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Elizabeth Cooney is a health reporter for the Worcester Telegram & Gazette.
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Thursday, June 21, 2007

NCI cancels breast cancer prevention study

By Elizabeth Cooney, Globe Correspondent

In an unusual step, the National Cancer Institute has canceled a $130 million clinical trial to compare how well two drugs prevent breast cancer.

Called the P-4 trial because it is the fourth such prevention study undertaken by the federal agency, it would have enrolled more than 12,000 women at high risk for breast cancer at 500 sites and followed them for years. The termination of the study before it began recruiting patients comes at a time when NCI is straining under four years of tight budgets.

The women would have received either raloxifene, an estrogen-blocking drug approved to treat osteoporosis but now prescribed to stop breast cancer, or letrozole, a compound from a newer class of drugs called aromatase inhibitors that deplete the production of estrogen. Both target estrogen because it promotes the growth of cancer cells.

Dr. Bruce Chabner, clinical director of the Massachusetts General Hospital Cancer Center, was on a scientific panel that last week advised NCI director Dr. John E. Niederhuber to pull back the P-4 trial. Niederhuber, who called for a review of the trial in January, visited Mass. General Monday and discussed the trial in previously scheduled sessions with Boston researchers and clinicians.

Chabner said the trial's cost was considered along with scientific concerns, including the desire to better match powerful drugs with the individuals who can be helped by them.

"I think in times when the budgets were really generous the NCI would probably have gone ahead with the study. It's not so much a criticism of the trial as it's expensive when there are other priorities that are very important," he said. "It is an unusual step. But these are unusual times."

The NCI's June 19 letter to the study's principal investigators at the University of Pittsburgh cited troubling complications caused by the two cancer prevention drugs and the relatively small number of women -- 3 or 4 out of 100 -- who benefit from them. The decision not to go forward with the study was first reported in Wednesday's Washington Post.

"While the P-4 study may provide another possible option for women at risk for breast cancer, the dangers of introducing these drugs, with their many known side effects, outweighs their potential until we are better able to determine who will benefit from these interventions and what the longer-term effect may be," the letter said.

Tamoxifen -- studied in 20,000 women in the P-1 trial of the early 1990s -- is currently the only drug approved for the prevention of breast cancer. Doctors prescribe it to treat women with breast cancer, to avoid a recurrence or in some cases to prevent it in the first place. Tamoxifen and raloxifene were compared in a large trial that last year reported they had just about the same effectiveness in preventing cancer, but raloxifene had fewer side effects.

Tamoxifen is linked to uterine cancer, blood clots and cataracts. Raloxifene was associated with a lower risk of these complications. Aromatase inhibitors are known to cause brittle bones, a particular worry for older women who might be taking them.

Chabner said the advisory panel's consensus was that this expensive trial was "not going to change the practice of medicine."

"Everybody agrees that the number-one priority is not to compare drug X to drug Y," he said. "It's to really define who is at highest risk for breast cancer so we don't have to treat 100 patients to prevent three or four or five cancers. If we can treat 10 patients and prevent 5 cancers, then it's going to be more reasonable."

NCI holds out hope for personalized medicine to better fit treatments to patients.

"Targeted chemoprevention must rely on individual genomic and proteomic signatures to identify those patients for whom the risk-benefit ratio justifies using a chemopreventive drug," its letter said. "NCI will continue to have a strong commitment to cancer prevention and search for ways in which such patients can be provided highly personalized approaches to prevention."

Other ongoing studies are examining how well other aromatase inhibitors protect women against breast cancer compared with placebos. One trial, funded by the National Cancer Institute of Canada and looking at exemestane, is led by Dr. Paul E. Goss, also of Mass. General.

"I feel strongly that aromatase inhibitors should be tested in prevention but always believed that the trial should be against a placebo," he said in an e-mail. "I am not privy to all the forces that fed into the NCI director's decision but I have no doubt that competing priorities were a big part of it. It is true that our trial would have reported before (P-4) and I agree that (P-4) may therefore not have changed practice."

Chabner said another weakness of the P-4 trial was that letrozole, the aromatase inhibitor being compared with raloxifene, will no longer be protected by its patent in 2011, meaning its manufacturer will have no incentive to seek FDA approval if it is shown to be effective.

Dr. Harold J. Burstein, a breast cancer specialist at the Dana-Farber Cancer Institute, said oncologists will have to infer from other studies in other countries how the different kinds of chemoprevention drugs compare. Dana-Farber would likely have been one of the many sites for the P-4 trial, he said.

"There's no doubt we need more studies in breast cancer prevention and the study being proposed was a very practical strategy to compare two likely effective strategies," he said. "There will be a void when a patient comes to see a doctor eight years from now and says, 'Which one should I take?'"

Posted by Elizabeth Cooney at 10:27 AM
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