Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 10 - Carcinoma of the Breast
Carcinoma of the Breast
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. Nonetheless, in 2005, more than 250,000 new cases of breast cancer were diagnosed, and there were approximately 40,000 women who died from this cancer. More women survive because of earlier diagnosis and better therapy. The disease-specific mortality from breast cancer is reported to have decreased by 2.2% per year since 1990.
The incidence of breast cancer varies widely among different populations. Women inWestern 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 and fat. White women in the United States are more likely to develop breast cancer as compared with African American women. Mortality from breast cancer, however, is higher in African American women than in other ethnic or racial groups. Although discrete causes of breast cancer cannot be identified in 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 familymember has developed breast cancer at an early age. Genetic linkage analysis has 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. However, if a woman with breast cancer is under the age of 50 and has any relative who developed breast cancer before shewas 50, her chance of having a mutation in BRCA1 or BRCA2 rises to 25%.Other factors that increase the 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. Other less common or less welldefined genetic mutations may be present in other familial breast cancers. Additional factors that increase breast cancer
Hormone replacement therapy can possibly increase the risk of breast cancer. In the Women Health Initiative study, researchers found an increased breast cancer risk of approximately 10% for every 5 years of use. There was a greater risk with combined estrogen and progesterone products than with estrogen therapy alone.
Until recently, it was unknown whether any preventive measures would be effective in reducing the incidence of breast cancer. Two trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3 to 5 years of preventive treatment with these agents reduces the rate of cancer development over a short term. Women at increased risk because of family history, age, and other risk factors, who are treated with tamoxifen, 20 mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast cancer as compared with women treated with placebo. Noninvasive disease and preneoplastic breast lesions are also decreased. Raloxifene, 60 or 120 mg/day, also appears to reduce the risk of breast cancer in postmenopausal women (who had osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of 0.26. Raloxifene appears to have a lower risk for the development of endometrial cancer than tamoxifen that has been associated with an increased risk for endometrial cancer of 1.5 to 2 times that in untreated women. Effects on survival, when used in breast cancer prevention, have not yet been demonstrated for either agent. The results of the STAR trial (Study of Tamoxifen against Raloxifene) have recently been published. Raloxifene was found not to decrease the incidence of preinvasive carcinomas despite a seemingly better outcome than tamoxifen for prevention of invasive cancers. This makes the initial enthusiasm about this drug (which is currently primarily used for treatment of osteoporosis) difficult to sustain. Clearly, decisions regarding prevention are complex and require consideration of cost, benefit, and potential side effects of drugs.
The approach to management of women at very high risk because of family history or known suppressor gene mutations is evolving. Increased surveillance, such as increasing the frequency of mammography to once in every 6 months, has been suggested as a reasonable conservative approach. In mutation carriers who are at risk for both breast and ovarian cancers, bilateral oophorectomy after child-bearing age has been recommended because of the inadequacy of screening tests for ovarian cancer. Some women may prefer prophylactic mastectomy. In a recent study from Mayo Clinic, bilateral simple mastectomy in mutation carriers was found to reduce
The role of SERMs inpatientswith these BRCA1 and BRCA2 mutations is evolving as well. Analysis of blood samples of women who participated in the prevention trial with tamoxifen showed that mutation carriers also had a 47% lower risk of breast cancer, suggesting a useful role for this group of drugs in mutation carriers. Another approach to managing high-risk patients is increased surveillance. This involves clinical examination and imaging of suspicious palpable findings in a timely manner. As discussed in the following text, the use ofmagnetic resonance imaging (MRI) is currently approved for screening high-risk populations in addition to regular mammography.
C. Detection, diagnosis, and pretreatment evaluation
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 are recommended. Notwithstanding some skepticism in the literature, most breast cancer specialists and statistical analyses have concluded that mammography, when done on a regular basis, can reduce mortality due to breast cancer 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. Mammography is recommended at age 40 as a baseline, once every 1 to 2 years between the ages of 40 and 50 (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 5 years earlier than the age of the youngest diagnosed relative. Patients with Hodgkin's disease (regardless of a history of mantle field irradiation) should have a baseline mammogram by age 25. In mutation BRCA1 or BRCA2 carriers, MRI of the breast has recently been approved for screening in addition to annual mammography. Although each method for early detection can be of some help in finding early lesions that can be successfully removed before metastasis has occurred, mammography is capable of detecting the smallest and therefore the most curable lesions. Therefore, despite the high cost of screening mammography ($75 to $140 in many areas of the United States), it is highly recommended that the guidelines mentioned in the preceding text be followed. Mammography has clearly led to the discovery of many earlier cancers and sharply increased the discovery of preinvasive cancers (ductal carcinoma in situ [DCIS]). Screening breast ultrasound is commonly used in Europe. Its role in the United States remains limited to evaluation
Presenting signs and symptoms. Although an increasing number of nonpalpable cancers are found by mammography, invasive breast cancer is still most 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, 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. At times, the primary lesion is not discovered, and the woman presents with symptoms of metastatic disease, such as pleural effusion, nodal disease, or bony metastases. Approximately half of all lesions are in the upper outer quadrant of the breast (where most of the glandular tissue of the breast is), approximately 20% are central masses, and 10% are in each of the other quadrants. Up to one fourth 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 mammography or other screening methods.
