Tamoxifen, the celebrated drug credited with slashing breast cancer death rates worldwide, could be eclipsed by a newer medicine that is even more effective at preventing a recurrence of the disease in women whose tumors were caught early and removed.

A large, international study of postmenopausal women with early-stage cancer found that those who took tamoxifen for 21/2 years and then switched to exemestane for another 21/2 years were one-third less likely to suffer a recurrence than those who took tamoxifen the whole time.

The women switching to exemestane also had less-serious side effects, were 56 percent less likely to get cancer in the other breast, and were half as likely to develop unrelated cancer in other parts of the body.

Lead researcher Dr. R.C. Coombes, professor of cancer medicine at Imperial College School of Medicine in London, predicted doctors will give exemestane to many women at high risk for recurrence, such as those whose breast cancer has spread to multiple lymph nodes.

Exemestane, which went on the market in 1999 for advanced breast cancer, is a hormonal drug sold under the brand Aromasin. It is part of a newer class of breast cancer drugs called aromatase inhibitors.

The findings were published in Thursday’s New England Journal of Medicine. The research was partly funded by Pfizer Inc., the maker of Aromasin.

Dr. Jeff Abrams, the National Cancer Institute’s associate chief of clinical research, said a recent study on exemestane “cousin” letrozole showed important advantages over tamoxifen for the class.

“I think with these two studies together, the strategy of switching from tamoxifen to these aromatase inhibitors will become a new standard,” said Abrams, who was not involved in the study.

Several recent studies have shown that exemestane and other aromatase inhibitors also work longer, with less toxicity, than tamoxifen in women whose breast cancer had spread to other areas. Exemestane also has been shown to prolong the survival of women with advanced breast cancer after tamoxifen and other drugs fail.

“This whole class of drugs looks very promising, very active,” said Dr. Julia Smith, clinical associate professor of oncology at the NYU medical school and cancer institute.

The study, which involved 4,742 postmenopausal women in 37 countries, focused on women with breast cancer in which the hormone estrogen fuels tumor growth – the type responsible for about 70 percent of breast cancer. The results do not apply to premenopausal women or those with tough-to-treat breast cancer not driven by estrogen.

Early-stage breast cancer is often treated with surgery to remove the tumor, plus radiation. Then, if the cancer cells were found to have spread to the underarm lymph nodes, the patient is given cancer drugs for years.

Women suffering the type of cancer fueled by estrogen are given daily tamoxifen pills for five years to prevent any cancer cells lurking in the body from later triggering cancer in another spot.

However, cancer cells grow resistant to tamoxifen in many patients, sometimes within 12 months, and prolonged use can cause uterine cancer and dangerous blood clots.

Those problems spurred interest in hormonal drugs such as aromatase inhibitors, which dramatically suppress estrogen production by blocking the effects of an enzyme called aromatase. Tamoxifen works differently; it binds to specific tumor cell sites to keep estrogen from attaching itself and directing the cancer cells to multiply.

In the study, exemestane caused more bone thinning, joint pain and diarrhea than tamoxifen but was less likely to cause blood clots, vaginal bleeding, muscle cramps and other gynecological symptoms. Rates of other side effects, including hot flashes, fatigue, insomnia, headaches and dizziness, were about the same for the two drugs.

Among the women switching to exemestane, 54 died of breast cancer, compared with 67 in the tamoxifen-only group. Overall, 91.5 percent of women in the exemestane group were cancer-free three years after switching drugs, compared with 86.8 percent for women who stayed on tamoxifen.

Aromatase inhibitors have been around since the 1970s, but high toxicity limited their use. Today’s “third generation” aromatase inhibitors – including Aromasin, Femara and Arimidex – work better and are less toxic but still increase bone loss, a serious problem for elderly women, Coombes said.

On the Net:

New England Journal of Medicine: http://www.nejm.org

National Cancer Institute breast cancer site: http://www.cancer.gov/cancer-information/cancer-type/breast

American Cancer Society breast cancer site: http://www.cancer.org/docroot/lrn/lrn-0.asp

AP-ES-03-10-04 1747EST

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