Prevention of hormone-related cancers: breast cancer.

Carcinogenesis in the breast is a hormonally dependent process. Evidence implicating estrogen as a key breast carcinogen comes from various lines of investigation. Traditional epidemiologic studies demonstrate associations between estrogen exposure, both exogenous and endogenous, and increased breast cancer risk. Ongoing genetic epidemiologic studies also show associations between specific polymorphisms in estrogen-metabolizing genes and risk, albeit inconsistently. The application of these findings to the treatment and, more recently, the prevention of breast cancer has led to the development of agents that either (1) inhibit estrogen action at the estrogen receptor (selective estrogen receptor modulators (SERMs]); or (2) inhibit estrogen-synthesizing enzymes, thereby abrogating synthesis of this hormone (aromatase inhibitors). Large phase III trials have evaluated the ability of such agents to reduce the incidence of breast cancer in women at increased risk of the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT) demonstrated the superiority of the SERM tamoxifen to placebo in reducing breast cancer risk, leading to the Food and Drug Administration approval of tamoxifen for risk reduction. The implementation of tamoxifen for this indication has not become widespread in clinical practice, however, for a variety of reasons that we discuss. Results from the NSABP Study of Tamoxifen and Raloxifene, which compares the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk population, will be available in the near future. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole, and exemestane, are being incorporated into trials evaluating their efficacy as preventive agents in women at increased risk.