Antiaromatase agents after adjuvant tamoxifen: rationale and clinical implications

Although tamoxifen is considered standard adjuvant hormonal therapy in receptor-positive, stage I and II breast cancer, information on its optimal duration of administration has only been reported recently and, for many, the subject is still a matter of scientific debate. Data suggest that there is a time period beyond which, if tamoxifen is continued, it may become ineffective or even detrimental to the patient. Tamoxifen is usually discontinued after approximately 5 years of therapy, at which time most patients are thought to be disease free; however, some patients may harbor residual micrometastases. A fraction of these patients will have micrometastatic tumor cells that are still responsive to tamoxifen, and tamoxifen discontinuation could result in cancer cell growth. The preponderance of clinical data, however, indicate that a greater fraction of patients will have micrometastatic tumor cells that have become progressively resistant to tamoxifen. In fact, tumor cell growth could be stimulated by continued therapy with the drug. Although in some patients the micrometastatic tumor cells may have become hormonally unresponsive, in most cases (tamoxifen-responsive or tamoxifen-stimulated micrometastases), the tumor remains hormonally responsive. Therefore, the use of anti-aromatase agents to reduce the level of estrogenic stimulation and, as a result, the risk of recurrence may prove to be a valuable approach at the time of tamoxifen discontinuation. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is in the final stages of developing a clinical trial (NSABP B-33) to evaluate the effect of administering 2 years of therapy with the aromatase inactivator exemestane to postmenopausal, receptor-positive patients who have completed 5 years of tamoxifen therapy and are disease free at the time of tamoxifen discontinuation.