clinically is the Oncotype DX recurrence score. The recurrence score is based on a quantitative assessment of 21 genes thought to be relevant to breast cancer biology, including hormone receptors, Ki67, and HER2, among others. In contrast to gene expression profiles that classify tumors into specific subsets or dichotomize tumors into good/poor prognostic groups, the recurrence score calculates a continuous, numeric result that correlates with distant metastatic recurrence in tamoxifen-treated patients with node-negative breast cancer,196 and has been shown to be a prognostic marker in postmenopausal women with node-negative or node-positive tumors receiving either tamoxifen or an AI.197 Although the recurrence score tends to correlate with features like tumor grade, size, nodal status, and quantitative levels of hormone receptor expression, multivariate analyses demonstrate that the score provides significant independent prognostic information. Oncotype DX has been applied to a common clinical question: whether a patient with ER+ breast cancer should receive chemotherapy in addition to hormonal therapy. Retrospective analyses from NSABP B-20—a trial of tamoxifen alone versus tamoxifen plus chemotherapy for ER+, node-negative patients—demonstrated that the recurrence score was a predictive factor for benefit from chemotherapy. Patients with tumors that had a low recurrence score had a very favorable overall prognosis that was not meaningfully improved by chemotherapy, while patients with high recurrence scores derived a substantial benefit from chemotherapy.198Qualitatively similar findings were seen in the Southwest Oncology Group (SWOG) 8814 study, a randomized trial of tamoxifen alone or tamoxifen plus cyclophosphamide/doxorubicin/5-fluorouracil chemotherapy for postmenopausal women with ER+, node-positive breast cancer, although the overall prognosis in this node-positive cohort was less favorable than in node-negative cases.199

There is substantial overlap between the various molecular diagnostic assays used to gauge prognosis and treatment for early-stage breast cancer.200 In particular, many assays appear capable of distinguishing node-negative, lower-grade tumors that are strongly ER+ and HER2, and are unlikely to benefit from adjuvant chemotherapy201 (Table 37.17). Collectively, these molecular tools have led to the evolution of specific treatment algorithms based on subtype classification, and clinical trials are increasingly designed for specific tumor types.

ADJUVANT SYSTEMIC THERAPY

The goal of adjuvant systemic therapy is to prevent the recurrence of breast cancer by eradicating occult, micrometastatic deposits of tumor present at the time of diagnosis. The rationale for adjuvant treatment stems from the systemic hypothesis of breast tumorigenesis, which argues that in the early stages of breast cancer development, tumor cells are disseminated throughout the body. To a large extent, this hypothesis has been validated through decades of clinical investigation, and approximately half of the recent decline in breast cancer mortality in the United States and Western Europe has been attributed to the widespread use of adjuvant therapy.5

In current practice, three systemic treatment modalities are widely used as adjuvant therapy for early-stage breast cancer. These modalities are (1) endocrine treatments such as tamoxifen, AIs, or ovarian suppression; (2) anti-HER2 therapy with the humanized monoclonal antibody, trastuzumab; and (3) chemotherapy. Selection of adjuvant treatment is determined by the biologic features of the breast cancer (Table 37.18). Patients with tumors that are hormone receptor positive (either for ER, PR, or both) are candidates for adjuvant endocrine therapy; patients with tumors that are HER2 overexpressing are candidates for trastuzumab. Chemotherapy is used for tumors that are hormone receptor negative, alongside trastuzumab in HER2+ tumors, and in addition to endocrine therapy in ER+ patients, based largely on features such as tumor size, nodal status, and the patient’s other health considerations.

Adjuvant Endocrine Therapy

Tamoxifen is the historic standard for adjuvant endocrine therapy for breast cancer. The EBCTCG has performed an overview of the randomized trials of adjuvant tamoxifen therapy.202 These results reflect data with 15 years of follow-up, from over 60 adjuvant trials including >80,000 women. Tamoxifen administered for 5 years results in a 41% reduction in the annual rate of breast cancer recurrence (HR = 0.59) and a 34% reduction in the annual death rate (HR = 0.66) for women with ER+ breast cancer. The gains associated with tamoxifen are achieved independent of patient age or menopausal status, with and without the use of adjuvant chemotherapy, and are durable, contributing to improved survival through at least 15 years of follow-up. Shorter durations of tamoxifen therapy are also beneficial, but appear to have less impact than 5-year treatment duration. Until recently, data had suggested that the optimal duration of tamoxifen therapy was 5 years; extending tamoxifen therapy beyond 5 years in patients with no evidence of tumor recurrence had not led to further improvements in DFS or OS.203 However, the Adjuvant Tamoxifen: Longer Against Shorter trial compared 10 years versus 5 years of adjuvant tamoxifen, and found an improvement in overall and DFS with the longer duration of tamoxifen treatment.204 This finding is of particular relevance for premenopausal women who lack the option of receiving extended adjuvant endocrine therapy with an AI (see the following). Based on the Adjuvant Tamoxifen: Longer Against Shorter trial, premenopausal women should consider longer duration of tamoxifen up to 10 years as adjuvant endocrine treatment. Tamoxifen is not effective in preventing recurrence of hormone receptor–negative breast cancer.205,206

Multiple clinical trials have examined the role of AIs as adjuvant endocrine therapy for early breast cancer. Although tamoxifen works by binding to the ER, AIs function through inhibition of the aromatase enzyme that converts androgens into estrogens,207 resulting in profound estrogen depletion. In postmenopausal patients, where only nonovarian, baseline levels of aromatase activity are present, AIs lower estrogen production by 90% to nearly undetectable levels.208 AIs are not appropriate for premenopausal patients, as residual ovarian function can lead to enhanced production of aromatase and thus overcome the effects of AIs.

Major trials have studied whether the incorporation of an AI improves the results seen with 5 years of tamoxifen in postmenopausal women with hormone receptor–positive breast cancer (Table 37.19). AI treatment has been explored as primary or up-front therapy instead of tamoxifen,209211 as sequential therapy after 2 or 3 years of tamoxifen,212,213 and as extended therapy after 5 years of tamoxifen.214216 In each setting, the use of an AI achieved modest improvements in DFS as a result of a lower risk of both distant metastasis as well as of in-breast recurrences and contralateral tumors. Two trials, BIG 1-98217and the Tamoxifen and Exemestane in Early Breast Cancer study,218 have compared up-front use of an AI against a sequential treatment with tamoxifen followed by an AI. These studies demonstrate equal rates of tumor recurrence with either 5 years of an AI or 2 to 3 years of tamoxifen followed by 2 to 3 years of an AI for a total of 5 years of therapy. Randomized trials have shown no important clinical differences between nonsteroidal or steroidal AIs as adjuvant therapy, demonstrating that different commercially available AIs can be used interchangeably.219

For women who begin taking an AI at the time of diagnosis, the appropriate duration of endocrine treatment is unknown, although at present, a maximum of 5 years is the only duration for which safety and efficacy data exist. Studies are ongoing to address this question. The option of starting with either an AI or tamoxifen appears reasonable for any patient. The up-front trials210,211 limited treatment to a total of 5 years’ duration, and the sequential trials212,213 used AI therapy for only 2 or 3 years as part of a total of 5 years of adjuvant endocrine treatment. The studies of extended endocrine therapy beyond 5 years204,214,216 underscore the long natural history of hormone receptor–positive breast cancer and demonstrate that antiestrogen treatments have ongoing benefits well beyond 5 years after diagnosis.

The recently updated ASCO guidelines on adjuvant endocrine therapy recommend that postmenopausal women consider an AI at some point in their treatment program as either initial therapy or as sequential therapy after several years of tamoxifen.220 Differences in side effect profiles between tamoxifen and AI therapy may inform treatment selection. Tamoxifen is associated with rare risks of thromboembolism and uterine cancer.203,210,211 AI treatment is associated with accelerated osteoporosis and an arthralgia syndrome221; patients receiving AI therapy require serial monitoring of bone mineral density.222 Both treatments are associated with menopausal symptoms, such as hot flashes, night sweats, and genitourinary symptoms, including sexual dysfunction. Postmenopausal women who are intolerant of either tamoxifen or AI therapy should be offered the alternative type of treatment. Because AI therapy is only effective in postmenopausal women, tamoxifen remains the treatment of choice in women who are pre- or perimenopausal, or in whom there is question of residual ovarian function. In particular, women with chemotherapy-induced amenorrhea may have recovery of ovarian function and are not suitable candidates for AI treatment.223

Despite longstanding interest in ovarian suppression as adjuvant therapy, its role in addition to tamoxifen or chemotherapy remains unclear because of confounding clinical factors. Early studies of ovarian suppression were not limited to patients with hormone receptor–positive tumors, did not necessarily include tamoxifen, and frequently included chemotherapy, which led to a high incidence of chemotherapy-induced menopause.224 Thus, despite the fact that multiple randomized trials have demonstrated that ovarian suppression can be effective adjuvant therapy for premenopausal women202 and have demonstrated that ovarian suppression is frequently at least as effective as adjuvant chemotherapy in preventing breast cancer recurrence,225 there remains little consensus on whether ovarian suppression adds meaningfully to results seen with tamoxifen with or without adjuvant chemotherapy.