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 10.1, and the stage grouping is outlined in Table 10.2. As of January 2003, the revised American Joint Commission on Cancer (AJCC) staging system for breast cancer has been officially adopted for use in tumor registries. Although preliminary staging is commonly done before surgery, definitive staging that can be used for prognostic and further treatment planning purposes usually must await postsurgical 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 on 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 metastatic lesions down to isolated tumor cell level. It is less certain whether there is prognostic value if cancer cells in nodes are detected bymolecularmarkers (reverse transcriptase-polymerase chain reaction [RT-PCR]). The current staging system designates nodes to be pathologically negative if cells are identified by polymerase chain reaction (PCR) and not by haematoxylin and eosin stain (H&E) or by IHC but a designator mol+ or molis added. Pathologists agree that the size of the metastatic deposit is of utmost significance as opposed to how the deposit was
Table 10.1. Abridged TNM classification of breast cancer
Table 10.2. Stage grouping of breast cancera
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 of involvement and to look for additional ipsilateral or contralateral disease.
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, overexpression of genes such as HER2, flow cytometric measurements of ploidy and the percentage of cells in the S phase, and other specialized tests.
After confirmation of the histology, the patient is evaluated for possible metastatic disease.
Mandatory studies include a chest radiograph, complete blood count, blood chemistry profile, and estrogen and progesterone receptor assays and HER2 assessment on the primary breast carcinoma and grossly cancerous nodal tissues.
Other studies, including radionuclide scan of the bones, skeletal survey (usually obtained only if the radionuclide scan is positive), and computed
Histology. Approximately 75% to 80% of all breast cancers are infiltrating ductal carcinomas, and 10% are infiltrating lobular carcinomas; these two types have similar biologic behavior. 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. With the recent development of microarray technology breast cancer is now thought of as a disease with distinct subtypes. One subtype (the basal epithelial subtype) is commonly referred to as triple negative or basaloid breast cancer. It constitutes approximately 15% of all invasive breast cancers and is distinctly different from tumors arising from inner milk-secreting luminal cells (luminal breast cancer) that constitute most breast cancers in the United States and Northern Europe. Basaloid breast cancer lacks hormone receptor expression and the cells do not overexpress her2-neu. Triple negative tumors are seen in association with BRCA1 mutations and in women of African ancestry. This type is associated with a poor prognosis.
D. Approach to therapy
Consultation with a surgeon, radiotherapist, andmedical oncologist is critical once the diagnosis of carcinoma is highly suspected or histologically confirmed. Multimodal therapy has had a more beneficial impact on carcinoma of the breast than on any other common cancer affecting adults. It is important to have all these oncology specialists see the patient before final decisions regarding therapy are made, so the primary physician and the patient can have opinions from several perspectives about optimal management. This is best achieved during multidisciplinary treatment planning conferences where opportunities arise to discuss treatment, identify patients who require psychosocial support, identify patients who may benefit from genetic testing, and those eligible for clinical trials. 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 option, 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 that is acceptable to her.
Goals of therapy differ depending on the stage of disease being treated.
For early disease, the goal of therapy is to eradicate micrometastases to render the patient free of disease and prevent recurrence. If eradication of cancer cells cannot be achieved, long-term suppression is desirable. This may be accomplished by tamoxifen and other SERMs (hormonal manipulation). Coincidentwith therapy is the
For locally advanced disease, defined as patients with stage IIIA or T3 4 disease, including inflammatory breast cancer and patients with positive ipsilateral supraclavicular or infraclavicular nodes, the goal of therapy (commonly referred to as neoadjuvant therapy) is to reduce the size of an initially unresectable tumor, improve local control and decrease the spread of metastatic disease. Such preoperative administration of chemotherapy allows the opportunity to test therapeutic efficacy of drugs as well as test novel therapies and biomarkers.
For advanced disease, the goal is usually to reduce the tumor burden and the resultant disability in order to alleviate the patient's symptoms, improve performance, and prolong meaningful survival (palliation). Whereas long-term toxicity is not usually of great importance, short-term toxicity is a major area of concern 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 time.
