Overview of the main outcomes in breast-cancer prevention trials

Background Early findings on the use of tamoxifen or raloxifene as prophylaxis against breast cancer have been mixed; we update available data and overview the combined results. Methods All five randomised prevention trials comparing tamoxifen or raloxifene with placebo were included. Relevant data on contralateral breast tumours and side-effects were included from an overview of adjuvant trials of tamoxifen versus control. Findings The tamoxifen prevention trials showed a 38% (95% CI 28–46; p<0•0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for oestrogen receptor (ER; hazard ratio 1•22 [0•89–1•67]; p=0•21), but ER-positive cancers were decreased by 48% (36–58; p<0•0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2•4 [1•5–4•0]; p=0•0005) and the adjuvant trials (relative risk 3•4 [1•8–6•4]; p=0•0002); no increase has been seen so far with raloxifene. Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1•9 [1•4–2•6] in the prevention trials; p<0•0001) and with raloxifene. Overall, there was no effect on non-breast-cancer mortality; the only cause showing a mortality increase was pulmonary embolism (six vs two). Interpretation The evidence now clearly shows that tamoxifen can reduce the risk of ER-positive breast cancer. New approaches are needed to prevent ER-negative breast cancer and to reduce the side-effects of tamoxifen. Newer agents such as raloxifene and the aromatase inhibitors need to be evaluated. Although tamoxifen cannot yet be recommended as a preventive agent (except possibly in women at very high risk with a low risk of side-effects), continued follow-up of the current trials is essential for identification of a subgroup of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive.