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EXPANDING ROLE FOR AROMATASE INHIBITORS IN BREAST CANCER

The estrogen-receptor antagonist tamoxifen has long been a key component of adjuvant therapy for breast cancer patients. Risk for recurrent breast cancer is reduced substantially when tamoxifen is used for 5 years after primary treatment. However, continuing tamoxifen for longer than 5 years confers no additional benefit and actually might be harmful. Because women remain at risk for recurrence beyond 5 years, investigators have turned to aromatase inhibitors, which block the synthesis of estrogens from androgens.

First, aromatase inhibitors were found to be effective as treatment in patients with disease progression despite tamoxifen therapy or as primary therapy in patients with advanced breast cancer (Journal Watch Dec 19 2000). Then, in a clinical trial of women with early-stage estrogen-receptor-positive breast cancer, 3-year disease-free survival rate was higher with the aromatase inhibitor anastrozole (Arimidex) than with tamoxifen (Journal Watch Aug 9 2002). Now, we have evidence that the aromatase inhibitor letrozole (Femara) reduces risk for breast cancer recurrence after adjuvant tamoxifen therapy (Journal Watch Oct 31 2003).

More than 5000 women who had completed 5 years of tamoxifen therapy for early-stage hormone-receptor-positive breast cancer, and who had no evidence of recurrence, were randomized to receive letrozole or placebo. Although the planned treatment period was 5 years, the trial was interrupted (according to a planned stopping rule) after a median follow-up of 2.4 years: At that point, a significant advantage was found for letrozole compared with placebo (estimated 4-year disease-free survival, 93% vs. 87%); a nonsignificant trend toward lower mortality with letrozole also was noted.

This trial is important because it gives us another way to reduce long-term risk for recurrent breast cancer. However, the trial is interesting for another reason: The decision to interrupt it stirred up considerable controversy. Proponents of early termination note that it would have been unethical to continue with placebo after a clear advantage for active treatment had emerged. But critics contend that we lost an opportunity to determine how long to give letrozole treatment, whether clinically important adverse effects will emerge with longer use, and whether the drug ultimately will reduce mortality. Several other trials of aromatase inhibitor therapy following tamoxifen treatment are in progress.

— Allan S. Brett, MD

Published in Journal Watch General Medicine December 31, 2003