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Executive Summary

TAMOXIFEN BREAST CANCER CHEMOPREVENTION STUDY PROPOSALS SOUGHT BY NCI by Oct. 1. The National Cancer Institute's Centers and Community Oncology Program sent letters on July 30 to eight cooperative groups and seven cancer centers requesting a "detailed concept" for a full clinical trial. Applicants are asked to include plans for recruitment of additional sites, budget estimates for the trial and the concept and budget of a feasibility/pilot phase, if proposed. NCI asked that study proposals "include measurable endpoints for breast cancer and cardiovascular disease as well as overall mortality." Additionally, the study should look at tamoxifen's effect on "bone mineral density and osteoporosis." NCI also expressed interest in "a factorial design using N-(4-hydroxyphenyl) retinamide (HPR)." According to the enclosure, "laboratory study suggests an independent or synergistic benefit of HPR and tamoxifen in breast cancer prevention." NCI noted that Veronesi et al. are in the midst of a trial in Milan testing HPR's effectiveness in preventing contralateral breast cancer. Researchers at the Wisconsin Tamoxifen Study (University of Wisconsin) are designing a "chemosuppression" trial, in which tamoxifen would be administered to postmenopausal women who have had a mastectomy but no further therapy ("The Pink Sheet" June 25, p. 20). In the Aug. 15 Journal of the National Cancer Institute, University of Wisconsin researchers (Love et al.) reported the results of a two-year, randomized, double-blind, placebo-controlled toxicity trial of tamoxifen therapy at a dosage of 10 mg twice daily. Having studied "postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes," the researchers also assessed the effects of tamoxifen therapy on lipid and lipoprotein levels in subjects. After 12 months, 65 tamoxifen-treated women showed an approximately 12% average decrease in total blood cholesterol and a 20% average decrease in low-density lipoprotein cholesterol, compared with the placebo group of 67 women. The treatment group experienced 20% average increases in plasma triglyceride levels and "small but significant" reductions in high-density lipoprotein cholesterol. However, the report notes that "ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably." The "preliminary incomplete" results of evaluation at 18 and 24 months showed "persistence" of the changes found in lipid and lipoprotein levels of the two groups. The study also found that tamoxifen leads to a 15% average increase in total serum estrogens. In an accompanying editorial in the Aug. 15 JNCI, Ross Prentice, MD, of the Seattle-based Fred Hutchinson Cancer Research Center discussed tamoxifen's potential as a "preventive agent in healthy postmenopausal women." Prentice stated: "If the results linking cholesterol lowering to the reduction of risk of coronary heart disease in men" apply to women in the 55-69 age range, "one would project that the lipid and lipoprotein changes observed by Love and co-workers would confer a substantial reduction, perhaps in the vicinity of 40%, in the risk of coronary heart disease." Prentice supported the initiation of a feasibility study before full-scale trials are attempted. He expressed concern that the reduction of HDL cholesterol in tamoxifen patients "could largely offset the benefits of the much larger LDL cholesterol reduction." The 20% rise in triglicyeride levels of tamoxifen-treated women is also cause for further research, Prentice said. At its June 29 meeting, FDA's Oncologic Drugs Advisory Committee recommended against approval of an IND proposing a 10-year, multicenter trial of ICI's Nolvadex (tamoxifen) in preventing breast cancer in healthy, high-risk women ("The Pink Sheet" July 9, T&G-2). Several committee members expressed the opinion that such a trial should be delayed until long-term safety data from animal and clinical studies could be used to assess the potential risk of liver, endometrial, and ovarian cancers. The IND proposal was forwarded by Philip Bretz of the Desert Breast Institute.



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