Selective oestrogen receptor modulators (SERMs: tamoxifen, raloxifene, arzoxifene, and lasofoxifene) significantly reduce the risk of developing the most common type of breast cancer among women at both high and average risk of the disease both during treatment, and for at least 5 years after stopping, according to the first comprehensive analysis of all SERM prevention trials to date published in The Lancet.

“Despite their effectiveness, many women have opted not to take SERMs because of concerns about toxic effects”, explains Jack Cuzick from Queen Mary, University of London who led the research funded by Cancer Research UK.

“But our longer-term findings clearly show that the benefit-harm balance is now more favourable than previously calculated for short-term follow up. The benefits of these drugs continue well after treatment has stopped, whilst most of the side effects do not.”

SERMs protect against disease that is sensitive to oestrogen (oestrogen receptor (ER)-positive disease; about 70% of all breast cancers) by binding to the oestrogen receptor and blocking the breast cells ability to grow and multiply.

In this new analysis, which represented 83 399 women who were tracked for a median (midpoint) 65 months, the investigators found that women taking SERMs were 38% less likely to develop breast cancer than those given placebo (due to a reduction in the risk of ER-positive disease). This reduction in incidence was larger in the earlier follow-up period (42% in first 5 years vs 25% in years 5–10 years). No effect was noted for ER-negative breast cancers.

The authors calculated that 42 women would need to be treated to prevent one breast cancer event in the first 10 years.

All SERMs significantly increased thromboembolic events (eg, deep vein thrombosis). Only tamoxifen was associated with significantly higher rates of endometrial cancer, although this difference disappeared after tamoxifen was stopped. No overall reduction in cardiovascular events (heart attacks, strokes, or transient ischemic attacks) was noted in patients taking SERMs compared to those taking placebo, despite a 10–20% reduction in LDL cholesterol.

According to Cuzick, lasofoxifene is likely to be a very promising candidate for prevention and should be a priority for prevention research: “It not only had a large effect on breast cancer incidence [reduction of 81%] but also showed benefit for stroke [reduction of 36%], cardiac events [32%], and vertebral fractures [42%], with no increase in endometrial cancer.”

But he adds: “Unfortunately, at the present time, none of these drugs are being actively marketed for breast cancer prevention, and approval by the US Food and Drug Administration or any other regulatory authority for this indication will probably not be sought for lasofoxifene or arzoxifene.”

Writing in a linked Comment, Anthony Howell and Gareth Evans from Genesis Breast Cancer Prevention at the University Hospital of South Manchester in the UK say: “The present study is testament to the persistence of clinical trials groups, industry, investigators, and the women volunteers, who have now collectively shown the long term effectiveness of the original SERM hypothesis. The future of breast cancer prevention will depend on prediction of breast cancer risk and responsiveness with more precision, improving the process by which patients are offered prevention, and developing drugs that prevent ER-negative breast cancer.”

Source: The Lancet

Watch an interview with Jack Cuzick here