Dr. Susan Love Research Foundation | Letrozole (Femara) After Tamoxifen: New Data, New Questions

In an early release article published on the New England Journal of Medicine website on October 9, 2003, researchers announced that they stopped a randomized trial that had enrolled postmenopausal women with early stage breast cancer who had already been treated with five years of tamoxifen after their interim results found letrozole (brand name Femara) to be superior to a placebo.

Studies have shown that taking tamoxifen for five years reduces the risk of recurrence for women with early stage breast cancer, and that the benefit from taking the drug appears to persist even after the drug has been stopped.

But with the introduction of the aromatase inhibitors—drugs that stop estrogen production and keep estrogen out of breast cells in a way different than tamoxifen does—another question had to be answered: What would happen if a woman began taking an aromatase inhibitor—in this case letrozole—after taking five years of tamoxifen?

To test that question, researchers randomized 5,187 women who had finished five years of tamoxifen to either letrozole or a placebo. At the first interim analysis, which was done after women had been in the study for an average of 2.4 years, the researchers found that there had been 75 local or metastatic recurrences of breast cancer or new primary cancers in the other breast in the letrozole group, compared with 132 in the placebo group.

Specifically:

In terms of local recurrences (recurrence in the same breast):
Letrozole: 14 (0.5%) Placebo: 30 (1.1%)

In terms of distant recurrences (metastases):
Letrozole: 47 (1.8%) Placebo: 76 (2.9%)

In terms of new cancers in the other (contralateral) breast:
Letrozole 14 (0.5%) Placebo: 26 (1%)

The total:
Letrozole: 75 (2.9%) Placebo: 132 (5%)

Another way to say this is that 5 percent of the women in the placebo group had a recurrence compared to 2.9 percent of the women who had been given letrozole.

Because this benefit was so clear, the independent data and safety monitoring committee overseeing the study recommended that the trial be stopped so that all of the women enrolled in the study could benefit from letrozole.

But stopping the study raises new questions. Because the study was stopped early, we don't know how long letrozole should be taken to get the maximum benefit. (Very few women in the study actually took letrozole for the full five years.) Also, because the study was stopped early, we don't know what the long-term complications of letrozole are. This is a concern because the aromatase inhibitors have been found to increase a woman's risk for developing osteoporosis. In fact, the study found that there were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group compared with 4.5 percent of the women in the placebo group.

The women who will benefit the most from taking letrozole after tamoxifen will be those who had the highest risk for recurrence before starting on tamoxifen. For those women who have a low risk of recurrence, it will be necessary to weigh the benefit letrozole may provide with the risk of osteoporosis.

Some women may be thinking, why take one drug after the other; why not take them both together? The answer to this question lies in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, which studied tamoxifen and the aromatase inhibitor anastrozole (brand name Arimidex). This trial randomized women to Arimidex, tamoxifen, or Arimidex and tamoxifen together, and found that the women who took both drugs actually had a higher risk for recurrence than did the women who took only Arimidex or tamoxifen.

The bottom line: This is an important study, and letrozole is going to be an important new option for many women who have completed five years of tamoxifen. What we can't forget about, though, are the side effects that accompany letrozole, and those have to be factored into the decision-making process, especially for women at low risk for recurrence.

Reference:

Goss PE, Ingle JN, et al. A Randomized Trial of Letrozole in Postmenopausal Women After Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer. New England Journal of Medicine 2003 Nov 6;349(19):1793–802. Originally published online on October 9, 2003.