Women with a history of ductal carcinomain situ (DCIS) are at increased risk (3.4%) for contralateral breast cancer but were not eligible for the BCPT because of competing treatment trials. In a trial of DCIS treatment, however, 13.4% of women treated with lumpectomy and radiation had breast cancer events within approximately 6 years, compared with 8.2% of those who also received tamoxifen. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 RCT evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS. The risk of all breast cancer events, invasive and noninvasive, was reduced with tamoxifen (rate ratio = 0.63; 95% CI, 0.47–0.83); the risk of contralateral breast cancer (invasive and noninvasive) associated with tamoxifen was 0.49 (95% CI, 0.26–0.87). Given the results of the NSABP B-24 trial and the BCPT, it is reasonable to consider the use of tamoxifen for breast cancer risk reduction among women with DCIS.
In addition to tamoxifen, other hormonal manipulations have been proposed to modulate the production of breast cell growth factors by suppressing ovarian function  or changing the endogenous hormonal environment. The list of chemoprevention agents that may be used in breast cancer prevention is long.
Raloxifene hydrochloride is a SERM that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial, evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint and therefore should be judged with caution. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%. Breast cancer was reported in 79 women and confirmed in 77 women. Invasive breast cancer occurred in 39 women treated with placebo and in 22 women who were randomly assigned to either of the two raloxifene arms (raloxifene 120 mg daily or raloxifene 60 mg; RR = 0.25; 95% CI, 0.17–0.45; 4.7–1.3 invasive breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). DCIS occurred in five women treated with a placebo and in 11 women treated with raloxifene. After combining noninvasive and invasive cancer occurrences, the RR of breast cancer among women in the raloxifene group was 0.38 (95% CI, 0.24–0.58; 5.3–1.9 breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). As with tamoxifen, raloxifene reduced the risk of ER–positive breast cancer but not ER–negative breast cancer. Similar to tamoxifen, raloxifene is associated with an excess risk of hot flashes and thromboembolic events. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 2.4 times higher in women assigned to the raloxifene groups compared with the placebo group. One woman (in the 60-mg raloxifene group) died from pulmonary embolism. There was little difference in the rate of venous thromboembolic disease between the 60-mg and 120-mg groups (3.32–3.63 events per 1,000 woman-years, respectively). No excess risk of endometrial cancer was observed after 47 months of follow-up; five cases occurred among women on placebo (0.77 cases per 1,000 woman-years), five cases among women treated with 60 mg of raloxifene (0.77 cases per 1,000 woman-years), and four cases among women treated with 120 mg of raloxifene (0.60 cases per 1,000 woman-years). Raloxifene did not increase the risk of endometrial hyperplasia. Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least one follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene groups and decreased by 0.27 mm in the placebo group after 3 years of follow-up (P < .01 for the difference between the two groups). Sixty participants (10.1%) in the placebo group and 168 women (14.2%) in the raloxifene groups (P = .02) had endometrial thickness that was greater than 5 mm on at least one follow-up ultrasound. Among the 196 women who still had a uterus (48 in the placebo group and 148 in the raloxifene group), there were three cases of hyperplasia and two cases of endometrial cancer in the placebo group and three cases of hyperplasia and two cases of endometrial cancer in the combined raloxifene group. Subgroup analyses after 4 years of follow-up suggest that, among women who have osteoporosis, raloxifene reduces breast cancer incidence for both women at higher and lower risk of developing breast cancer.