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Breast Cancer Drug Shows Great Promise

Major trial halted early due to encouraging findings

THURSDAY, Oct. 9, 2003 (HealthDayNews) -- Breast cancer patients taking letrozole, one of a new class of drugs called aromatase inhibitors, had about half the rate of cancer recurrences as women taking a placebo.

Because the results were so promising, investigators halted a major international trial of the new drug early.

"The results are absolute, confirmed and credible," study investigator Dr. Paul Goss said at news conference Thursday. "An independent monitoring committee recommended that we stop the study by preset statistical boundaries, which we exceeded by at least 10-fold."

Goss is also the lead author of a special, early-release article detailing the findings in the Nov. 6 issue of the New England Journal of Medicine.

Tamoxifen has been a great boon to women who have estrogen-receptor-positive breast cancer, meaning cancer that is fueled by the hormone estrogen. The drug reduces the risk of recurrence by 47 percent and the risk of death by 26 percent for five years after surgery. Unfortunately, tamoxifen stops working after that time and may even reverse its action, promoting the growth of cancer cells. This group of women represents the largest subgroup of women with breast cancer, Goss said.

"What is unrecognized is that over 50 percent of recurrences unfortunately occur beyond five years after diagnosis," Goss said. "Because it continues to relapse almost indefinitely, there is no limit to the disease."

Doctors have lacked any appropriate tools for the hundreds of thousands of women worldwide who enter that post-five-year wilderness every year.

Until now.

The letrozole trial started enrolling participants in 1998 and ended up with 5,187 women in Canada, the United States and Europe who were postmenopausal, had hormone-receptor-positive tumors and had been on tamoxifen for about five years (the range was four-and-a-half to six years). All of the women had to be within three months of stopping tamoxifen and all were disease-free when enrolled. The trial was coordinated by the National Cancer Institute of Canada.

The participants were randomly assigned to receive either 2.5 milligrams of letrozole or a placebo daily for five years. Letrozole reduced the risk of recurrence by 43 percent.

The median follow-up was only 2.4 years when the trial was stopped.

While tamoxifen works by occupying the estrogen receptor and preventing the hormone from binding, letrozole goes further and actually blocks production of the hormone.

"We're not competing with the fertilizer. We're totally removing the fertilizer" Goss said.

Side effects in the placebo and letrozole groups were roughly equivalent, except the rate of bone thinning was slightly higher with letrozole. Tamoxifen, by contrast, provides protection against bone fractures, although it contributes to endometrial cancer and blood clots. Women considering taking letrozole need to talk to their doctor about ways to mitigate the risk of osteoporosis.

Letrozole has already been approved by the U.S. Food and Drug Administration (FDA) for some forms of breast cancer.

"I would think that there would be sufficient basis to use this as a pivotal trial to justify an amendment to their indication," said Dr. James Ingle of the Mayo Clinic and another investigator on the trial. Ultimately, getting another [FDA] approval would be up to the drug's maker, Novartis, which funded part of the new study.

There are some drawbacks to stopping a trial early, namely the number of unanswered questions about side effects and the continued effectiveness of the drug over time.

Current and future studies of aromatase inhibitors will look at a range of issues, including whether letrozole could be used instead of tamoxifen, whether it could be used if women had been off for tamoxifen for longer than three months, whether it works in an equivalent fashion, and whether the success of letrozole will continue over longer time frames.

"Waiting for the other shoe to drop really wears people [breast cancer patients] down," Goss says. "We're going to fell this tree. We're chopping away at it. This is one big chunk that makes me go to the clinic tomorrow with a lighter step."

More information

The American Cancer Society has information on cancer drugs. Visit the National Cancer Institute for more on breast cancer.

SOURCES: Teleconference with Paul Goss, M.D., Ph.D., Princess Margaret Hospital, Toronto; James Ingle, M.D., Mayo Clinic, Rochester, Minn.; Oct. 9, 2003, online release, New England Journal of Medicine
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