Preventing hormone-dependent breast cancer in high-risk women.

Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent the progression of premalignant lesions to invasive carcinoma. Four major trials have used tamoxifen, the prototypical selective estrogen receptor modulator (SERM), as a breast cancer chemopreventive agent with differing results. The Royal Marsden trial (1), a pilot study for the International Breast Cancer Intervention Study (IBIS-I) trial (2), and the initial analysis of the Italian tamoxifen prevention study (3) showed no decrease in the incidence of breast cancer among women using tamoxifen. By contrast, both the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study (4) and the IBIS-I trial (2) did show reduction in breast cancer risk with tamoxifen. In this issue of the Journal, the authors of the Italian study have re-analyzed their data after a median follow-up of 81.2 months (5). By contrast with their two earlier publications (3,6), their re-analysis shows a reduction in the development of breast cancer in a high-risk population assigned to tamoxifen. These current data update the previous publications that have reported preliminary and essentially identical overall results from this trial. The data provided here are new in their identification of the high-risk cohort. In the Italian study, 5408 women with hysterectomies were assigned randomly either to tamoxifen (20 mg per day) or placebo for 5 years. At the time of entry, almost half of the women (48.3%) had bilateral oophorectomy, 18.6% had a unilateral oophorectomy, and only 26.3% had conservation of both ovaries. Oophorectomy reduces the risk of developing invasive breast cancer (7), and menopause is associated with an increased likelihood that breast cancer will be estrogen receptor (ER)positive. This cohort of Italian women, therefore, was at low to normal risk for the development of breast cancer. Initial results published after a median follow-up of 46 months showed no statistically significant difference in breast cancer development between the two groups (3). In that subgroup analysis, there was a statistically significant reduction of breast cancer risk among women in the tamoxifen group who also used hormone replacement therapy (HRT) during the trial. Among 390 women on HRT and assigned to placebo, eight cases of breast cancer were diagnosed. By contrast, among 362 women taking both HRT and tamoxifen, only one case of breast cancer was diagnosed (P .022). An update of the results from the trial published in 2002 reported an 81.2-month median follow-up and did not show a statistically significant difference in breast cancer development in women who were at usual or reduced risk (6). Breast cancer was diagnosed in 1.7% of women in the control group compared with 1.3% of women in the tamoxifen group (P .215). There was a benefit of tamoxifen in those who used HRT where the cumulative incidence of breast cancer was 0.92%. By contrast, the group of women who used HRT and were assigned to the placebo group had a cumulative incidence of breast cancer of 2.58%. Breast cancer was detected in 2% of women who used HRT at any point in the study and who were in the placebo group versus 1% of women HRT users assigned to tamoxifen (P .022). Because the HRT users were a subgroup not originally defined in the protocol, the results, however, should be interpreted with caution. The risk of breast cancer is increased by using combined estrogen/progestin HRT for 24 months or longer (8). We are not given information about what hormone preparation(s) were used by women in the Italian trial, but it is likely that they received estrogen alone after hysterectomy. Regardless of the HRT preparations used, the rate of breast cancer development after 81.2 months of follow-up in the Italian trial was 2.58% among HRT users in the placebo group but only 1.59% among the women assigned either to placebo or tamoxifen who had never used HRT (6). In this issue of the Journal, the data were re-analyzed after stratifying the women into two groups: those who are at increased risk of developing ER-positive tumors (high risk), and those at low risk. Factors that placed a woman in the highrisk group included reproductive and hormonal characteristics (i.e., height >160 cm, age at menarche <13 years, nulliparity, age at first birth after age 24, and no oophorectomy). When the participants were divided into high-risk (702 women, 13% of the study population) or low-risk groups (4693 women, 87% of the study population), tamoxifen had a protective effect on the development of breast cancer among women in the high-risk group (n 3 versus n 15 among placebo users, P .003). The overall risk of breast cancer in the high-risk group increased threefold compared with the overall risk in the low-risk group (hazard ratio [HR] 3.32, 95% confidence interval [CI] 1.78 to 6.17). Tamoxifen use decreased the incidence of breast cancer by 82% in the high-risk group but not in the low-risk group (tamoxifen 31, placebo 30; P .89). These findings can be compared with other published data. The IBIS-I trial, a multinational study, showed a 32% reduction in the risk of developing invasive breast cancer among high-risk women treated with tamoxifen with 50 months median followup (2). Participation in that trial required at least a twofold relative risk for breast cancer for women aged 45–70 years, a fourfold relative risk for women aged 40–44 years, and a 10-fold relative risk for women aged 35–39 years. Risk factors used