Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

9. Carcinoma of the Breast

Patrick Glyn Morris and Clifford A. Hudis

I. NATURAL HISTORY, EVALUATION, AND MODES OF TREATMENT

A. Epidemiology and risk factors

Carcinoma of the breast gave way to carcinoma of the lung as the most common cause of cancer deaths among women in the United States in 1986. Despite a decline in incidence since 2003, in 2009, more than 192,000 new cases of breast cancer were diagnosed, and there were about 40,000 women who died from this disease. Currently, more women survive due to earlier diagnosis and better therapy, and the absolute number of deaths per year has been declining since about 1990 with a disease-specific mortality decrease of 2.2% per year since then.

The incidence of breast cancer varies widely among different populations. Women in Western Europe and the United States have a higher incidence than women in most other parts of the world, possibly in part because of the high intake of animal protein, fat, and probably linked to total caloric intake and increased rates of obesity. Caucasian women in the United States are more likely to develop breast cancer compared with African-American women. Mortality from breast cancer, however, is higher in African-American women than other ethnic or racial groups, although this is confounded by the general increase in cancer-related mortality for lower socioeconomic groups regardless of specific ethnicity. While discrete causes of breast cancer cannot be identified in most individual women, many factors increase a woman’s risk of developing the disease. Among the strongest of the risk factors is family history, particularly if more than one family member has developed breast cancer at an early age. More precisely, genetic linkage analysis led to the discovery of dominant germ-line mutations in two tumor-suppressor genes, BRCA1 and BRCA2, localized to chromosomes 17 and 13, respectively, which are associated with a high risk of female breast cancer as well as ovarian cancer (BRCA1 and BRCA2), male breast cancer (BRCA2), and other cancers. Although these mutations account for less than 10% of all cases of breast cancer, together they may account for over 70% of inherited cases in high-risk populations. It is important to note that most patients with a family history of breast cancer do not have a defined inherited mutation and other, less common, causative mutations are sometimes seen. However, if a woman with breast cancer is under the age of 50 years and has any relative who developed breast cancer before she was 50 years old, her chance of having a mutation in BRCA1 or BRCA2 rises to as much as 25%. Other factors that increase her probability of a mutation include any relative with ovarian cancer or a personal history of bilateral breast cancer or ovarian cancer. Carriers of these mutations have up to a 70% lifetime risk of breast cancer, depending on familial history, perhaps the specific mutation, and other cellular genes that may modify penetrance. The 5-year survival rate of patients with either of the BRCA mutations is not significantly less than for other patients with breast cancer after adjusting for the specific subtypes of breast cancer carriers tend to develop. Additional factors that increase breast cancer risk are early menarche, late age at birth of first child, and prior benign breast disease (particularly if there is a high degree of benign epithelial atypia). Present use of birth control pills appears to have a small effect on the risk of developing breast cancer (relative risk, 1.24); risk from prior use diminishes over time. Although breast cancer may occur among men, such cases represent less than 1% of all breast cancers and are infrequently seen in most hospitals. Male carriers of BRCA2 mutations have a 6% lifetime risk of breast cancer, significantly increasing their risk in comparison to the general population.

Hormone replacement therapy (HRT) can increase the risk of breast cancer. In the Women Health Initiative study, researchers found an increased breast cancer risk of about 10% for every 5 years of HRT use. There was a greater risk with combined estrogen/progesterone products than with estrogen therapy alone; following the publication of this report, there was a marked decrease in the use of HRT followed in short order by a decline in the incidence of postmenopausal hormone-receptor–positive breast cancer.

B. Prevention

The risk of hormone-receptor–positive breast cancer can be reduced. At least three trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3 to 5 years of preventive treatment with these agents reduces the rate of breast cancer development over the short term. Women at increased risk because of family history, age, and other risk factors, who are treated with the SERM tamoxifen, 20 mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast cancer compared with women treated with placebo. Noninvasive disease and preneoplastic breast lesions were also decreased. Raloxifene, 60 or 120 mg/day, also appears to reduce the risk of breast cancer in postmeno-pausal women (who had osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of 0.26. Despite these benefits, SERMs are associated with an increased risk of both venous thromboembolism and endometrial cancer, although the risks with raloxifene appear to be lower than tamoxifen, which has been associated with an increased risk for endometrial cancer of1.5 to 2 times that of untreated women. In addition, neither of these agents has demonstrated an improvement in survival when used for breast cancer prevention. In the Study of Tamoxifen against Raloxifene trial, these agents were compared and raloxifene was found not to decrease the incidence of preinvasive carcinomas despite a seemingly better outcome than tamoxifen for prevention of invasive cancers. Lasofoxifene, in a trial addressing osteoporosis, similarly reduced the incidence of breast cancer. These agents have similar but not identical toxicity profiles that may guide clinical decisions.

There are several options in the management of women at very high risk because of family history or known gene mutations. Increased surveillance, through the addition of magnetic resonance imaging (MRI) screening on a yearly basis as a supplement to standard mammography, was effective in a high-risk population. In mutation carriers who are at risk for both breast and ovarian cancer, bilateral oophorectomy after childbearing age has been recommended because of the inadequacy of screening tests for ovarian cancer and because it reduces the risk of primary breast cancer. Risk-reducing mastectomy is an effective option with a relative risk reduction of about 90%. Note that despite risk-reducing mastectomy, there is always a small risk of breast cancer in residual breast glandular tissue. SERMs may be useful in patients with BRCA1 and BRCA2 mutations as well. Analysis of blood samples of women who participated in the P-01 (tamoxifen) trial showed that mutation carriers also had a 47% lower risk of breast cancer.

