Background: Although tamoxifen and raloxifene (Evista) are approved by the U.S. Food and Drug Administration to reduce the risk of primary invasive breast cancer in high-risk women (i.e., those with atypical hyperplasia or lobular carcinoma found on breast biopsy, one or more first-degree relatives with breast cancer, or a five-year predicted risk of 1.66 percent or more via the modified Gail model), their use for this purpose remains low. In many other countries, tibolone (not available in the United States) also has been reported to reduce the risk of primary breast cancer. However, the relative effectiveness and safety of these agents are unclear. Nelson and colleagues reviewed the medical literature to determine the comparative effectiveness and safety of tamoxifen, raloxifene, and tibolone for reducing the risk of primary breast cancer in women who did not have a breast cancer susceptibility mutation.

The Study: The authors searched abstracts and articles through January 2009 in Medline, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. Comparative benefits were assessed using randomized controlled trials, and comparative harms were assessed using randomized trials and observational studies.

Results: Compared with placebo, tamoxifen, raloxifene, and tibolone all reduced the risk of invasive breast cancer (overall risk ratios = 0.70, 0.44, and 0.32, respectively). Tamoxifen and raloxifene similarly reduced the risk of estrogen receptor–positive invasive breast cancers, but neither reduced the risk of non-invasive or estrogen receptor–negative invasive breast cancers. Tamoxifen continued to reduce the risk of invasive breast cancer for at least three to five years after discontinuation of therapy, but no posttreatment follow-up data were available for the other agents.

With regard to adverse events, tamoxifen and raloxifene increased the risk of thromboembolism (risk ratio = 1.93 and 1.60, respectively) compared with placebo. Tibolone caused more strokes than placebo (risk ratio = 2.19). Risk of coronary heart disease was not increased with any agent. Tamoxifen also increased the risk of endometrial cancer (risk ratio = 2.13) and cataracts (risk ratio = 1.57), but this did not occur with raloxifene.

Conclusion: The authors conclude that tamoxifen, raloxifene, and tibolone all reduce the risk of primary invasive breast cancer, with tamoxifen exerting a residual protective benefit after its discontinuation. Tibolone increases stroke risk, whereas thromboembolic events are more common with tamoxifen and raloxifene. Endometrial cancer and cataracts are also more common in women using tamoxifen.

editor's note: Preliminary evidence from the Women's Health Initiative study suggests that bisphosphonates such as alendronate (Fosamax) and etidronate (Didronel) may also be associated with a 31 percent reduction in the incidence of invasive breast cancer.^1,2 As with tamoxifen and raloxifene in the above study, this only applied to estrogen receptor–positive cancers. However, bisphosphonate use was also associated with a 41 percent greater incidence of in situ breast cancers. Until randomized studies examining this effect are available, bisphosphonates should not be used solely to reduce the risk of invasive breast cancer, especially with the better quality evidence supporting tamoxifen and raloxifene for this indication.—k.t.m.