Dr. Susan Love Research Foundation | ASCO Issues New Guidelines on the Use of Aromatase Inhibitors

A committee that the American Society of Clinical Oncology convened to assess the adjuvant (postsurgical) use of aromatase inhibitors has concluded that most postmenopausal women should be treated with an aromatase inhibitor to reduce their risk for a breast cancer recurrence.

Significantly, this means that tamoxifen, which first began to be used in the adjuvant setting in the 1980s, will, after more than 20 years, no longer be the standard of care for postmenopausal women. Tamoxifen does, however, remain the standard of care for premenopausal women.

The recommendation only applies to postmenopausal women with hormone-sensitive tumors. These are tumors that are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive. Women whose tumors are ER-negative and PR-negative do not benefit from hormonal therapy.

Aromatase inhibitors are not effective in premenopausal women. That's because premenopausal women get most of their estrogen directly from their ovaries, and the aromatase inhibitors can't block this estrogen. The drugs work in postmenopausal women because these women get most of their estrogen from the conversion of androgens (which are produced by the adrenal glands and ovaries) into estrogen peripherally (in fat, muscle, brain, and breast tissue) by the aromatase enzyme.

(The only time aromatase inhibitors can be used in premenopausal women is when they are given along with a drug to suppress ovarian functioning. Because there is currently no data on the effectiveness of this treatment regimen, it should not be used outside of a clinical trial.)

The committee's decision was based on a review of the four Phase III randomized trials that have compared tamoxifen with the three aromatase inhibitors approved for use in the United States—anastrozole (brand name Arimidex), letrozole (brand name Femara), and exemestane (brand name Aromasin).

These four trials are:

The ATAC trial, which compared anastrozole and tamoxifen head-to-head. Both were used as initial therapy and taken for five years.
The Italian trial and the Intergroup Exemestane trial, both of which enrolled women who had been on tamoxifen for two to three years and then randomized them to either stay on tamoxifen for the rest of their five years of treatment or to switch to anastrozole (in the Italian trial) or exemestane.
The MA-17 trial, in which women who had completed five years of tamoxifen were randomly assigned to then go on to letrozole or a placebo for five years. (This trial was stopped after two and one-half years when it appeared that women assigned to letrozole were doing significantly better than those on placebo.) You can read more about this here. This was the only trial to show a statistically significant survival advantage; however, this advantage was only seen in women with node-positive disease.

The committee also noted that:

It is not yet known if it is better to start on an aromatase inhibitor or to start on tamoxifen and then switch to an aromatase inhibitor.
It is not yet known how long women should stay on an aromatase inhibitor.
If a woman starts on an aromatase inhibitor but finds the side effects unmanageable, she should switch to tamoxifen or another aromatase inhibitor.
The long-term side effects of the aromatase inhibitors are not known.
Presence of a gene mutation in either the BRCA1 or BRCA2 gene
The estrogen deprivation that the aromatase inhibitors cause has been found to increase a woman's risk of developing osteoporosis or fractures. Because of this, drugs used to treat osteoporosis, called bisphosphonates, may become a standard treatment along with the aromatase inhibitor.
Other side effects associated with the aromatase inhibitors include a decrease in sexual functioning, hot flashes, and joint pain.

Susan says:

This is a significant development in the adjuvant breast cancer care of postmenopausal women with hormone-sensitive tumors.

It is not uncommon for physicians to decide to recommend a new drug or class of drugs before we know as much as we might like to know about that treatment regimen. In this instance, because the aromatase inhibitors are relatively new, we still don’t know what long-term side effects they might have or even the optimal amount of time they should be taken for. These are things we know about tamoxifen because the drug has been studied widely and has been used in the adjuvant setting for more than 20 years. We also still don’t know whether it is better to use an aromatase inhibitor for five years or to start with tamoxifen and then switch to an aromatase inhibitor. Answers to these and other questions will come from research studies that are now underway.

Until then, I’d encourage postmenopausal women with hormone-sensitive tumors to discuss with their oncologists the benefits and risks of starting on tamoxifen and then switching to an aromatase inhibitor with the benefits and risks of starting on an aromatase inhibitor. I’d also encourage all women on aromatase inhibitors to take calcium and vitamin D to help maintain bone strength, and to be monitored closely for signs of osteoporosis.

If, for some reason, you can’t tolerate any of the aromatase inhibitors because of the joint or bone pain they may cause, or due to any other side effects, that’s fine. Tamoxifen has been and remains an excellent drug for reducing a woman’s risk of a breast cancer recurrence.

Reference:

Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women with Hormone Receptor-Positive Breast Cancer: Status Report 2004. Journal of Clinical Oncology2005 Jan 20;23(3):619–29. Published in advance online on Nov. 15, 2004.