Determining the ER, PR, and HER2 status of the tumor at the time of diagnosis of early breast cancer and, if possible, at the time of recurrence is critical, both to gauge a patient’s prognosis and to determine the best treatment regimen. In addition to ER status and PR status, the rate at which tumor divides (assessed by an immunohistochemical stain for Ki-67) and the grade and differentiation of the cells are also important prognostic factors. These markers may be obtained on core biopsy or surgical specimens. Patients whose tumors are hormone receptor-positive tend to have a more indolent disease course than those whose tumors are receptor-negative. Moreover, treatment with an antihormonal agent is an essential component of therapy for hormone-receptor positive breast cancer at any stage. While up to 60% of patients with metastatic breast cancer will respond to hormonal manipulation if their tumors are ER-positive, less than 5% of patients with metastatic, ER-negative tumors will respond.
Another key element in determining treatment and prognosis is the amount of the HER2 oncogene present in the cancer. HER2 overexpression is measured by an immunohistochemical assay that is scored using a numerical system: 0 and 1+ are considered negative for overexpression, 2+ is borderline/indeterminate, and 3+ is overexpression. In the case of 2+ expression, fluorescence in situ hybridization (FISH) is recommended to more accurately assess HER2 amplification. According to the College of American Pathologists, a FISH score of less than 1.8 is negative for amplification, 1.8-2.2 is indeterminant, and greater than 2.2 is amplified. The presence of HER2 amplification and overexpression is of prognostic significance and predicts the response to trastuzumab.
Individually these biomarkers are predictive and thus provide insight to guide appropriate therapy. Moreover, when combined they provide useful information regarding risk of recurrence and prognosis. In general, tumors that lack expression of HER2, ER, and PR (“triple negative”) have a higher risk of recurrence and metastases and are associated with a worse survival compared with other types. Neither endocrine therapy nor HER2-targeted agents are useful for this type of breast cancer, leaving chemotherapy as the only treatment option. In contrast, patients with early stage, hormone receptor-positive breast cancer may not benefit from the addition of chemotherapy to hormonal treatments. Several molecular tests have been developed to assess risk of recurrence and to predict which patients are most likely to benefit from chemotherapy. Oncotype DX (Genomic Health) evaluates the expression of 21 genes relating to ER, PR, HER2, and proliferation in a tumor specimen and categorizes a patient’s risk of recurrence (recurrence score) as high, intermediate, or low risk. In addition to providing prognostic information, the test also has predictive value since studies have shown that patients in the high-risk category are most likely to respond to chemotherapy. This test is primarily indicated for ER-positive, node-negative tumors but at least one study has shown that it may also have value in node-positive tumors. Centralized testing for ER, PR, HER2, and Ki67 by standard immunohistochemical techniques is able to provide as much prognostic information as Oncotype DX. Mammaprint (Agendia) is another assay that is available for evaluating prognosis. This 70-gene signature is FDA-approved and may be performed on fresh frozen tumor tissue taken at the time of a patient’s surgery. This test classifies patients into good and poor prognostic groups to predict clinical outcome and may be used on patients with hormone receptor positive or negative breast cancer. Several other assays are in development to better stratify patients based on risk assessment.
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Clearly, not all breast cancer is systemic at the time of diagnosis. For this reason, a pessimistic attitude concerning the management of breast cancer is unwarranted. Most patients with early breast cancer can be cured. Treatment with a curative intent is advised for clinical stage I, II, and III disease (see Tables 17–3 and 39–4). Patients with locally advanced (T3, T4) and even inflammatory tumors may be cured with multimodality therapy, but in most, palliation is all that can be expected. Treatment with palliative intent is appropriate for all patients with stage IV disease and for patients with unresectable local cancers.
A. Choice and Timing of Primary Therapy
The extent of disease and its biologic aggressiveness are the principal determinants of the outcome of primary therapy. Clinical and pathologic staging help in assessing extent of disease (Table 17–3), but each is to some extent imprecise. Other factors such as tumor grade, hormone receptor assays, and HER2 oncogene amplification are of prognostic value and are key to determining systemic therapy, but are not important in determining the type of local therapy.
Controversy has surrounded the choice of primary therapy of stages I, II, and III breast carcinoma. Currently, the standard of care for stage I, stage II, and most stage III cancer is surgical resection followed by adjuvant radiation or systemic therapy, or both, when indicated. Neoadjuvant therapy is becoming more popular since large tumors may be shrunk by chemotherapy prior to surgery, making some patients who require mastectomy candidates for lumpectomy. It is important for patients to understand all of the surgical options, including reconstructive options, prior to having surgery. Patients with large primary tumors, inflammatory cancer, or palpably enlarged lymph nodes should have staging scans performed to rule out distant metastatic disease prior to definitive surgery. In general, adjuvant systemic therapy is started when the breast has adequately healed, usually within 4-8 weeks after surgery. While no prospective studies have defined the appropriate timing of adjuvant chemotherapy, one retrospective population-based study has suggested that chemotherapy should be initiated within 12 weeks of surgery to avoid a compromise in relapse-free and overall survival.
1. Breast-conserving therapy
Multiple, large, randomized studies including the Milan and NSABP trials show that disease-free and overall survival rates are similar for patients with stage I and stage II breast cancer treated with partial mastectomy (breast-conserving lumpectomy) plus axillary dissection followed by radiation therapy and for those treated by modified radical mastectomy (total mastectomy plus axillary dissection).
Tumor size is a major consideration in determining the feasibility of breast conservation. The lumpectomy trial of the NSABP randomized patients with tumors as large as 4 cm. To achieve an acceptable cosmetic result, the patient must have a breast of sufficient size to enable excision of a 4-cm tumor without considerable deformity. Therefore, large tumor size is only a relative contraindication. Subareolar tumors, also difficult to excise without deformity, are not contraindications to breast conservation. Clinically detectable multifocality is a relative contraindication to breast-conserving surgery, as is fixation to the chest wall or skin or involvement of the nipple or overlying skin. The patient—not the surgeon—should be the judge of what is cosmetically acceptable. Given the relatively high risk of poor outcome after radiation, concomitant scleroderma is a contraindication to breast-conserving surgery. A history of prior therapeutic radiation to the ipsilateral breast or chest wall (or both) is also a contraindication for breast conservation.
Axillary dissection is primarily used to properly stage cancer and plan radiation and systemic therapy. Intraoperative lymphatic mapping and sentinel node biopsy identify lymph nodes most likely to harbor metastases if present (Figure 17–8). Sentinel node biopsy is a reasonable alternative to axillary dissection in selected patients with invasive cancer. If sentinel node biopsy reveals no evidence of axillary metastases, it is highly likely that the remaining lymph nodes are free of disease and axillary dissection may be omitted. An important study from the American College of Surgeons Oncology group randomized women with sentinel node metastases to undergo completion of axillary dissection or to receive no further axillary treatment after lumpectomy; no difference in survival was found, showing that axillary dissection for selected node-positive women is not necessary. These results challenge standard treatment regimens.
Sentinel node. (Used with permission from Giuliano AE.)
Breast-conserving surgery with radiation is the preferred form of treatment for patients with early-stage breast cancer. Despite the numerous randomized trials showing no survival benefit of mastectomy over breast-conserving partial mastectomy and irradiation, breast-conserving surgery still appears to be underutilized.
