Risks associated with tamoxifen and raloxifene limit the appeal of these agents for prevention of primary breast cancer.

The selective estrogen receptor modulators (SERMs) tamoxifen (TAM) and raloxifene (RAL) — and the selective tissue estrogenic activity regulator tibolone — are all associated with lower risk for primary invasive breast cancer. TAM and RAL are approved in the U.S. for chemoprophylaxis in high-risk women (RAL in postmenopausal women only). In a review of seven placebo-controlled trials and one head-to-head trial involving women without histories of breast cancer, investigators assessed the effectiveness and safety of these three agents (tibolone is not available in the U.S.).

Overall, TAM and RAL lowered the incidence of invasive breast cancer by 7 to 10 women per 1000 annually (risk ratios, 0.70 and 0.44, respectively). In both pre- and postmenopausal women, these SERMs reduced risk for estrogen-receptor–positive tumors (but not estrogen-receptor–negative tumors), noninvasive breast cancers, and mortality from breast cancer. Both agents also reduced risk for osteoporotic fractures. TAM and RAL raised risk for venous thromboembolic events (VTEs) by 4 to 7 women per 1000 annually (RRs, 1.93 and 1.60, respectively). TAM (but not RAL) raised the endometrial cancer risk (RR, 2.13) and was also associated with excess risk for abnormal uterine bleeding and hysterectomy for benign disease. Both SERMs were associated with greater likelihood of hot flashes.

Comment: In the U.S., tamoxifen is most often prescribed as adjuvant endocrine therapy following initial treatment for estrogen-receptor–positive breast cancer in pre- and postmenopausal women; raloxifene is approved for prevention of osteoporotic fractures in postmenopausal women. Because most trial participants were white and relatively healthy, the relevance of these findings to women of other ethnicities or with comorbidities is uncertain. Risks and side effects associated with SERMs have limited their use for breast cancer chemoprophylaxis in the U.S. In particular, VTE risk is an issue in overweight and older women — and risk for malignant and benign gynecologic disease is cause for concern in premenopausal women with intact uteri. Clinicians of women at risk for breast cancer should help those who are considering chemoprophylaxis to understand the benefits and risks of SERMs in the context of their own personal circumstances. Moreover, aromatase inhibitors represent a potential alternative that is now being evaluated.