C. Detection, diagnosis, and pretreatment evaluation

1. Screening. Because more lives can be saved if breast cancer is diagnosed at an early stage, many screening programs have been designed to detect small, early cancers. Monthly breast self-examination for all women after puberty and yearly breast examinations by a physician or other trained professional after a woman is 20 years of age is generally recommended, although evidence of effectiveness is limited. Mammography reduces breast cancer mortality by 25% to 30% in women older than 50 years. The benefit for women aged 40 to 50 years has been more difficult to demonstrate because the incidence of breast cancer is lower. Hence, more examinations are needed to find a cancer and save a life. However, additional benefits of early detection via mammography include the option for less disfiguring surgery, reduced utilization of radiation therapy, and decreased need for chemotherapy and other systemic treatments. Therefore, the absolute benefits extend beyond the simple end-point of survival. As a result, mammography is recommended at age 40 years as a baseline, once every 1 to 2 years between the ages of 40 and 50 years (depending on risk factors and the recommending organization), and yearly after 50 years of age. An upper age of effectiveness is not established. For high-risk women and in family members of mutation-positive patients, annual mammography should be initiated 10 years earlier than the youngest diagnosed relative. Patients with Hodgkin lymphoma (regardless of a history of mantle field irradiation) should have a baseline mammogram by age 25. In BRCA1/ BRCA2 mutation carriers, MRI of the breast has recently been approved for screening in addition to annual mammography. Mammography has clearly led to the discovery of many earlier cancers and sharply increased the discovery of preinvasive cancers (ductal carcinoma in situ). These latter are not (yet) invasive and their treatment can be far less complicated than that of invasive breast cancer. Other screening modalities can include ultrasound, but it is more typically used diagnostically to evaluate palpable lesions.

2. Presenting signs and symptoms. Although a large number of non-palpable cancers are found by mammography, invasive breast cancer is still often discovered by a woman herself as an isolated, painless lump in the breast. If the mass has gone unnoticed, ignored, or neglected for a time (or if it is particularly rapidly growing or aggressive), there may be fixation to the skin or underlying chest wall, ulceration, pain, or inflammation. Some early lesions present with discharge or bleeding from the nipple. Occasionally, the primary lesion is not discovered, and the woman presents with symptoms of metastatic disease, such as pleural effusion, nodal disease, or bony metastases. About half of all lesions are in the upper outer quadrant of the breast (where most of the glandular tissue of the breast is). About 20% are central masses and 10% are in each of the other quadrants. Up to one-quarter of all women with breast cancer have axillary node metastasis at the time of diagnosis, although this is less common when the primary tumor has been detected by screening.

3. Staging. Carcinoma of the breast is staged according to the size and characteristics of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence of metastatic disease (M). An abridged version of the commonly used TNM classification of breast cancer is shown in Table 9.1, and the stage grouping is outlined in Table 9.2. In 2010, the revised American Joint Commission on Cancer staging system for breast cancer was published. Although preliminary staging is commonly done before surgery, definitive staging that can be used for prognostic and further treatment planning purposes usually must await post-surgical pathologic evaluation when the primary tumor size and the histologic involvement of the lymph nodes are established. In up to 30% of patients with palpable breast masses (not found by mammography) but without clinical evidence of axillary lymph node involvement, the histologic evaluation of the nodes reveals cancer. In patients with negative nodes by routine histologic evaluation, serial sectioning may reveal microscopic cancer deposits in additional patients. The principal changes in the new staging system take into consideration the widespread use of immunohistochemical (IHC) and molecular biologic techniques that afford pathologists the ability to detect microscopic meta-static lesions down to the level of isolated tumor cells. It is not clear that there is prognostic value if cancer cells in nodes are detected by enhanced examination, and the current staging system designates nodes as pathologically negative if cells are identified by IHC alone and are in clusters of less than 0.2 mm. The identifier “(i)” is used to indicate isolated tumor cells such that pN0(i+) indicates node-negative disease but the presence of such cells in the node. Similarly, “(mol + )” indicates that a molecular examination such as polymerase chain reaction has found evidence of malignant cells. These changes are included in Table 9.1.

D. Diagnostic evaluation

1. Before biopsy the woman should have a careful history, during which attention should be paid to risk factors, and a physical examination, with a focus not only on the involved breast but also on the opposite breast, all regional lymph node areas, the lungs, bone, and liver. This examination should be followed by bilateral mammography to help assess the extent ofinvolvement and to look for additional ipsilateral or contralateral disease.

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2. Excisional or core needle biopsy of the primary lesion is performed, and the specimen is given intact (not in formalin) to the pathologist, who can divide the specimen for histologic examination, hormone receptor assays, and HER2 testing (by immunohistochemistry examination or fluorescence in-situ hybridization [FISH]).

3. After confirmation of the histology, the patient is evaluated for possible metastatic disease. It is important to emphasize that history and physical examination are the most critical components of this assessment.

a. Typical studies include a chest radiograph, complete blood count, and blood chemistry profile.

b. Other studies, including radionuclide scan of the bones, skeletal survey (usually obtained only if the radionuclide scan is positive), and computed tomography (CT) scan of the fiver (abdomen), are optional unless the history, physical examination, or blood studies suggest a poor prognosis or point to specific organ involvement. There is continued evolution in imaging recommendations, and recent data suggest that integrated positron emission tomography-CT may replace most or all other imaging tests.

c. Histology. About 75% to 90% of all breast cancers are infiltrating ductal carcinomas, and up to 10% are infiltrating lobular carcinomas; these two types have similar overall behavior but the latter tend to be hormone responsive and HER2-negative. In addition, their patterns of metastatic spread can vary even if the overall risks of metastases are similar. The remainder of the histologic types of invasive breast carcinoma may have a somewhat better prognosis but are usually managed more according to the stage than to the histologic type. Microarray technology has added nuance to the traditional, histology-based categorization of breast cancer and supports the view that this is a disease with distinct subtypes. About 15% of breast cancers are basal-like (basal epithelial subtype) with a relatively high concordance with the conventionally defined basal epithelial subtype) with a relatively high concordance with the conventionally defined “triple negative” (hormone-receptor and HER2-negative) subset. Luminal tumors are generally hormone receptor-positive, but it is the luminal A subtype that is most clearly hormone responsive. Triple negative tumors are seen in association with BRCA1 mutations and in women of lower socioeconomic status. Each of these subtypes (luminal A, B, basal-like, HER2-positive, etc.) is associated with a distinct typical natural history in terms of time to develop distant metastases.