Surgery has been and remains the most frequently used mode of primary therapy for most women with carcinoma of the breast. The role of surgery in the primary management of carcinoma of the breast has been evolving with a trend to lesser surgery (lumpectomy) together with axillary node dissection. Surgical margins should be free (3 4 mm). Complete axillary node dissection may become unnecessary when the reliability of sentinel node identification, removal, and histologic assessment is established with greater certainty. This technique may spare many women the additional surgical procedure of axillary node dissection and its attendant risk of lymphedema. At this point, full axillary dissection remains the standard of care if the sentinel node(s) was found to be positive for breast cancer cells. Lumpectomy and axillary node evaluation are followed by radiotherapy to control the microscopic cancer remaining in the breast. Depending on the stage of the cancer, additional radiotherapy may be used to treat upper internal mammary nodes. For most women, this therapy yields therapeutic results that are as good as with modified radical mastectomy without the need for amputating the breast and its attendant physical deformity and psychological trauma. Many surgeons believe that in the modern management of breast cancer, and unless requested by the patient herself, a mastectomy is only indicated in cases of inability to completely excise the primary tumor, if the patient has multicentric disease or if she has a contraindication to radiation therapy.
Although many women and their physicians are opting for lesser surgery, some version of themodified radicalmastectomy is still more commonly performed in many areas of the United States; in this operation, the breast, pectoralis fascia (with or without the pectoralis minor muscle), and lymph nodes are removed. There are wide geographic variations in the use of breast-conserving surgery throughout the United States. For most women, surgeries more extensive than the modified radical mastectomy are probably of no benefit, and lesser surgeries that are not combined with radiotherapy are insufficient in terms of providing important prognostic information regarding the status of the axillary lymph nodes and controlling the local disease (40% of women treated with excisional biopsy alone have recurrence in the ipsilateral breast).
For patients who have had mastectomy, reconstruction is being done with increasing frequency. It may be done at the time of mastectomy or delayed for a period (usually 1 to 2 years). Options include insertion of a silicone or saline implant or transposition of a muscle flap. Neither procedure has resulted in worsening of the prognosis from the breast cancer or a significant increase in the difficulty in detecting local recurrences.
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 lumpectomy as part of the primary therapy. In this circumstance, radiotherapy is commonly delivered using external-beam therapy to the entire breast with a boost of therapy to the tumor bed using either external-beam therapy or implantation of radioactive substances. Radiotherapy may also be given after mastectomy in women who have a high likelihood of local recurrence, and it is highly effective in preventing the reappearance of disease in the treated fields. In some circumstances it may also improve survival. Postmastectomy radiation is indicated if the primary is larger than 5 cmor if four or more positive lymph nodes were found in the axilla. Radiation may be omitted in patients older than 70 years with estrogen receptor positive tumors smaller than 2 cm if they were treated with antiestrogen therapy. Radiation therapy is usually started after completion of cytotoxic therapy. Many trials (e.g., MammoSite) are currently defining the role of brachytherapy in the management of patients with early breast cancer. Such therapy is given over a short period of time (typically 5 days) and delivers a higher dose of radiation through a catheter or balloon placed in the lumpectomy cavity. Patients are treated twice a day. This allows patients to complete their radiation therapy before initiating systemic therapy if indicated. Radiation therapy is also helpful as adjunct therapy for advanced disease. Local recurrences and distant metastases also are frequently treated successfully with radiotherapy. This mode of treatment is particularly critical to the management of painful bony lesions or sites of impending pathologic fracture.
Chemotherapy and endocrine therapy (systemic therapy) are used to reduce the likelihood of recurrence in early disease and to treat more advanced disease with or without distant metastasis. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) analysis of adjuvant therapy demonstrated a clear benefit of postoperative chemotherapy or hormonal therapy (including ovarian ablation in premenopausal women). Such therapy will on average reduce the risk of recurrence by 20% to 35%. Similarly the odds of death were also reduced by 15% to 30%. The same proportional risk reduction was seen in node-positive as well as node-negative patients. Patients with node-negative disease benefit from adjuvant therapy with a percentage decrease in mortality similar to that for node-positive women but the lower baseline mortality for node-negative women results in less absolute benefit per 100 women treated. Current clinical trials use tumor size, hormone receptor status, DNA synthesis rate (percentage of cells in S phase), and other factors to aid in identifying the patients, among those with negative nodes, who are most likely to relapse and thereby most likely to benefit from adjuvant therapy. Commercially available tests that map out a gene profile for node-negative cancers (see Section I.E. in the following text) may also help in treatment decisions in this population and thereby help clinicians avoid unnecessary treatment. The physiologic age of the patient and comorbid conditions will become important considerations in adjuvant therapy decisions.
