The synthetic antiestrogen tamoxifen is demonstrating significant value as adjuvant therapy for female breast cancer. It is currently standard therapy for postmenopausal women with axillary node-positive, hormone- receptor-positive disease. Recent studies suggest it is also effective in increasing disease-free survival in both pre- and postmenopausal women with hormone-receptor-positive breast cancers without axillary node metastases. Data from several sources suggest that therapy of long duration is necessary to maintain control of micrometastatic disease. Major acute toxicity from tamoxifen is thought to be rare. However, because large and increasing numbers of women are taking tamoxifen for long periods, detailed data about its effect on other tissues are critical. The current proposal is designed to increase the scientific value of a single institution, double-blind, placebo-controlled, randomized toxicity study of tamoxifen in postmenopausal women with node-negative breast cancer. Study endpoints are: 1. Bone mineral content at the radius and lumbar spine measured by photon absorptiometry; 2. Plasma cholesterol, triglyceride and lipoprotein levels; 3. Coagulation proteins: antithrombin III, proteins C and S, and plasminogen; and 4. Calciotropic hormones: osteocalcin and 1,25-dihydroxyvitamin D. Planned accrual of 140 to this study has been completed. Limited interim analyses indicate that the very low drop out and high compliance rates should lead to excellent data addressing the impact of tamoxifen on the named endpoints. Support requested in this application will make possible a more comprehensive picture of tamoxifen's critical biological and clinical effects. The final year of study would be completed during the project period. Detailed analysis and consideration of the clinical implications and significance, and widespread dissemination of the findings would be the major focus of the project. It is expected that these analyses will define investigational directions for the future.
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