E. Approach to therapy

Many institutions have established multidisciplinary teams or centers to facilitate coordinated treatment planning. It may be useful in some settings to pursue this particular clinical care structure, but there are other reasonable strategies to employ in the development of an optimal care plan for individual patients.

1. Consultation with a surgeon, radiotherapist, and medical oncologist is generally required once the diagnosis of carcinoma is suspected or histologically confirmed or after definitive surgery has been accomplished. Multimodal therapy has had a profound impact on the outcome of breast cancer as it has allowed for organ preservation and improved disease-free survival (DFS) and overall survival. Any clinician treating patients for breast cancer should be very familiar with the roles and interventions offered by the other members of the team. It is also critical to have the patient (and her family if she desires) share in the therapy decisions after hearing the options, the relative advantages and disadvantages of each approach, and the recommendations of the consultants. The patient should be given an opportunity to hear why the recommended treatment is thought by the physicians to be best and to decide whether the treatment is appropriate for her.

2. Goals of therapy differ depending on the stage of disease being treated.

a. For early-stage invasive disease, the goal of therapy is to eradicate the primary tumor and to suppress the growth of or eliminate micrometastases, thereby preventing recurrence and death. In the postoperative setting, this is called adjuvant therapy. There are three broad classes of systemic adjuvant therapy: hormone therapy (tamoxifen or, in postmenopausal women, an aromatase inhibitor), chemotherapy (any of a large number of standard combination regimens), and immunotherapy (trastuzumab for patients with HER2-positive tumors). These options are weighed and combined on an individualized basis based on careful risk-benefit analyses. Of course, while treating postoperative patients who may be cured by their surgery (and radiation therapy), we seek to avoid unnecessary short- and long-term drug-induced toxicities. Of particular concern is the increased incidence of second cancers (myelodysplasia and leukemias in particular with chemotherapy, and uterine cancer with tamoxifen) arising years after the completion of therapy. Other risks can include osteoporosis with aromatase inhibitors (AIs) and cardiac dysfunction following anthracycline or trastuzumab use. It is important to emphasize that despite these toxicities, overall survival has generally been improved in the patient populations treated with these modalities. However, one goal of ongoing investigational studies is to determine the minimum therapy that is effective for preventing the maximum number of recurrences in any given clinical situation.

b. For locally advanced disease, defined as stage IIIA or T3–4 disease or more, including inflammatory breast cancer, the goal of systemic therapy changes somewhat. In addition to critically important systemic control, there is the added potential benefit of local response facilitating less disfiguring surgery and, in some cases, any surgery. This is referred to as neoadjuvant or preoperative systemic therapy,and it specifically can reduce the size of an initially unresectable tumor or convert the planned surgical intervention from mastectomy to breast conservation. In the research setting, preoperative administration of systemic therapy allows the opportunity to test both the therapeutic efficacy of novel drugs and regimens as well as the ability to conduct correlative science studies, thereby potentially optimizing drug development.

c. For advanced (metastatic) disease, the goal of therapy is to lengthen survival when possible and to palliate or limit symptoms and signs of the disease using therapy with an acceptable toxicity profile. In this setting, long-term toxicity is not usually of great importance, but short-term toxicity is a major focus for both physician and patient because the aim of therapy is to improve how the patient feels (quality of life) as well as to prolong survival. The general approach is to use hormone therapy if possible, anti-HER2 therapies when HER2 is amplified or overexpressed in the tumor, and chemotherapy as sequential single agents. There are myriad novel targeted therapies in development and an increasing number of treatments with proven impact on overall survival.

3. Surgery remains the most frequently used mode of primary therapy for the vast majority of women with breast cancer. Over the past half century, the extent of surgery has evolved toward less disfiguring procedures. Hence, breast conservation (lumpectomy) with radiation therapy and an examination of the sentinel nodes (or in some cases, an axillary node dissection) is now routine. Surgical margins should be free of tumor, but an exact definition of the safe width is not uniformly accepted. Complete axillary node dissection is unnecessary in most cases when a sentinel node procedure, performed by an experienced surgeon, reveals no cancer. Following breast conservation (and generally after the completion of chemotherapy), radiotherapy is delivered to control any microscopic cancer remaining in the breast. The decision to radiate nodal fields varies with the stage of the cancer. In terms of distant DFS and overall survival, appropriate candidates for breast conservation have the same outcomes as if they were treated with mastectomy. Therefore, many patients opt for breast conserving surgery and radiotherapy over mastectomy. Apart from patient preference, mastectomy is indicated when the tumor is too large or locally advanced to allow breast conservation (although preoperative systemic therapy can facilitate breast conservation in this situation), if the tumor is multi-centric/multifocal, when the patient has a contraindication to radiation therapy, if it is an ipsilateral recurrence in a previously radiated breast (again, a contraindication to additional radiation therapy), or when margins free of tumor cannot be obtained.

There remain wide geographic variations in the use of breast-conserving surgery throughout the United States and without obvious medical justification. For patients who have had mastectomy, reconstruction can be accomplished by several approaches and requires a skilled plastic surgeon. It may be done at the time of mastectomy or delayed for a period (usually 1 to 2 years). There is no evidence that any (or no) reconstructive approach has any impact on the natural history of breast cancer.