Modified radical mastectomy is the standard therapy for most patients with early-stage breast cancer. This operation removes the entire breast, overlying skin, nipple, and areolar complex as well as the underlying pectoralis fascia with the axillary lymph nodes in continuity. The major advantage of modified radical mastectomy is that radiation therapy may not be necessary, although radiation may be used when lymph nodes are involved with cancer or when the primary tumor is large (≥ 5 cm). The disadvantage of mastectomy is the cosmetic and psychological impact associated with breast loss. Radical mastectomy, which removes the underlying pectoralis muscle, should be performed rarely, if at all. Axillary node dissection is not indicated for noninfiltrating cancers because nodal metastases are rarely present. Skin-sparing and nipple-sparing mastectomy is currently gaining favor but is not appropriate for all patients. Breast-conserving surgery and radiation should be offered whenever possible, since most patients would prefer to save the breast. Breast reconstruction, immediate or delayed, should be discussed with patients who choose or require mastectomy. Patients should have an interview with a reconstructive plastic surgeon to discuss options prior to making a decision regarding reconstruction. Time is well spent preoperatively in educating the patient and family about these matters.
Radiotherapy after partial mastectomy consists of 5-7 weeks of five daily fractions to a total dose of 5000-6000 cGy. Most radiation oncologists use a boost dose to the cancer location. Early results of studies examining the utility and recurrence rates after intraoperative radiation or dose dense radiation in which the time course of radiation is shortened show promising results similar to standard techniques. Accelerated partial breast irradiation, in which only the portion of the breast from which the tumor was resected is irradiated for 1-2 weeks, appears effective in achieving local control. The American Society of Breast Surgeons Registry Trial reported that in 1440 patients treated with brachytherapy, the 3-year actuarial rate of ipsilateral breast cancer recurrence was 2.15% and no unexpected adverse events were seen. Long-term follow-up will be necessary as will results from ongoing randomized clinical trials comparing brachytherapy to standard external beam radiation.
Current studies suggest that radiotherapy after mastectomy may improve recurrence rates and survival in patients with tumors 5 cm or more or positive lymph nodes. Researchers are also examining the utility of axillary irradiation as an alternative to axillary dissection in the clinically node-negative patient with sentinel node micrometastases. A Canadian trial (MA20) of postoperative nodal irradiation after lumpectomy and axillary dissection shows improved survival with nodal irradiation.
D. Adjuvant Systemic Therapy
The goal of systemic therapy, including hormone modulating drugs (endocrine therapy), cytotoxic chemotherapy, and the HER2-targeted agent trastuzumab, is to kill cancer cells that have escaped the breast and axillary lymph nodes as micrometastases before they become macrometastases (ie, stage IV cancer). Systemic therapy improves survival and is advocated for most patients with curable breast cancer. In practice, most medical oncologists are currently using adjuvant chemotherapy for patients with either node-positive or higher-risk (eg, hormone receptor-negative or HER2-positive) node-negative breast cancer and using endocrine therapy for all hormone receptor–positive invasive breast cancer unless contraindicated. Prognostic factors other than nodal status that are used to determine the patient’s risks of recurrence are tumor size, ER and PR status, nuclear grade, histologic type, proliferative rate, oncogene expression (Table 17–5), and patient’s age and menopausal status. In general, systemic chemotherapy decreases the chance of recurrence by about 30% and hormonal modulation decreases the risk of recurrence by 40%-50% (for hormone receptor–positive cancer). Systemic chemotherapy is usually given sequentially, rather than concurrently with radiation. In terms of sequencing, typically chemotherapy is given before radiation and endocrine therapy is started concurrent with or after radiation therapy.
Table 17–5.Prognostic factors in node-negative breast cancer. ||Download (.pdf) Table 17–5. Prognostic factors in node-negative breast cancer.
|Prognostic Factors ||Increased Recurrence ||Decreased Recurrence |
|Size ||T3, T2 ||T1, T0 |
|Hormone receptors ||Negative ||Positive |
|DNA flow cytometry ||Aneuploid ||Diploid |
|Histologic grade ||High ||Low |
|Tumor labeling index ||< 3% ||> 3% |
|S phase fraction ||> 5% ||< 5% |
|Lymphatic or vascular invasion ||Present ||Absent |
|Cathepsin D ||High ||Low |
|HER-2/neu oncogene ||High ||Low |
|Epidermal growth factor receptor ||High ||Low |
The long-term advantage of systemic therapy has been well established. All patients with invasive hormone receptor–positive tumors should consider the use of hormone-modulating therapy. Most patients with HER2-positive tumors should receive trastuzumab-containing chemotherapy regimens. In general, adjuvant systemic chemotherapy should not be given to women who have small node-negative breast cancers with favorable histologic findings and tumor markers. The ability to predict more accurately which patients with HER2-negative, hormone receptor-positive, lymph node-negative tumors should receive chemotherapy is improving with the advent of prognostic tools, such as Oncotype DX and mammaprint. These tests are undergoing prospective evaluation in two clinical trials (TAILORx and MINDACT).
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis involving over 28,000 women enrolled in 60 trials of adjuvant polychemotherapy versus no chemotherapy demonstrated a significant beneficial impact of chemotherapy on clinical outcome in early breast cancer. This study showed that adjuvant chemotherapy reduces the risk of recurrence and breast cancer–specific mortality in all women but also showed that women under the age of 50 derive the greatest benefit. On the basis of the superiority of anthracycline-containing regimens in metastatic breast cancer, both doxorubicin and epirubicin have been studied extensively in the adjuvant setting. Studies comparing Adriamycin (doxorubicin) and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) to cyclophosphamide-methotrexate-5-fluorouracil (CMF) have shown that treatments with anthracycline-containing regimens are at least as effective, and perhaps more effective, than treatment with CMF. The EBCTCG analysis including over 14,000 patients enrolled in trials comparing anthracycline-based regimens to CMF, showed a small but statistically significant improved disease-free and overall survival with the use of anthracycline-based regimens. It should be noted, however, that most of these studies included a mixed population of HER2-positive and HER2-negative breast cancer patients and were performed before the development of trastuzumab. Retrospective analyses of a number of these studies suggest that anthracyclines may be primarily effective in tumors with HER2 overexpression or alteration in the expression of topoisomerase IIa (the target of anthracyclines and close to the HER2 gene). Given this, for HER2-negative, node-negative breast cancer, four cycles of AC or six cycles of CMF are probably equally effective.
When taxanes (T = paclitaxel and docetaxel) emerged in the 1990s, multiple trials were conducted to evaluate their use in combination with anthracycline-based regimens. The majority of these trials showed an improvement in disease-free survival and at least one showed an improvement in overall survival with the taxane-based regimen. A meta-analysis of taxane versus nontaxane anthracycline-based regimen trials showed an improvement in disease-free and overall survival for the taxane-based regimens.
