Dr. Susan Love Research Foundation | I just completed five years of tamoxifen. My doctor is now recommending that I take the aromatase inhibitor Femara for five years. Do you think this makes sense? I want to do all that I can to prevent a recurrence.

For more than 15 years the standard hormonal treatment for women with hormone-positive (estrogen receptor [ER]-positive and/or progesterone receptor [PR]-positive) breast cancer has been five years of tamoxifen. Now, there are new drugs called aromatase inhibitors that have increased women's options as well as raised new questions about how women can best benefit from hormone therapy.

Currently three aromatase inhibitors are approved for use by the US Food and Drug Administration (FDA): anastrozole (brand name Arimidex), letrozole (brand name Femara), and exemestane (brand name Aromasin).

One of the first questions doctors had was whether women could benefit from taking an aromatase inhibitor after already having completed a course of tamoxifen. To answer this question, researchers started a large trial of postmenopausal women with early stage breast cancer who had taken tamoxifen for five years.

For this study, which was published online on October 2003 in the New England Journal of Medicine, 5,187 postmenopausal women with ER-positive or PR-positive early stage breast cancer were randomly divided into two groups. One group was given Femara; the other group was given a placebo. Neither the women nor the researchers knew who was taking Femara and who was taking the placebo.

At the first interim analysis, which was done after the women had been in the study for an average of 2.4 years, the researchers found that there had been 75 recurrences or new primary cancers in the opposite breast in the Femara group, compared with 132 in the placebo group.

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

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

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

The total:
Femara: 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 taken Femara, an absolute benefit of 2.1 percent.

Based on these findings, an independent data and safety monitoring committee recommended that the trial be stopped so that all of the women enrolled in the study could benefit from Femara. This may sound like a good thing. But stopping the study not only left many questions unanswered, it also raised an array of new questions.

Because the study was stopped early, we don't know how long Femara should be taken to get the maximum benefit. (Very few women in the study actually took Femara for the full five years.) We also don't know the long-term complications of taking Femara for five years after tamoxifen. This is a concern because aromatase inhibitors have been found to increase a woman's risk for developing osteoporosis. The study found that there were new diagnoses of osteoporosis in 5.8 percent of the women in the Femara group compared with 4.5 percent of the women in the placebo group. But this only tells us what happens after about 2.5 years, not five years.

Despite these outstanding questions and concerns, in October 2004, the FDA approved the use of Femara as extended adjuvant treatment of early breast cancer in postmenopausal women who had already received five years of tamoxifen.

The women who will benefit the most from taking Femara 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 Femara 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 trial, which studied tamoxifen and the aromatase inhibitor anastrozole (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. Femara 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 Femara, and those have to be factored into the decision-making process, especially for women at low risk for recurrence.

I would suggest that you speak with your oncologist about what your risk for recurrence was before you started on tamoxifen. If you had a high risk for recurrence, then you are one of the women who will probably benefit the most from taking Femara. If you were at low risk for recurrence, then you will need to weigh the benefit that Femara may have with the side effects you may experience and the risk of developing osteoporosis.

References:

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):1793–1802.

Bryant J, Wolmark N. Letrozole After Tamoxifen for Breast Cancer—What Is the Price of Success? Editorial. New England Journal of Medicine 2003 Nov 6;349(19):1855–57.