In the past decade, the reports of significant side effects associated with the prolonged use of tamoxifen have stimulated research directed toward the development of other selective estrogen receptor modulators (SERMs). Among the various products investigated, raloxifene has demonstrated antitumor activity and a favorable toxicity profile and is being further investigated.97-99
Preclinical data have shown that raloxifene, an antiestrogen with no estrogen-agonist effect on the uterus, inhibits mammary carcinogenesis in a rat model of breast cancer in a manner similar to tamoxifen when raloxifene is used in combination with 9-cis retinoic acid.97 Clinical trials have been started in an attempt to establish the role of raloxifene in preventing osteoporosis in postmenopausal women, and preliminary results from two randomized clinical trials have recently become available. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was specifically designed to evaluate the possibility of reducing the risk of fractures in post-menopausal women receiving raloxifene; a markedly reduced risk of newly diagnosed breast cancer was demonstrated with raloxifene compared with placebo (0.21% versus 0.82%).100 Jordan and colleagues recently reported the results of a multicenter, double-blind randomized trial conducted in about 12,000 women. Treatment with raloxifene was associated with a 58 percent reduction in the risk of developing primary breast cancer.101 These results have stimulated the design of a second major breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR) that will compare the toxicity, risks, and benefits of raloxifene with those of tamoxifen. Women enrolled in the study will be randomly assigned to receive either 20 mg of tamoxifen or 60 mg of ralox-ifene for 5 years, with follow-up planned for an additional 2 years.
A number of other SERMs have emerged (eg, toremifene, trioxifene, droloxifene, TAT-59) for clinical use.102105 The majority of these drugs are presently in phase I to II clinical trials and have already demonstrated their clinical activity in the management of breast cancer. They represent possible candidates for future chemoprevention studies.
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