Several regimens have been reported including AC followed by paclitaxel or docetaxel (AC-T), TAC (docetaxel concurrent with AC), 5-fluorouracil (F)EC-docetaxel, and FEC-paclitaxel. Results from CALGB 9741 showed that compared with a standard dose regimen, administration of “dose-dense” AC-P chemotherapy (that is, in an accelerated fashion, in which the frequency of administration is increased without changing total dose or duration) with granulocyte colony stimulating factor (G-CSF) support led to improved both disease-free (82% vs 75% at 4 years) and overall survival (92% vs 90%). Exploratory subset analysis suggested that patients with hormone receptor–negative tumors derived the most benefit from the dose-dense approach.
The US Oncology trial 9735 compared four cycles of AC with four cycles of taxotere (docetaxel) and cyclophosphamide (TC). With a median of 7 years follow-up, this study showed a statistically significantly improved disease-free survival and overall survival in the patients who received TC. Until this, no trial had compared a nonanthracycline taxane-based regimen to an anthracycline-based regimen.
An important ongoing study (US Oncology 06090) is prospectively evaluating whether anthracyclines add any incremental benefit to a taxane-based regimen by comparing six cycles of TAC to six cycles of TC in HER2-negative breast cancer patients. A third arm was added to evaluate the benefit of adding bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), to TC. While awaiting the results of this trial, oncologists are faced with choosing from among the above treatment regimens for HER2-negative breast cancer. It is interesting to note a sharp decline in the use of anthracyclines has been observed since 2006. Given the benefits described above, taxanes are now used for most patients receiving chemotherapy for early breast cancer.
The overall duration of adjuvant chemotherapy still remains uncertain. However, based on the meta-analysis performed in the Oxford Overview (EBCTCG), the current recommendation is for 3-6 months of the commonly used regimens. Although it is clear that dose intensity to a specific threshold is essential, there is little, if any, evidence to support the long-term survival benefit of high-dose chemotherapy with stem cell support.
Chemotherapy side effects are now generally well controlled. Nausea and vomiting are abated with drugs that directly affect the central nervous system, such as ondansetron and granisetron. Infertility and premature ovarian failure are common side effects of chemotherapy, especially in women over the age of 40, and should be discussed with patients prior to starting treatment. The risk of life-threatening neutropenia associated with chemotherapy can be reduced by use of growth factors such as pegfilgrastim and filgrastim (G-CSF), which stimulate proliferation and differentiation of hematopoietic cells. Long-term toxicities from chemotherapy, including cardiomyopathy (anthracyclines), peripheral neuropathy (taxanes), and leukemia/myelodysplasia (anthracyclines and alkylating agents), remain a small but significant risk.
HER2 overexpression Approximately 20% of breast cancers are characterized by amplification of the HER2 oncogene leading to overexpression of the HER2 oncoprotein. The poor prognosis associated with HER2 overexpression has been drastically improved with the development of HER2-targeted therapy. Trastuzumab (Herceptin [H]), a monoclonal antibody that binds to HER2, has proved effective in combination with chemotherapy in patients with HER2 overexpressing metastatic and early breast cancer. In the adjuvant setting, the first and most commonly studied chemotherapy backbone used with trastuzumab is AC-T. Subsequently, the BCIRG006 study showed similar efficacy for AC-TH and a nonanthracycline-containing regimen, TCH (docetaxel, carboplatin, trastuzumab). Both were significantly better than AC-T in terms of disease-free and overall survival and TCH had a lower risk of cardiac toxicity. Both AC-TH and TCH are FDA-approved for nonmetastatic, HER2-positive breast cancer. In these regimens, trastuzumab is given with chemotherapy and then continues beyond the course of chemotherapy to complete a full year. The reporting of two trials in 2012 (the Herceptin Adjuvant [HERA] evaluating 1 vs 2 years of trastuzumab and the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure [PHARE] study evaluating 6 vs 12 months of trastuzumab) have thus far confirmed that 1 year of trastuzumab should remain the standard of care. At least one study (N9831) suggests that concurrent, rather than sequential, delivery of trastuzumab with chemotherapy may be more beneficial. Another question being addressed in trials is whether to treat small (> 1 cm), node-negative tumors with trastuzumab plus chemotherapy. Retrospective studies have shown that even small (stage T1a,b) HER2-positive tumors have a worse prognosis compared with same-sized HER2-negative tumors. The NSABP B43 study is also ongoing to evaluate whether the addition of trastuzumab to radiation therapy is warranted for DCIS.
Cardiomyopathy develops in a small but significant percent (1%-4%) of patients who receive trastuzumab-based regimens. For this reason, anthracyclines and trastuzumab are rarely given concurrently and cardiac function is monitored periodically throughout therapy.
Endocrine Therapy Adjuvant hormone modulation therapy is highly effective in decreasing recurrence and mortality by 25% in women with hormone receptor–positive tumors regardless of menopausal status. The traditional regimen has been 5 years of the estrogen-receptor antagonist/agonist tamoxifen until the 2012 reporting of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial in which 5 versus 10 years of adjuvant tamoxifen were compared. In this study, women who received 10 years of tamoxifen had a significantly improved disease free as well as overall survival, particularly after year 10. Though these results are impressive and potentially practice changing, the clinical application of long-term tamoxifen use must be discussed with patients individually, taking into consideration risks of tamoxifen such as secondary uterine cancers, venous thromboembolic events as well as side effects that impact quality of life. Ovarian ablation in premenopausal patients with ER-positive tumors may produce a benefit similar to that of adjuvant systemic chemotherapy. Whether the use of ovarian ablation plus tamoxifen (or an AI) is more effective than either measure alone is still unclear. In the Stockholm subset of the Zoladex in Premenopausal Patients (ZIPP) study, 927 premenopausal women were randomly assigned to goserelin, tamoxifen, the combination of both, or to no endocrine therapy for 2 years. With a median follow-up of 12.3 years, this substudy showed that goserelin and tamoxifen each significantly reduce the risk of recurrence of hormone receptor–positive breast cancer compared to control (goserelin 32%, [P = 0.005] and tamoxifen 27% [P = 0.018]), yet the combination of goserelin and tamoxifen was not superior to either treatment alone. This issue is still not settled and is being addressed in ongoing clinical trials (Suppression of Ovarian Function Trial [SOFT] and Tamoxifen and Exemestane Trial [TEXT]) that have not yet reported. AIs, including anastrozole, letrozole, and exemestane, reduce estrogen production and are also effective in the adjuvant setting for postmenopausal women. Approximately seven large randomized trials enrolling more than 24,000 patients have compared the use of AIs with tamoxifen or placebo as adjuvant therapy. All of these studies have shown small but statistically significant improvements in disease-free survival (absolute benefits of 2%-6%) with the use of AIs. In addition, AIs have been shown to reduce the risk of contralateral breast cancers and to have fewer associated serious side effects (such as endometrial cancers and thromboembolic events) than tamoxifen. However, they are associated with accelerated bone loss and an increased risk of fractures as well as a musculoskeletal syndrome characterized by arthralgias or myalgias (or both) in up to 50% of patients. The American Society of Clinical Oncology and the NCCN have recommended that postmenopausal women with hormone receptor–positive breast cancer be offered an AI either initially or after tamoxifen therapy. HER2 status should not affect the use or choice of hormone therapy.