Very young women—typically those <35 years of age—who do not routinely experience amenorrhea with adjuvant chemotherapy, appear to have a substantially worse prognosis than patients who do enter menopause with chemotherapy.226 A randomized trial has compared chemotherapy alone, chemotherapy plus ovarian suppression and tamoxifen, and ovarian suppression plus tamoxifen as adjuvant treatment. The addition of tamoxifen clearly improved results compared to chemotherapy with or without ovarian suppression. In subset analyses, younger women (<40 years of age) who were less likely to experience chemotherapy-induced amenorrhea did appear to benefit from ovarian suppression in addition to chemotherapy.227 The Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial compared tamoxifen alone versus tamoxifen with ovarian suppression in premenopausal women and did not show a substantial improvement in DFS with the addition of ovarian suppression.228 However, in this study, only 40% of patients were known to have ER+ breast cancer, and 80% of patients additionally received adjuvant chemotherapy, profoundly limiting study interpretation. Ongoing trials are specifically testing the role of ovarian suppression in addition to tamoxifen for premenopausal patients.

Tamoxifen is metabolized by the cytochrome P-450 system into biologically active metabolites. Pharmacogenomic variation in P-450 alleles or the concurrent use of tamoxifen and P-450 inhibitors might affect tamoxifen metabolism, with clinically significant effects.229233 Larger retrospective studies have not found consistent relationships between CYP2D6 metabolism and long-term outcomes with tamoxifen treatment.234,235 At present, neither the full significance of pharmacogenomic allelic variation nor the adequacy of testing for such variation is well characterized.

Multiple studies have documented high rates of noncompliance and early termination of adjuvant endocrine treatments.236 Factors associated with limited compliance or adherence to tamoxifen and AIs include age, treatment-related symptoms, costs of therapy, and patient-specific perceptions of therapeutic benefit. While the precise impact of noncompliance or nonpersistence with adjuvant endocrine treatment is unclear, clinicians should inquire about treatment utilization given the importance of these agents at improving survival.

Adjuvant Chemotherapy

Adjuvant chemotherapy consisting of multiple cycles of polychemotherapy is well established as an important strategy for lowering the risk of breast cancer recurrence and improving survival. Initial studies of adjuvant chemotherapy were conducted in women with higher-risk, lymph node–positive breast cancer. Subsequent trials have extended the benefits of adjuvant chemotherapy into lower risk, node-negative patient populations.237 Long-term follow-up from the EBCTCG overview demonstrated benefit from chemotherapy for women irrespective of age, tumor ER status, or whether patients also receive adjuvant endocrine therapy. In addition, the overview suggests that there are advantages for multiple cycles (four to eight) of chemotherapy compared with single-cycle regimens, and demonstrates the superiority of taxane-based and anthracycline-based chemotherapy over cyclophosphamide, methotrexate, 5-fluorouracil (CMF)-based, nonanthracycline regimens.

Multiple cycles of adjuvant chemotherapy, typically including taxanes and anthracyclines as part of the regimen, are recommended for the majority of patients with node-positive and higher-risk node-negative tumors.238 The current challenges in adjuvant chemotherapy treatment are to select subsets of patients that might preferentially benefit from chemotherapy or conversely be spared adjuvant chemotherapy and to optimize the dosing and scheduling of chemotherapy to achieve the best clinical results and improve the side effect profile of treatment.

The introduction of taxanes into early-stage breast cancer treatment constitutes an important advance over the historic experience with alkylator and anthracycline-based chemotherapy. The first report on adjuvant taxane therapy, Cancer and Leukemia Group B 9344, demonstrated that the addition of sequential paclitaxel therapy improved both DFS and OS among women with node-positive breast cancer compared to women receiving four cycles of cyclophosphamide-doxorubicin (AC) chemotherapy.239 Since that time, nearly one dozen studies have reported on breast cancer outcomes with the incorporation of taxanes—either paclitaxel or docetaxel—either as substitutes or sequential additions to anthracycline-based regimens. Studies to define the optimal taxane-based regimen have yielded the following important results. The Cancer and Leukemia Group B 9741 trial compared AC followed by paclitaxel given either every 3 weeks or every 2 weeks at the same doses and schedules.240 Accelerated, every 2-week treatment (so-called dose-dense) led to lower risk of recurrence and improved survival. A randomized comparison of AC followed by either docetaxel or paclitaxel, with taxanes given either every 3 weeks or on a weekly schedule, did not show significant differences between the taxanes with respect to breast cancer recurrence, though weekly paclitaxel was the best tolerated option.241 Sequential therapy with anthracyclines/alkylators followed by taxanes proved superior to concurrent taxane-anthracycline-alkylator treatments.242 Sequential dose-dense AC followed by paclitaxel was at least as effective, and better tolerated, than concurrent docetaxel/doxorubicin/cyclophosphamide chemotherapy.243

Meanwhile, neither additional chemotherapy doses nor agents have improved outcomes. Multiple studies have failed to demonstrate that dose escalation of cyclophosphamide244 or doxorubicin239 results in a lower risk of recurrence. The addition of capecitabine or gemcitabine to anthracycline- and taxane-based chemotherapy regimens did not improve efficacy.243,245

For women who warrant chemotherapy, sequential anthracycline- and taxane-based treatment remains the “gold standard.” While multiple possible variations on this regimen exist, the experience to date has not demonstrated that any regimen is better tolerated or more effective than AC for four cycles followed by paclitaxel chemotherapy, with paclitaxel given as either four cycles every 2 weeks, or as 12 weeks of weekly therapy.

There is growing interest in adjuvant chemotherapy regimens that might spare patients exposure to anthracycline-based chemotherapy. Historical options include CMF chemotherapy, which was shown to be equivalent to doxorubicin/cyclophosphamide.240 The two-drug combination regimen of docetaxel plus cyclophosphamide was superior to doxorubicin/cyclophosphamide (each regimen given for a total of four cycles)246 in a trial of 1,016 women with node-negative or one to three positive lymph nodes, establishing docetaxel plus cyclophosphamide as an option for these intermediate-risk patients. Six cycles of chemotherapy with AC or taxanes is not better than four cycles of the same regimen.247 Among higher-risk patients, it is unclear that anthracyclines can be safely omitted.

Clinical studies have shown that chemotherapy can be of benefit to women with node-positive and node-negative breast cancers, with tumors that are either hormone receptor–positive or –negative, regardless of age or menopausal status. Retrospective analyses have even shown that chemotherapy can be beneficial to women with tumors as small as ≤1 cm, including both ER+ and ER tumors.248 However, not all patients warrant chemotherapy. While chemotherapy often leads to statistically significant risk reduction, the differences in the absolute risk of recurrence for patients, especially patients with small cancers249or ER+ cancers who also receive adjuvant endocrine therapy, tend to be very small (single percentage points). Third, most benchmark trial results did not take into account the existence of molecularly defined breast cancer subsets and may overestimate the benefits of chemotherapy in certain subtypes of breast cancer, while underestimating the benefits in others. Finally, for patients in whom the absolute advantages of chemotherapy are modest, efforts to weigh patient preferences and directly quantify chemotherapy benefits for specific patients, as opposed to large cohorts in clinical trials, have led to further individualization of chemotherapy choices.

Hormone receptor status may be an important predictor of benefit from chemotherapy. Tumors that are low or nonexpressors of ER derive substantial benefit from the addition of chemotherapy to tamoxifen; by contrast, tumors with high quantitative levels of ER do not appear to gain substantially from adding chemotherapy to endocrine therapy.205 A retrospective review of trials for node-positive breast cancer found the gains associated with chemotherapy innovations in anthracycline- and taxane-based treatments were most noticeable among patients with ER tumors, while patients with ER+ tumors derived more limited benefit.250 However, not all retrospective studies have shown a clear relationship between ER status and the benefit of chemotherapy,251 and precise thresholds of ER expression and chemotherapy benefit are not well established.

HER2 is also a marker that has been widely studied as a predictor of benefit from adjuvant chemotherapy. HER2 overexpression is associated with a relative benefit from anthracycline-based chemotherapy,252and HER2 tumors do not selectively benefit from anthracyclines, as opposed to CMF-type chemotherapy treatments. Other retrospective work based on characterizing both HER2 status and ER status of tumors suggests that chemotherapy with taxanes may be especially critical in tumors that either lack ER expression or express HER2.253 However, these chemotherapy trials all predate the widespread use of adjuvant trastuzumab, which may render moot the details of chemotherapy selection for HER2+ tumors.

