Letrozole reduces cancer recurrence after tamoxifen therapy ends

The aromatase inhibitor letrozole improves the outcome of patients with breast cancer when initiated after tamoxifen therapy has ended, according to findings of a study terminated early because of letrozole’s documented efficacy.

Tamoxifen is both an antagonist and a partial agonist of the estrogen receptor. After 5 years of treatment, adjuvant tamoxifen is no longer beneficial, lead author Dr. Paul E. Goss and colleagues report in a study released early by The New England Journal of Medicine. The paper is scheduled for publication in the November 6th issue.Aromatase inhibitors reportedly improve the outcome of women who develop progressive metastatic disease, despite treatment with tamoxifen, Dr. Goss, of Princess Margaret Hospital, Toronto, and colleagues note. His team began a phase III trial of letrozole that included postmenopausal women with primary breast cancer who had completed approximately 5 years of adjuvant tamoxifen therapy. The subjects were randomly assigned to letrozole 2.5 mg daily (n = 2575) or placebo (n = 2582) for 5 years. At the first interim follow-up (median 2.4 years), 75 patients in the letrozole group and 132 in the placebo group had experienced recurrence or new primary cancer in the contralateral breast (hazard ratio 0.57, p = 0.00008). The trial was then terminated and the results were relayed to the study participants.The estimated 4-year disease-free survival rates were 87% for the placebo group versus 93% for the treatment group (p < 0.001). Overall survival was not affected by treatment group."The reduction in the rates of recurrent and new disease in the letrozole group confirms the continuous dependence of hormone-receptor-positive breast cancer on estrogen," Dr. Goss' team writes.Relatively mild symptoms, including hot flashes, arthritis, arthralgia and myalgia were more common in those treated with letrozole (p < 0.05), while vaginal bleeding was less common (p = 0.01). Osteoporosis was diagnosed in 5.8% of the letrozole-treated subjects and in 4.5% of the placebo-treated subjects, but the difference did not attain statistical significance.The authors note that their findings are not pertinent to premenopausal women, because aromatase inhibitor therapy alone does not adequately suppress estrogen in ovulating women.In two separate editorials, experts decry the lost opportunity to document long-term survival advantages, optimal duration of treatment or safety issues of adjuvant letrozole therapy because of early trial termination.Since these results will affect other ongoing trials of this therapy, "there may be no opportunity to collect data from a placebo-controlled trial that will help to evaluate the risks of long-term adverse events," write Drs. John Bryant and Norman Wolmark. Dr. Bryant is on the faculty at the University of Pittsburgh and Dr. Wolmark with Allegheny General Hospital.Also, Dr. Harold J. Burstein of Harvard Medical School speculates that "the benefits of letrozole might have been less pronounced in women who had undergone ipsilateral or bilateral mastectomy or who were at lower risk for regional recurrence by virtue of improved techniques for surgical or radiation therapy." (Source: N Engl J Med 2003;349: Reuters Health: October 9, 2003: Oncolink)