4. Radiation therapy. The role of radiation therapy in the management of carcinoma of the breast has been expanded since the early 1970s. Radiotherapy is now commonly used in conjunction with breast conservation as part of the primary therapy. In this circumstance, the radiotherapy is commonly delivered to the entire breast with a boost of therapy to the tumor bed using external-beam therapy. More recently, shorter courses of external-beam radiation may be considered for treating the breast only. In addition, radiation therapy to only the affected part of the breast is now used in early-stage disease. Partial breast irradiation may be delivered by brachytherapy or focused external-beam treatment. Radiotherapy may also be employed following mastectomy in women who have a particularly high likelihood of local recurrence. When the risk of local recurrence is high, radiation therapy is associated with improved overall survival. Typically, postmastectomy radiation is indicated if the primary tumor is larger than 5 cm or if four or more positive lymph nodes were found in the axilla, although there is potential benefit on survival even in lower risk patients, such as those with one to three positive axillary lymph nodes. Following breast conservation, radiation may be omitted in patients older than 70 years of age with estrogen receptor–positive tumors smaller than 2 cm if they are treated with antiestrogen therapy. However, with longer follow-up, an increase in breast recurrences is found without radiation, but with no detectable impact on survival. Radiation therapy is generally administered after completion of cytotoxic therapy (when indicated). Radiation therapy is also helpful as adjunctive therapy for metastatic or locally advanced and unresectable disease. Local recurrences and isolated or specific (e.g., painful bone lesions particularly with impending fracture) distant metastases also are frequently treated successfully with radiotherapy.

5. Systemic therapy is used to reduce the likelihood of recurrence after local therapy for early-stage disease and to treat more advanced disease with or without distant metastasis. For operable (curable) breast cancer, The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) analysis of adjuvant therapy demonstrates a clear benefit of postoperative chemotherapy or hormonal therapy (including ovarian ablation in premenopausal women). Although the precise estimates of benefit vary with each half-decade review and update, in very general terms systemic therapy reduces the risk of recurrence by as much as 50%. Similarly, the odds of death are also reduced by as much as 30%. Similar proportional risk reductions are seen in node-positive as well as node-negative disease with the proviso that lower risk disease yields proportionately smaller absolute benefits for therapy. Historically, medical oncologists relied on node status, tumor size, hormone receptor status, HER2 status, and perhaps DNA synthesis rate (percentage of cells in the synthesis phase), as well as any of a number of other factors to aid in determining risk for individual patients so that the oncologists could then estimate the benefits of specific systemic therapies and guide patients. More recently, commercially available tests that provide prognosis, or more importantly, prediction of benefit for specific systemic therapies, have become available. As always, physiologic age of the patient and comorbid conditions are also important considerations in adjuvant therapy decisions.

6. Endocrine therapy includes surgical, radiotherapeutic, or drug-induced ablation or inhibition of ovarian function. It also includes antiestrogens (typically SERMs), aromatase inhibitors, progestins, androgens, and even corticosteroids. Tumors with no expression of either the estrogen or the progesterone receptor will generally not respond to hormone therapies, and the greater the expression of these receptors the greater the probability of benefit. However, there is no clear threshold (above zero) below which one can be certain that endocrine therapy will be ineffective. Similarly, when the estrogen receptor is detected, it is not clear that the level of the progesterone receptor is important. Variations in test quality and results remain important challenges in this area.

F. Prognosis

Breast cancer can vary from aggressive and rapidly fatal to relatively indolent disease with late-appearing metastasis. Molecular studies increasingly support the view that breast cancer is a collection of diseases rather than one single entity. At present, clinicians can use the following factors to provide crude estimates of the likelihood of relapse and survival, but this is an area where newer diagnostics may rapidly improve our current approach.

1. Stage. Axillary node involvement and the size of the primary tumor are major determinants of the likelihood of survival.

a. Nodes. In one large National Surgical Adjuvant Breast and Bowel Project (NSABP) study, before the use of modern adjuvant therapy, 65% of all patients who underwent radical mastectomy survived 5 years, and 45% survived 10 years. When no axillary nodes were positive, the 5-year survival rate was nearly 80% and the 10-year survival rate 65%. If any axillary nodes were positive, the 5-year survival rate was less than 50% and the 10-year survival rate 25%. If four or more nodes were positive, the 5-year survival rate was 30% and the 10-year survival rate less than 15%. Since that time (1975), there has been improvement, with 5-year survival rates of 87% for stage I, 75% for stage II, 45% for stage III, and 13% for stage IV breast cancer. Lymph node involvement by conventional light microscopy remains the single most important prognostic factor in making survival predictions and treatment decisions. It is important to distinguish modern cases in which malignant cells are detected in lymph nodes using higher sensitivity techniques. Their prognosis is not as clearly established.

b. Primary tumor. Patients with large primary tumors generally face higher risks of relapse and death compared to patients with small tumors, irrespective of the nodal status, although patients with large primary tumors are more likely to have node involvement. Tumors that are fixed to the skin or to the chest wall have worsened prognoses compared to those that are not. Patients with inflammatory carcinomas have a particularly poor prognosis, with a median survival time of less than 2 years and a 5-year survival rate of less than 10% in some series. Neoadjuvant systemic therapy has improved the outcome significantly for this subset of patients by enabling local control surgery and improving long-term rates of relapse and death.

2. Estrogen and progesterone receptors. Although stage of disease is critical in determining the risk of recurrence, the timing of events is heavily influenced by tumor biology, particularly hormone receptor status. Patients with tumors that do not express estrogen or progesterone receptors (or do so at only very low levels) are much more likely to experience recurrence during the first few years after diagnosis than those who have receptor-positive disease. This observation is true for both premenopausal and postmenopausal patients within each major node group (zero, one to three, and four or more). Over decades, the risk of relapse and death is approximately the same but the distribution of these events is more even with hormone receptor–positive disease and skewed to the earlier years when the receptors are absent.