Molecular assays that integrate larger numbers of biomarkers can clarify the role of chemotherapeutic agents in adjuvant treatment. The 21-gene recurrence score (Oncotype DX, discussed in the section “Prognostic and Predictive Factors in Breast Cancer” on page 468) predicts outcome for ER+, node-negative breast cancers treated with tamoxifen196 or tamoxifen plus chemotherapy in node-negative197 and node-positive199 patients. Patients with tumors with higher recurrence scores derive substantial benefit from the addition of chemotherapy to endocrine treatment, while patients with low recurrence scores have both a more favorable overall prognosis and do not appear to benefit meaningfully from the addition of chemotherapy. Pathologic features such as low or no expression of hormone receptors, expression ofHER2, and high tumor grade all tend to be predictors of likely sensitivity of tumors to chemotherapy.177,200 Tumors at the other end of the molecular spectrum—low grade, high levels of hormone receptors, lack of HER2 expression—tend to be more sensitive to endocrine therapies and less sensitive to adjuvant chemotherapy. Various chemotherapy regimens have distinctive side effect profiles that can inform regimen selection for an individual patient. For example, anthracyclines are associated with a low risk of cardiomyopathy and may not be appropriate for patients with previous anthracycline exposure or preexisting cardiac disease. Taxane-based treatments are associated with neuropathy that may be worse in patients with preexisting peripheral neuropathy.

Patients and doctors should gauge the absolute gains associated with chemotherapy by considering rigorously the tumor stage, comorbid conditions, age of the patient, and the biologic features of the tumor. Adjuvant!, an online tool that quantifies the benefits of adjuvant treatment, integrates tumor size and biomarker information, patient age and health status, and the relative benefits of chemotherapy as measured in clinical trials, and reports in bar graph format the absolute benefits that the given patient is likely to achieve with adjuvant chemotherapy.179,254 There are limitations to Adjuvant!, which neither factors into account intrinsic subtypes, nor the efficacy of adjuvant trastuzumab for HER2+ tumors. Nonetheless, Adjuvant! can be valuable for framing the realistic benefits of chemotherapy for a variety of clinical situations. Patient surveys, inevitably performed after patients have endured adjuvant chemotherapy, suggest that many women would prefer adjuvant chemotherapy for extraordinarily small gains (1% improvement in outcome), and most women would accept chemotherapy for modest differences on the order of a 3% to 5% improvement in chance of recurrence.255

Adjuvant Trastuzumab Therapy for HER2-Overexpressing Breast Cancer

HER2 expression was historically an adverse prognostic factor associated with a higher risk of recurrence, lack of or lower levels of ER expression, and relative resistance to endocrine therapy and CMF-based chemotherapy.256,257 In 2005, reports became available from five randomized clinical trials that examined the addition of trastuzumab, the humanized monoclonal antibody against the HER2 protein, to chemotherapy as adjuvant treatment for HER2-overexpressing breast cancer (Table 37.20).258261 Although these trials used a variety of different adjuvant chemotherapy regimens and employed trastuzumab in different schedules and sequences, they all showed significant improvements in DFS (reduction in risk of 50% on average) and OS. Subset analyses demonstrated comparable RR reduction regardless of tumor size, nodal status, or hormone receptor status, resulting in the rapid incorporation of trastuzumab into standard treatment recommendations for women with HER2+ breast cancer.

Cardiomyopathy is a novel side effect of trastuzumab therapy.260 Cardiac dysfunction is more frequent in patients receiving anthracycline-based than nonanthracycline adjuvant chemotherapy (2% versus 1%) in addition to trastuzumab. Other risk factors for cardiac dysfunction with adjuvant trastuzumab include preexisting cardiac disease, such as borderline normal left ventricular ejection fraction or hypertension, and age >65 years. All patients being considered for adjuvant trastuzumab require baseline determination of left ventricular ejection fraction and serial monitoring of cardiac function.

Adjuvant trastuzumab is only known to be effective in tumors with aberrant expression of HER2.262 The optimal duration of trastuzumab therapy is 1 year. While short exposure (9 weeks) of concurrent chemotherapy-trastuzumab treatment is better than no trastuzumab,258 a comparison of 6 months versus 12 months of trastuzumab therapy showed superiority for the 12 month duration.263 The HERA (Herceptin Adjuvant) trial compared 1 year versus 2 years of therapy and found no benefit for a second year of treatment.259,264

Trastuzumab is active when delivered sequentially after chemotherapy (as done in the HERA trial259) or concurrently with chemotherapy (as done in the NSABP B-31/North Central Cancer Treatment Group N9831,260 and Breast Cancer International Research Group trials261). However, concurrent trastuzumab-chemotherapy administration yielded superior results compared to sequential therapy.265 All of the adjuvant trastuzumab trials gave chemotherapy; there are no data on whether trastuzumab would be effective without adjuvant chemotherapy.

The optimal chemotherapy backbone for trastuzumab-based adjuvant treatment is uncertain.266 Most patients treated on the extant clinical trials received sequential anthracyclines and taxane-based treatment, with concurrent use of trastuzumab during taxane treatment. The results from Breast Cancer International Research Group 006 suggest that the nonanthracycline trastuzumab/docetaxel/carboplatin regimen is superior to chemotherapy given without trastuzumab.261 However, the study was not powered to adequately compare trastuzumab/docetaxel/carboplatin against the doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab treatment arms, and numerically, the anthracycline-based regimen followed by trastuzumab was associated with a lower risk of cancer recurrence.261Trastuzumab/docetaxel/carboplatin is an important treatment option, particularly in patients with contraindications to anthracycline-based treatment. Concomitant RT and maintenance trastuzumab can be safely delivered after chemotherapy.

Most of the patients in the major trastuzumab trials had node-positive or high-risk, node-negative breast cancers. The role of trastuzumab treatment for women with smaller, node-negative tumors, particularly tumors <1 cm, remains unproven in randomized trials. Historical studies have suggested that these smaller, HER2+ breast cancers still carried a substantial risk of tumor recurrence (on the order of 15% to 20% through 5 to 10 years of therapy).267Recent retrospective analyses of small HER2+ tumors suggest a benefit may exist for this subgroup with the addition of trastuzumab.268 A prospective trial of 12 weeks of paclitaxel plus trastuzumab, followed by conclusion of 1 year of adjuvant trastuzumab, yielded a remarkably low risk of recurrence when studied in stage 1, HER2+ breast cancers.269 Patients with HER2+tumors ≥5 mm are likely to benefit substantially from adjuvant chemotherapy and trastuzumab.

INTEGRATION OF MULTIMODALITY PRIMARY THERAPY

Current consensus recommendations for adjuvant therapy are summarized in Table 37.21. The majority of women with breast cancer receive some form of adjuvant therapy, which requires integration of systemic treatments with local therapy including surgery and RT. Low rates of LR are seen regardless of the sequence of RT and chemotherapy.270 A nonsignificant trend toward a greater risk of distant recurrence in patients receiving RT first was seen in one study,270 and because of the primary importance of preventing distant relapse, the convention has been to administer chemotherapy first. Tamoxifen therapy should not be given concurrently with chemotherapy because in one randomized study, concurrent tamoxifen and chemotherapy was associated with greater risk of recurrence than sequential treatment of chemotherapy followed by tamoxifen.271 There are no compelling data that the concurrent administration of endocrine therapy and RT has deleterious consequences, nor that it has particular advantages.272The timing of surgery either before (neo) or after adjuvant chemotherapy does not alter long-term survival for women with breast cancer.119 Thus, patients may comfortably proceed in a linear fashion of treatment, receiving one therapeutic modality (surgery, RT, chemotherapy, biologic therapy) after another, as they receive definitive treatment for early-stage breast cancer.

FOLLOW-UP FOR BREAST CANCER SURVIVORS

Following initial treatment for breast cancer, patients require surveillance for local-regional tumor recurrence, contralateral breast cancer, and the development of distant metastatic disease. In addition, medical follow-up allows clinicians to monitor for late effects of chemotherapy, RT, or surgery, to gauge ongoing side effects from cancer treatments, such as antiestrogen therapies, and to facilitate opportunities to update patients on new developments that may affect their treatment plan.273 Although the greatest risk of recurrence is in the first 5 years after breast cancer diagnosis, women remain at risk for many years after their treatment, especially those with hormone receptor–positive breast cancer. (These experiences justify ongoing follow-up with breast cancer specialists, although particularly in later years, follow-up is often shared with primary care physicians.)