Two randomized studies (ZO-FAST and ABCSG-12) have evaluated the use of an adjuvant intravenous bisphosphonate (zoledronic acid) in addition to standard local and systemic therapy. The results showed a 32%-40% relative reduction in the risk of cancer recurrence for hormone receptor–positive nonmetastatic breast cancer. In fact, at the San Antonio Breast Cancer Symposium in 2011, with a median follow-up of 76 months, the ABCSG-12 study reported improved overall survival for patients treated with zoledronic acid. Conflicting results have been reported from the AZURE study. In this randomized study that enrolled premenopausal and postmenopausal patients, there was no disease-free or overall survival benefits associated with the addition of zoledronic acid to endocrine therapy for the overall study population. However, a prespecified subset analysis in patients who were postmenopausal for at least 5 years did demonstrate a significant disease-free and overall survival benefit with the addition of the bisphosphonate. Side effects associated with intravenous bisphosphonate therapy include bone pain, fever, osteonecrosis of the jaw (rare), and renal failure. Currently, the adjuvant use of bisphosphonates and other bone stabilizing drugs, such as inhibitors of receptor activator of nuclear factor kappa B ligand (RANK-B), remains investigational.
4. Adjuvant therapy in older women
Data relating to the optimal use of adjuvant systemic treatment for women over the age of 65 are limited. Results from the EBCTCG overview indicates that while adjuvant chemotherapy yields a smaller benefit for older women compared with younger women, it still improves clinical outcomes. Moreover, individual studies do show that older women with higher risk disease derive benefits from chemotherapy. One study compared the use of oral chemotherapy (capecitabine) to standard chemotherapy in older women and concluded that standard chemotherapy is preferred. Another study (USO TC vs AC) showed that women over the age of 65 derive similar benefits from the taxane-based regimen as women who are younger. The benefits of endocrine therapy for hormone receptor-positive disease appear to be independent of age. In general, decisions relating to the use of systemic therapy should take into account a patient’s comorbidities and physiological age, more so than chronologic age.
The use of chemotherapy or endocrine therapy prior to resection of the primary tumor (neoadjuvant) is gaining popularity. This enables the assessment of in vivo chemosensitivity. Patients with hormone receptor–negative or HER2 positive breast cancer (or both) are more likely to have a pathologic complete response to neoadjuvant chemotherapy than those with hormone receptor–positive breast cancer. A complete pathologic response at the time of surgery is associated with improvement in survival. Neoadjuvant chemotherapy also increases the chance of breast conservation by shrinking the primary tumor in women who would otherwise need mastectomy for local control. Survival after neoadjuvant chemotherapy is similar to that seen with postoperative adjuvant chemotherapy. Neoadjuvant AI therapy has been evaluated in a phase II study involving 115 postmenopausal patients with hormone receptor-positive breast cancer. The overall response rate was 62% in this study, and 38% of patients initially ineligible for breast conservation were able to have lumpectomy. There is considerable concern as to the timing of sentinel lymph node biopsy (SLNB), since the chemotherapy may affect any cancer present in the lymph nodes. Several studies have shown that sentinel node biopsy can be done after neoadjuvant therapy. However, a large multicenter study, ACOSOG 1071, demonstrated a false-negative rate of 10.7%, well above the false-negative rate outside the neoadjuvant setting (< 1%-5%). Many physicians recommend performing SLNB before administering the chemotherapy in order to avoid a false-negative result and to aid in planning subsequent radiation therapy. Others prefer to perform SLNB after neoadjuvant therapy to avoid a second operation and assess postchemotherapy nodal status. If a complete dissection is necessary, this can be performed at the time of the definitive breast surgery.
Important questions remaining to be answered are the timing and duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, the use of combinations of hormonal therapy and chemotherapy as well as possibly targeted therapy, and the value of prognostic factors other than hormone receptors in predicting response to therapy.
Palliative treatments are those to manage symptoms, improve quality of life, and even prolong survival, without the expectation of achieving cure. Only 10% of patients have de novo metastatic breast cancer at the time of diagnosis. However, in most patients who have a breast cancer recurrence after initial local and adjuvant therapy, the recurrence presents as metastatic rather than local (in breast) disease. Breast cancer most commonly metastasizes to the liver, lungs, and bone, causing symptoms such as fatigue, change in appetite, abdominal pain, respiratory symptoms, or bone pain. Triple negative (ER-, PR-, HER2-negative) and HER2-positive tumors have a higher rate of brain metastases than hormone-receptor positive, HER2-negative tumors. Headaches, imbalance, vision changes, vertigo, and other neurologic symptoms may be signs of brain metastases.
A. Radiotherapy and Bisphosphonates
Palliative radiotherapy may be advised for primary treatment of locally advanced cancers with distant metastases to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement.
Palliative irradiation is of value also in the treatment of certain bone or soft-tissue metastases to control pain or avoid fracture. Radiotherapy is especially useful in the treatment of isolated bony metastases, chest wall recurrences, brain metastases, and acute spinal cord compression.
In addition to radiotherapy, bisphosphonate therapy has shown excellent results in delaying and reducing skeletal events in women with bony metastases. Zoledronic acid is an FDA-approved intravenous bisphosphonate given monthly for bone metastases from breast cancer. Denosumab, a fully human monoclonal antibody that targets RANK-ligand, was approved by the FDA in 2010 for the treatment of advanced breast cancer causing bone metastases, based on data showing that it reduced the time to first skeletal-related event (eg, pathologic fracture) compared to zoledronic acid.
Caution should be exercised when combining radiation therapy with chemotherapy because toxicity of either or both may be augmented by their concurrent administration. In general, only one type of therapy should be given at a time unless it is necessary to irradiate a destructive lesion of weight-bearing bone while the patient is receiving another regimen. The regimen should be changed only if the disease is clearly progressing. This is especially difficult to determine for patients with destructive bone metastases, since changes in the status of these lesions are difficult to determine radiographically.
1. Endocrine Therapy for Metastatic Disease
Targeted therapy refers to agents that are directed specifically against a protein or molecule expressed uniquely on tumor cells or in the tumor microenvironment. The first targeted therapy was the use of antiestrogen therapy in hormone receptor–positive breast cancer. The administration of hormones (eg, estrogens, androgens, progestins; Table 17–6); ablation of the ovaries, adrenals, or pituitary; administration of drugs that block hormone receptors (such as tamoxifen) or drugs that block the synthesis of hormones (such as AIs) have all been shown to be effective in hormone receptor–positive metastatic breast cancer. Palliative treatment of metastatic cancer should be based on the ER status of the primary tumor or the metastases. Because only 5%-10% of women with ER-negative tumors respond, they should not receive endocrine therapy except in unusual circumstances, for example, in an older patient who cannot tolerate chemotherapy. The rate of response is nearly equal in premenopausal and postmenopausal women with ER-positive tumors. A favorable response to hormonal manipulation occurs in about one-third of patients with metastatic breast cancer. Of those whose tumors contain ER, the response is about 60% and perhaps as high as 80% for patients whose tumors contain PR as well. The choice of endocrine therapy depends on the menopausal status of the patient. Women within 1 year of their last menstrual period are arbitrarily considered to be premenopausal and should receive tamoxifen therapy or rarely ovarian ablation, whereas women whose menses ceased more than a year before are postmenopausal and may receive tamoxifen or an AI. Women with ER-positive tumors who do not respond to first-line endocrine therapy or experience progression should be given a different form of hormonal manipulation. Because the quality of life during endocrine manipulation is usually superior to that during cytotoxic chemotherapy, it is best to try endocrine manipulation whenever possible. However, when receptor status is unknown, disease is progressing rapidly or involves visceral organs, chemotherapy should be used as first-line treatment.
