We included nine trials with 83 399 participants and 306 617 women-years of follow-up (). Median follow-up was 65 months (IQR 54–93). shows Kaplan-Meier curves for all breast cancers and invasive ER-positive breast cancer for all trials except the STAR trial. Annual rates of breast cancer incidence varied substantially between trials (), probably because of different entry criteria. The overall reduction in all breast cancer (including ductal carcinoma in situ) was 38% (p<0·0001; ), with an estimated 10 year cumulative incidence of 6·3% in the control groups and 4·2% in the SERM groups. We noted the reduction in both years 0–5 of follow-up (42%, p<0·0001) and years 5–10 (25%, p=0·007; and ). Despite the smaller effect in years 5–10, there was no evidence of heterogeneity between trials (p=0·3). Random-effects models produced similar HRs to those for the fixed-effects models, but larger 95% CIs ().
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
Breast cancer incidence in the chemoprevention trials
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 models23
Overall, the frequency of invasive ER-positive cancer was reduced from 4·0% to 2·1% (p<0·0001; ). This reduction was apparent in years 0–5 (p<0·0001) and in years 5–10 (p<0·0001; and ). The number needed to treat to prevent one diagnosis of breast cancer in the first 10 years was 42; when restricted to invasive ER-positive breast cancer the number was 53. Although all trials showed a reduction in breast cancer incidence, we noted substantial heterogeneity between trials in the size of the effect for all breast cancers and invasive ER-positive cancers (), and for invasive cancers. We noted a non-significant increase in invasive ER-negative breast cancers (p=0·3; ). The incidence of ductal carcinoma in situ was significantly reduced overall by 31% (p=0·006; ). We noted a 38% reduction in incidence in the tamoxifen trials, but no effect for raloxifene; however, significant heterogeneity was shown between trials. Little information was available for the effect of lasofoxifene and arzoxifene on ductal carcinoma in situ.
All breast cancers, invasive breast cancer, and DCIS in years 0–10
For tamoxifen trials, we noted a significant reduction of 33% (p<0·0001) in all breast cancers compared with placebo ( and ). This reduction was mainly due to a large effect on ER-positive invasive breast cancer, for which we noted a reduction of 44% (p<0·0001; ) and a significant reduction in DCIS (p=0·009; ), but a non-significant increase in ER-negative tumours was recorded (p=0·4; ). Significant heterogeneity was shown between trials for all breast cancers (p=0·02) and invasive ER-positive breast cancers (p=0·03). For raloxifene trials, we noted a significant reduction in incidence of all breast cancer (p<0·0001; ) due to a reduction in invasive ER-positive breast cancers, with a non-significant increase in the incidence of invasive ER-negative breast cancers and no effect on DCIS ( and ). When we compared raloxifene with tamoxifen, the only significant difference in effect size was a greater effect for tamoxifen in DCIS (HR 0·78, 95% CI 0·61–0·99; p=0·04).
The PEARL and GENERATIONS trials had follow-up results for only years 0–5. All breast cancers (p<0·0001) and ER-positive cancers (p<0·0001; ) were significantly reduced with 0·5 mg per day of lasofoxifene compared with placebo, whereas only a small effect was noted for women receiving 0·25 mg per day ( and ). We noted a non-significant increase in incidence for invasive ER-negative breast cancer (HR 1·43, 95% CI 0·43–1·66) and a non-significant decrease for ductal carcinoma in situ (0·76, 0·26–2·21; p=0·6) when both treatment groups were combined. Arzoxifene reduced all breast cancer occurrence by 58% (p=0·001; ). Invasive ER-positive breast cancers were reduced by 70% (p=0·002), whereas no effect was noted for invasive ER-negative breast cancers (p=0·9; and ). Incidence of ductal carcinoma in situ was reduced, but not substantially so (p=0·07; ).
No trial was designed to look at mortality as an endpoint, and no effect of any SERM was reported for all causes of death (). Data for cause-specific mortality was not available for most of the non-tamoxifen trials. No effect on breast cancer death was reported in the tamoxifen trials on the basis of a total of 59 deaths ().
and present major events for each trial. Overall, women receiving a SERM had a higher rate of endometrial cancer than did those given placebo (p=0·007; ) but the increase was confined to the first 5 years of follow-up (HR 1·64, 1·14–2·36; p=0·007) and was not apparent during years 5–10, the period after treatment (0·85, 0·38–1·89; p=0·7). The effect seemed to be limited to the tamoxifen trials (2·18, 1·39–3·42; p=0·001) and no increase was shown in the raloxifene trials (1·09, 0·74–1·62; p=0·7). Too few endometrial cancers were reported with lasofoxifene to make a meaningful interpretation, but an increase of 2·3 times was noted with arzoxifene (2·26, 0·70–7·32; p=0·2).
Major non-breast cancer events in the prevention trials
1586 cancers other than breast or endometrial cancer were reported. These cancers were evenly distributed between the treatment groups (p=0·8; ) and no heterogeneity between trials was noted (p=0·8). A non-significant reduction was noted for ovarian cancer (OR 0·84, 95% CI 0·60–1·19; p=0·3) and there was no effect on colorectal cancer (1·04, 0·85–1·27; p=0·7). Venous thromboembolic events were significantly increased overall (p<0·0001; and ). We noted similar ORs in the tamoxifen and raloxifene trials (1·60, 1·21–2·12; p=0·001 vs 1·45, 1·18–1·76; p<0·0001; ), but the rate was higher for arzoxifene (2·55, 1·45–4·47; p=0·001) and lasofoxifene (ORpooled 2·38, 1·43–3·97; p=0·001), and no significant heterogeneity was noted between trials. Overall, no effect of SERMs was noted for myocardial infarction, stroke, or transient ischaemic attacks, and there was no evidence for heterogeneity, except for a significant reduction in strokes for lasofoxifene (OR 0·67, 0·48–0·92; p=0·01; ).
All fractures were significantly reduced by SERMs (p<0·001; and ). This reduction was mainly driven by a decrease in the PEARL trial (0·73, 0·66–0·81; p<0·0001), but decreases were also noted in the raloxifene and GENERATIONS trials (). By contrast, no effect was seen with tamoxifen (0·92, 0·83–1·02). We noted a greater effect when we restricted findings to those for vertebral fractures; however, such fractures were rare in the tamoxifen and STAR trials, and not recorded in the Italian trial, and only well documented in the osteoporosis trials in which follow-up spinal radiographs were done (MORE and CORE, PEARL, and GENERATIONS trials). When restricted to these trials, we noted a 41% reduction in vertebral fractures (0·59, 0·52–0·67; p<0·0001). We recorded a small effect for non-vertebral fractures overall (), which seemed to be greatly affected by the 0·5 mg dose of lasofoxifene (OR 0·81, 0·67–0·98; ); however, no heterogeneity was shown (p=0·8). Overall cataracts were evenly distributed between treatment groups (), but a small increase was observed with tamoxifen (1·10, 1·01–1·21; p=0·04).