LR and new contralateral cancers are potentially cureable, so women should undergo regular breast examinations and annual mammography, with supplemental breast imaging as clinically indicated. LR is often associated with concurrent metastatic disease, and evaluation for distant metastases is indicated prior to local therapy in this setting. By contrast, it is not clear that early detection of distant metastatic disease contributes to substantial improvement in clinically important end points. Most distant recurrences are detected following patient-reported symptoms, such as bone discomfort, lymphadenopathy, chest wall/breast changes, or respiratory symptoms; asymptomatic detection through screening laboratory tests or radiology studies occurs in only a modest fraction of patients, even with intensive surveillance.273Randomized trials have compared vigorous surveillance with radiologic imaging (chest radiography, bone scanning, and liver ultrasound) and laboratory testing (blood counts, liver function tests, and serum tumor markers) against standard care consisting of regular physical examination and mammography, with additional testing performed only if indicated by symptoms or physical examination.274,275 More intensive surveillance achieved modest gains in early detection of metastatic breast cancer, with a small increase in the fraction of patients diagnosed while asymptomatic, but no improvement in OS was noted.

Based on these data, ASCO has issued surveillance guidelines for women with early-stage breast cancer276 (Table 37.22). These guidelines emphasize the importance of a careful history and examination to elicit symptoms or signs of recurrent breast cancer, but minimize the role of routine imaging studies including plain films and CT scans, and do not recommend routine laboratory testing in the absence of symptoms. Patients should be encouraged to perform breast self-examination and to contact their physicians if they develop symptoms possibly suggestive of breast cancer recurrence. Understandably, patients often request additional testing to provide reassurance and to “catch” early recurrences. Clinical experience suggests, however, that patients respond well to discussions regarding optimal testing strategies, the role of surveillance for breast cancer recurrence, the challenges of false-positive and false-negative test results, and the limited need for testing in the absence of symptoms or physical examination findings.277

SPECIAL THERAPEUTIC PROBLEMS

Paget Disease

Paget disease represents in situ carcinoma in the nipple epidermis. The classic pathologic finding is the presence of Paget cells (large cells with clear cytoplasm and atypical nuclei) within the epidermis of the nipple. The clinical manifestations of Paget disease include eczematoid changes, crusting, redness, irritation, erosion, discharge, retraction, and inversion. Rarely, Paget disease is bilateral or occurs in a male patient.

Paget disease may occur in the nipple (1) in conjunction with an underlying invasive cancer (staged by the invasive cancer), (2) with underlying DCIS (staged Tis), or (3) alone without any underlying invasive breast carcinoma or DCIS (also staged Tis). The associated underlying cancer may be located centrally in the breast adjacent to the nipple or it may be located peripherally. It is uncertain whether the origin of Paget disease is primarily an in situ intraepidermal malignancy with secondary extension to adjacent structures (intraepidermal theory) or migration of tumor cells into the nipple epidermis from an underlying carcinoma of the breast (epidermotropic theory).

The age-adjusted incidence rates of female Paget disease peaked in 1985 and have decreased yearly thereafter through 2002,278 perhaps because of earlier detection of breast lesions by mammography prior to the development of pagetoid changes. More recently, Paget disease has been observed as a form of recurrence after nipple-sparing mastectomy.

The workup for the patient with Paget disease includes mammography and physical examination of the breast to rule out an underlying invasive cancer or DCIS. In patients with negative findings on physical examination and mammogram, breast MRI should be considered for patients who are candidates for BCT.

Historically, Paget disease was treated with mastectomy. Prognosis is determined by the stage of the underlying malignancy, if present. Small studies examining the use of excision and WBI for Paget disease have reported LR rates of 5% to 8%279,280 and no survival differences between BCT and mastectomy, suggesting that BCT with WBI is a reasonable alternative to mastectomy. Local excision alone, without RT, has been used to treat a small number of patients. In one series of 33 patients prospectively treated with local excision alone, the LR rate was 33%281 and 10 of 11 recurrences were invasive carcinoma. Because of the small numbers of patients treated without RT and the high rate of local failure, such treatment must be considered as nonstandard at the present time.

For patients treated with BCT, surgery should include excision of the full NAC with a cone of underlying retroareolar tissue and complete excision of any tissue with abnormal radiologic findings. For patients with positive margins after central lumpectomy, additional surgery is indicated. Patients with negative surgical margins should undergo irradiation based on criteria generally used to select patients with DCIS and invasive cancer for RT and discussed previously. The decision for axillary node surgery should be based on the presence of an invasive breast cancer; sentinel node biopsy has been used successfully in this setting. Recommendations for adjuvant systemic therapy are based on the final pathology.

Occult Primary with Axillary Metastases

Axillary metastases in the absence of a clinically or mammographically detectable breast tumor are an uncommon presentation of breast carcinoma, seen in <1% of cases. The initial evaluation should include a detailed history and physical examination, bilateral mammogram, breast MRI (if the mammogram is unrevealing), and a chest radiograph. The presence of ER, PR, or HER2 overexpression is strongly suggestive of metastatic breast carcinoma, although their absence does not exclude a primary breast tumor. MRI identifies the primary tumor in the breast in a significant number of patients with a normal mammogram and breast examination. In a meta-analysis of 220 patients with occult primary tumors, MRI identified a suspicious lesion in 72% with a sensitivity of 90% and a specificity of 31%. The size of tumors identified on pathologic exam ranged from 5 mm to 16 mm.282 The identification of the primary tumor within the breast simplifies local management, allowing these patients to be treated with BCT or mastectomy according to standard guidelines.

In cases in which a primary tumor cannot be identified, treatment has traditionally been with mastectomy. This strategy was based on the observation that approximately 50% of patients who do not receive therapy to the breast will develop clinically evident disease in the breast. In addition, prior to the era of modern mammography and the availability of MRI, the occult cancers found in the breast at mastectomy were sometimes quite large.283 More recently, WBI has been used in these patients. Fourquet et al.283 treated 54 patients with WBI without removal of the primary tumor. The 5- and 10-year rates of IBTR were 7.5% and 20%, respectively. Other small studies antedating the use of MRI confirm that although rates of LR after BCT are higher than in patients treated with excision of a known primary tumor and a boost dose of RT to the tumor bed, WBI with a dose of about 50 Gy is an acceptable alternative to mastectomy in this patient population.

Regardless of the management approach chosen for the breast, ALND should be carried out because of the limited ability of radiation to control gross axillary disease. OS for women with occult primary tumors is similar to that of patients with comparable axillary involvement and a known primary tumor, and some investigators have suggested that survival is actually superior for those with occult primary tumors.284 Because of the small size of most studies of occult primary cancer, the heterogeneous treatments employed, and the variable durations of follow-up, this claim is difficult to substantiate. Systemic treatment for patients with occult primary breast cancer and axillary involvement should follow the current guidelines for patients with node-positive breast cancer.

Breast Cancer and Pregnancy

Breast carcinoma is one of the most commonly diagnosed malignancies during pregnancy. Older studies estimated that breast cancer developed in 2.2 in 10,000 pregnancies285; however, the trend toward later age at first childbirth has increased the number of breast cancer cases coexistent with pregnancy, and breast cancer is now estimated to occur in 1 in 1,000 pregnancies.286 Delay in diagnosis remains a problem due to the nodularity of the pregnant breast and the assumption that new breast masses are normal physiologic changes. Dominant breast masses developing during pregnancy require biopsy before assuming that they are benign. This can be readily accomplished with a core-cutting needle biopsy in the majority of women. If excisional biopsy is necessary, it should be undertaken; concerns about the development of a milk fistula appear to be overstated.287 Mammography is not as useful in pregnant patients as in those who are not pregnant because of the increased density in the breast parenchyma associated with pregnancy. Ultrasound may be helpful in confirming the presence of a dominant mass, but, as in the nonpregnant patient, normal imaging studies should not lead to a decision to forgo biopsy in the patient with a dominant breast mass.

