Metastatic breast cancer is incurable with currently available therapies. Median survival ranges from 2 to 3 years; however, there is substantial variability in survival, with as many as 10% of patients living more than 10 years. Factors associated with longer survival include disease involving soft tissue and bone only (rather than visceral organs), hormone receptor positivity in the tumor, a long disease-free interval from diagnosis to recurrence, and limited number of metastatic sites. Response to therapy is also quite variable. Patients with the better prognostic factors for survival as just described are more likely to respond well to hormonal therapy. The heterogeneity among breast cancer patients with metastatic disease must be considered carefully in the care of these patients.

The primary goals of treatment of metastatic breast cancer are palliation of symptoms, prolongation of survival, and improvement in quality of life. Only a few randomized studies have incorporated quality of life endpoints.

Comparing a variety of treatments, each of these trials has shown that quality of life was better with the treatment that had the higher objective response rate, even if that treatment was more toxic. Treatment of metastatic breast cancer may prolong survival, but proving that a survival benefit exists is difficult because trials have not randomized patients to a supportive- care-only arm. In a meta-analysis of 50 randomized chemotherapy trials comparing a more effective treatment to a lesser one, the more effective chemotherapy prolonged median survival by as much as 6 months. This small improvement in average survival should not be used as routine justification to treat asymptomatic or minimally symptomatic patients with toxic therapy, particularly because there is no evidence that early initiation of therapy extends life.

Management of metastatic disease involves the judicious use of local and systemic therapies that best palliate the patient’s symptoms with the least toxicity. In certain clinical situations, local therapy may be preferable to systemic therapy, such as in the situation of an isolated local recurrence. Such a recurrence can often be managed with local excision, radiotherapy, or both. A small percentage of patients with local regional recurrence will do well without evidence of progressive disease for an extended period of time. Other situations when local therapy is preferable include impending fracture from a bone metastasis, spinal cord compression, and brain metastases. In each of these cases, radiation therapy can result in significant palliation. Surgery may also play an important role in these situations.

Systemic treatment for metastatic breast cancer includes hormonal therapy and chemotherapy. Hormonal therapy should be considered first as it is usually much better tolerated than cytotoxic chemotherapy and can result in long remissions. Patient characteristics that predict for response to hormonal therapy include estrogen or progesterone receptor positivity, a long disease-free interval (from time of diagnosis to recurrence), the absence of visceral disease, postmenopausal status, and prior response to hormonal therapy. The majority of elderly patients have hormone receptor-positive tumors, and hormonal therapy is usually the initial treatment of choice. Overall objective response rates to hormonal therapy are in the range of 20% to 40%, depending on the patient population, with higher response rates seen in patients with multiple characteristics as just listed. In most randomized trials comparing two different hormonal treatments, response rates and duration of response have been similar. Tamoxifen, which is one of the least toxic hormonal agents, has traditionally been the first agent administered, followed by an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane). Recent data also suggest that aromatase inhibitors are at least at active as tamoxifen in the first-line setting in postmenopausal women with metastatic breast cancer.

Table 33.12 lists the principally used hormonal therapies and their main toxicities. Patients who respond to one hormonal treatment should usually be treated with another hormonal agent at the time of disease progression, unless they have extensive visceral disease or rapid disease progression, in which case chemot herapy should be considered. Studying initial therapy for metastatic disease in elderly women, the Eastern Cooperative Oncology Group randomized 181 women over the age of 65 to receive either tamoxifen or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with crossover to the other treatment at the time of progression. Response rates were not significantly different between the two groups: initial response rates were 45% with tamoxifen and 38% with CMF, and response rates after crossover were 29% with tamoxifen and 31% with CMF. Survival was slightly higher in the group treated initially with tamoxifen. Combined endocrine treatment (combinations of tamoxifen, aminoglutethamide, hydrocortisone, and fluoxymesterone) has been studied in older patients and thus far shown no significant benefit. Newer specific aromatase inhibitors may show more promise, and combinations with them are currently being evaluated in clinical trials.

