Breast cancer prevention trials: Large and small trials

Breast cancer is the most common cancer among women in the United States, with 192,870 new cases and 40,170 deaths due to this disease estimated to have occurred 2009. An emphasis on prevention has been increasing in view of a persisting high incidence of disease. Seventy percent of breast cancers are estrogen receptor (ER)-positive, and are therefore presumed to be hormone-responsive and potentially treatable or preventable by anti-estrogenic agents. To date, the large, phase III randomized controlled breast cancer prevention trials have tested and are testing only hormonal drugs designed to antagonize the carcinogenic effect of endogenous estrogen; these agents are either selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). The SERMs, tamoxifen and raloxifene, have been shown in these large trials to reduce the risk of ER-positive breast cancers; prevention trials of AIs are ongoing. Interest is now focusing on developing agents with a broader spectrum of preventive activity, particularly with regard to ER-negative subtypes of breast cancer. A number of phase I and II trials using tissue-derived surrogate endpoint biomarkers (SEBs) as outcomes have been implemented. These smaller trials address prevention not only of ER-negative but also ER-positive breast cancers, since approximately 50% of the latter have been shown to be resistant to the estrogen-targeting drugs used in the large trials. Issues of importance in these smaller trials include choice of agent, selection of appropriate trial participants, trial design, method of access to breast tissue in women without cancer, selection and monitoring of SEBs, and monitoring of drug toxicity.