After a diagnosis is made, the initial evaluation should include an assessment of the extent of the disease. Computed tomography and bone scans are not recommended during pregnancy because of concerns about radiation exposure to the fetus. In patients with symptoms suggestive of metastases, MRI without contrast can be used to evaluate bony sites and the intra-abdominal viscera.287

Breast cancers occurring during pregnancy are usually high-grade infiltrating ductal carcinomas. In a prospective study of 38 pregnant women who developed breast cancer, only 28% had ER+ tumors and 24% had PR+ tumors.288In general, the characteristics of cancers occurring during pregnancy are similar to those of nonpregnant women of the same age. Data from retrospective case-control series suggest that after adjusting for age and disease stage, the prognosis of women with breast cancer occurring during pregnancy differs little from that of nonpregnant patients.287

For women diagnosed in the first or second trimester, the question of pregnancy termination is inevitably raised. Although some treatment approaches are feasible during pregnancy, others are contraindicated. Depending on the patient’s specific situation, continuing the pregnancy may or may not compromise the breast cancer treatment. Even when deviations from standard treatment are required, it is unclear to what extent such changes or delays affect a woman’s odds of remaining free from recurrent breast cancer. The concerns about compromising care must be balanced by the woman, her family, and her physicians, with the desire to continue the pregnancy. The woman facing these issues must also consider the possibility that if she receives chemotherapy, her ability to conceive another child could be compromised.224 There is no clear evidence that pregnancy termination changes OS.289

Breast surgery can be safely performed during any trimester of pregnancy. Mastectomy is the treatment that has traditionally been undertaken because of the inability to safely deliver RT to the breast without excessive fetal exposure during any trimester. The effect of delaying RT on LR, in the absence of systemic therapy, is unknown and is of concern. Guidelines for BCS66 consider this an appropriate approach for cancers diagnosed in the third trimester and one that must be considered on a case-by-case basis for cancers diagnosed earlier in pregnancy. In the woman who will receive systemic chemotherapy, the delay in the delivery of RT is often no greater than in the nonpregnant patient. The success rate of lymphatic mapping and sentinel node biopsy in the pregnant woman is unknown. Isosulfan blue dye is not approved by the US Food and Drug Administration for use during pregnancy. The radiation exposure to the fetus from the use of technetium has been estimated to be low, and it has been suggested that mapping with technetium alone could be discussed with patients as an appropriate management strategy.290 In the absence of definitive data on the safety and accuracy of sentinel node biopsy in the pregnant woman, ALND remains the standard management strategy.

The risk of congenital malformation from cytotoxic chemotherapy varies with the fetal age at exposure and the agent used. Exposure in the first trimester is associated with risks of 10% to 20% and should be avoided. Risks decline to <2% with exposure in the second and third trimesters, enabling chemotherapy administration in those trimesters.291 Chemotherapy during pregnancy may also contribute to intrauterine growth retardation, and the long-term consequences of exposure remain uncertain. In a prospective study of 24 pregnant women treated with fluorouracil, doxorubicin, and cyclophosphamide during the second and third trimesters of pregnancy, no complications were observed for the fetus or infant.292 Experience with the taxanes in pregnancy is limited, but appears feasible after the first trimester.293

The use of trastuzumab in pregnancy is associated with oligohydramnios,294 and more information on the safety of this agent in pregnancy is needed. Methotrexate should be avoided during pregnancy because of the risk of abortion and severe fetal malformation. Similarly, tamoxifen should be withheld until after delivery because its safety is uncertain. When chemotherapy or tamoxifen is given postpartum, breastfeeding should be avoided, as these agents may be excreted in the breast milk.

The management of breast cancer during pregnancy is difficult, as there is often a conflict between optimal therapy for the mother and the fetus. Multidisciplinary management by a team including medical, surgical, and radiation oncologists, an obstetrician, a maternal-fetal medicine specialist, and a psychologist will facilitate the development of a strategy that optimizes the outcome for both mother and child.

Male Breast Cancer

The incidence of male breast cancer varies on a worldwide basis, with the highest rates in some sub-Saharan countries. In the United States, it is estimated that in 2012, 2,190 men were diagnosed with breast cancer, and 410 died of the disease. Worldwide, the female to male incidence ratio is 122:1.295 In recent years, as the incidence of female breast cancer has declined by 42%, a 28% decline in male breast cancer has been observed.296 The risk of male breast cancer is related to an increased lifelong exposure to estrogen (as with female breast cancer) or to reduced androgen. The strongest association is in men with Klinefelter syndrome (XXY); they have a 14- to 50-fold increased risk of developing male breast cancer and account for about 3% of all male breast cancer cases. Also, men who carry a BRCA1 or, particularly, a BRCA2 mutation, have an increased risk of developing breast cancer. The following conditions have been reported to be associated with an increased risk of breast cancer in men: chronic liver disorders, such as cirrhosis, chronic alcoholism, and schistosomiasis; a history of mumps orchitis, undescended testes, or testicular injury; and feminization, genetically or by environmental exposure. In contrast, gynecomastia alone does not appear to be a risk factor.297

The clinical presentation of male breast cancer is similar to that of female breast cancer, but the median age of onset is later than in women (60 years versus 53 years). Because the diagnosis of breast cancer is often not considered as promptly in men and screening mammography is not used, men often present with more advanced stage than do women. All known histopathologic types of breast cancer have been described in men, with infiltrating ductal carcinoma accounting for at least 70% of cases. However, ILC in men is rare. A majority of male breast cancers are ER/PR+, and the percentage positive is greater than for female breast cancer. As for women, stage is the predominant prognostic indicator, and most studies report that stage for stage, men with breast cancer have the same outcome following treatment as women with breast cancer. A recent study, however, from the Veterans Affairs reports a worse prognosis for men than women in early-stage breast cancer.298 There appears to be a substantial negative disparity in outcome for blacks with male breast cancer compared with whites.299

Primary local treatment is typically total mastectomy. In some patients with early disease, BCT can be considered. However, the subareolar location of most male breast cancers and the small amount of breast tissue present in most men limits eligibility for BCT. The same considerations regarding nodal surgery pertain for men as for women, with sentinel node biopsy the preferred treatment in clinically node-negative patients. The use of postmastectomy RT follows the same guidelines as for female breast cancer. Similarly, the use of systemic therapy follows the same guidelines as for women with postmenopausal breast cancer. Adjuvant systemic chemotherapy is used in men, although no controlled trials have confirmed its value.300 Tamoxifen is the mainstay for adjuvant systemic therapy in ER+ male breast cancer; a study of 257 male breast cancer patients demonstrated a 1.5-fold increase in mortality in those treated with an AI versus tamoxifen.301 Metastatic breast cancer in men is treated identically to metastatic disease in women.

Phyllodes Tumor

The term phyllodes tumor includes a group of lesions of varying malignant potential, ranging from completely benign tumors to fully malignant sarcomas. Clinically, phyllodes tumors are smooth, rounded, usually painless multinodular lesions that may be indistinguishable from fibroadenomas. The average age at diagnosis is in the fourth decade. Skin ulceration may be seen with large tumors, but this is usually due to pressure necrosis rather than invasion of the skin by malignant cells. Histologically, phyllodes tumor, like fibroadenoma, is composed of epithelial elements and a connective tissue stroma.

Phyllodes tumors are classified as benign, borderline, or malignant on the basis of the nature of the tumor margins (pushing or infiltrative) and presence of cellular atypia, mitotic activity, and overgrowth in the stroma. There is disagreement about which of these criteria is most important, although most experts favor stromal overgrowth. The percentage of phyllodes tumors classified as malignant ranges from 23% to 50%. Local excision to negative margins is an appropriate management strategy for both benign and malignant phyllodes tumors if this can be accomplished with a satisfactory cosmetic outcome. The optimal margin width is not known, but wider excisions appear to reduce the risk of LR. Approximately 20% of phyllodes tumors recur locally if excised with no margin or a margin of a few millimeters of normal breast tissue, regardless of whether they are benign or malignant.302 In a review of 821 patients with nonmetastatic malignant phyllodes tumors reported to the Surveillance, Epidemiology, and End Results registry between 1983 and 2002, 52% were treated with mastectomy and the remainder with local excision. The 10-year cause-specific survival was 89%, and no survival benefit for mastectomy was observed.302

The role of RT and systemic therapy in phyllodes tumor is unclear. RT is not used for benign or borderline lesions, but has been combined with wide excision in the management of malignant phyllodes tumors. When phyllodes tumors metastasize, they tend to behave like sarcomas, with the lung as the most common site. Axillary metastases are seen in <5% of cases, and axillary surgery is not indicated unless worrisome nodes are clinically evident. When systemic therapy is used for malignant phyllodes tumors, treatment is based on the guidelines for treating sarcomas.

Locally Advanced Breast Cancer and Inflammatory Breast Cancer

LABC and IBC refer to a heterogeneous group of breast cancers without evidence of distant metastases (M0) and represent only 2% to 5% of all breast cancers in the United States. The term LABC encompasses patients with (1) operable disease at presentation (clinical stage T3N1), (2) inoperable disease at presentation (clinical stage T4 and/or N2-3), and (3) IBC (clinical stage T4dN0-3, also inoperable). (All stages refer to the AJCC Cancer Staging Manual, seventh edition, 2010).79 Subdividing patients into these three broad groups facilitates clinical management.