Endocrine therapy may result from surgical, radiotherapeutic, or chemotherapeutic ablation or inhibition of the ovaries or adrenal glands; or it may consist of additive therapy with antiestrogens, aromatase inhibitors (AIs), progestins, androgens, or luteinizing hormone releasing hormone (LHRH) agonists. Endocrine therapy is generally ineffective (as sole therapy) for the treatment of metastatic disease in patients with low levels of estrogen and progesterone receptors in the cancer cells and is increasingly effective as the level of receptors rises. The best responses can be expected in women in whom the estrogen receptor level is high and progesterone receptors are present.
There is a broad spectrum in the biologic behavior of breast carcinoma from aggressive, rapidly fatal, inflammatory carcinoma to relatively indolent disease with late-appearing metastasis and survival time of 10 to 15 years. The likelihood of relapse and survival are influenced by a number of factors:
Stage. Axillary node involvement and the size of the primary tumor are major determinants of the likelihood of survival.
Nodes. In one large National Surgical Adjuvant Breast 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 approximately 80% and the 10-year survival rate was 65%. If any axillary nodes were
Primary tumor. Patients with large primary tumors do not do as well as 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 do worse than 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. Aggressive initial (neoadjuvant) chemotherapy has improved the outcome of many of these patients.
Estrogen and progesterone receptors. Patients without estrogen or progesterone receptors (or with very low levels) are twice as likely to relapse during the first 2 years after diagnosis as those who are receptor positive. This observation is true for both premenopausal and postmenopausal patients within each major node group (0, 1 to 3, and 4 or more).
Her-2/neu amplification is associated with impaired survival in early-stage breast cancer. This is a protooncogene that codes for a transmembrane receptor of the epidermal growth factor receptor family. Amplification (as is seen in 25% 30% of early breast cancer) results in worse prognosis with earlier appearance of metastatic disease.
Gene profiling. As of January 2004, the U.S. Food and Drug Administration (FDA) approved the use of a 21-gene PCR assay, the Oncotype Dx (Genomic Health, Inc., Redwood City, California) breast cancer assay, for use in patients who are hormone-receptor positive with negative nodes. These patients tend to be overtreated (~50% of the time). This technology is based on gene expression studies on tumors in paraffin-embedded tissues. After a detailed selection process of candidate genes, a panel of 16 cancer genes and 5 reference genes was selected. The gene expression levels were formulated in an algorithm that allows computation of a recurrence score (RS) for each tumor. The test demonstrated the ability (in randomized clinical trials) to quantify the risk of recurrence as well as predict benefit from chemotherapy for this group of hormone-dependent tumors. A report is sent out on each patient, with a number representing their RS (a continuum from 0 100).
Patients with a RS less than 18 (~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
Other prognostic factors are still under study as to whether they can provide information as independent prognostic factors, particularly for node-negative cancers. These include the percentage of cells in DNA synthesis (low percentage in S phase better than high percentage) and the ploidy of the breast cancer cells (diploid better than aneuploid). Additional tumor markers that may have predictive value include cathepsin D, c-myc oncogene amplification, and p53 suppressor gene expression.
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. It is clear, however, that combinations of drugs are considerably more effective in the adjuvant setting than single agents (although how many is enough is not as certain). Nearly all treatment programs use the drugs in various combinations, at least during initial therapy. In addition to their cytotoxic effects, chemotherapeutic agents may induce menopause in premenopausal women, thereby affecting estrogen production as well as killing cells directly. Recent studies suggest a trend toward a lower recurrence rate in women who develop chemotherapy-induced amenorrhea.
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, because there are no parameters to measure. New testing modalities for chemotherapy responsiveness are being evaluated. Currently, they are used more commonly in the metastatic setting but we anticipate widespread use in the next few years. The effectiveness of adjuvant therapy must therefore depend on population studies. Because breast cancer may have a long natural history, and the disease may recur even beyond 10 years, it is critical to defer final conclusions regarding any study until at least 5 years and preferably 10 years have passed.
Chemotherapy improves both disease-free survival (DFS) and overall survival (OS) by approximately 25% in all groups of patients. Although the proportional reduction 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 of recurrence and death (e.g., younger patients with positive nodes).
