Tamoxifen for Breast Cancer Prevention

The case for tamoxifen to be tested as a preventive for breast cancer has merit. Animal studies demonstrate that tamoxifen prevents mammary carcinogenesis (1–5) and clinical studies now confirm that adjuvant tamoxifen therapy is the only systemic treatment that will prevent contralateral breast cancer (6). Developing clinical studies (7–10) confirm the laboratory data (11–13) that tamoxifen will maintain post-menopausal bone density in the lumbar spine and the neck of the femur; two important skeletal sites for the ultimate prevention of osteoporosis. However, a most important target site-specific effect of tamoxifen is the decrease in low-density lipoprotein cholesterol levels in postmenopausal women (14–17). This positive property of tamoxifen may be responsible for the recorded decreases in hospital visits for the treatment of cardiac conditions (18) and the significant decrease in fatal myocardial infarction for women treated with 5 years of adjuvant tamoxifen (19, 20). These data provide the scientific basis to undertake randomized, placebo-controlled clinical trials to test the worth of tamoxifen to prevent breast cancer. Concern has been expressed (21) about the use of tamoxifen by premenopausal women in prevention trials because there is less clinical experience in premenopausal patients. The complicating factors are an increase in ovarian steroidogenesis (22) and the possibility of pregnancy and teratogenesis (23). Each concern has theoretical merit, but the supporting data are somewhat ambiguous. It is possible that increased steroidogenesis might negate the preventive effect of tamoxifen in the developing tumor; however, animal studies indicate that it is not easy to reverse the antitumor action of tamoxifen with estradiol (24). Much higher levels of estrogen are required to reverse the actions of tamoxifen than are observed clinically. Nevertheless, some mature clinical studies (25, 26) appear to show that tamoxifen is ineffective in premenopausal women for the prevention of secondary primary breast cancers (25) and that tamoxifen is significantly inferior to chemotherapy-induced ovarian ablation in preventing breast cancer recurrence in premenopausal patients (26).