Older women should be offered chemotherapy when they are judged to be poor candidates for endocrine therapy (i.e., hormone receptor-negative tumors) or when their disease becomes refractory to hormonal treatment. Unfortunately, most trials evaluating chemotherapy in metastatic breast cancer have included few women over age 65. With combination regimens, approximately 40% to 50% of patients will have an objective response, and a small percentage will have a complete response (complete disappearance of disease). Patients with a good performance status, limited number of metastatic sites, and long disease-free interval (from diagnosis to recurrence) are most likely to respond to chemotherapy. Age and menopausal status have not been shown to predict for response. Response rates and toxicity profiles of standard regimens for metastatic breast cancer have not been found to be significantly different in older patients. In a case comparison study of patients with metastatic breast cancer treated in five clinical trials, 70 women aged 70 or older were compared to 60 patients aged 50 to 69 and 40 patients less than 50 years old. Evaluation of response rates, time to progression, survival, and toxicity revealed no significant differences between the three groups. Response rates were 40%, 30%, and 29%, respectively (p = 0.53) among the three groups. Estimates of time to progression and survival were 9.1 and 17.9 months, 6.2 and 12.8 months, and 7.2 and 14.2 months, respectively. Importantly, there were no significant differences in toxic effects, dose delivery, and dose delays among the three groups. Based on information from studies such as this, women age 70 or greater should not be excluded from chemotherapy clinical trials for advanced breast cancer based on age alone.

Combination chemotherapy has been compared to single-agent chemotherapy in women with advanced breast cancer. Although response rates and duration of response tend to be increased, there is no significant difference in survival when combination chemotherapy is compared to single-agent sequential chemotherapy. Furthermore, treatment-related toxicity tends to be higher and quality of life worse with multiagent regimens. For these reasons, single-agent chemotherapy is used increasingly in the treatment of advanced breast cancer. In a patient who responds to therapy, physicians are often faced with the decision of how long to continue treatment. Therapy should be administered for at least 3 to 6 months. Continuing beyond that time will extend the time to disease progression but will not change overall survival. The decision to continue treatment must be individualized based on the toxicity profile of the treatment regimen, disease-related symptoms, and patient preferences.

Concern regarding toxicity will weigh heavily on a decision to treat an elderly woman with cytotoxic chemotherapy. Although organ function and metabolism of drugs may be compromised in older patients, comparative studies show that chemotherapy-related toxicity is similar in older and younger patients. Hematologic reserve is decreased in older individuals; therefore, hematologic toxicity from chemotherapy may be more severe in elderly patients. Cardiotoxicity, gastrointestinal effects, and neurotoxicity may also be more common in older patients. For chemotherapeutic agents that are primarily renally excreted, such as methotrexate and cyclophosphamide, dose adjustment based on creatinine clearance is recommended in older patients. Agents such as vinorelbine and 5-fluoruracil derivatives such as capecitabine, which have favorable side effect profiles, are particularly suitable for treatment of elderly patients. Although elderly women do not have a high proportion of Her-2/neu-positive tumors, the efficacy and favorable toxicity profile of traztuzumab make this a reasonable treatment option for older women with Her-2/neu-positive tumors. Future randomized trials evaluating these drugs in elderly women with metastatic breast cancer are warranted.

After failure of first-line chemotherapy, response rates to other regimens are lower in women of all ages. Second-line and subsequent chemotherapy regimens can be considered, but the potential toxicities of treatment must be weighed against potential benefits. Palliation of symptoms, pain management, other supportive care, and consideration of visiting nurse services and hospice care are of utmost importance. Bisphosphonate therapy (e.g., pamidronate) has resulted in significant reductions in skeletal complications, that is, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia in women with metastatic breast cancer. Intravenous (i.v.) pamidronate every 3 to 4 weeks is currently recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy.