Breast Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI] - Description of Evidence
Other trials of tamoxifen for primary prevention of breast cancer have been completed.[84,85,86] Initial analyses from two smaller trials, one in the United Kingdom (U.K.)  and one primarily in Italy, showed no protective effect, perhaps because of differences between target populations and study designs and those in the U.S. study. The U.K. study focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer; about 36% of participants were from families that had a greater than 80% chance of carrying a breast cancer susceptibility gene. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR = 1.06). Subsequent follow-up shows that at a median of 13 years, there was a statistically nonsignificant reduction in breast cancer risk in the tamoxifen arm compared with the placebo arm (HR = 0.78; 95% CI, 0.58–1.04). However, risk of ER–positive breast cancer was significantly reduced in the treatment arm (HR = 0.61; 95% CI, 0.43–0.86), an effect noted predominantly in the posttreatment period. The Italian study focused on 5,408 women who had undergone hysterectomy and who were described as "low-to-normal risk" women. At the initial report, after a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in the Italian trial found a protective effect of tamoxifen among women at high risk for hormone receptor–positive breast cancer (RR = 0.24; 95% CI, 0.10–0.59) and among women who were taking HT during the trial (RR = 0.43; 95% CI, 0.20–0.95).[88,89]
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 in the tamoxifen arm developing breast cancer than did women in the placebo arm (142 vs. 195 cases, respectively; RR = 0.73, 95% CI, 0.58–0.91) over the full study period 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.