Treatment of early disease (adjuvant therapy). Standard treatment of early disease depends on primary tumor size, nodal status, menopausal status of the patient, hormone receptor status of the tumor, and other tumor characteristics. Because there is no optimal therapy yet for any subset of women with breast cancer, the patient and her physician should be encouraged to participate in clinical trials. If none is available or the patient declines, Table 10.3
Table 10.3. Prognostic factors for assessing risk of recurrence of breast cancer
Table 10.4. Systemic adjuvant therapy for breast cancer suggested guidelines
Many practicing oncologists use AC (doxorubicin [Adriamycin] and cyclophosphamide) more commonly in women with a higher risk of recurrence, and CMF (cyclophosphamide, methotrexate, and fluorouracil) more in those who have lesser risks (e.g., are node negative), who have comorbid conditions, or in whom cardiac risk of doxorubicin is deemed important. Anthracyclines, however, remain the minimum standard of care in healthy nodepositive patients. In 1998, the International Consensus Panel on the Treatment of Breast Cancer in St. Gallen, Switzerland agreed that anthracycline-based therapy is superior to CMF. The Oxford overview and the EBCTCG update showed a 3% absolute survival and recurrence benefit with anthracycline-based regimens as compared with CMF at 5 years and 4% benefit at 10 years. Retrospective analysis suggests that the superiority of anthracyclines may be limited to her-2-neu positive disease. We highly recommend reviewing the EBCTCG update Lancet 2005 paper (included in our list of Suggested Readings) for a better understanding of the evolution of breast cancer therapy.
Use of taxanes in node-positive disease. Three phase III trials have evaluated the addition of taxanes (paclitaxel or docetaxel) in node-positive patients. These patients have a higher risk for relapse. Both the pivotal Cancer and Leukemia Group B (CALGB) protocol 9934 and the NSABP B28 trial supported the use of paclitaxel after AC for node-positive breast cancer regardless of the receptor status, tamoxifen use, age of the patient, or the number of positive lymph nodes. Although all patients benefit, hormone receptor negative patients benefit to a greater extent. Both trials were positive for DFS. There was a 14% improved OS in the CALGB trial. A slightly differently designed trial (BCIRG 001) addressed the same question. In this trial, six cycles of TAC (docetaxel, doxorubicin, and cyclophosphamide) were compared to six cycles of FAC (fluorouracil, doxorubicin and cyclophosphamide) as adjuvant therapy for node-positive patients. The study showed superiority of TAC in all patient groups. Long-term follow-up (at 55 months) showed a reduction of relapse by 28% and an improvement of 30% in OS. This improvement was independent of all variables. There were more episodes of febrile neutropenia in the TAC arm but no septic deaths. Similar findings were noted when epirubicin was used instead of doxorubicin. Three cycles of FEC followed by three cycles of docetaxel were found to be superior to six
Dose-dense therapy. A superior DFS (albeit with a very small difference [2%] for OS) was seen when chemotherapy was administered on a 2-weekly basis (AC-T) in the CALGB 9741 landmark trial. All patients had early breast cancer with positive nodes. Such regimen requires growth factor support. Longer follow-up is needed before the oncology community switches to every 2 weeks therapy. It was apparent, however, that it is feasible to administer chemotherapy with an absolute neutrophil count of 1,000 cells/ L.
Trastuzumab in the adjuvant setting. Her-2-neu positive breast cancer accounts for 20% of all cases of breast cancer. Such patients have a higher risk of recurrence and a more aggressive course in the adjuvant setting. Trastuzumab has been used for the past 7 years in combination with chemotherapy as standard therapy for metastatic her-2-neu positive disease. Results from large adjuvant trials have now established the role of trastuzumab in the adjuvant setting as well. The detailed description of these trials is beyond the scope of this book. At this point, the use of trastuzumab along with chemotherapy (a taxane was included in four 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. We have also learned from these trials that earlier use of the monoclonal antibody is associated with survival benefit (as opposed to using trastuzumab when patients recur). We still do not understand the mechanism of trastuzumab resistance. Trastuzumab does not cross the blood brain barrier (BBB). Newer small molecules (e.g., lapatinib) are awaiting FDA approval after their promising role in this subset of patients when combined with capecitabine if resistance to trastuzumab develops. Smallermolecules also cross the BBB and provide potential for reducing brain metastasis in this patient population.
High-dose chemotherapy. Moderate escalation of the doses of the standard chemotherapy regimens does not appear to be of benefit in improving survival and may increase the risk for treatment-related myelodysplasia and leukemia. Very high-dose chemotherapy with autologous bone marrow or peripheral blood progenitor cell reinfusion has not fulfilled the promise of improving the survival of women at very high risk of recurrence. After analysis of recently completed clinical trials, it has become clear that no single group of patients with advanced breast cancer, regardless of tumor factors or clinical features demonstrated benefits from high-dose chemotherapy. The potential benefit for women with a large number of positive lymph nodes remains investigational.
Some commonly used regimens. (Please refer to discussion in the preceding text about choice of regimen based on nodal status.)
