Expert Commentary

Does benefit always outweigh risk when a SERM is used to prevent primary breast cancer?

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The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene have been shown to reduce the risk of primary invasive breast cancer, as has the selective tissue estrogenic activity regulator tibolone. Tamoxifen and raloxifene are approved for use in high-risk women—although raloxifene is approved for this indication in postmenopausal women only. Tibolone is not available in the United States and is therefore not included in this discussion, although it was included in the review by Nelson and associates.

In the United States, tamoxifen is usually prescribed as adjuvant endocrine therapy after treatment of estrogen-receptor–positive breast cancer in both premenopausal and post-menopausal women. Raloxifene is most often prescribed for the prevention and treatment of osteoporosis in postmenopausal women. Use of these agents as chemoprophylaxis in women who have no history of breast cancer is less common, largely because of the risks and side effects of these drugs.

The increase in venous thromboembolism is of particular concern for women who have an elevated risk of this outcome, including overweight women and those of advanced age. The elevated risk of malignant and benign gynecologic disease associated with tamoxifen is of concern in all women who have an intact uterus.

Details of the review

Nelson and colleagues performed a systematic review, funded by the Agency for Health-care Research and Quality, that involved the aggregation of findings from seven placebo-controlled trials and one head-to-head, randomized, clinical trial involving women who had no history of preinvasive or invasive breast cancer. In the process, they focused on harms as well as benefits associated with use of these chemoprophylactic agents.

Tamoxifen and raloxifene reduced the risk of invasive breast cancer by 7 to 10 cases in every 1,000 women annually. These agents reduced the risk of estrogen-receptor–positive malignancy, but not estrogen-receptor–negative tumors, noninvasive cancer, or breast cancer–related mortality.

Tamoxifen and raloxifene were similarly effective in premenopausal and postmenopausal populations; both drugs also reduced the rate of osteoporotic fracture.

Most of the participants in the prevention trials were white and relatively healthy. Therefore, the relevance of these findings to women of other racial and ethnic groups and to women who have chronic disease or other morbidity is uncertain.

Aromatase inhibitors are being assessed for chemoprophylaxis, so we should have information on their risk-benefit ratio in the near future.


Clinicians who care for women at high risk of primary breast cancer should thoroughly counsel each candidate for chemoprophylaxis about the potential benefits and risks of these agents in her particular circumstances. It may be that the risks outweigh the benefits in some women—such as those who already have an elevated risk of venous thromboembolism.

In addition, because most of the participants in the studies included in this review were healthy and white, we cannot be certain how generalizable these findings are to other subpopulations.—ANDREW M. KAUNITZ, MD

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