The Premenopausal Patient
Primary Hormonal Therapy The potent SERM tamoxifen is by far the most common and preferred method of hormonal manipulation in the premenopausal patient, in large part because it can be given with less morbidity and fewer side effects than cytotoxic chemotherapy and does not require oophorectomy. Tamoxifen is given orally in a dose of 20 mg daily. The average remission associated with tamoxifen lasts about 12 months.
There is no significant difference in survival or response between tamoxifen therapy and bilateral oophorectomy. Bilateral oophorectomy is less desirable than tamoxifen in premenopausal women because tamoxifen is so well tolerated. However, oophorectomy can be achieved rapidly and safely either by surgery, by irradiation of the ovaries if the patient is a poor surgical candidate, or by chemical ovarian ablation using a gonadotropin-releasing hormone (GnRH) analog. Oophorectomy presumably works by eliminating estrogens, progestins, and androgens, which stimulate growth of the tumor. AIs should not be used in a patient with functioning ovaries since they do not block ovarian production of estrogen.
Secondary or Tertiary Hormonal Therapy Patients who do not respond to tamoxifen or ovarian ablation may be treated with chemotherapy or may try a second endocrine regimen, such as GnRH analog plus AI. Whether to opt for chemotherapy or another endocrine measure depends largely on the sites of metastatic disease (visceral being more serious than bone-only, thus sometimes warranting the use of chemotherapy), the disease burden, the rate of growth of disease, and patient preference. Patients who take chemotherapy and then later have progressive disease may subsequently respond to another form of endocrine treatment (Table 17–6). The optimal choice for secondary endocrine manipulation has not been clearly defined for the premenopausal patient.
Patients who improve after oophorectomy but subsequently relapse should receive tamoxifen or an AI; if one fails, the other may be tried. Megestrol acetate, a progesterone agent, may also be considered. Adrenalectomy or hypophysectomy, procedures rarely done today, induced regression in 30%-50% of patients who previously responded to oophorectomy. Pharmacologic hormonal manipulation has replaced these invasive procedures.
The Postmenopausal Patient
Primary Hormonal Therapy For postmenopausal women with metastatic breast cancer amenable to endocrine manipulation, tamoxifen or an AI is the initial therapy of choice. The side effect profile of AIs differs from tamoxifen and may be more effective. The main side effects of tamoxifen are nausea, skin rash, and hot flushes. Rarely, tamoxifen induces hypercalcemia in patients with bony metastases. Tamoxifen also increases the risk of venous thromboembolic events and uterine hyperplasia and cancer. The main side effects of AIs include hot flushes, vaginal dryness, and joint stiffness; however, osteoporosis and bone fractures are significantly higher than with tamoxifen. Phase II data from the randomized Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST) suggest that the pure estrogen antagonist, fulvestrant may be even more effective than front-line anastrozole in terms of time to progression. The combination of fulvestrant plus anastrozole may also be more effective than anastrozole alone, though two studies evaluating this question have yielded conflicting results.
Secondary or Tertiary Hormonal Therapy AIs are also used for the treatment of advanced breast cancer in postmenopausal women after tamoxifen treatment. In the event that the patient responds to AI but then has progression of disease, fulvestrant, has shown efficacy with about 20%-30% of women benefiting from use. Postmenopausal women who respond initially to a SERM or AI but later manifest progressive disease may be crossed over to another hormonal therapy. Until recently, patients who experienced disease progression on or after treatment with a SERM or AI were routinely offered chemotherapy. This standard practice changed in 2012 with the approval of everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (MTOR)—a protein whose activation has been associated with the development of endocrine resistance. A phase III, placebo-controlled trial (BOLERO-2) evaluated exemestane with or without everolimus in 724 patients with AI-resistant, hormone receptor–positive metastatic breast cancer, and at interim analysis found that patients treated with everolimus had a significantly improved progression free survival (10.6 months vs 4.1 months; HR, 0.36; 95% CI, 0.27-0.47; P < 0.001). Androgens (such as testosterone) have many toxicities and should be used infrequently. As in premenopausal patients, neither hypophysectomy nor adrenalectomy should be performed. High-dose estrogen therapy has also paradoxically been shown to induce responses in advanced breast cancer. A study that evaluated the use of low-dose (6 mg) versus high-dose (30 mg) estradiol daily orally for postmenopausal women with metastatic AI-resistant breast cancer showed that the two doses yielded similar clinical benefit rates (29% and 28%, respectively) and, as expected, the higher dose was associated with more adverse events than the low dose.
Newer Agents in Development Although endocrine therapy can lead to disease control for months to years in some patients, de novo and acquired resistance to hormonal manipulation remains an enormous barrier to the effective treatment of these patients. Thus, molecularly targeted agents are still needed to circumvent signaling pathways that lead to drug resistance. A randomized phase II study evaluating letrozole with or without an oral cyclin-D kinase (cdk) 4/6 inhibitor for the first-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer was reported at the San Antonio Breast Cancer Symposium in December 2012. A striking and highly significant 18.6 months improvement in progression free survival was observed with the cdk4/6-inhibitor (26.1 months with cdk 4/6 inhibitor vs 7.5 months in control arm). Phase III evaluation of this promising molecule is being planned.
For patients with HER2 overexpressing or amplified tumors, trastuzumab plus chemotherapy has been shown to significantly improve clinical outcomes including survival compared to chemotherapy alone. Trastuzumab plus chemotherapy was therefore the standard first-line treatment for HER2-positive metastatic breast cancer until 2012 when pertuzumab was granted FDA approval. Pertuzumab is a monoclonal antibody that targets the extracellular domain of HER2 at a different epitope than targeted by trastuzumab and inhibits receptor dimerization. A phase III placebo-controlled randomized study (CLEOPATRA) showed that patients treated with the combination of pertuzumab, trastuzumab, and docetaxel had a significantly longer progression free survival (18.5 months vs 12.4 months; HR, 0.62; 95% CI, 0.51-0.75; P < 0.001) compared with those treated with docetaxel and trastuzumab. Longer follow up revealed a significant overall survival benefit associated with pertuzumab as well.
Lapatinib is an oral targeted drug that works by inhibiting the intracellular tyrosine kinases of the epidermal growth factor and HER2 receptors. This drug is FDA-approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer in combination with capecitabine, thus, a completely oral regimen. The combination of trastuzumab plus lapatinib has been shown to be more effective than lapatinib alone for trastuzumab-resistant metastatic breast cancer. Moreover, several trials have shown a significant clinical benefit for continuing HER2-targeted agents beyond progression. T-DM1 (trastuzumab emtansine) is a novel antibody drug conjugate in which trastuzumab is stably linked to a derivative of maytansine, enabling targeted delivery of the cytotoxic chemotherapy to HER2-overexpressing cells. The phase III trial (EMILIA) that evaluated T-DM1 in patients with HER2-positive, trastuzumab-pretreated advanced disease showed that T-DM1 is associated with improved progression free and overall survival compared to lapatinib plus capecitabine (EMILIA). Regulatory approval of T-DM1 is expected in 2013. Evaluation of T-DM1 in combination with pertuzumab for the first-line treatment of advanced breast cancer is ongoing in the phase III MARIANNE study and trials evaluating the use of these agents in early breast cancer are being planned. Several other drugs targeting the HER2 pathway are in development including everolimus, afatinib, neratinib, and HER2-targeted vaccines.
