Drug Gives One-Two Punch Against Breast Cancer

Exemestane after tamoxifen reduces risk of recurrence

WEDNESDAY, March 10, 2004 (HealthDayNews) -- Researchers believe a new class of drugs gives them a potent new option in the war against recurring breast cancer.

Taking the aromatase inhibitor exemestane after an initial course of tamoxifen decreased the risk of recurrence and new malignancies in postmenopausal women who had had breast cancer, a new study finds. This was compared to the current gold standard, which is to take tamoxifen for five years after initial treatment for the disease.

The interim results of this study appear in the March 11 issue of the New England Journal of Medicine. The study received sponsorship from the drug's maker, Pfizer Inc., which markets it under the name Aromasin, but the company "had no access to trial data base or interim analyses," the authors say.

"This kind of data is very exciting," says Dr. Robert J. Morgan, a staff physician in the division of medical oncology and therapeutics research at City of Hope Comprehensive Cancer Center in Duarte, Calif. "Until last year, all we had was tamoxifen."

Currently, postmenopausal women with estrogen-receptor-positive breast cancer -- which accounts for about two-thirds of all cases -- are routinely treated with tamoxifen after initial treatment to help prevent a recurrence. Studies have shown tamoxifen, which interferes with the ability of estrogen to fuel tumor growth, reduces the risk of breast cancer recurrence by 47 percent and the risk of death by 26 percent.

Not all patients respond to tamoxifen, however, and the drug also appears to lose its effectiveness after about five years.

This new class of drugs, aromatase inhibitors, has been gaining ascendancy. As their name implies, these compounds inhibit aromatase, an enzyme that helps makes estrogen. The U.S. Food and Drug Administration has so far approved three aromatase inhibitors: anastrazole, letrozole and exemestane. Last November, a study showed that giving letrozole after tamoxifen also improved disease-free survival.

In the current study, 4,742 patients from 37 countries were randomly assigned to receive either tamoxifen followed by oral exemestane or tamoxifen on its own. The women had undergone different combinations of surgery, radiation and chemotherapy, depending on which treatment practices were recommended in their country.

At the end of almost three years, the women in the exemestane group showed a 32 percent reduction in the risk of recurrence as compared to the tamoxifen group. This translated into an absolute reduction of 4.7 percent.

Women in the exemestane group demonstrated a greatly reduced (56 percent) risk of developing cancer in the opposite breast compared to the control group.

Overall survival was not significantly different between the two groups (91.5 percent in the exemestane group vs. 86.8 percent in the control group), but this may be because the follow-up period was not long enough.

Exemestane also had a better safety profile than tamoxifen, says study co-author Dr. Stephen Jones, medical director of U.S. Oncology Research in Houston. About 2 percent of women in the exemestane group had joint aches and pains, while anther 2 percent had diarrhea. Women in the tamoxifen group had more gynecological symptoms, such as vaginal bleeding, as well as an increased risk of uterine cancer and blood clots. The authors report there was a "suggestion" of an increased incidence of osteoporosis in the exemestane group, which needs to be investigated. Tamoxifen has a beneficial effect on bone mineral density and cholesterol levels.

As with so much research, this study raises many more questions than it answers. "We don't have any idea of the sequencing yet," Morgan says. "We don't know which aromatase inhibitor is better for what. We don't have any idea of the optimal duration. The other thing we don't have any answer to is, what about premenopausal women?"

"There are a zillion questions that are opening up but we now know that we have options that we can explore," he continues. "Until last year we only had one answer. Now, all of a sudden, within a six-month period, we've unearthed all of these questions. I think it's a major step forward."

The current trial is not closed, but it is essentially over, Jones says. "Over 90 percent of the women have completed their treatment. Only 10 percent are still on treatment," he explains.

All the women will continue to be followed, even as additional research starts investigating these new questions. Meanwhile, there appears to be room for this tamoxifen-followed-by-exemestane regimen in clinical practice.

"I've been involved in clinical trials in breast cancer for 30 years and this is one of the more important ones," Jones says. "Worldwide, probably one-and-a-half million women are already on tamoxifen for some period of time. Many postmenopausal women are candidates to be switched and, if you did that, with a 32 percent reduction in the risk of recurrence, you could prevent lots of recurrences and ultimately lots of deaths. The global implications are huge."

More information

The National Cancer Institute has more on aromatase inhibitors and on tamoxifen.

SOURCES: Robert J. Morgan, M.D., staff physician, division of medical oncology and therapeutics research, City of Hope Comprehensive Cancer Center, Duarte, Calif.; Stephen Jones, M.D., medical director, U.S. Oncology Research, Houston; March 11, 2004, New England Journal of Medicine
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