Letrozole Therapy for Breast Cancer Goss PE, Ingle JN, Martino S, 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 2003;349(19):1793-802.

Bryant J, Wolmark N: Letrozole after tamoxifen for breast cancer- what is the price of success? N Engl J Med 2003;349(19):1855-57 (editorial).

Burstein HF: Beyond tamoxifen-extending endocrine treatment for early-stage breast cancer. N Engl J Med 2003;349(19): 1857-59 (editorial).

In hormone-dependent breast cancer, 5 years of postoperative treatment with tamoxifen, an antagonist of the estrogen receptor, prolongs disease-free and overall survival, but more than 5 years of therapy does not provide added benefit. Goss and coauthors investigated the benefits of extended therapy with the aromatase inhibitor letrozole, which suppresses estrogen production. More than 5,000 women were recruited and an interim analysis was conducted after a median of 2.4 years of follow-up. There were 207 local or metastatic recurrences of breast cancer or new primary cancers, 75 in the letrozole group and 132 in the placebo group, with an estimated 4-year disease-free survival rate of 93% and 87% respectively (p<0.001). The women in the treatment group had more frequent low-grade hot flashes, arthritis, arthralgia, and myalgia. In contrast to tamoxifen, which protects against bone fractures and lowers serum cholesterol, aromatase inhibitors may reduce bone mineral density and cause hypercholesterolemia. New diagnoses of osteoporosis were reported less often in the women who received placebo (4.5% compared to 5.8%; p=0.07). Because the study was stopped early, the optimal duration of treatment is undefined and the question of long-term toxicity is unanswered. Post-menopausal women who are considering letrozole therapy will need careful education about the benefits of increased disease-free survival and the likely side effects of the therapy.