Tamoxifen for prevention of breast cancer – encouraging results but risks still unclear

Early findings from a randomised trial investigating the effectiveness of tamoxifen to prevent breast cancer are reported in this week’s issue of THE LANCET. Although tamoxifen reduced breast cancer incidence by a third compared with women given placebo, the authors of the study caution that it is still too early to fully assess the risk to benefit ratio of tamoxifen as a preventative strategy for breast cancer.

Tamoxifen is well known in its effect to decrease recurrence of (and death from) breast cancer; however, three clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results. The overall evidence supports a reduction in the risk of breast cancer, but whether this benefit outweighs the risks and side-effects associated with tamoxifen is unclear.

Jack Cuzick from Cancer Research UK, lead investigator of the International Breast Cancer Intervention Study (IBIS-I) and colleagues undertook a double-blind placebo-controlled randomised trial of tamoxifen, 20 mg/day for 5 years, in around 7000 women from the UK, Europe, Australia and New Zealand who were aged 35-70 years and who were at an increased risk of breast cancer (eg. They had a Family history of the disease or had a benign lesion associated with an increased risk of breast cancer).

The frequency of breast cancer was reduced by a third among Women given tamoxifen (69 breast cancers in 3578 women in the tamoxifen group and 101 breast cancers in 3566 in the placebo group). Endometrial cancer-considered to be increased by tamoxifen use-was doubled in the tamoxifen group (11 instances compared with 5 in the control group), but this increase was not statistically significant, and all cases were localised (stage 1) and curable by hysterectomy.

However, tamoxifen use was associated with more than a doubling in the risk of blood-clotting complications, especially after surgery or long periods of immobilisation. The investigators comment that the increased risk of blood-clotting complications could also contribute to the higher death rate from all causes in women given tamoxifen.

Jack Cuzick comments: “Although when used as adjuvant therapy for breast cancer, tamoxifen can clearly reduce the risk of recurrence and death, at present the overall risk to benefit ratio in the preventive setting is still unclear. Further long-term follow-up to study breast-cancer incidence and mortality, other causes of death, and side-effects in the current trials remains essential.”

In an accompanying Commentary (p 813), Linda Kinsinger from the University of North Carolina, USA, states: “For chemoprevention to find a prominent role in reducing the burden of breast cancer, research must develop along at least three paths. First, longer-term research must find that the reduction in incidence translates into a reduction in breast cancer mortality. Second, newer drugs that have a better safety profile need to be developed. Finally, better ways are needed to target the drugs to those women who will benefit most.” She concludes: “The promising results from the tamoxifen and raloxifene trials, and especially their large effect size, give hope for a new and more effective strategy for reducing the burden of breast cancer. But until the research agenda is further advanced, chemoprevention of breast cancer will remain a promising idea with an uncertain future.”