Adjuvant exemestane therapy after 5 years of tamoxifen: rationale for the NSABP B-33 trial.

Tamoxifen (Nolvadex) has long been established as "standard" adjuvant therapy for receptor-positive, early-stage breast cancer. Results from clinical trials suggest that after approximately 5 years, tamoxifen may lose its effectiveness and may even become harmful if not stopped. At the time of tamoxifen discontinuation, "seemingly" disease-free patients may still have residual micrometastatic tumor cells. In a proportion of such patients, these cells may still be responsive to tamoxifen and thus could grow as a result of stopping the drug. The majority of clinical information, however, suggests that by 5 years of therapy, a greater proportion of patients will have micrometastatic tumor cells that have become resistant to tamoxifen and will be stimulated by continuation of the drug for a longer time. Because in both such cases the micrometastases are hormonally sensitive, a reasonable approach--in addition to stopping tamoxifen--is to decrease the level of estrogenic stimulation by introducing an aromatase inhibitor. The National Surgical Adjuvant Breast and Bowel Project is launching a clinical trial (NSABP B-33) to evaluate the sequential administration of 2 years of exemestane (Aromasin), a steroidal aromatase inactivator, after 5 years of tamoxifen in postmenopausal, receptor-positive patients who are disease-free at the time of tamoxifen discontinuation.