Cyclophosphamide 100 mg/m2 PO on days 1 to 14 Doxorubicin 30 mg/m2 IV on days 1 and 8 Fluorouracil 500 mg/m2 IV on days 1 and 8.
Repeat the cycle every 4 weeks.
Doxorubicin 60 mg/m2 IV push through a rapidly running IV
Cyclophosphamide 600 mg/m2 IV.
Repeat every 3 weeks.
Cyclophosphamide 100 mg/m2 PO on days 1 to 14 Methotrexate 40 mg/m2 IV on days 1 and 8 Fluorouracil 600 mg/m2 IV on days 1 and 8 Prednisone 40 mg/m2 PO on days 1 to 14, during the first three cycles only.
Repeat the cycle every 4 weeks.
Doxorubicin plus paclitaxel with or without filgrastim (Neupogen)
Doxorubicin 50 to 60 mg/m2 IV, followed in 4 hours by Paclitaxel 150 mg/m2 IV over 3 to 24 hours Filgrastim 300 g/day SC starting 24 hours after the end of chemotherapy, for 10 days.
Repeat every three weeks.
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.
Taxotere (docetaxel) 75 mg/m2 on day 1
Adriamycin (doxorubicin) 50 mg/m2 on day 1
Cyclophosphamide 500 mg/m2 on day 1.
Repeat cycle every 21 days.
Trastuzumab may be added to paclitaxel after completion of four cycles of AC
Paclitaxel 80 mg/m2 weekly x 12 given concurrently with trastuzumab 4 mg/m2 as an initial loading dose, followed by 2 mg/m2 weekly, which is continued for 52 weeks.
Limit the number of cycles of doxorubicin in any combination regimen to six (300 to 360 mg/m2) to reduce enhanced cardiotoxicity from the combination.
No safety data for trastuzumab (Herceptin) in combination with anthracyclines in the adjuvant setting, so administer sequentially.
Monitor for peripheral neuropathy especially in patients with diabetes and older patients with paclitaxel.
Cytotoxic therapy of advanced (metastatic) disease. Among the cytotoxic drugs, the most commonly used agents include doxorubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, gemcitabine, capecitabine, vinorelbine, mitoxantrone, thiotepa, and vincristine. Each of these agents has a response rate of 20% to 40% when used as a single agent. Because combinations are so much more effective (60% 80% response rate) than single agents, these drugs are rarely used alone as initial therapy. With very few exceptions, the data have not supported a survival advantage in the metastatic setting with combination chemotherapy. The choice of single agent therapy versus a combination regimen should be made on the basis of the tempo of the metastatic process, the patient's age, performance status, and access to care.
Cytotoxic combination chemotherapy is used as firstline treatment for advanced disease, in hormone receptor negative patients, and at times in patients with several organs involved because the responses are more rapid and the rate of response is greater when drugs are used in combination than when endocrine therapy is used alone. For patients over 65 years of age, however, initiation of hormone therapy alone may be justified, with cytotoxic therapy being reserved for patients who have failed one or more hormonal treatments.
Cytotoxic chemotherapy produces responses in 60% to 80% of patients regardless of their estrogen receptor status. The responses to therapy are at times durable, but the median duration in most studies is less than 1 year. Clearly, improved survival is desirable. This is not achievable with most current regimens with the exception of regimens that include trastuzumab. The benefits of trastuzumab (Herceptin) are limited to patients who are HER2 3+ by immunohistochemistry or those who are FISH positive. Carboplatin in combination with paclitaxel and trastuzumab (TCH) is being tested in various schedules with the hope of finding an active regimen without the cardiotoxicity of the doxorubicin trastuzumab combination. Other forms of taxanes are a new addition to the drugs active in the metastatic setting. Nanoparticle albumin-bound (nab) paclitaxel (Abraxane) is the first in a novel class of compounds combining human albumin with paclitaxel in the nanoparticle state. A phase III trial showed superiority of the drug given in this form to paclitaxel given every 3 weeks. There were fewer associated hypersensitivity reactions, a shorter infusion time, and a more reversible peripheral neuropathy.
Second-line therapy depends on what treatment the patient has initially received. If the patient relapses while on treatment or within 6 months of 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. Because doxorubicin is among the most effective agents against breast carcinoma, it should be used in any combination in this situation,
Paclitaxel 150 to 175 mg/m2 IV over 3 hours every 3 weeks, or 80 mg/m2 over 1 hour weekly.
Docetaxel, 60 to 100mg/m2 IV over 1 hour every 3 weeks (premedication with oral corticosteroids such as dexamethasone, 8 mg b.i.d., for 3 days starting 1 day before starting docetaxel is necessary to reduce the severity of fluid retention and hypersensitivity reactions), or
Vinorelbine, 30 mg/m2 IV over 6 to 10 minutes weekly.