Comparison of studies of LABC and IBC is problematic due to a high degree of heterogeneity within T and N classification, small numbers of patients in stage subgroups, and variation in the definition of LABC according to AJCC staging criteria over time.79 For example, supraclavicular lymphadenopathy, now classified as N3 disease, was previously classified as M1.303 IBC accounts for 1% to 5% of all cases of breast cancer in the United States and is an aggressive variant of LABC. IBC is a clinicopathologic entity characterized by diffuse erythema and edema (peau d’orange) of the skin of the breast, often without a discreet, underlying palpable mass, although the breast is usually diffusely thickened. IBC typically has a rapid onset and is often initially mistaken as infection and treated with antibiotics before the diagnosis is established. The clinical presentation results from tumor emboli in the dermal lymphatics. According to the AJCC staging rules,79 IBC is primarily a clinical diagnosis. Involvement of dermal lymphatics in the absence of clinical findings does not indicate IBC. A skin biopsy may be performed to confirm the clinical impression of IBC, but the absence of dermal lymphatic involvement does not affect staging. IBCs are more likely to be high-grade, HER2-overexpressing, and lacking in hormone receptor expression compared with other presentations of breast cancer. Because both LABC and IBC are associated with substantial risk of metastatic disease, patients with these cancers should undergo full workup for distant metastases prior to initiation of therapy.

Patients with LABC or IBC should be evaluated by a multidisciplinary team (ideally, around the time of diagnosis). Treatment typically includes neoadjuvant chemotherapy, surgery, and RT. Prior to the use of neoadjuvant chemotherapy, long-term survival was uncommon. Long-term survival has been greatly improved with aggressive trimodality treatment. As with early-stage breast cancer, biologic tumor markers should affect treatment selection: patients with HER2+ cancers should receive trastuzumab-based therapy, and patients with hormone receptor–positive cancers should receive adjuvant endocrine therapy. Anthracycline- and taxane-based chemotherapy regimens are appropriate as induction chemotherapy for women with LABC or IBC. The vast majority of patients will have clinical response to therapy, and roughly 15% to 25% will experience a pCR. The addition of paclitaxel to anthracycline-based therapy appears to improve long-term disease outcomes for women with LABC and IBC.304 There are no studies of trastuzumab specifically for LABC/IBC; however, by extrapolation of results using trastuzumab for early-stage breast cancer, it should be incorporated into the treatment of women with HER2+ LABC or IBC. As with other experiences using neoadjuvant chemotherapy, complete pathologic eradication of the tumor is associated with superior outcomes among women with LABC or IBC.305 However, even among patients with pCR to neoadjuvant chemotherapy, those with LABC or IBC at baseline have a higher risk of recurrence than patients with earlier-stage breast cancer at baseline.306 Patients with LABC or IBC should be routinely treated with postmastectomy RT, regardless of the pathologic response.307

Some women with LABC may be candidates for BCT following neoadjuvant chemotherapy. In one series, local-regional control following this approach appeared to be excellent except in patients with one or more of the following features: (1) clinical N2-3 disease, (2) lymphovascular invasion, (3) residual primary pathologic size >2 cm and (4) multifocal residual disease.308 However, there is still limited experience with this approach. In contrast, BCT is contraindicated in patients with IBC, even after a complete clinical response to neoadjuvant therapy. In a small study of 13 patients with IBC treated with preoperative chemotherapy and BCT, 7 of 13 experienced LR.309 This, coupled with the diffuse nature of IBC, indicates that BCT is contraindicated in women with this diagnosis.

Although most women have a clinical response to neoadjuvant chemotherapy, some patients will experience tumor progression or remain inoperable. Such patients may be candidates for non–cross-resistant chemotherapy or novel treatments. Surgery is contraindicated in IBC unless there is complete resolution of the inflammatory skin changes. In modern studies, 85% to 90% of patients become operable after initial chemotherapy.310 RT may facilitate conversion of inoperable to operable disease. Despite modern multimodality therapy, approximately 20% of patients with IBC treated with chemotherapy, surgery, and RT will experience LRR.310 Patients with chest wall recurrence after chemotherapy, surgery, and RT are at high risk for both extensive local-regional tumor spread and for developing metastatic disease to visceral organ sites, and are treated according to guidelines for metastatic breast cancer.

MANAGEMENT OF LOCAL-REGIONAL RECURRENCE

LRR after primary therapy for breast cancer includes in-breast recurrence after BCS, chest wall recurrence after mastectomy, and regional nodal recurrences, and accounts for about 15% of all breast cancer recurrences.107 Predictors of LR include higher initial tumor stage, young patient age involved, surgical margins, and intrinsic subtype (greater risk with basal-like, luminal B, or HER2+ cancers). More than 60% of patients with LRR after either BCT or mastectomy will eventually develop metastatic disease.311,312 Short disease-free intervals, lymph node recurrence, skin lesions, and tumor lack of ER expression all portend greater risk of disseminated cancer. Patients with LRR warrant comprehensive restaging to exclude concurrent metastatic disease.

Despite the high-risk nature of LRR, patients are treated with curative intent in multidisciplinary fashion, with treatment plans individualized based on the nature of the LRR, prior local therapy, and prior adjuvant systemic therapy. The initial management step is usually surgical resection. Women previously treated with BCS are offered salvage mastectomy. Patients with localized chest wall recurrences should undergo surgical excision, while ALND is indicated for axillary nodal recurrences occurring after sentinel lymph node biopsy. RT to sites of regional recurrence and additional regional lymph nodes is standard. Patients with prior RT after either BCS or mastectomy need careful planning to minimize overlap with prior RT fields.

Current treatment standards for LRR recommend introduction of systemic therapy following local management. Recurrences that are ER+ warrant introduction or switching of endocrine therapy. Patients with recurrence on tamoxifen should consider treatment with AIs. Patients who have recurrences on AI therapy may consider tamoxifen or fulvestrant. Patients with HER2+ tumors should consider initiation or re-institution of anti-HER2 therapy in an adjuvant fashion. The role of chemotherapy in the management of LRR has been controversial, especially among those previously treated with adjuvant chemotherapy. The Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer study was a randomized trial of “adjuvant” chemotherapy following optimal resection of LRR.313 Chemotherapy reduced the risk of subsequent cancer recurrence and improved OS, especially in ER tumors, though modest benefits were seen among patients with ER+ tumors. Patients without prior chemotherapy exposure would be suitable for any standard adjuvant chemotherapy regimen. Those patients with prior chemotherapy treatment may consider nonoverlapping regimens.

METASTATIC DISEASE

Metastatic (stage IV) breast cancer is defined by tumor spread beyond the breast, chest wall, and ipsilateral regional lymph nodes. The most common sites for breast cancer metastasis include the bone, lung, liver, lymph nodes, chest wall, and brain. However, case reports have documented breast cancer dissemination to almost every organ in the body. Hormone receptor–positive tumors are more likely to spread to bone as the initial site of metastasis; hormone receptor–negative and/or HER2+ tumors are more likely to recur initially in viscera.314 Lobular (as opposed to ductal) cancers are more often associated with serosal metastases to the pleura and abdomen. Most women with metastatic disease will have been initially diagnosed with early-stage breast cancer, treated with curative intent, and then experience metastatic recurrence. Only about 10% of patients with newly diagnosed breast cancer in the United States have metastatic disease at presentation; this proportion is far higher in areas where screening programs are not available.

Symptoms of metastatic breast cancer are related to the location and extent of the tumor. Common symptoms or physical examination findings include bone discomfort, lymphadenopathy, skin changes, cough or shortness of breath, and fatigue. These clinical findings are all nonspecific, and appropriate evaluation is warranted in patients with breast cancer with new or evolving symptoms. In some cases, physical examination or radiologic findings will demonstrate unequivocal evidence of metastatic breast cancer. In instances when radiologic or clinical findings are equivocal, tissue biopsy is imperative. If a biopsy is performed, ER, PR, and HER2 should be redetermined.

The treatment goals in women with advanced breast cancer include prolongation of life, control of tumor burden, reduction in cancer-related symptoms or complications, and maintenance of quality of life and function. Therapy is not generally considered curative. A small fraction of patients, often those with limited sites of metastatic disease or bearing tumors with exquisite sensitivity to treatment, may experience very long periods of remission and tumor control. Treatment of metastatic breast cancer, like treatment of early-stage breast cancer, is based on consideration of tumor biology and clinical history. Thus, characterization of tumor ER, PR, and HER2 status is critical for all patients, and a detailed assessment of past treatment, including timing of therapies as well as patient symptoms and functional assessment, is essential. Patients with endocrine-sensitive tumors, particularly those with minimal symptoms and limited visceral involvement, are candidates for initial treatment with endocrine therapy alone; initial treatment using combined chemoendocrine therapy has not been shown to improve survival compared with sequential treatment programs. Patients with hormone receptor–negative tumors or those with hormone receptor–positive tumors progressing despite the use of endocrine therapy are candidates for chemotherapy. If the tumor is HER2+, then anti-HER2 treatment is employed in combination with chemotherapy.