3. Targeting angiogenesis
Bevacizumab is a monoclonal antibody directed against VEGF. This growth factor stimulates endothelial proliferation and neoangiogenesis in cancer. A phase III randomized trial (E2100) in women with metastatic breast cancer showed increased response rate and progression-free survival rate with the combination of bevacizumab and paclitaxel as first-line treatment compared with paclitaxel alone; however, there was no significant overall survival benefit. This led to the accelerated FDA approval of bevacizumab in early 2008. Since that time, two additional prospective randomized clinical trials (AVADO and RIBBON-1) have reported that the addition of bevacizumab to standard chemotherapy improves disease-free survival and objective response rates compared with single-agent chemotherapy alone. A benefit in overall survival has not been demonstrated. Side effects from bevacizumab include hypertension, bleeding, and thromboembolic events.
While initial results were promising, the lack of both survival benefit and data to identify those tumor types most likely to benefit from bevacizumab resulted in the FDA revoking its approval of bevacizumab for metastatic breast cancer in 2011.
4. Targeting “triple-negative” breast cancer
Until very recently, breast cancers lacking expression of the hormone receptors ER and PR, and HER2 have only been amenable to therapy with cytotoxic chemotherapy. This type of “triple-negative” breast cancer, while heterogeneous, generally behaves aggressively and is associated with a poor prognosis. Newer classes of targeted agents are being evaluated specifically for triple-negative breast cancer. Some triple-negative breast cancers may be characterized by an inability to repair double-strand DNA breaks (due to mutation or epigenetic silencing of the BRCA gene). Poly-ADP ribose-polymerase (PARP) inhibitors are a class of agents that prevent the repair of single strand DNA breaks and are showing promise in BRCA-mutated and triple-negative breast cancer. One relatively small randomized phase II clinical trial evaluating gemcitabine plus carboplatin with or without an agent that inhibits PARP (BSI-201) for triple-negative metastatic breast cancer showed improved clinical outcomes, including improved overall survival for PARP inhibitor–treated patients. However, the phase III randomized study of this agent failed to meet its endpoints, possibly relating to its relative weak inhibition of PARP. Research in this area is rapidly expanding with multiple clinical trials of other PARP inhibitors and other molecularly targeted agents ongoing.
Table 17–6.Agents commonly used for hormonal management of metastatic breast cancer. ||Download (.pdf) Table 17–6. Agents commonly used for hormonal management of metastatic breast cancer.
|Drug ||Action ||Dose, Route, Frequency ||Major Side Effects |
|Tamoxifen citrate (Nolvadex) ||SERM ||20 mg orally daily ||Hot flushes, uterine bleeding, thrombophlebitis, rash |
|Fulvestrant (Faslodex) ||Steroidal estrogen receptor antagonist ||500 mg intramuscularly day 1, 15, 29 and then monthly ||Gastrointestinal upset, headache, back pain, hot flushes, pharyngitis |
|Toremifene citrate (Fareston) ||SERM ||40 mg orally daily ||Hot flushes, sweating, nausea, vaginal discharge, dry eyes, dizziness |
|Diethylstilbestrol (DES) ||Estrogen ||5 mg orally three times daily ||Fluid retention, uterine bleeding, thrombophlebitis, nausea |
|Goserelin (Zoladex) ||Synthetic luteinizing hormone releasing analogue ||3.6 mg subcutaneously monthly ||Arthralgias, blood pressure changes, hot flushes, headaches, vaginal dryness |
|Megestrol acetate (Megace) ||Progestin ||40 mg orally four times daily ||Fluid retention |
|Letrozole (Femara) ||AI ||2.5 mg orally daily ||Hot flushes, arthralgia/arthritis, myalgia, bone loss |
|Anastrozole (Arimidex) ||AI ||1 mg orally daily ||Hot flushes, skin rashes, nausea and vomiting, bone loss |
|Exemestane (Aromasin) ||AI ||25 mg orally daily ||Hot flushes, increased arthralgia/arthritis, myalgia, bone loss |
Cytotoxic drugs should be considered for the treatment of metastatic breast cancer: (1) if visceral metastases are present (especially brain, liver, or lymphangitic pulmonary); (2) if hormonal treatment is unsuccessful or the disease has progressed after an initial response to hormonal manipulation; or (3) if the tumor is ER-negative or HER2-positive. Prior adjuvant chemotherapy does not seem to alter response rates in patients who relapse. A number of chemotherapy drugs (including vinorelbine, paclitaxel, docetaxel, gemcitabine, ixabepilone, carboplatin, cisplatin, capecitabine, albumin-bound paclitaxel, eribulin, and liposomal doxorubicin) may be used as single agents with first-line objective response rates ranging from 30% to 50%.
Combination chemotherapy yields statistically significantly higher response rates and progression-free survival rates, but has not been conclusively shown to improve overall survival rates compared with sequential single-agent therapy. Combinations that have been tested in phase III studies and have proven efficacy compared with single-agent therapy include capecitabine/docetaxel, gemcitabine/paclitaxel, and capecitabine/ixabepilone. Various other combinations of drugs have been tested in phase II studies, and a number of clinical trials are ongoing to identify effective combinations. For patients whose tumors have progressed after several lines of therapy and who are considering additional therapy, clinical trial participation with experimental drugs in phase I, II, or III testing should be encouraged.
In the past, high-dose chemotherapy and autologous bone marrow or stem cell transplantation aroused widespread interest for the treatment of metastatic breast cancer. However, multiple clinical trials failed to show any improvement in survival with high-dose chemotherapy with stem cell transplant over conventional chemotherapy and the procedure is now rarely, if ever, performed for stage IV breast cancer.
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Stage of breast cancer is the most reliable indicator of prognosis (Table 17–7). Axillary lymph node status is the best-analyzed prognostic factor and correlates with survival at all tumor sizes. When cancer is localized to the breast with no evidence of regional spread after pathologic examination, the clinical cure rate with most accepted methods of therapy ranges from 75% to greater than 90%. In fact, patients with small mammographically detected biologically favorable tumors and no evidence of axillary spread have a 5-year survival rate greater than 95%. When the axillary lymph nodes are involved with tumor, the survival rate drops to 50%-70% at 5 years and probably around 25%-40% at 10 years. Increasingly, the use of biologic markers, such as ER, PR, grade, and HER2, is helping to identify high-risk tumor types as well as direct treatment used (see Biomarkers & Gene Expression Profiling). Tumors with marked aneuploidy have a poor prognosis (Table 17–5). Gene analysis studies, such as Oncotype Dx, can predict disease-free survival for some subsets of patients.
