ABSTRACT: Breast cancer is the second leading cause of cancer-related death in women in the United States, and for nearly all with metastatic disease at presentation or relapse it will be incurable. The goals of therapy are to optimize quality of life and, if possible, prolong time to progression of disease and death. For a select group of patients an aggressive surgical approach may be considered. Initial palliation with endocrine therapy should be the primary consideration for patients with metastatic hormone receptor–positive tumors. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. If a tumor overexpresses HER2, targeted treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) is possible. Consequently, accurate determination of the status of these predictive markers in tissue (possibly from a recurrence site) is key. Other novel agents are adding to the wide choices of standard chemotherapies already available. This review offers an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer.
Breast cancer is the second leading cause of cancer-related death in women in the United States, and for nearly all with metastatic disease at presentation or relapse it will be incurable. The goals of therapy are to optimize quality of life and, if possible, prolong time to progression of disease and death. A larger armamentarium of therapeutic options is available to physicians in 2008 than ever before. This wide choice brings its own challenges.
In this review, we offer an approach to the selection of individualized and rational therapies for patients with metastatic breast cancer (Figure 1). Given the context of this special issue of ONCOLOGY—a tribute to the late Dr. Martin Abeloff—it is interesting to note how very much these therapies evolved over the course of Dr. Abeloff’s career (Figure 2).
Wherever possible, tissue samples should be obtained for histologic confirmation of metastatic disease, particularly in the case of isolated lung or liver lesions where competing cancers may present and for a current assessment of hormonal receptor and HER2 status. Management of these patients is best conducted within a multidisciplinary team including palliative medicine, surgical, and radiation oncology. Here, we will focus on available systemic treatments for the patient with metastatic breast cancer.
Diagnostic Evaluation of Patients With Presumptive Diagnosis of Metastatic Disease
Metastatic breast cancer may be an incidental finding in asymptomatic patients or may present with nonspecific symptoms of malaise or weight loss. The earlier detection of asymptomatic lesions on imaging studies prompted by elevated circulating markers (neither recommended for routine surveillance in an asymptomatic patient after adjuvant therapy), with or without the earlier initiation of treatment, will not necessarily increase overall survival and may only result in lead-time bias.
Wherever possible, tissue samples should be obtained for histologic confirmation of metastatic disease, particularly in the case of isolated lung or liver lesions, where competing cancers may present, and for current assessment of hormonal-receptor and HER2 status to assist with therapy selection. These can also be used as modest prognostic factors along with time to recurrence, extent of the disease, location, prior therapy, symptoms related to the disease, and performance status. Solitary lesions on isotope bone scans or computed tomography should be interpreted with caution. Imaging studies without tissue confirmation may be acceptable in the appropriate setting, such as when multiple areas of osseous metastases or multiple sites with visceral involvement are present.
Adequate baseline staging also serves to allow evaluation of response to planned therapy. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is being used increasingly in the detection of occult recurrent breast cancer, but remains inferior to bone scans for the assessment of blastic lesions and should not be used without concomitant computed tomography (CT) for fusion images. An FDG-PET/CT study is costlier than a CT scan with oral/IV contrast and a bone scan, and data showing improved decision-making and outcomes are lacking at present.
Evidence is insufficient to support using tumor markers like CA 27-29 or carcinoembryonic antigen (CEA) on their own to monitor response to therapy, although these assessments may help determine tumor progression in patients with metastatic (but no measurable) disease.
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, 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. 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.
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. Direct comparison as second-line therapy in metastatic breast cancer shows no convincing clinical advantage of one aromatase inhibitor over another. 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. 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.
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