Role of aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer

Question: What is the role of aromatase inhibitors as first-, second-, and third-line treatment of postmenopausal women with stage IV (metastatic) breast cancer? Perspectives: This practice guideline was developed to review the evidence for the use of selective aromatase inhibitors as a treatment for postmenopausal women with advanced breast cancer and to make recommendations for the placement of those agents in the hormonal therapy pathway. Outcomes: Outcomes of interest included survival, quality of life, tumour response, time to disease progression, and adverse effects of treatment. Methodology: The MEDLINE, CANCERLIT, and Cochrane Library databases, and the proceedings of the annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the San Antonio Breast Cancer Symposium were systematically searched up to October 2003 for evidence relevant to the present practice guideline report. Randomised trials, meta-analyses, and evidence-based clinical practice guidelines were of primary interest. Non-comparative trials were included in the absence of randomised controlled trials. Response and time-to-progression results abstracted from the published reports of individual randomised trials were pooled to estimate the overall effect of aromatase inhibitors versus tamoxifen as first-line therapy. Results: In randomised trials, first-line treatment with selective aromatase inhibitors was associated with higher objective response rates and prolonged time-to-disease progression than was treatment with tamoxifen, but definitive survival data were not available. As compared with megestrol acetate or aminoglutethimide, second-line treatment with selective aromatase inhibitors was associated with equivalent or better objective response rates and time-to-disease progression, a modest but statistically significant survival advantage, and a superior toxicity profile. In randomised trials, aromatase inhibitors and control therapy failed to demonstrate consistent differences in quality-of-life measures. Exemestane (as third- or greater-line hormonal therapy) was associated with modest but appreciable rates of objective response and was well tolerated in phase II trials. Practice Guideline: Target Population: The recommendations that follow apply to postmenopausal women with stage IV breast cancer who are candidates for hormonal therapy. First-Line Therapy: Letrozole and anastrozole are, in terms of objective response rate and time to disease progression, modestly superior to tamoxifen as first-line therapy and are the preferred treatment option in the first-line setting. Tamoxifen remains an acceptable alternative. Data are insufficient to recommend any one aromatase inhibitor over the others. Second-Line Therapy: Letrozole, anastrozole, and exemestane are superior to megestrol acetate or aminoglutethimide as second-line hormonal therapy and are the preferred treatment option in the second-line setting. Data are insufficient to recommend any one aromatase inhibitor over others. Third- or Greater-Line Therapy: For women who have been heavily pretreated with hormonal agents and chemotherapy, exemestane is an acceptable third- or greater-line therapy. Qualifying Statement: Selective aromatase inhibitors are contraindicated in premenopausal women.