3. Her-2/neu gene amplification and overexpression of its transmem-brane receptor is associated with impaired survival in early-stage breast cancer. Amplification (as is seen in 20% to 30% of early breast cancer) results in worse prognosis with earlier appearance of metastatic disease. However, it is now clear that this gene and receptor are predictive factors for response to trastuzumab and with that therapy the outcome for patients with HER2-positive disease may be superior to that of other subtypes.

4. Gene profiling. There are several tools and assays using divergent technologies to provide more precise individualized estimates of the risk of relapse (“prognosis”) and the benefits of specific treatments (“prediction”). The MammaPrint test (Agendia, Inc., Huntington Beach, CA) provides prognosis for node-negative breast cancer regardless of receptor status. The OncotypeDx (Genomic Health, Inc., Redwood City, CA) provides prognosis for node-negative, hormone receptor–positive breast cancer treated with tamoxifen and predicts the benefits of conventional combination chemotherapy as an additional treatment for this cohort. It may be similarly useful in hormone receptor-positive, node-positive disease. These technologies are based on our ability to determine gene expression on fresh frozen or paraffin embedded tissues.

With regard to the OncotypeDx, the following are some considerations:

■ Patients with a result (recurrence score [RS]) of less than 18 (about 50% of patients in most series) are considered low risk and will probably not benefit from the addition of cytotoxic therapy to their hormonal manipulation.

■ Patients with an RS of greater than 30 have a high risk of systemic disease and will obtain the maximum benefit from chemotherapy.

■ Patients with an intermediate score (18 to 30) currently represent a decision-making dilemma and a large trial is under way to better define the value of chemotherapy in this patient population.

5. Other prognostic factors are still undergoing study as to whether they can provide information as independent prognostic factors, particularly for node-negative cancers. In all cases, the key is whether or not they are reliable, validated, reproducible, and additive or supplemental in a meaningful way to the existing tools.

6. Adjuvant! Online is a web-based decision-making tool (see www.adjuvantonline.com) that allows clinicians and patients to input key individual variables, model the impact of specific treatments, and display the benefits both numerically and graphically. There are well-recognized limits to this approach, but it can be very useful in providing easily interpretable information.

II. SYSTEMIC THERAPY OF BREAST CANCER

A. Cytotoxic therapy

As with other cancers, the basis for the effectiveness of cytotoxic drugs in the treatment of carcinoma of the breast is not completely understood. In general, a combination of two or more drugs is more effective in the adjuvant setting than single agents, and nearly all treatment programs use a variety of drugs either in concurrent combination or sequentially. In addition to their cytotoxic effects, chemotherapeutic agents may induce menopause in premenopausal women and this may represent an additional anticancer effect.

1. Response to therapy. In the adjuvant setting, it is impossible to determine whether individual patients have responded to treatment for micrometastatic disease unless they relapse as there are no parameters to measure. Relapse means that treatment did not eradicate all disease, did not prevent the development of new disease, or only slowed the growth of microscopic me-tastases. Determination of the appropriate adjuvant therapy option for individuals must therefore depend on extrapolations from large randomized studies.

2. Treatment of early disease (adjuvant therapy). As discussed previously, standard treatment of early disease depends on a variety of factors; there is not yet a single agreed-on optimal chemotherapy regimen for any subset of women with breast cancer. Therefore, as a first priority, patients should be encouraged to participate in clinical trials. If none is available or the patient declines, Table 9.3 can be used as a guide for assessing risk,

a. Choice of therapy. Cytotoxic therapy is recommended for most otherwise healthy patients with hormone receptor–negative tumors that are 0.5 to 1 cm in size or greater regardless of node status. Patients with HER2 overexpression or gene amplification generally receive chemotherapy and trastuzumab. Regardless of whether they receive cytotoxic therapy, most patients with hormone receptor–positive invasive cancer of any size should be treated with hormone therapy (tamoxifen if premenopausal and an aromatase inhibitor—alone or after tamoxifen—if postmenopausal). The goal of adjuvant chemotherapy is to decrease the risk of death and systemic disease. Due to the risks of competing causes of death, cytotoxic therapy is less commonly recommended in the adjuvant treatment of older women (based on physiologic and not solely on absolute chronologic age). The value of cytotoxic therapy when added to antiestrogen therapy in low-risk node-negative, hormone receptor–positive patients is partially addressed by the OncotypeDx discussed previously, although a number of additional tests may become available for this purpose.

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b. Traditional chemotherapy options. Currently, a wide range of chemotherapy options exists, which generally developed as sequential experimental arms in lineages of clinical research. Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) remains an option for some low- risk patients and may actually be a superior regimen for the basal-like subtype of triple-negative disease. Four cycles of doxorubicin (Adriamycin) and cyclophosphamide (AC) is a standard regimen, which has been improved with the addition of taxanes and every other week (“dose-dense”) scheduling. With regard to the anthracyclines, the Oxford overview and the EBCTCG update showed a 3% absolute survival and recurrence benefit with anthracycline-based regimens compared with CMF at 5 years and 4% survival benefit at 10 years notwithstanding the special toxicities (cardiac in particular and leukemia) these regimens may cause. We highly recommend reviewing the EBCTCG update in Lancet 2005 (included in our list of “Selected Readings”) for a better understanding of the evolution of breast cancer therapy.

