Letrozole following tamoxifen may benefit women with breast cancer

Switching to the drug letrozole following 5 years of treatment with tamoxifen reduces the risk of hormone-dependent breast cancer recurrence, but not overall survival, among postmenopausal women, according to a new study in the September 7 issue of the Journal of the National Cancer Institute.

The standard treatment for women with estrogen receptor-positive breast cancer is 5 years of tamoxifen. Extending the treatment past 5 years has not been associated with any additional improvement in survival, and many women experience new primary tumors and relapses after they go off the drug.

Tamoxifen works by inhibiting the effects of estrogen. However, after 5 years of exposure to the drug, cancer cells may become resistant to or even dependent on it. Newer drugs, called aromatase inhibitors, can selectively inhibit the enzyme aromatase, thus lowering the levels of estrogen. Previous reports have suggested that the tumor cells involved with cancer recurrence may be vulnerable to these drugs after building up a resistance to tamoxifen.

To test whether an aromatase inhibitor called letrozole (Femara) could extend the protective effect of tamoxifen beyond 5 years, the National Cancer Institute of Canada's Clinical Trials Group in collaboration with the North American Breast Intergroup launched a clinical trial called the MA.17 trial. They randomly assigned 5,187 postmenopausal women who had already received 5 years of tamoxifen for breast cancer to take either a placebo or letrozole for an additional 5 years.

After median follow-up of 30 months, in the current study Paul E. Goss, M.D., Ph.D., of the Massachusetts General Hospital in Boston, and colleagues reported that the women taking letrozole had a significantly better overall disease-free survival rate and distant disease-free survival rate (survival without metastasis) than women in the placebo group. They found that 92 (3.6%) of the 2,583 in the letrozole group experienced a recurrence or contralateral breast cancer (cancer in the opposite breast), compared with 155 (6%) of the 2,587 taking the placebo.

Although the authors originally planned for a 5-year study, the trial was halted after 4 years, and the placebo patients were given the option of switching to the letrozole treatment. Some of the interim results were previously published in 2003, however this new study includes a full analysis of the results, including information on patient subsets. For example, although the authors found similar overall survival rates throughout the whole study population, they also found that the subset of patients with lymph node-positive cancer had better overall survival on letrozole then on the placebo.

The women taking letrozole experienced more side effects from their treatment then the women taking placebo. For example, 8.1% of women taking letrozole were diagnosed with osteoporosis, compared with 6.0% in the placebo group; 58% of the letrozole group reported having hot flashes, compared with 54% of those on placebo. The authors attribute many of these events to the estrogen depletion caused by the drug.

The authors note that their study is based on a relatively short median follow-up. However, they remain encouraged that the data confirms a "substantial reduction in risk of recurrence and excellent tolerability with extended adjuvant letrozole." They conclude, "Adjuvant letrozole should be discussed with all postmenopausal women completing standard adjuvant tamoxifen therapy."