Well-established clinical factors can inform the likelihood of response to therapy and long-term outcomes in women with metastatic breast cancer. Patients who have received less therapy, a longer disease-free interval since initial diagnosis, soft tissue or bone metastases, fewer symptoms and better performance status, and tumors that are hormone receptor–positive or HER2+ are likely to experience longer survival with metastatic disease than more heavily treated patients with shorter intervals since treatment, visceral metastases, and greater symptoms.

In clinical trials, the measured end points for defining efficacy of therapy for metastatic breast cancer are response rate, time to tumor progression, and OS. These landmarks are important for guiding clinical practice as well, although formal measures of response/progression are often difficult to apply owing to inconsistencies in imaging studies, the prevalence of nonmeasurable disease such as bone lesions, subcentimeter tumor deposits, and pleural effusions or ascites. The art of treating patients with metastatic breast cancer involves careful, thoughtful repetition of a process of treatment initiation, evaluation including assessment of patient functional status and symptom profile, and serial measurement of tumor burden and response to therapy, through multiple lines of therapy. Clinical guidelines for the management of metastatic carcinoma66 are often quite open-ended, acknowledging the multiple treatment pathways that might be legitimately pursued, arguing for judicious use of clinical decision making and treatment selection based on tumor biology, and focusing clinicians on the continuous considerations of patient preference and illness experience.

Endocrine Therapy for Metastatic Breast Cancer

Endocrine treatment is a key intervention for women with hormone receptor–positive, metastatic breast cancer. Table 37.23 lists available endocrine drugs for treating advanced breast cancer. Single-agent therapy is the standard approach; combining endocrine agents has not in general been shown to improve outcomes. Many women will be candidates for multiple lines of endocrine therapy to control metastatic breast cancer. On average, first-line treatment is associated with 8 to 12 months of tumor control, and second-line treatment with 4 to 6 months. Individual patients may experience substantially longer time to progression. Sequential single-agent second- and third-line endocrine treatments are often effective, although typically for shorter durations than initial therapy. Patients with either overt tumor shrinkage or stabilization of disease in response to endocrine treatment can have equivalent long-term tumor control. Endocrine therapy can cause regression of soft tissue and bone and visceral metastases.

Recently, several studies have examined the combined use of an AI with fulvestrant for de novo or progressive, ER+, metastatic breast cancer.315317 In treatment-naïve patients, the SWOG 0226 trial suggested that combining anastrozole with fulvestrant improved progression-free survival and OS. By contrast, in patients who had received prior tamoxifen in the SWOG and Fulvestrant and Anastrozole Combination Therapy trials, or prior AI therapy in the Study of Faslodex vs Exemestane with/without Arimidex trial, the combination of fulvestrant plus an AI was not superior to monotherapy approaches. Thus, the combined use of an AI with fulvestrant is appropriate primarily among women with endocrine-naïve cancers.

Eventually, most women with hormone receptor–positive metastatic breast cancer will progress despite first-line endocrine therapy, and be candidates for second-, third-, and even subsequent lines of endocrine therapy. Resistance to treatment does not seem to be associated with loss of hormone receptor expression by the tumor cells. The results of the Breast Cancer Trials of Oral Everolimus-2 trial have recently led to the approval of the mammalian target of rapamycin inhibitor everolimus in the advanced setting.318 In this randomized clinical trial, patients with advanced disease resistant to letrozole or anastrozole were assigned to exemestane plus everolimus or placebo. The combination of exemestane and everolimus extended progression-free survival, but was associated with significant side effects, including stomatitis, hyperglycemia, and pneumonitis.

Indications for chemotherapy include symptomatic tumor progression, pending visceral crisis, or resistance to multiple endocrine therapies. Patients presenting with extensive visceral metastases or profound symptoms from breast cancer may benefit from induction chemotherapy, which should then be followed with endocrine therapy.

Tamoxifen was the historic standard as treatment for ER+ metastatic breast cancer, associated with a 50% response rate and median duration of response of 12 to 18 months among treatment-naïve patients. A “tamoxifen flare” reaction, typically characterized by intensification of bone pain, transient tumor progression, and hypercalcemia, can arise in 5% to 10% of patients within the first days or weeks of tamoxifen treatment. Flare reactions are often harbingers of exquisite tumor sensitivity to endocrine manipulation, but must be distinguished from overt tumor progression. Flare reactions are not frequently seen with other endocrine therapies.

In premenopausal women with metastatic breast cancer, combined endocrine therapy with ovarian suppression and tamoxifen can improve survival compared with treatment with either tamoxifen or ovarian suppression alone.319Thus, the first intervention for premenopausal women with breast cancer recurrence is ovarian suppression or ablation, with initiation of tamoxifen treatment. Premenopausal women with metastatic tumor despite tamoxifen use are candidates for ovarian suppression/ablation and AI therapy. Postmenopausal women are candidates for either tamoxifen, AIs, fulvestrant, or progestational agents as palliation for metastatic breast cancer. AIs appear to be the preferred initial agents for women who received prior tamoxifen treatment in the adjuvant setting,319,320 and may have modest clinical advantages over tamoxifen as initial treatment for metastatic disease.321,322 Fulvestrant appears to have comparable activity to AIs in women previously treated with tamoxifen.323,324

The optimal sequencing of endocrine therapy for postmenopausal women treated with adjuvant AIs is not clear, as few trials have rigorously explored different treatments among such patients. Tamoxifen, fulvestrant, progestins, and possibly different AIs are all reasonable options among such patients.

Chemotherapy for Metastatic Breast Cancer

Cytotoxic chemotherapy remains a mainstay of treatment for women with metastatic breast cancer, irrespective of hormone receptor status, and is the backbone of many novel treatments incorporating biologic therapy.325Chemotherapy has substantial side effects, including fatigue, nausea, vomiting, myelosuppression, neuropathy, diarrhea, and alopecia, making for tradeoffs between cancer palliation and toxicities of therapy. Chemotherapy is used in patients with hormone-refractory or hormone-insensitive tumors.

Tumor response to chemotherapy is a surrogate for longer cancer control and survival.326,327 First-line chemotherapy is associated with higher response rates and longer tumor control than second-line, and so forth. There are relatively few studies of fourth or higher lines of chemotherapy, although patients often receive many lines of treatment. Trials have demonstrated palliative benefits of chemotherapy in patients with refractory tumors receiving third-line or subsequent chemotherapy treatment, but the magnitude of such gains must be realistically weighed against the side effects of treatment. Chemotherapy treatment can be interrupted in patients who have had significant response or palliation following initiation of therapy and reintroduced when there is tumor progression or symptom recurrence.

Since the advent of chemotherapy administration for metastatic breast cancer, it has been debated whether single-agent sequential treatment or combination treatment with multiple agents is the best strategy. Combination chemotherapy may be associated with higher response rates and improved time to progression compared with single-agent therapy. However, studies that have specifically planned for crossover treatment with second-line sequential therapy have not shown improved survival compared with a sequential treatment program.328 Patients with extensive visceral disease or pending visceral crisis may preferentially require initiation of combination chemotherapy, but this has not been demonstrated in prospective studies. Because single-agent chemotherapy facilitates better understanding of which drugs are contributing to benefit or side effects and is generally associated with less toxicity, it remains the preferred approach.

A large number of chemotherapy agents and combinations are effective in treatment of metastatic breast cancer (Table 37.24).66 A variety of specific drugs and combinations are considered preferred based on a large historical experience, results from randomized trials, and consideration of toxicity profiles. A single “best” approach for all patients with metastatic cancer is not supported by the literature. Although anthracycline- and taxane-based treatments are generally considered to be among the most active in treatment of metastatic breast cancer, their utility has led to their incorporation into adjuvant chemotherapy regimens. Thus, many women with metastatic breast cancer will already have been treated with anthracyclines and/or taxanes, diminishing the utility of these agents in the palliation of metastatic disease.

Capecitabine is an orally available fluoropyrimidine, metabolized in tissues into 5-fluorouracil. Capecitabine has clinical activity in anthracycline- and taxane-resistant breast cancer,329 and improves response and survival as first-line treatment when added to single-agent docetaxel.329 The antimetabolite gemcitabine similarly yields higher response rates and survival when paired with paclitaxel compared with paclitaxel therapy alone.330 Ixabepilone, an epothilone chemotherapy agent, has substantial activity as a single agent or in combination with capecitabine in patients previously treated with anthracyclines and taxanes.331,332 Eribulin, a synthetic analog of halochondrin B, is a nontaxane microtubule dynamics inhibitor that was evaluated against physician’s choice of chemotherapy in a randomized phase 3 study, the 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event trial,333 and led to improved OS in patients with locally recurrent or metastatic breast cancer with at least two prior regimens.