Capecitabine 1,250 mg/m2 orally twice daily on days 1 to 14 followed by 1-week rest, plus
Docetaxel 75 mg/m2 IV over 1 hour on day 1
Repeat cycle every 3 weeks.
Gemcitabine 1,250 mg/m2 IV on days 1 and 8 followed by a week's rest, plus
Paclitaxel 175 mg/m2 IV on day 1
Repeat every 3 weeks.
Weekly trastuzumab and paclitaxel
Trastuzumab 4 mg/m2 IV as an initial loading dose, followed by 2 mg/m2 weekly and
Paclitaxel 200 mg/m2 IV every 3 weeks.
Lapatinib plus Capecitabine (after failure on anthracyclline, taxane, and trastuzumab)
Lapatinib 1250 mg PO daily and
Capecitabine 2000 mg/m2 in two divided doses daily on days 1 through 14 of a 21-day cycle.
Abraxane 260 mg/m2 IV over 30 minutes given every 3 weeks.
TCH(Taxotere [docetaxel] /carboplatin/ Herceptin[trastuzumab])
Carboplatin at an area under the curve (AUC) of 6 IV day 1
Docetaxel 75 mg/m2 IV day 1
Trastuzumab (see dose mentioned earlier).
Note: This is by no means an all-inclusive list. Regimens listed are what the author commonly uses.
Dose modifications are outlined in Table 10.5.
Endocrine (hormonal) therapy of advanced disease is presumed to be effective because the breast cancer tissue retains some of the endocrine sensitivity of the normal breast tissue. 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 an LHRH agonist logically results in regression of the cancer at least those tumor cells that are dependent on the estrogen. (The dependent cells seem to be those that have the estrogen receptors.) Other
Table 10.5. Dose modification for chemotherapy of breast carcinoma
Treatment of early disease (adjuvant therapy). Among the antihormonal drugs, the most commonly used agent is tamoxifen (the other SERMs toremifene and raloxifene are not as widely used). The AIs (anastrozole, letrozole, and exemestane) block estrogen production at the cellular level by inhibiting reversibly or irreversibly the aromatase enzyme (responsible for conversion of male hormones to estrogen in postmenopausal patients). Current data support that in postmenopausal women, AIs offer additional benefit to what was observed with 5 years of tamoxifen including a survival advantage in node-positive receptor-positive patients. Both the ATAC (Arimidex or Tamoxifen Alone or in Combination) trial and the Breast International Group (BIG) 1 98 trials demonstrated an advantage to upfront use of an AI (Arimidex and letrozole, respectively). Results of the Intergroup Exemestane Study (IES) study demonstrated a superior DFS with sequential therapy using exemestane following 2 to 3 years of tamoxifen as compared to 5 years of tamoxifen alone. Fewer side effects are seen in this population with the use of AIs in comparison to that of tamoxifen. Of the most clinical relevance is the lower incidence of venous thromboembolic events and endometrial carcinoma with AIs. These drugs, however, are associated with a higher incidence of osteoporosis and musculoskeletal complaints.
Tamoxifen (and probably other SERMs) improves DFS and OS in most estrogen receptor positive patients. Although the proportional reduction (~25%) in death rate is similar for both high- and low-risk patients (e.g., nodepositive and node-negative), the absolute benefit is greater for those at higher risk of recurrence 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.
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. It is not generally recommended as the sole therapy for women who have low receptor levels or have previously been shown to be unresponsive to hormonal manipulation. It is also not the appropriate therapy for women with brain metastasis, lymphangitic pulmonary metastasis, or other dire visceral disease, such as extensive liver metastasis, in which a slow response could jeopardize survival. For premenopausal women, oophorectomy may still 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. For postmenopausal women, an AI should be used as the initial hormonal therapy. Adrenal suppression with aminoglutethimide is less commonly used because of greater side effects but is still effective. Responses to endocrine therapy tend to last longer than responses to cytotoxic chemotherapy, frequently lasting for 12 to 24 months. Second-line hormonal manipulation, for example, using a SERD (selective estrogen receptor downregulator), is a reasonable option if the tempo of disease progression allows it. This approach is usually helpful in patients who present with skeletal metastases. We also use IV bisphosphonates in this patient population because of their role in reduction of skeletal events.
Doses of commonly used drugs:
Tamoxifen, 20 mg PO daily
Anastrozole, 1 mg PO daily (alternative letrozole, 2.5 mg PO daily, or exemestane, 25 mg PO daily)
Fulvestrant, 250 mg IM (into buttock) monthly as either a single 5-mL or two 2.5-mL injections
Megestrol acetate, 40 mg PO q.i.d.
