Background Initial findings of the Italian Randomized Tamoxifen Prevention Trial found no reduction in risk of breast cancer with tamoxifen use, whereas the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial showed that tamoxifen treatment reduces risk of estrogen receptor-positive breast cancer. Here we present an extended follow-up of the Italian trial. Methods From October 1, 1992, to December 31, 1997, 5408 otherwise healthy women who had undergone hysterectomy were randomly assigned in a double-blind manner to tamoxifen (20 mg daily) or placebo for 5 years. Rates of breast cancer and other events in the two groups were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Results After 11 years of follow-up, 136 women (74 placebo, 62 tamoxifen) developed breast cancer (RR = 0.84, 95% Cl = 0.60 to 1.17; annual rates were 2.48 and 2.07 per 1000 women-years, respectively). The rates of breast cancer in the two study groups were similar among women who had had bilateral oophorectomy and among women at low risk for hormone receptor-positive (HR+) disease but were much lower in the tamoxifen group among women at high risk (placebo, 6.26 per 1000 women-years, tamoxifen, 1.50 per 1000 women-years; RR = 0.24, 95% Cl = 0.10 to 0.59). During the treatment period, women in the tamoxifen group reported more hot flashes (RR = 1.78, 95% Cl = 1.57 to 2.00), vaginal discharge (RR = 3.44, 95% Cl = 2.90 to 4.09), and urinary disturbances (RR = 1.52, 95% Cl = 1.23 to 1.89) but fewer headaches (RR 0.68, 95% Cl = 0.50 to 0.94) than women in the placebo group. Hypertriglyceridemia (RR = 4.33, 95% Cl 1.96 to 9.53), thromboembolic events (RR = 1.63, 95% Cl = 1.02 to 2.62), and cardiac arrhythmia or atrial fibrillation (RR 1.73, 95% Cl = 1.01 to 2.98) were also more frequent in the tamoxifen group than in the placebo group. Conclusions Appropriate selection of women at high risk for HR+ disease may improve the risk-benefit ratio of tamoxifen intervention.