Dose escalation of taxane therapy with paclitaxel has not been shown to result in clinically important improvements. However, weekly administration of paclitaxel therapy does appear to improve response rate and time to progression compared with less frequent, every-3-week administration.334,335

As a strategy to overcome chemotherapy resistance, many investigators in the 1990s explored high-dose chemotherapy with autologous bone marrow or stem cell support as treatment for breast cancer. Preliminary studies suggested favorable clinical outcomes, prompting both widespread use of high-dose chemotherapy in clinical practice and randomized trials for patients with either metastatic or high-risk, node-positive breast cancer. Despite initial hopes, clinical trials found no difference in outcome between standard chemotherapy followed by treatment with either high-dose chemotherapy and autologous stem cell rescue or maintenance chemotherapy at conventional doses.336There is no current role for bone marrow or stem cell transplant in management of either early- or late-stage breast cancer.

Anti-HER2 Therapy for Metastatic Breast Cancer

First-Line Treatment

Just as hormonal therapy radically alters that natural history of ER+ metastatic breast cancer, so has anti-HER2 treatment revolutionized outcomes for patients with HER2+ breast cancer. Trastuzumab, the humanized anti-HER2monoclonal antibody, was the first anti-HER2 agent to enter clinical practice. When added to first-line chemotherapy for HER2+ metastatic breast cancer, trastuzumab improved response rates, time to progression, and OS.337,338Cardiomyopathy is a known side effect of trastuzumab therapy, and concurrent administration of trastuzumab and anthracyclines should be avoided. Serial determinations of left ventricular ejection fraction should be performed to screen for changes related to trastuzumab.339

Pertuzumab is a different anti-HER2 antibody than trastuzumab, which binds to both HER2 and HER3 proteins, and is believed to prevent dimerization of those receptors. Clinically, the activity of pertuzumab seems dependent on coadministration of trastuzumab.340 The Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer study compared docetaxel/trastuzumab versus docetaxel/trastuzumab/pertuzumab as first-line treatment for HER2+ breast cancer, and showed improvement in both progression-free survival and OS with the addition of pertuzumab.341

As the first anti-HER2 agent, trastuzumab has served as the model for treatment principles for anti-HER2–based therapy. While responses can be seen with either single-agent trastuzumab or trastuzumab plus pertuzumab anti-HER2 therapy,340,342 the major benefits of these therapies have only been proven in combination with chemotherapy. The addition of anti-HER2 treatments to endocrine therapy yields modest improvements in progression-free survival.343,344 After an induction phase of therapy, the chemotherapy can be withheld, and endocrine therapy initiated (if appropriate), while continuing maintenance treatments with the antibodies. Currently, data for use of pertuzumab and trastuzumab are limited to concurrent administration with taxane-based chemotherapy. A variety of chemotherapy agents have shown clinical activity and safety when paired with trastuzumab, including taxanes, vinorelbine, and platinum analogs.

Refractory, HER2+ Breast Cancer

A variety of clinical approaches are used to treat trastuzumab-refractory, HER2+ metastatic breast cancer. Continuation of trastuzumab treatment beyond progression is associated with improvements in time to progression,344,345 and justifies the practice of continued anti-HER2 blockade in association with multiple lines of treatment for HER2+ metastatic breast cancer. Lapatinib is a dual-kinase inhibitor that targets both the HER2 and EGFR tyrosine kinase signaling pathways. Lapatinib has been studied as second-line anti-HER2 therapy for patients progressing after chemotherapy and trastuzumab.346 In comparison with the administration of capecitabine chemotherapy alone, the combination of lapatinib plus capecitabine was associated with a longer period of tumor control and improvement in response rate, but not survival.

Trastuzumab emtansine (TDM1) is a novel antibody-drug conjugate in which the trastuzumab antibody has been linked chemically to a potent chemotherapy moiety. The resulting conjugated antibody has been shown to have substantial activity in trastuzumab-refractory breast cancer, without the traditional side effects of chemotherapy, such as neutropenia or alopecia.347 In a randomized trial of trastuzumab-resistant breast cancer, TDM1 was found to be superior to the combination of lapatinib/capecitabine with respect to progression-free survival, OS, and tolerability.348 A study of first-line therapy for HER2+breast cancer found that TDM1 was more effective than docetaxel/trastuzumab, and led to dramatic improvements in quality of life.349 Ongoing studies are examining the combination of TDM1 with pertuzumab, and assessing whether treatment beyond progression will prove clinically valuable.

Patients with HER2+ metastatic breast cancer continue to receive clinical benefit from multiple lines of anti-HER2 therapy,350 and can have tumor responses even following progression on TDM1.351

Emerging Options for BRCA1- or BRCA2-Associated Breast Cancer

A novel class of therapeutics, drugs that inhibit the poly(adenosine diphosphate-ribose) polymerase (PARP) enzyme, are emerging as potentially valuable drugs in treatment of advanced breast cancer, particularly in hereditary breast cancer. In a proof of principle open-label phase 2 study, the PARP inhibitor olaparib was studied in patients with BRCA1- or BRCA2-associated cancers. This select group of patients was chosen because of preclinical data that suggested that tumors with BRCA deficiency might be particularly dependent on the DNA repair function of the PARP enzyme complex, and thus suitable targets for PARP inhibition. Initial observations have suggested robust responses among BRCA-associated breast cancers when patients are given single-agent therapy with olaparib.352,353 In addition to PARP inhibitors, platinum-based chemotherapy may have a clinical role in hereditary breast cancers. Limited experience using platinum-based chemotherapy as neoadjuvant treatment for early-stage breast cancer has shown dramatic rates of pCR.354 It remains unclear how important these findings are for either the long-term natural history of BRCA-associated breast cancer or treatment of metastatic disease.

Treatment of Special Metastatic Sites in Patients with Breast Cancer

Specialized treatment options are available for patients with breast cancer with metastases to selective anatomic sites. Patients with lytic bone metastases should receive bone targeted therapy either with intravenous bisphosphonate therapy, such as pamidronate or zoledronic acid, or the RANK-ligand inhibitor, denosumab.355 These agents lessen the pain associated with bone lesions and prevent complications of skeletal metastases, including fracture and hypercalcemia.356 Extended therapy can be associated with osteonecrosis of the jaw, so patients should be monitored for atypical oral lesions. Patients with focal pain at sites of skeletal metastases, pending fracture, or pathologic fracture may also benefit from external-beam RT at selected tumor sites and, when necessary, surgical stabilization or repair of the bone or joint.

Improvements in survival in metastatic breast cancer achieved through chemotherapy and trastuzumab-based treatment have led to an increase in the incidence of central nervous system metastases, especially those with HER2-overexpressing or hormone receptor–negative tumors.357 Therapy for brain metastases remains inadequate, but generally includes WBI. Patients with isolated lesions, dominant masses, or recurrence after WBI may additionally be candidates for surgical resection or stereotactic RT to specific lesions. Patients with leptomeningeal disease may achieve symptomatic improvement with WBI or, in some cases, intrathecal chemotherapy with methotrexate or cytarabine. Very limited clinical experience suggests that some systemic therapies, including endocrine treatments, chemotherapy agents including anthracyclines, alkylators, and capecitabine, and lapatinib, may have antitumor activity in the brain.358 However, none of these are a substitute for local therapy to the brain.

Some patients with breast cancer will have limited sites of metastatic disease, such as isolated pulmonary nodules, isolated contralateral lymph node recurrence, or bone lesions. Single-institutional experience from the MD Anderson Cancer Center suggests that a fraction of such patients may be treated “aggressively” with curative intent, with favorable long-term results.359 In a cohort of patients without previous adjuvant therapy and with oligometastatic disease that could be definitively treated with local therapy, “stage IV–NED” (no evidence of disease) the use of adjuvant chemotherapy, and, where appropriate, endocrine therapy resulted in 25% to 30% of patients remaining free of further recurrence through 10 years of follow-up.359

The treatment of the primary tumor in the breast in women who present with metastatic disease is another area of controversy. Historically, surgery or RT to the breast was limited to patients with local tumor complications, such as pain or skin erosion, and systemic drug therapy was the primary form of treatment. An analysis of 16,023 patients presenting with stage IV disease and an intact primary tumor compared outcomes between patients having surgery of the primary tumor to negative margins or no surgery. In a multivariate analysis adjusting for known prognostic factors, surgery reduced the HR for death to 0.61 (95% CI = 0.58 to 0.65).83 Multiple other retrospective studies from single institutions, registries, and population-based cohorts have confirmed this initial observation, but it is uncertain whether these studies reflect a real benefit for surgery or consistent selection bias. Three prospective randomized trials are examining the role of surgery in patients presenting with stage IV disease and an intact primary tumor. While awaiting the results of these trials, it is not known precisely how or when to integrate such surgical management into standard medical therapy for metastatic breast cancer or which patients in particular are most likely to benefit from such treatment. Local therapy should not be used as an initial approach to the patient with metastatic disease, but may be considered in a highly selected group of patients with a good response to systemic therapy and a limited number of metastatic sites.

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