Tamoxifen is a well-known and extensively researched compound. Tamoxifen has been adapted for application in both the treatment and prevention of breast cancer.5,6 Four major prevention trials7–15 have been completed and published updated results on the use of tamoxifen as a preventive agent (Table 1). Overall, a reduction of 38% in the risk of breast cancer has been observed.6 Although no effect on breast cancers with ER-negative origin has been observed, the results from an overview of all the trials suggest that 50% of ER-positive breast cancers can be prevented with 5 years of active tamoxifen use. The updated results from the SERM overview have reported that an extended beneficial effect of tamoxifen is observed even after 5 years of treatment completion.16
Although tamoxifen has been proven to significantly reduce the incidence of breast cancer, increases in endometrial cancer and venous thromboembolic events are the most serious adverse events of this drug. Overall, both adverse events were increased between 2 and 2.5 fold in tamoxifen users, but analysis of long-term follow-up data has shown that thromboembolic events were not in excess after tamoxifen treatment was stopped.10 In summary, tamoxifen prevents ER-positive breast cancer during the first 5 years of treatment and also after treatment cessation. The benefits could persist even longer, and therefore tamoxifen is an attractive chemopreventive option, specifically in premenopausal women, where life expectancy is long.
(To see a larger version of the table, click here.)
Raloxifene is also a SERM developed for the prevention of osteoporosis in postmenopausal women. Like tamoxifen, it has both estrogen-agonistic effects on the bone and lipid metabolisms and estrogen-antagonistic effects on the endometrial and breast tissues. All the studies investigating raloxifene as a preventive agent for the reduction in breast cancer incidence were initially developed as osteoporosis or cardiovascular prevention trials, and breast cancer incidence was a secondary endpoint.
Four trials have reported their results using raloxifene as a preventive agent (Table 1). Both the Multiple Outcomes of Raloxifene Evaluation17 and the Continuing Outcomes Relevant to Evista18 reported a significant reduction (65% and 50%, respectively) in breast cancer overall. Like tamoxifen, an increase in thromboembolic events has been observed with raloxifene, but no significant excess in endometrial cancers or other gynecological problems has been found.
Another study was the Raloxifene Use for The Heart study,19 where an overall reduction of 44% for invasive breast cancer was found with raloxifene, which is similar in size to that seen for tamoxifen in other studies. A direct comparison between tamoxifen and raloxifene was performed in the Study of Tamoxifen and Raloxifene trial.20 The efficacy was about 25% lower for raloxifene compared with tamoxifen, but there were fewer thromboembolic events and gynecological problems with raloxifene. Although raloxifene is widely used in the prevention of osteoporosis, its use in the preventive setting for breast cancer is not common.
Two other SERMs (lasofoxifene and arzoxifene) have been investigated in postmenopausal women. The PEARL (Postmenopausal Evaluation and Risk Reduction With Lasofoxifene) trial recruited 8,556 postmenopausal healthy women to three treatment arms: placebo versus 0.25 mg/day lasofoxifene versus 0.5 mg/day lasofoxifene for 5 years in a 1:1:1 ratio (Table 1).21
All breast cancers (including ductal carcinoma in situ [DCIS]) were significantly reduced by 0.5 mg/day lasofoxifene when compared to placebo, whereas no significant effect was seen for women receiving 0.25 mg/day lasofoxifene, although a beneficial trend was seen. An even greater reduction was seen for invasive ER-positive breast cancer with 0.5 mg/day lasofoxifene. Furthermore, lasofoxifene significantly reduced major coronary events, strokes, and both vertebral and non-vertebral fractures, so may be ideal for prevention where the total benefit/harm balance is particularly important. Overall, there were no differences between the groups in terms of other serious adverse events.
The GENERATIONS trial evaluated the effect of arzoxifene (20 mg/day) versus placebo in 9,354 postmenopausal women with osteoporosis (Table 1).22 Arzoxifene reduced all breast cancer occurrences by 58%. The incidence of DCIS was substantially but nonsignificantly reduced. Arzoxifene also reduced vertebral fractures by 41% but an increase was seen for thromboembolic events, hot flushes, muscle cramps, and gynecological events.
A recently published SERM overview16 is the only comprehensive analysis of all SERM prevention trials to date. The meta-analysis reported on a substantial update on all SERM trials with long-term follow-up (except for the arzoxifene and lasofoxifene trials) and the results clearly showed that all SERMs significantly reduce the incidence on invasive ER-positive breast cancer (Figure 1). However, as seen in all individual trials as well, no effect of SERMs was seen for ER-negative breast cancers, and it is clear that new approaches have to be found to reduce the incidence of these cancers in a high-risk population. Another important finding was that benefits from SERMs were not only seen during the active 5 years of follow-up but also after treatment was completed, indicating a long-term effect of SERMs in the prevention of breast cancer. The decision to use a SERM for breast cancer prevention should not solely be based on the effect on breast cancer incidence. Adverse effects, notably thromboembolic events and, for tamoxifen only, endometrial cancers, have to be taken into account when assessing the risk–benefit ratio for each individual patient. This decision making is a very complex, individual, and complicated matter, but an improved risk–benefit ratio for SERMs might be indicated for women who are at high risk of breast cancer at any age compared to those with average risk. However, currently, the only chemopreventive option for premenopausal women is tamoxifen. Recently, in the UK, the National Institute for Health and Care Excellence has published updated guidelines for the use of tamoxifen (and raloxifene) for women at high risk of developing breast cancer, although these drugs are not licensed for this purpose in the UK.23
(To see a larger version of the figure, click here.)