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Keywords

Breast cancer, exemestane, Aromasin®, tamoxifen, aromatase inhibitor. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Postmenopausal women with breast cancer who switched to the drug exemestane (Aromasin®) after two or three years on tamoxifen had fewer cancer recurrences than women who stayed on tamoxifen for five years, a large international phase III clinical trial has found.

Source

New England Journal of Medicine, March 11, 2004.

Background

Following surgery for breast cancer, women whose tumors grow in response to the hormone estrogen usually take the anti-estrogen drug tamoxifen for five years to reduce their risk that the disease will recur. However, tamoxifen does not prevent all recurrences, and breast cancer cells can become resistant to this drug. In addition, tamoxifen increases a woman's risk for endometrial cancer, severe blood clots, and stroke.

Tamoxifen and exemestane both block the growth of breast tumors that respond to estrogen, but the two drugs work in different ways. Tamoxifen interferes with the ability of breast cancer cells to use estrogen for growth, whereas exemestane interferes with the body's ability to make estrogen.

Exemestane inactivates the enzyme aromatase, which the body uses to make estrogen. Before menopause, most estrogen is produced in the ovaries, which contain more aromatase than exemestane can block. After menopause, however, the ovaries are no longer a major source of estrogen, and exemestane is able to block estrogen production by other tissues. Therefore, exemestane and other so-called aromatase inhibitors (AIs) are effective only in postmenopausal women.

Early findings from several large international trials have suggested that cancer is less likely to recur in women who take an AI after five years of tamoxifen or switch to an AI after a shorter period on tamoxifen. These studies involved other drugs in the AI class, specifically anastrozole (Arimidex®) and letrozole (Femara®). Unlike tamoxifen, AIs do not increase the risk of endometrial cancer, blood clots, or stroke.

The Study

A total of 4,742 postmenopausal women from 37 countries, who were disease-free after two or three years of treatment with tamoxifen, were enrolled in the study. The women were assigned at random either to switch to exemestane or to continue on tamoxifen until they had completed five years of treatment with one or both drugs. The trial's principal investigator was R. Charles Coombes, M.D., Ph.D., of Imperial College and Charing Cross Hospital in London, England.

Results

After a median follow-up period of about two and a half years, 266 (11.2 percent) of the 2,380 women who took tamoxifen alone -- but just 183 (7.7 percent) of the 2,362 women who took tamoxifen followed by exemestane -- had a recurrence of breast cancer, were diagnosed with cancer in the other breast, or died. Disease-free survival after 3 years of therapy was 91.5 percent for women in the exemestane group compared with 86.8 percent for women in the tamoxifen-only group. This difference was statistically significant.

Side effects such as joint pain, diarrhea, bone loss and fractures, and vision disturbances were more likely in women who took exemestane. Women who took tamoxifen were more likely to have blood clots, gynecologic symptoms, vaginal bleeding, and muscle cramps.

Limitations

It is too early to say whether this trial will show improved overall survival for women who took exemestane, writes Martine J. Piccart-Gebhart, M.D., Ph.D., of the Jules Bordet Institute, Brussels, Belgium, in an accompanying editorial. A median follow-up period of two and a half years is not long enough to thoroughly understand the long-term effects of AIs as adjuvant therapy, she adds.

For example, women who took exemestane suffered more bone fractures than those who took tamoxifen alone, notes JoAnne Zujewski, M.D., a medical oncologist who specializes in breast cancer at the National Institutes of Health Clinical Center in Bethesda, Maryland. Some studies of other AIs have also shown an increase in fractures and all have shown that AIs promote bone loss. Longer follow-up is needed to determine the severity of the fracture risk in women who take exemestane or other AIs, Zujewski says.

Comment

"This is the fourth study to show that treatment with an AI increases disease-free survival among early-stage postmenopausal breast cancer patients," says Zujewski. "These findings will encourage doctors to consider switching patients to exemestane or another AI after two to five years of tamoxifen therapy." However, she adds, AIs may not be appropriate for women who already have or are at high risk for bone fractures.

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