c. Addition of taxanes. Multiple phase III trials have evaluated the addition of taxanes (paclitaxel or docetaxel) to chemotherapy regimens for early-stage breast cancer. Both the pivotal Cancer and Leukemia Group B protocol 9344 and the NSABP B28 trial supported the use of paclitaxel after AC for node-positive breast cancer regardless of receptor status, tamoxifen use, patient age, or the number of positive lymph nodes. Retrospective analysis suggests that the benefit is limited in patients with hormone receptor–positive, HER2-negative disease, but other studies have not been consistent in this regard. A slightly differently designed trial (Breast Cancer International Research Group 001) addressed the same question. In this trial, six cycles of concurrent docetaxel, doxorubicin, and cyclophosphamide (TAC) were compared to six cycles of fluorouracil, doxorubicin, and cyclophosphamide as adjuvant therapy for node-positive patients. The study showed superiority of TAC in all patient groups. Similar findings were noted when epirubicin was used instead of doxorubicin. Three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel were found to be superior to six cycles of FEC in node-positive patients by the French Adjuvant Study Group. (Selected readings includes an overview [meta-analysis] of the available taxane studies by DeLaurentiis et al.)

d. Use of trastuzumab in the adjuvant setting. HER-neu–positive breast cancer accounts for 20% to 30% of all cases of breast cancer. In the absence of treatment, these patients have a higher risk of recurrence and earlier death. Trastuzumab prolongs survival in the metastatic setting and prevents recurrence and death in the adjuvant setting as well. The use of trastuzumab along with chemotherapy (a taxane was included in most of these trials) in high-risk node-negative as well as node-positive patients was associated with a 39% to 52% reduction in the risk of recurrence and significant improvements in survival. Trastuzumab does not cross the blood-brain barrier, and the rates of recurrence in the brain, as opposed to all other sites, may not be reduced in the adjuvant setting. There are many active anti-HER2 agents in development for metastatic disease and one small molecule tyrosine kinase inhibitor (lapatinib) has been approved. La-patinib is currently being tested as adjuvant therapy in ran-domized control trials. Additional agents with activity in the metastatic setting include trastuzumab-DM1, pertuzumab, neratinib, and several heat shock protein-90 inhibitors. These drugs may be tested in the adjuvant setting in the future.

e. High-dose chemotherapy. Dose escalation beyond “standard” dose levels, including those that require support with autologous bone marrow or peripheral blood progenitor cell reinfusion, has not been shown to offer advantage over conventional therapy and should not be offered. Dose-dense therapy was developed in recognition of the lack of benefit for higher dose regimens and instead relies on the increased cytotoxicity of more frequent standard doses. This approach requires growth factor support and has been shown to be superior in several randomized trials. For AC and paclitaxel, this is now a standard approach.

f. Some commonly used regimens (refer to previous discussion about choice of regimen based on nodal status) are as follows.

■ Cyclophosphamide, doxorubicin, and fluorouracil:

■ Cyclophosphamide 100 mg/m2 by mouth on days 1 to 14.

■ D oxorubicin 30 mg/m2 intravenously (IV) on days 1 and 8.

■ Fluorouracil 500 mg/m2 IV on days 1 and 8. Repeat the cycle every 4 weeks.

■ Docetaxel and cyclophosphamide:

■ Docetaxel 75 mg/m2 IV push through a rapidly running intravenous line.

■ Cyclophosphamide 600 mg/m2 IV. Repeat every 3 weeks.

■ AC plus taxane (dose-dense)

■ Doxorubicin 60 mg/m2 IV push through a rapidly running intravenous line.

■ Cyclophosphamide 600 mg/m2 IV. Repeat every 2 weeks with growth factor support. After four cycles, switch to paclitaxel 175 mg/m2 IV 3-hour infusion every 2 weeks for four cycles.

■ FEC

■ Fluorouracil 500 mg/m2 IV on day 1.

■ Epirubicin 100 mg/m2 IV on day 1.

■ Cyclophosphamide 500 mg/m2 IV on day 1. Repeat cycle every 21 days.

■ TAC

■ Docetaxel 75 mg/m2 on day 1.

■ Doxorubicin 50 mg/m2 on day 1.

■ Cyclophosphamide 500 mg/m2 on day 1. Repeat cycle every 21 days.

For patients with HER2-positive disease, trastuzumab may be added to a taxane after completion of four cycles of AC. Options include the following:

■ Paclitaxel 80 mg/m2 weekly for 12 weeks given concurrently with

■ Trastuzumab 4 mg/m2 as an initial loading dose, followed by 2 mg/m2 weekly, which is continued for 52 weeks or

■ During the paclitaxel component of the dose-dense therapy using the same schedule of trastuzumab as previously mentioned or

■ Conventionally administered docetaxel (100 mg/m2 every 3 weeks for four cycles) with trastuzumab.

Alternatively, adjunctive therapy for positive patients may begin with docetaxel 100 mg/m2 with carboplatin (area under the curve = 6) once every 3 weeks for six cycles with trastuzumab.

In all cases, trastuzumab is generally administered with and after chemotherapy for 1 full year, although the optimum duration of trastuzumab is the subject of ongoing clinical trials.

g. Tips

(1) Limit the number of cycles of doxorubicin in any combination regimen to six (300 to 360 mg/m2 or less) to limit enhanced cardiotoxicity from the combination

(2) Avoid concurrent administration of trastuzumab in combination with anthracyclines.

(3) Monitor for peripheral neuropathy with taxanes, especially in diabetics and older patients.

3. Cytotoxic therapy of advanced (metastatic) disease. Among the cytotoxic drugs, the most commonly used agents include doxorubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, albumin-bound paclitaxel, gemcitabine, capecitabine, vinorelbine, and ixabepilone. Each of these agents has a response rate of 15% to 40% when used as a single agent (depending on the prior therapies and patient population). With very few exceptions, the data have not supported a survival advantage in the metastatic setting with combination chemotherapy, and toxicity is generally greater so most patients are best palliated with sequential single agents.

