Multimodality Therapy With Curative Intent for Those With Oligometastatic Disease
For a select group of patients, an aggressive surgical approach may be considered. One retrospective review found an increased survival in women with limited advanced disease who underwent resection of the primary tumor in addition to systemic therapy,[6] but these studies are frequently affected by selection bias. A single prospective study reported a 24% 15-year disease-free survival among women who were treated with systemic anthracycline-based therapy following locoregional salvage therapy (surgical resection with or without radiation) of a solitary metastasis.[7] A planned prospective trial to be led by the Eastern Cooperative Oncology Group (ECOG) will randomize newly diagnosed metastatic breast cancer patients with intact primary tumors and disease responsive to initial systemic therapy to have surgical resection and radiotherapy vs no local therapy.
Therapy for Hormone Receptor–Positive Disease
In view of its highly preferable toxicity profile, initial palliation with endocrine therapy should be the primary consideration for patients with metastatic hormone-receptor–positive tumors. Only in the rare setting of imminent vital organ failure or symptomatic visceral disease should a rapid response from cytotoxic chemotherapy be sought over a trial of endocrine therapy (Table 1). There is no justification for combining antiestrogens with chemotherapy, and data from the adjuvant setting suggest inferior outcome with this strategy.[8]
Daily tamoxifen is the most commonly used selective estrogen-receptor modulator (SERM). Third-generation aromatase inhibitors including anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are associated with improved progression-free and overall survival compared to tamoxifen in postmenopausal women.[9] Direct comparison as second-line therapy in metastatic breast cancer shows no convincing clinical advantage of one aromatase inhibitor over another.[10] There is little evidence regarding the optimal sequence of therapy (ie, a SERM followed by an aromatase inhibitor or vice versa), and most patients will be treated with both during the course of their disease.
Prior exposure to specific antiestrogens in the adjuvant setting may influence choice of antiestrogen therapy in the metastatic setting. The selective estrogen-receptor downregulator fulvestrant (Faslodex) is active in postmenopausal women with tamoxifen-resistant disease, is as effective as aromatase inhibitors in the second-line setting, and can also be used after progression on an aromatase inhibitor.[11,12]
The combination of tamoxifen and a luteinizing hormone-releasing hormone (LHRH) agonist is associated with increased overall and progression-free survival in premenopausal women with metastatic disease and functional ovaries.[13] Combination therapy is associated with an increased incidence of menopausal symptoms, and it is not unreasonable to use tamoxifen alone in women with low-volume disease. Few data are available regarding the use of LHRH agonists with an aromatase inhibitor.
Women whose tumors do not express hormone receptors and those who have shown progression following hormonal interventions are considered hormone-insensitive and should be recommended for chemotherapy-based therapies if possible.
When to Initiate Systemic Chemotherapy and Choosing a Chemotherapy Drug
Breast cancer is a relatively chemosensitive disease. As discussed above, endocrine manipulation should be considered for all patients with hormone-receptor–positive disease and small volume, bone-only or asymptomatic visceral disease. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. It is the only therapeutic option for patients with HER2-negative, hormone-resistant metastatic breast cancer.
Given the wide choice of available agents, it is paramount to individualize therapy as much as possible. Pertinent physician and patient factors in treatment choice include performance status, personal preference or experience, compliance, drug administration route, comorbidities, drug toxicities, efficacy, and prior exposure to the same drug class (Table 2). Circulating tumor cells can be detected in a small percentage of patients with metastatic disease and are an early predictor of progression.[14,15] However, their clinical utility in directing a change in therapy and their impact on clinical outcome has not yet been determined and is the subject of a prospective randomized trial.
Sequential Single Agents vs Combination Chemotherapy
A Cochrane review in 2005 found that, compared with single chemotherapeutic agents, combination regimens showed a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival, and significantly worse toxicities.[16] Administering agents sequentially has the advantage of giving each drug at its maximum tolerated dose without overlapping toxic effects. The emergence of newer targeted agents that do not or only modestly exacerbate the adverse effects of most conventional cytotoxic agents allow for safe combinations and, in some cases, improved survival (eg, trastuzumab [Herceptin]). At present, combination chemotherapy in the metastatic setting is best reserved for select, fit patients with rapidly progressing disease. Improved prognostic and predictive tools will hopefully help with drug selection in the future.
