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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
Interest in the study of antiprogestins in breast cancer is understandable, given the known prognostic importance of the progesterone receptor in this disease and the current use of diverse endocrine interventions in its treatment. Approximately 30 percent all metastatic breast cancer patients, and 50 to 80 percent of the subset of patients whose tumors have estrogen or progesterone receptors, respond to a variety of endocrine interventions (e.g., drugs such as tamoxifen or progestins, or surgical removal of the ovaries for premenopausal women). Although such patients may improve in response to these treatments, the treatment results are relatively short-lived, lasting about 8 to 12 months. The antiprogestins have potential as growth inhibitory compounds against breast cancers. Whether this antitumor activity will be unique among the many other available endocrine therapies for breast cancer remains to be seen. In reviewing the literature, the committee concluded that too few clinical data are currently available to assess adequately the clinical potential of antiprogestins in the treatment of metastatic breast cancer, much less to assess their potential applications for adjuvant therapy (postoperative therapy undertaken when no detectable tumor is present to reduce the risk of recurrence) or chemoprevention (treatment of well women to lower the risk of initial development of cancer).
The exact mechanism by which antiprogestins exert their antitumor effect is unclear at present. However, data suggest that more than one mechanism exists. Although animal models can provide hypotheses, the biologic complexity and heterogeneity of breast cancer, and the limitations of these models, will require that many questions be addressed in basic research and in human clinical trials.
Recommendation No. 15. The committee recommends research to clarify the activity of antiprogestins in women with advanced (metastatic) breast cancer. Trials should be conducted by using more homogeneous groups of patients. Potential sources of heterogeneity should be reduced by including patients with only minimal prior therapy for their breast cancer and by performing pharmacokinetic evaluations to ensure consistent drug exposure and to facilitate concentration-response correlations. In these studies, tumor progesterone-receptor and estrogen-receptor status should be measured routinely.
Recommendation No. 16. Clinical trials of antiprogestins for treatment of breast cancer should include ancillary investigations to clarify mechanisms underlying the activity of antiprogestins. Examples of such studies include