Cytotoxic chemotherapy is used as first-line treatment for advanced disease in patients with hormone receptor–negative disease. Its use in lieu of hormone therapy in patients with hormone receptor–positive disease when multiple organ systems are involved is controversial, as some clinicians believe it offers more rapid responses whereas endocrine therapy may offer longer disease stabilization.

Cytotoxic chemotherapy produces clinical benefit (response and disease stabilization) in 60% to 80% of patients regardless of their estrogen receptor status. The responses to therapy at times are durable, but the median duration of treatment in most studies is less than 1 year. Clearly, improved survival is desirable, but the impact of many regimens on survival is modest. However, for patients with HER2-positive metastatic breast cancer, trastuzumab has improved survival, demonstrating that translational science can lead to therapeutic advances once the appropriate biological target is identified. In support of this, the benefits of trastuzumab are limited to patients who are HER2 3+ positive by immunohistochemistry or those who are FISH positive. Second-line chemotherapy is dependent on the specific prior treatments received by an individual patient. If the patient relapses while on treatment or within 6 months after finishing treatment for micrometastatic disease (adjuvant therapy), it is not likely that these drugs used in combination can be helpful in achieving a second remission. In addition, in selecting appropriate therapeutic approaches, the side-effect profiles of the multiple treatment options should be considered in conjunction with patient-related considerations such as symptoms and residual toxicities from prior treatments.

Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial factor. Its use in combination with a variety of chemotherapy agents is associated with higher response rates and longer time to progression, but it has not had an impact on overall survival. Additional antiangiogenic agents are currently in clinical trials, and bevacizumab is being studied in the adjuvant setting. Other novel therapeutics include the poly(ADP-ribose) polymerase inhibitors, one of which has been associated with a survival advantage in combination with conventional combination therapy in triple-negative breast cancer in a randomized phase II study. Effective individual drugs and regimens in addition to those used in the adjuvant setting include the following (note: This is by no means an all-inclusive list. Regimens listed are commonly used in clinical practice):

■ Paclitaxel 150 to 175 mg/m2 IV over 3 hours every 3 weeks, or 80 mg/m2 over 1 hour weekly.

■ Docetaxel 60 to 100 mg/m2 IV over 1 hour every 3 weeks (pre-medication with oral corticosteroids such as dexamethasone 8 mg twice a day for 5 days starting 1 day prior to starting docetaxel is necessary to reduce the severity of fluid retention and hypersensitivity reactions).

■ Vinorelbine 20 to 30 mg/m2 IV over 6 to 10 minutes weekly.

■ Capecitabine 1250 mg/m2 orally twice daily on days 1 to 14 followed by a 1-week rest. Repeat cycle every 3 weeks.

■ Gemcitabine/paclitaxel

■ Gemcitabine 1250 mg/m2 IV days 1 and 8 followed by a 1-week rest, plus

■ Paclitaxel 175 mg/m2 IV on day 1. Repeat every 3 weeks.

■ Nab-paclitaxel 260 mg/m2 IV over 30 minutes given every 3 weeks or 100 to 130 mg/m2 over 30 minutes weekly.

■ Weekly trastuzumab and paclitaxel (for HER2-positive disease)

■ Trastuzumab 4 mg/m2 IV as an initial loading dose, followed by 2 mg/m2 weekly with

■ Paclitaxel 200 mg/m2 IV every 3 weeks, or Nab-paclitaxel as discussed previously.

■ Bevacizumab may be given with first- or second-line chemotherapy typically at a dose of 15 mg/kg every third week or 10 mg/kg every other week. It is not clear that there is only one appropriate chemotherapy “partner” for bevacizumab.

■ Lapatinib may be given at a dose of 1250 mg orally once a day on days 1 to 21 continuously in combination with capecitabine 2,000 mg/m2/day on days 1 to 14 in patients with advanced, refractory HER2-positive breast cancer who have failed prior therapies including anthracyclines, taxanes, or trastuzumab. Lapatinib can also be given in combination with letrozole (2.5 mg daily) in postmenopausal, HER2-positive, hormone receptor-positive breast cancer at a dose of 1500 mg.

4. Dose modifications are regimen-specific. Readers must review the original source references for any regimen they administer.

B. Endocrine (hormonal) therapy

This therapy is effective because breast cancers retain hormone dependence. In premenopausal women, if the breast cancer growth is supported by estrogen production from the ovary, antiestrogen therapy, removal of endogenous estrogen by oophorectomy, or suppression of estrogen production using a leuteinizing hormone–releasing hormone (LHRH) agonist, regression of the cancer can result. Complicating the anticipated actions of SERMS are the presence of different classes of estrogen receptors, different ligands, many receptor-interacting proteins, a host of transcription-activating factors, and several response elements. In some tissues, this class of “antiestrogen” has estrogenic effects (i.e., bone).

1. Treatment of early disease (adjuvant therapy). Among the antihormonal drugs, the most commonly used agents are tamoxifen (a SERM), anastrozole, and letrozole and exemestane (aromatase inhibitors). Toremifene is an alternative to tamoxifen, but raloxifene is used for the treatment of osteopenia and as a chemopreventative and not as adjuvant therapy. The AIs (anastrozole, letrozole, and exemestane) block estrogen production at the cellular level by inhibiting reversibly or irreversibly to the aromatase enzyme (responsible for conversion of male hormones and other precursors to estrogen). Aromatase inhibition has not been shown to be effective in premenopausal patients and therefore tamoxifen is the hormone therapy of first choice. In postmenopausal women, AIs offer additional benefit to what was observed with 5 years of tamoxifen, including a survival advantage in patients with node-positive, receptor-positive tumors. Both the ATAC trial and the BIG 1–98 trials demonstrated an advantage to upfront use of an AI (anastrozole and letrozole, respectively) over tamoxifen therapy. Results of the IES study demonstrated a superior DFS with sequential therapy using exemestane following 2 to 3 years of tamoxifen to 5 years of tamoxifen alone. Fewer side effects are seen in this population with the use of AIs in comparison to tamoxifen. Letrozole after about 5 years of tamoxifen was effective, and a clinical trial is now evaluating a third 5-year period of treatment (i.e., 10 years versus 5 years of letrozole following 5 years of tamoxifen). Importantly, the AIs offer lower incidence of venous thromboembolic events and endometrial carcinoma compared to tamoxifen but are associated with a higher incidence of osteoporosis and musculoskeletal complaints.

