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Cancer Treatment and Prevention

The “Basic Biology of SERMs” papers offered insight into the mechanism of action of selective estrogen modulators (SERMs) at the molecular level. Clearly, the bestdefined route of SERM action appears to be via interaction with the estrogen receptor(s) (ER). The chief molecular consequence of this interaction is competition with estrogen for the ER, with resulting estrogen agonism or antagonism depending on the nature of this alternative SERM ligand-receptor interaction. While the net impact of the SERM-ER complex on target gene activation and cellular proliferation emerges in part from the molecular characteristics of the SERM in question, the specific cellular environment, that is, the presence of coactivators and corepressors, also contributes to this outcome. Since ERs are observed in multiple tissue types and the cellular environment varies with the target tissue, the clinical consequences of SERMER interaction encompass multiple organ systems, each of which is characterized by a distinct proestrogenic or antiestrogenic profile from intervention with a given SERM. The best-studied clinical application of SERMs involves the target disease site breast cancer. In fact, the best-studied SERM, tamoxifen, a first-generation triphenylethylene, although initially investigated as a fertility drug, was ultimately developed primarily for its efficacy in breast cancer.1,2 Following the traditional sequence of clinical testing first in metastatic disease, then in localized disease, and finally in high-risk women for its efficacy as a breast cancer preventive agent,3–5 tamoxifen has proven to be a major success story among anticancer drugs. Tamoxifen is the most commonly used hormonal agent for ER-positive disease in both the adjuvant and metastatic settings, and it is approved to reduce the risk of breast cancer in women at increased risk for the disease.6,7 Despite its efficacy and widespread use in breast cancer, tamoxifen has two major limitations: limited range of efficacy and toxicity. First, tamoxifen is limited by its lack of 100% efficacy in the various breast cancer settings in which it is currently the standard of care. On the one hand, its predominant mechanism of action restricts its