Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data

Abstract

Background: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence.

Methods: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat.

Results: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99).

Interpretation: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs.

Funding: Cancer Research UK.

Figure 1

Cumulative incidence for all breast cancer (including ductal carcinoma in situ) and all ER-positive invasive cancers in years 0–10 according to treatment allocation SERM=selective oestrogen receptor modulator. ER=oestrogen receptor.

Figure 2

Annual hazard rate for all breast cancers (including ductal carcinoma in situ) and invasive ER-positive breast cancer in years 0–10 with fixed-effects models ER=oestrogen receptor. SERM=selective oestrogen receptor modulator.

Figure 3

All breast cancers, invasive breast cancer, and DCIS in years 0–10 ER=oestrogen receptor. DCIS=ductal carcinoma in situ. *Adjusted by overall tamoxifen effect to give raloxifene versus placebo comparisons. † STAR data not included in comparisons. ‡Data for ER-invasive cancer are pooled.

Figure 4

Forest plots for adverse events (A) Endometrial cancer, other cancer, venous thromboembolic events, and cardiac or stroke events. (B) All fractures, vertebral fractures and non-vertebral fractures. *Adjusted by overall tamoxifen effect to give raloxifene versus placebo comparisons. † STAR data not included in comparisons. ‡Data are pooled.