The last trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomly assigned 7,152 women aged 35 to 70 years who were at increased risk of breast cancer to receive tamoxifen (20 mg/day for 5 years) or placebo. After a median follow-up of 50 months, 32% fewer women (95% CI, 8%-50%) in the tamoxifen group than in the placebo group had developed breast cancer (invasive plus carcinoma in situ with an absolute reduction from 6.75 to 4.6 breast cancers per 1,000 woman-years). The RR reduction in ER-positive invasive breast cancer was 31%; there was no reduction in ER-negative cancers. In this trial, but in none of the other tamoxifen trials, there was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The prophylactic effect of tamoxifen on breast cancer persisted after active treatment, with 27% fewer women (95% CI, 0.58-0.91) in the tamoxifen arm developing breast cancer over the full study period (absolute RR from 6.82-4.97 per 1,000 women-years) after a further 46 months of median follow-up. In this report, most of the additional follow-up time accrued after the discontinuation of active treatment in the treatment arm.
A meta-analysis of the early report of these primary prevention trials was performed, and its findings showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity. ER-positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR = 2.4; 95% CI, 1.5-4.0), as were venous thromboembolic events (RR = 1.9; 95% CI, 1.4-2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Treatment decisions are complex and need to be individualized, weighing estimates of a woman's chance of reducing breast cancer and fracture risks against the chance of developing detrimental side effects, some of which may be life threatening. The risks and benefits of taking tamoxifen have been estimated for women according to age, race, and risk group based on the results of the BCPT, additional risk/benefit analyses, and review of the literature. Because adverse effects of tamoxifen increase with age, tamoxifen is most beneficial for women younger than 50 years who have an increased risk of developing breast cancer. Overall, the net benefit or risk depends on age, whether a woman has a uterus, and her baseline risk of breast cancer.
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.