Advance for aromatase inhibitors

A large international clinical trial has led to the discovery that postmenopausal survivors ofearly-stage breast cancer who take the drug letrozole after completing 5 years oftamoxifen therapy have a significantly reduced risk ofcancer recurrence.

Tamoxifen is widely used to prevent breast cancer recurrence in postmenopausal women with hormone-responsive tumours.It initially functions as both an antagonist and a partial agonist ofthe oestrogen receptor,but over time,its agonistic action increases, which is believed to reduce its antitumour activity.Additional treatment approaches are therefore needed.Aromatase inhibitors, which prevent oestrogen synthesis,are good candidates,as they have been shown to be effective in treating women with metastatic disease that progresses despite tamoxifen therapy.

In the 6 November issue ofthe New England Journal of Medicine, Goss et al. analysed the efficacy ofthe aromatase inhibitor letrozole as a second-line therapy in women with oestrogen-responsive breast cancer.In a Phase III double-blind clinical trial that involved 5,187 women,they found that letrozole, when taken after 5 years oftamoxifen therapy,significantly improves the odds for disease-free survival.In total,132 women in the placebo group experienced disease recurrence,compared with 75 women on letrozole.The 4-year disease-free survival rate for women who received letrozole was 93%,compared with 87% ofthe women in the placebo group.Women who received letrozole had a reduction in the number ofrecurrences ofcancer in their previously affected breast,a reduction in the number of new cancers in the opposite breast and also a reduction in metastatic tumours.

The side effects of letrozole,which was taken once a day in pill form,are very similar to those experienced by women undergoing menopause.More women in the letrozole group experienced low-grade hot flashes,arthritis,arthralgia and myalgia.Furthermore,they developed osteoporosis and fractures more frequently than women in the control group.As aromatase inhibitors decrease oestrogen levels,they are likely to reduce bone-mineral density.

The clinical trial was halted early,after a median follow up of only 2.4 years,because ofthe positive results.However,in an accompanying editorial,John Bryant and Norman Wolmark state that the short period offollow-up diminishes the clinical utility of the data.They point out that an overall survival effect,which was not statistically significantmarked/large in this trial,might never be documented.Furthermore,nothing is known about optimal duration oftreatment beyond 2–3 years,or about the long-term side effects ofletrozole therapy.Less than 1% ofwomen in the trial received over 4 years ofletrozole therapy.

In a second editorial,Harold Burstein also warns that these data should not be interpreted as a recommendation for the use of aromatase inhibitors as primary adjuvant therapy.Several other trials are underway to compare aromatase inhibitors with tamoxifen as adjuvant therapy for the first 5 years after diagnosis. ORIGINAL RESEARCH PAPER Goss, P. E. et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N. Engl. J. Med. 9 Oct 2003 (doi: 10.1056/NEJMoa032312) FURTHER READING Bryant, J. & Wolmark, N. Letrozole after tamoxifen for breast cancer: what is the price of success? N. Engl. J. Med. 9 Oct 2003 (doi: 10.1056/NEJMe038167) Burstein, H. Beyond Tamoxifen: extending endocrine treatment for early-stage breast cancer. N. Engl. J. Med. 9 Oct 2003 (doi: 10.1056/NEJMe038174)