Table 17–7.Approximate survival (%) of patients with breast cancer by TNM stage. ||Download (.pdf) Table 17–7. Approximate survival (%) of patients with breast cancer by TNM stage.
|TNM Stage ||5 Years ||10 Years |
|0 ||95 ||90 |
|I ||85 ||70 |
|IIA ||70 ||50 |
|IIB ||60 ||40 |
|IIIA ||55 ||30 |
|IIIB ||30 ||20 |
|IV ||5-10 ||2 |
|All ||65 ||30 |
The mortality rate of breast cancer patients exceeds that of age-matched normal controls for nearly 20 years. Thereafter, the mortality rates are equal, though deaths that occur among breast cancer patients are often directly the result of tumor. Five-year statistics do not accurately reflect the final outcome of therapy.
In general, breast cancer appears to be somewhat more malignant in younger than in older women, and this may be related to the fact that fewer younger women have ER-positive tumors. Adjuvant systemic chemotherapy, in general, improves survival by about 30% and adjuvant hormonal therapy by about 25%.
For those patients whose disease progresses despite treatment, studies suggest supportive group therapy may improve survival. As they approach the end of life, such patients will require meticulous palliative care (see Chapter 5).
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After primary therapy, patients with breast cancer should be monitored long-term in order to detect recurrences and to observe the opposite breast for a second primary carcinoma. Local and distant recurrences occur most frequently within the first 2-5 years. During the first 2 years, most patients should be examined every 6 months (with mammogram every 6 months on the affected breast), then annually thereafter. Since these women are at an increased risk for local or contralateral breast tumor, MRI is being used by many breast surgeons to monitor patients with prior malignancies. Most insurance companies will reimburse for this. Special attention is paid to the contralateral breast because a new primary breast malignancy will develop in 20%-25% of patients. In some cases, metastases are dormant for long periods and may appear 10-15 years or longer after removal of the primary tumor. Although studies have failed to show an adverse effect of hormonal replacement in disease-free patients, it is rarely used after breast cancer treatment, particularly if the tumor was hormone receptor positive. Even pregnancy has not been associated with shortened survival of patients rendered disease free—yet many oncologists are reluctant to advise a young patient with breast cancer that it is safe to become pregnant, and most will not support prescribing hormone replacement for the postmenopausal breast cancer patient. The use of estrogen replacement for conditions such as osteoporosis, vaginal dryness, and hot flushes may be considered for a woman with a history of breast cancer after discussion of the benefits and risks; however, it is not routinely recommended, especially given the availability of nonhormonal agents for these conditions (such as bisphosphonates and denosumab for osteoporosis). Vaginal estrogen is frequently used to treat vaginal atrophy with no obvious ill effects.
The incidence of local recurrence correlates with tumor size, the presence and number of involved axillary nodes, the histologic type of tumor, the presence of skin edema or skin and fascia fixation with the primary tumor, and the type of definitive surgery and local irradiation. Local recurrence on the chest wall after total mastectomy and axillary dissection develops in as many as 8% of patients. When the axillary nodes are not involved, the local recurrence rate is less than 5%, but the rate is as high as 25% when they are heavily involved. A similar difference in local recurrence rate was noted between small and large tumors. Factors such as multifocal cancer, in situ tumors, positive resection margins, chemotherapy, and radiotherapy have an effect on local recurrence in patients treated with breast-conserving surgery. Adjuvant systemic therapy greatly decreases the rate of local recurrence.
Chest wall recurrences usually appear within the first several years but may occur as late as 15 or more years after mastectomy. All suspicious nodules and skin lesions should be biopsied. Local excision or localized radiotherapy may be feasible if an isolated nodule is present. If lesions are multiple or accompanied by evidence of regional involvement in the internal mammary or supraclavicular nodes, the disease is best managed by radiation treatment of the entire chest wall including the parasternal, supraclavicular, and axillary areas and usually by systemic therapy.
Local recurrence after mastectomy usually signals the presence of widespread disease and is an indication for studies to search for evidence of metastases. Distant metastases will develop within a few years in most patients with locally recurrent tumor after mastectomy. When there is no evidence of metastases beyond the chest wall and regional nodes, irradiation for cure after complete local excision should be attempted. After partial mastectomy, local recurrence does not have as serious a prognostic significance as after mastectomy. However, those patients in whom a recurrence develops have a worse prognosis than those who do not. It is speculated that the ability of a cancer to recur locally after radiotherapy is a sign of aggressiveness and resistance to therapy. Completion of the mastectomy should be done for local recurrence after partial mastectomy; some of these patients will survive for prolonged periods, especially if the breast recurrence is DCIS or occurs more than 5 years after initial treatment. Systemic chemotherapy or hormonal treatment should be used for women in whom disseminated disease develops or those in whom local recurrence occurs.
B. Breast Cancer Survivorship Issues
Given that most women with nonmetastatic breast cancer will be cured, a significant number of women face survivorship issues stemming from either the diagnosis or the treatment of the breast cancer. These challenges include psychological struggles, upper extremity lymphedema, cognitive decline (also called “chemo brain”), weight management problems, cardiovascular issues, bone loss, postmenopausal side effects, and fatigue. One randomized study reported that survivors who received psychological intervention from the time of diagnosis had a lower risk of recurrence and breast cancer–related mortality. A randomized study in older, overweight cancer survivors showed that diet and exercise reduced the rate of self-reported functional decline compared with no intervention. Cognitive dysfunction is a commonly reported symptom experienced by women who have undergone systemic treatment for early breast cancer. Studies are ongoing to understand the pathophysiology leading to this syndrome. An interesting study reported that 200 mg of modafinil daily improved speed and quality of memory as well as attention for breast cancer survivors dealing with cognitive dysfunction. This promising study requires validation in a larger clinical trial.
Significant edema of the arm occurs in about 10%-30% of patients after axillary dissection with or without mastectomy. It occurs more commonly if radiotherapy has been given or if there was postoperative infection. Partial mastectomy with radiation to the axillary lymph nodes is followed by chronic edema of the arm in 10%-20% of patients. Sentinel lymph node dissection has proved to be a more accurate form of axillary staging without the side effects of edema or infection. Judicious use of radiotherapy, with treatment fields carefully planned to spare the axilla as much as possible, can greatly diminish the incidence of edema, which will occur in only 5% of patients if no radiotherapy is given to the axilla after a partial mastectomy and lymph node dissection.
Late or secondary edema of the arm may develop years after treatment, as a result of axillary recurrence or infection in the hand or arm, with obliteration of lymphatic channels. When edema develops, a careful examination of the axilla for recurrence or infection is performed. Infection in the arm or hand on the dissected side s hould be treated with antibiotics, rest, and elevation. If there is no sign of recurrence or infection, the swollen extremity should be treated with rest and elevation. A mild diuretic may be helpful. If there is no improvement, a compressor pump or manual compression decreases the swelling, and the patient is then fitted with an elastic glove or sleeve. Most patients are not bothered enough by mild edema to wear an uncomfortable glove or sleeve and will treat themselves with elevation or manual compression alone. Benzopyrones have been reported to decrease lymphedema but are not approved for this use in the United States. Rarely, edema may be severe enough to interfere with use of the limb. Traditionally, patients were advised to avoid weight lifting with the ipsilateral arm to prevent a worsening in lymphedema. However, a prospective randomized study has shown that twice weekly progressive weight lifting improves lymphedema symptoms and exacerbations and improves extremity strength.