Tamoxifen, 20 mg daily, is recommended in premenopausal women with hormone receptor–positive disease. It should be continued for 5 years. Longer durations do not improve survival.

In receptor-positive patients, its benefits are additive to those of chemotherapy (when used), and it is not clear whether ovarian suppression adds to chemotherapy and tamoxifen. It has a rela-tively low risk in the adjuvant setting, and our current recommendations generally include tamoxifen where it is indicated in addition to chemotherapy in Table 9.4.

Tamoxifen and AIs ( for postmenopausal patients) improve DFS and overall survival in most patients with estrogen receptor–positive tumors. Although the proportional reduction (about 25%) in death rate is similar for both high- and low-risk patients (e.g., node-positive and node-negative), the absolute benefit is greater for those at higher risk ofrecurrence and death. The improvement in DFS is superior with all AIs, and there is an associated more significant reduction in contralateral breast cancer with these drugs in comparison to tamoxifen.

Tamoxifen is metabolized by CYP2D6, and this activity can be inhibited by certain selective serotonin reuptake inhibitor antidepressants and by inherited variations in single nucleotide polymorphisms (SNPs). However, there is no prospective evidence that SNP testing can yet guide individual patients to better selection of hormone therapy and improved outcomes.

2. Treatment of advanced (metastatic) disease. Hormonal therapy is indicated in women who have had a positive test for estrogen or progesterone receptors in their tumor tissue. This approach is not generally recommended for women who have previously been shown to be unresponsive to hormonal manipulation. It is also not appropriate therapy for women with visceral crises. For premenopausal women, oophorectomy still may be the treatment of choice. The LHRH analogs goserelin and leuprolide can achieve the equivalent of a medical oophorectomy. This treatment may then be combined with an AI or tamoxifen in such patients. For postmenopausal women, an AI should be used as the initial hormonal therapy. Responses to endocrine therapy tend to last longer than responses to cytotoxic chemotherapy, frequently lasting 12 to 24 months. Second-line hormonal manipulation (e.g., using fulvestrant, a selective estrogen receptor down-regulator) is a reasonable option if the tempo of disease progression allows such. Sequential hormone manipulation may be most appropriate for patients with indolent hormone receptor–positive breast cancer, such as those with bone-dominant disease.

Doses of commonly used drugs are the following:

■ Tamoxifen 20 mg by mouth daily

■ Anastrozole 1 mg by mouth daily

■ Letrozole 2.5 mg by mouth daily

■ Exemestane 25 mg by mouth daily

■ Fulvestrant 250 to 500 mg intramuscularly (into buttock) monthly after loading with 500 mg on days 1 and 15

■ Megestrol acetate 40 mg by mouth four times a day.

C. Complications of therapy

A large range of possible side effects have been associated with treatments for breast cancer and vary extensively between agents and individuals. Acute toxicities are primarily hematologic and gastrointestinal. Subacute toxicities include alopecia, hemorrhagic cystitis, hypertension, edema, and neurologic abnormalities. Chronic or long-term toxicities may be cardiac, neoplastic, or neurologic. Premenopausal women need to be aware of menstrual irregularities, early menopause, and infertility as a consequence of chemotherapy and should be referred for consideration of fertility preservation when desired. Dose modifications for specific regimens must be based on the original sources. Readers are urged to review the original reports for any regimen they prescribe. In addition, because of individual differences, toxicities that are worse than expected may occur, and the responsible physician must always be alert to special circumstances that dictate further attenuation of the drug doses. The drug data listed in Chapter 33 should be consulted for the individual toxicities, precautions, and toxicity prevention measures for each drug.

Like all therapeutic interventions, adjuvant tamoxifen therapy also has consequences. These include a twofold to fourfold increase in endometrial cancer, an increase in cataracts, and an increase in thromboembolic disease. Hot flashes are common but can be ameliorated in some women with venlafaxine 25 to 50 mg daily. While there is also reduction in the hot flashes from using a progestin, such as megestrol, 20 mg twice a day, the effect of the progestin on the risk of recurrence is not known. Adverse effects on vaginal mucosa may be ameliorated with minimal systemic estrogen effect by the estradiol vaginal ring or by an estradiol tablet administered intravaginally (Vagifem). While fractures related to osteoporosis decrease with tamoxifen, there does not appear to be any reduction in cardiovascular events. AIs, on the other hand, may worsen osteoporosis despite an absence of increased fracture incidence in many trials. Caution and possibly anticoagulation should be exercised in treating women with Factor V Leiden who begin treatment with tamoxifen in the prevention or adjuvant setting.

Bisphosphonates are commonly administered IV to all patients with bone metastases due to their role in reduction of skeletal events. Recently, randomized studies in the adjuvant setting have demonstrated reductions in the risk of bone and other metastases but no impact on survival. These agents may become part of standard adjuvant therapy if additional trials are positive.

IV bisphosphonate options include zoledronic acid 4 mg over 15 minutes or pamidronate 60 to 90 mg over 1 to 2 hours.

Acknowledgments

The authors are indebted to Dr. Iman Mohamed, who contributed to previ-ous editions of this chapter. Several sections in this revision of the handbook represent her work.

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