New breast cancer drug leaves questions

New York - The announcement last week that a clinical trial on a breast cancer drug was being halted because the results were so promising leaves women with much hope but also many questions.

The study, which appears in the Nov. 6 issue of the New England Journal of Medicine but whose results were released early, found that women 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.

"We've had an enormous number of phone calls coming in and have decided as a group that it really is exciting data, but that it shouldn't result in knee-jerk action," says Dr. Amy Tiersten, an associate professor of medicine at New York University School of Medicine in New York City. "It requires a visit with the doctor to go over the pros and cons."

The women enrolled in the study were all postmenopausal, had had breast cancer but were free of malignancies when they enrolled in the study, and had stopped taking tamoxifen within the past three months.

Tamoxifen has been successful in preventing recurrences in women who have estrogen-receptor-positive breast cancer (when the cancer 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.

While tamoxifen works by occupying the estrogen receptor and preventing the hormone from binding, letrozole goes further and actually blocks production of the hormone. The women in this study had good results when they started taking letrozole within three months of stopping tamoxifen.

About the only thing experts know right now is that women who match the profile of the study participants should strongly consider taking letrozole. That is, these women have to be postmenopausal, have had receptor-positive cancer (but are currently cancer-free), and have finished tamoxifen within the last three months.

"If you fit the profile it's very, very clear," says Dr. James Doroshow, chairman of the division of medical oncology and therapeutics at City of Hope Cancer Center in Duarte, Calif. "[The study] involved many, many patients and I would think that even if you are within the first six months to a year after tamoxifen, extrapolating those results is probably not an enormous stretch."

The questions begin when doctors consider women who have been off tamoxifen for two, three or more years, although the study authors believe these women could also benefit.

"There isn't any plausible biological reason to think that the drug would not work if there had been a greater gap from tamoxifen for three months," study author Dr. Paul Goff said at an Oct. 9 press conference. "It is my belief that any woman who had receptor-positive tumors could be accepted but . . . trying to individualize that patient's risk will be important. If they are 14 years out with low-risk cancer, that will be a very borderline decision."

There's also an issue of how long a woman should take letrozole. The study was halted after a median follow-up of 2.4 years. "So it really only tells us about women who receive letrozole for two to three years," Tiersten says. "The design of the study was meant to randomize patients to five years, so that's a big question as to how long women should be taking aromatase inhibitors -- and it raises a lot of big questions in terms of what the best adjuvant hormonal therapy is for women."

The issue is complicated not just by timing, but by sequencing as well. In what order should women be taking tamoxifen and letrozole or another aromatase inhibitor, or should they skip tamoxifen altogether? There are currently three aromatase inhibitors available and, Goff said, "at this point for the research that's been done in humans, there isn't an easy way to distinguish between them. They all look as if they act in a similar way." Trials are underway to try to find subtle differences.

One study did find that anastrozole, another aromatase inhibitor, was superior to tamoxifen and to a combination of tamoxifen and anastrozole, Doroshow says. It was, however, just one study and should probably be duplicated before current practice is changed.

Letrozole also has some side effects. Because it eliminates production of estrogen, it can exacerbate menopausal symptoms. It may also have an effect on bone density.

Finally, there is the question of cost. Letrozole, which comes in pill form and costs about $200 a month, is already approved for metastatic breast cancer. Gloria Stone, a spokesman for Novartis, which makes the drug, says the company will be filing for a new indication with European authorities and with the U.S. Food and Drug Administration (news - web sites), probably in the second half of next year. She doesn't foresee any insurance problems in the meantime. "There's probably some variety with insurance but, in general, we don't anticipate significant problems for reimbursement if the doctor thought it was appropriate," Stone says.

But, as Tiersten points out, a good proportion of the women who would qualify for letrozole under the new indication are over 65 and have Medicare, which has limited prescription coverage.

That particular quagmire will have to be worked out at the policy level. For women who can afford the drug, Doroshow says, "the only reasonable strategy is to discuss all the risks and benefits, the limits of the data as they exist, and the fact that it will be a considerable amount of time before one knows more about how to deal with these questions." -- Health Day News

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