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Study of breast cancer pill raises questions

The use of high-risk, but healthy women to test promising new breast cancer drugs is raising ethical concerns among scientists who worry whether long-term side effects may pose a greater danger than the disease the drugs are meant to prevent.
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Neva Hart's mother, grandmother and aunt all battled breast cancer. So when Hart heard about an experiment testing a pill that might protect women like her from the malignancy, she jumped at the chance to volunteer.

"I wish science could find something aside from chopping off parts of the body to fight this disease," said Hart, 57, of Wirtz, Va. "I decided to donate my body so people might not have to go through that kind of torture."

The study that Hart joined and a similar one based in Europe are raising hopes that a new class of drugs may offer women at high risk of breast cancer a safe way to protect themselves. But the experiments also raise thorny questions about whether the potential benefits outweigh the possible risks.

Host of unknowns
"Studies like this raise serious ethical issues," said Michael A. Grodin, a bioethicist at the Boston University School of Public Health. "What you're comparing here is the risk of getting cancer, which is unknown, against the potential risk of side effects from the prevention, which also is unknown. You're not treating people who are sick. These are healthy women."

These kinds of questions are becoming increasingly common as researchers focus more and more on trying to prevent, rather than treat, disease — often testing powerful drugs on people who have theoretical risks based on nebulous attributes such as age and family history rather than more concrete risk factors such as high cholesterol or high blood pressure.

"It's not like someone has the disease. In this case you're treating a statistic — the chance of getting the disease," Grodin said. "If you knew this drug had no side effects, then it wouldn't be as concerning. But you don't know that."

Breast cancer is diagnosed in about 211,000 U.S. women each year, and about 40,000 die of the disease, making it the most common cancer and the second most deadly cancer, after lung cancer, among women.

Focus on prevention
Surgery, radiation, chemotherapy and estrogen-blocking drugs have cut the breast cancer death rate. But with the incidence still rising, researchers, patient advocates and women at risk for the disease desperately want ways to prevent the cancer in the first place. Last week, new research suggested that low-fat diets may minimize the likelihood that breast cancer will recur after treatment, a strategy also being tested to prevent first tumors. But that approach remains far from proven.

The study that Hart joined, dubbed the ExCel trial, is testing a drug known as exemestane, or Aromasin, one of a class of new drugs called aromatase inhibitors. Aromatase inhibitors block formation of estrogen, which can fuel the growth of breast cancer cells. The drugs have been shown to cut the relapse rate for breast cancer at least as effectively as the only other estrogen-blocking drug available, tamoxifen. Tamoxifen reduces the risk of breast cancer, but it also raises the risk of blood clots and uterine cancer, which has discouraged many women from taking it.

Seeking an alternative, researchers launched the ExCel trial and a similar study testing another aromatase inhibitor called anastrozole, or Arimidex, to see whether the drugs can prevent first cancers. Anastrozole is being tested in Europe, the Middle East and other parts of the world.

"There is abundant evidence that inhibiting estrogen can prevent new primary breast cancers. We estimate that we may be able to reduce the risk by 60 to 80 percent," said Paul Goss, director of breast cancer research at Massachusetts General Hospital in Boston, who is leading the ExCel study. "We're very optimistic."

Researchers have started recruiting what they hope will be about 4,500 postmenopausal women in the United States, Canada and Spain who are considered at high risk for breast cancer because of age, family history or other factors. For five years, half the women will take the drug while the other half take a placebo. The study is being sponsored by the Canadian Cancer Society, the National Cancer Institute of Canada and the drug's maker, Pfizer Inc.; the company is not directly involved in the study.

Excitement, caution surround drugs
Aside from sometimes causing symptoms similar to those experienced during menopause, exemestane so far appears very safe. Nevertheless, some advocates in the field are worried about giving healthy women a powerful hormone-blocking drug for years before long-term studies have been conducted to ensure its safety.

"I understand the excitement about these drugs. I hope they prove to be everything everyone hopes them to be. But the lack of long-term use and side-effect data are a big problem," said Barbara Brenner of Breast Cancer Action, a patient advocacy group based in San Francisco. "Without long-term side-effect data on this drug, you can't really get informed consent from people you are trying to enroll in the study."

Some evidence suggests that aromatase inhibitors may, for example, increase the risk of the bone-thinning disease osteoporosis, which makes women prone to potentially serious fractures.

"Any drug that is powerful enough to reduce your risk for breast cancer is almost inevitably going to have side effects," Brenner said. "What we could end up having is disease substitution instead of disease prevention."

The ExCel trial originally planned to test whether the painkiller Celebrex also prevents breast cancer, but that part of the study was discontinued after evidence surfaced that drugs of its class may cause heart problems. Skeptics also point to once-popular hormone replacement therapy as an example of a drug treatment designed to prevent disease that initially appeared to be safe.

"I would like to know more about the long-term side effects of these drugs before I would take them into the preventive setting," said Carolina Hinestrosa of the National Breast Cancer Coalition, a Washington-based advocacy group. "Before you expose a vast group of healthy women to a drug, you need to be extremely careful."

Questions of consent
Even though the researchers are explaining the potential risks to volunteers, some worry that it is particularly difficult to get true informed consent in a breast cancer prevention study because women tend to be so afraid of the disease.

"Women have an increased fear of getting breast cancer over and above what the true likelihood is," said Heidi Malm, associate professor of bioethics at Loyola University Chicago. "That could lead people to enroll in studies with probably a bigger hope of benefit than is actually realistic."

While endorsing the concept of testing aromatase inhibitors for breast cancer prevention, Suzanne Fletcher, professor of ambulatory care and prevention at Harvard Medical School, said she was concerned that the study may be too small to detect side effects.

"What you desperately need in a prevention trial is a good handle on the adverse effects," Fletcher said. "Adverse events are much more important in a prevention trial than in a treatment trial. That's got to be part of the objectives the researchers have."

Goss, his colleagues and other researchers say the drugs have been tested in thousands of women who have taken them for as many as seven years, and no signs of serious side effects have surfaced.

‘No frightening risks’
"It isn't as if the drug has never been used. It's been used relatively extensively in thousands of women for a reasonably long period of time," said Joe Pater, director of the National Cancer Institute of Canada Clinical Trials Group in Ontario. "On the basis of what we know today, there are no frightening risks."

In fact, some preliminary evidence suggests that the drugs may offer additional benefits. Exemestane in particular may turn out to protect bone, Goss said.

"People who are expressing concern about this really have to wait for the data rather than have a kind of knee-jerk response that this is all going to be bad," Goss said.

The project will be monitored by an independent panel of experts who will evaluate the data every six months for any signs of unexpected side effects, Goss and others said.

"We don't know whether there's more risks than benefits. Anything can happen. That's why you do research," Pater said. "But I think everyone would be incredibly surprised if there was no overall benefit."

In addition, the researchers hope the data will identify which women are most likely to be protected by the drugs, enabling them to target therapy more specifically.

"Our honest belief is that overall the drug will tip in favor of the participants in the trial," Goss said. "There's no denying that many women in this study would never have gotten cancer. But the evidence for efficacy is highly established, and the likelihood of a positive result is very high."

For her part, Hart is willing to participate in the hopes of sparing other women from the fate that befell those in her family.

"I'm going into this with my eyes wide open," Hart said. "I'm donating myself to research. I see that as a great way to be able to contribute to medical research. I'm willing to take the risks."