Aminoglutethimide, 250 mg PO q.i.d.; hydrocortisone, 100 mg PO in divided doses daily for the first 2 weeks, then 40mg PO in divided doses daily. Fludrocortisone, 0.05 to 0.1 mg PO may be given daily or every other day if there is evidence of salt wasting.
IV bisphosphonates Zoledronic acid 4 mg over 15 minutes Pamidronate 60 to 90 mg over 1 to 2 hours.
Complications of therapy. Acute toxicities are primarily hematologic and gastrointestinal. Subacute toxicities include alopecia, hemorrhagic cystitis, hypertension, edema, and psychoneurologic abnormalities. Chronic or long-term toxicities may be cardiac, neoplastic, or psychoneurologic. Dose modifications for the more common problems are given in Table 10.5. These guidelines are designed to be helpful in selecting a course of therapy that will be effective with the least risk of life-threatening Toxicity. 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 4 should be consulted for the individual toxicities, precautions, and toxicity-prevention measures for each drug.
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 b.i.d., 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. Whereas 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 treatingwomen with Factor V Leiden who begin treatment with tamoxifen, AIs or other SERMs in the prevention or adjuvant setting.
Albain K, Nag S, Calderillo-Ruiz G, et al. Global phase III study of gemcitabine plus paclitaxel vs. paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival. Proc Am Soc Clin Oncol 2004;23:5. Abstract 510. American Joint Committee on Cancer. Breast. AJCC staging manual, 6th ed. New York:Springer-Verlag, 2002:221 240.
Auquier A, Rutqvist LE, Host H, et al. Post-mastectomy megavoltage radiotherapy: the Oslo and Stockholm trials. Eur J Cancer 1992;28(2 3):433 437.
Bonadonna G, Valagussa P. Adjuvant systemic therapy for resectable breast cancer. J Clin Oncol 1985;3:259 275.
The Breast International Group (BIG) 1 98 Collaborative Group. A comparison of letrozole and tamoxifen in post-menopausal women with early breast cancer. N Engl J Med 2005;353:2747 2757.
Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347(9017):1713 1727.
Coombes RC, Hall E, Gibson LJ, et al. The Intergroup Exemestane Study: a randomized trial of exemestane after 2 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081 1092.
Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996;348:1189 1196.
Early Breast Cancer Trialists'Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and a 15-year survival :an overview of the randomized trials. Lancet 2005;365:1687 1717.
Fisher B, Costantino JP, Wickerham DL, et al. Surgical adjuvant breast and bowel project P 1 Study. J Natl Cancer Inst 1998; 90:1371 1388.
Fisher B, Dignam J, Mamounas EP, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eightyear results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14(7):1982 1992.
Fowble BL, Solin LJ, Schultz DJ, et al. Ten year results of conservative surgery and irradiation for stage I and II breast cancer. Int J Radiat Oncol Biol Phys 1991;21:269 277.
Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh international conference on adjuvant therapy of primary breast cancer. J Clin Oncol 2001;19:3817 3827.
Henderson IC, Berry D, Demetri G, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive breast cancer. Proc Am Soc Clin Oncol 1998;17:101a. Howell A, Cuzick J, Baum M, et al. Results, of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial after completion of 5 years of adjuvant treatment for breast cancer. Lancet 2005; 365:60 62.
Ingle JN, Krook JE, Green SJ, et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol 1986;4:178 185.
Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole (Femara) versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596 2606.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence in tamoxifen-treated, node negative breast cancer. N Engl J Med 2004;351:2817 2826.
Phillips K-A, Andrulis IL, Goodwin PH. Breast Carcinomas arising in carriers of mutations in BRCA1 or BRCA2: are they prognostically different? J Clin Oncol 1999;17:3653 3663.
Pickle LW, Johnson KA. Estimating the long-term probability of developing breast cancer. J Natl Cancer Inst 1989;81:1854 1855.
PritchardKI, Paterson AH, PaulNA, et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy forwomen with breast cancer. J Clin Oncol 1996;14(10):2731 2737.
Rivkin SE, Green S, Metch B, et al. Adjuvant CMFVP vs tamoxifen vs concurrent CMFVP and tamoxifen for postmenopausal, nodepositive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol 1994;12:2078 2085.
Ross RK, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328 332.
Singeltary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20:3628 3636.
Slamon DJ, Leyland-Jones B, Shak S, et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783 792.
Smith IE, Ross Gm. Breast radiotherapy after lumpectomy-no longer always necessary. N Engl J Med 2004;351:1021 1023.
Taylor SG, Gelman RSFalkson G, et al. IV Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med 1986;104:455 461.
Van Dam FSAM, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for highrisk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90:210 218.