Breast reconstruction is usually feasible after total or modified radical mastectomy. Reconstruction should be discussed with patients prior to mastectomy, because it offers an important psychological focal point for recovery. Reconstruction is not an obstacle to the diagnosis of recurrent cancer. The most common breast reconstruction has been implantation of a silicone gel or saline prosthesis in the subpectoral plane between the pectoralis minor and pectoralis major muscles. Alternatively, autologous tissue can be used for reconstruction.
Autologous tissue flaps are aesthetically superior to implant reconstruction in most patients. They also have the advantage of not feeling like a foreign body to the patient. The most popular autologous technique currently is the transrectus abdominis muscle flap (TRAM flap), which is done by rotating the rectus abdominis muscle with attached fat and skin cephalad to make a breast mound. The free TRAM flap is done by completely removing a small portion of the rectus with overlying fat and skin and using microvascular surgical techniques to reconstruct the vascular supply on the chest wall. A latissimus dorsi flap can be swung from the back but offers less fullness than the TRAM flap and is therefore less acceptable cosmetically. An implant often is used to increase the fullness with a latissimus dorsi flap. Reconstruction may be performed immediately (at the time of initial mastectomy) or may be delayed until later, usually when the patient has completed adjuvant therapy. When considering reconstructive options, concomitant illnesses should be considered, since the ability of an autologous flap to survive depends on medical comorbidities. In addition, the need for radiotherapy may affect the choice of reconstruction as radiation may increase fibrosis around an implant or decrease the volume of a flap.
Data are insufficient to determine whether interruption of pregnancy improves the prognosis of patients who are identified to have potentially curable breast cancer and who receive definitive treatment during pregnancy. Theoretically, the high levels of estrogen produced by the placenta as the pregnancy progresses could be detrimental to the patient with occult metastases of hormone-sensitive breast cancer. However, retrospective studies have not shown a worse prognosis for women with gestational breast cancer. The decision whether or not to terminate the pregnancy must be made on an individual basis, taking into account the clinical stage of the cancer, the overall prognosis for the patient, the gestational age of the fetus, the potential for premature ovarian failure in the future with systemic therapy, and the patient’s wishes. Women with early-stage gestational breast cancer who choose to continue their pregnancy should undergo surgery to remove the tumor and systemic therapy if indicated. Retrospective reviews of patients treated with anthracycline-containing regimens for gestational cancers (including leukemia and lymphomas) have established the relative safety of these regimens during pregnancy for both the patient and the fetus. Taxane-based and trastuzumab-based regimens have not been evaluated extensively, however. Radiation therapy should be delayed until the pregnant patient has delivered.
Equally important is the advice regarding future pregnancy (or abortion in case of pregnancy) to be given to women of child-bearing age who have had definitive treatment for breast cancer. To date, no adverse effect of pregnancy on survival of women who have had breast cancer has been demonstrated. When counseling patients, oncologists must take into consideration the patients’ overall prognosis, age, comorbidities, and life goals.
In patients with inoperable or metastatic cancer (stage IV disease), induced abortion is usually advisable because of the possible adverse effects of hormonal treatment, radiotherapy, or chemotherapy upon the fetus in addition to the expectant mother’s poor prognosis.
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CARCINOMA OF THE MALE BREAST
ESSENTIALS OF DIAGNOSIS
A painless lump beneath the areola in a man usually over 50 years of age
Nipple discharge, retraction, or ulceration may be present
Generally poorer prognosis than in women
Breast cancer in men is a rare disease; the incidence is only about 1% of that in women. The average age at occurrence is about 70 years and there may be an increased incidence of breast cancer in men with prostate cancer. As in women, hormonal influences are probably related to the development of male breast cancer. There is a high incidence of both breast cancer and gynecomastia in Bantu men, theoretically owing to failure of estrogen inactivation by a liver damaged by associated liver disease. It is important to note that first-degree relatives of men with breast cancer are considered to be at high risk. This risk should be taken into account when discussing options with the patient and family. In addition, BRCA2 mutations are common in men with breast cancer. Men with breast cancer, especially with a history of prostate cancer, should receive genetic counseling. The prognosis, even in stage I cases, is worse in men than in women. Blood-borne metastases are commonly present when the male patient appears for initial treatment. These metastases may be latent and may not become manifest for many years.
A painless lump, occasionally associated with nipple discharge, retraction, erosion, or ulceration, is the primary complaint. Examination usually shows a hard, ill-defined, nontender mass beneath the nipple or areola. Gynecomastia not uncommonly precedes or accompanies breast cancer in men. Nipple discharge is an uncommon presentation for breast cancer in men but is an ominous finding associated with carcinoma in nearly 75% of cases.
Breast cancer staging is the same in men as in women. Gynecomastia and metastatic cancer from another site (eg, prostate) must be considered in the differential diagnosis. Benign tumors are rare, and biopsy should be performed on all males with a defined breast mass.
Treatment consists of modified radical mastectomy in operable patients, who should be chosen by the same criteria as women with the disease. Breast conserving therapy is rarely performed. Irradiation is the first step in treating localized metastases in the skin, lymph nodes, or skeleton that are causing symptoms. Examination of the cancer for hormone receptor proteins and HER2 overexpression is of value in determining adjuvant therapy. Men commonly have ER-positive tumors and rarely have overexpression of HER2. Adjuvant systemic therapy and radiation is used for the same indications as in breast cancer in women.
Because breast cancer in men is frequently a disseminated disease, endocrine therapy is of considerable importance in its management. Tamoxifen is the main drug for management of advanced breast cancer in men. Tamoxifen (20 mg orally daily) should be the initial treatment. There is little experience with AIs though they should be effective. Castration in advanced breast cancer is a successful measure and more beneficial than the same procedure in women but is rarely used. Objective evidence of regression may be seen in 60%-70% of men with hormonal therapy for metastatic disease—approximately twice the proportion in women. The average duration of tumor growth remission is about 30 months, and life is prolonged. Bone is the most frequent site of metastases from breast cancer in men (as in women), and hormonal therapy relieves bone pain in most patients so treated. The longer the interval between mastectomy and recurrence, the longer the remission following treatment is likely. As in women, there is correlation between ERs of the tumor and the likelihood of remission following hormonal therapy.
AIs should replace adrenalectomy in men as they have in women. Corticosteroid therapy alone has been considered to be efficacious but probably has no value when compared with major endocrine ablation. Either tamoxifen or AIs may be primary or secondary hormonal manipulation.
Estrogen therapy—5 mg of diethylstilbestrol three times daily orally—may be effective hormonal manipulation after others have been successful and failed, just as in women. Androgen therapy may exacerbate bone pain. Chemotherapy should be administered for the same indications and using the same dosage schedules as for women with metastatic disease or for adjuvant treatment.
Men with breast cancer seem to have a worse prognosis than women with breast cancer because breast cancer is diagnosed in men at a later stage. However, a large population based, international study reported that after adjustment for prognostic features (age, stage, treatment), men had a significantly improved relative survival from breast cancer compared to women. For node-positive disease, 5-year survival is approximately 69%, and for node-negative disease, it is 88%. A practice-patterns database study reported that based on NCCN guidelines, only 59% of patients received the recommended chemotherapy, 82% received the recommended hormonal therapy, and 71% received the recommended postmastectomy radiation, indicating a relatively low adherence to NCCN guidelines for men.
For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5).
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