Journal of the National Cancer Institute Advance Access originally published online on June 12, 2007
JNCI Journal of the National Cancer Institute 2007 99(12):913-914; doi:10.1093/jnci/djm032
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© Oxford University Press 2007.
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Researchers Wonder Why High-Risk Women Are Not Taking Chemoprevention Drugs
Many women at high risk for breast cancer could be taking a powerful anticancer drug to slash their risk in half. Yet only a minority takes the drug.
Cancer prevention experts still aren't sure why. Are they abstaining because they believe the odds against breast cancer are in their favor? Are they unwilling to commit to a daily pill for a disease they don't yet have? Do they feel the harms outweigh the benefits? Or are their doctors reluctant to prescribe the drug?
As is often the case, it's probably a bit of all four.
No one knows the exact number of women taking tamoxifen to prevent breast cancer, currently the only breast cancer prevention drug with U.S. Food and Drug Administration approval. A few studies have attempted to quantify women's interest in chemoprevention, but the estimates vary widely. Anecdotally, at least, the number is believed to be low, and this assumption is being used to make funding decisions. Earlier this year, National Cancer Institute Director John Niederhuber cited lack of interest in chemoprevention when postponing the next big chemoprevention trial, known as STELLAR. "There has been a significant reluctance on the part of patients to embrace those [chemoprevention drugs]. So there is more to this that I think needs very careful consideration," Niederhuber told the Cancer Letter.
Many point to primary-care doctors as a critical factor in the low adoption of tamoxifen. "As we know, it's not a huge number [prescribing the drug]. But I think that reflects a history that we've known quite a bit because primary-care physicians have historically not really liked to handle our oncology drugs. That has not been part of what they do on a day-to-day basis," said Worta McCaskill-Stevens, M.D., a medical oncologist and program director in the National Cancer Institute's division of cancer prevention.
About 25% of physicians surveyed have prescribed tamoxifen to their patients for breast cancer prevention, according to a study by Katrina Armstrong, M.D., a primary-care physician and cancer epidemiologist at the University of Pennsylvania in Philadelphia. This figure, she says, might surprise people, given the meager estimates of women taking tamoxifen. "But if considering the number of women who would be eligible for tamoxifen, then almost all of these physicians are going to have women who are eligible in their practices. So compared to the number of women who are eligible, I think the number is quite low," Armstrong said.
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The problem is that not all women who are eligible to take tamoxifen will benefit from it. According to a study by NCI researchers, more than 10 million U.S. women are eligible for tamoxifen, but only about 2.5 million would benefit from the treatment. The FDA recommends the drug for women whose 5-year breast cancer risk is at least 1.67%, based on the Gail breast cancer risk model. Yet for most women near this cutoff, the risks associated with tamoxifen—uterine cancer, blood clots, or stroke—outweigh the potential benefits of preventing breast cancer.
Joy Melnikow, M.D., and her colleagues at the University of California, Davis, performed a cost-effectiveness analysis of tamoxifen and concluded that the 1.67% 5-year risk might be too low. Their study found that the benefits of tamoxifen don't outweigh the risks until women have at least a 2% or 3% 5-year risk of breast cancer.
Deciding whether to take tamoxifen is a difficult choice for many women, one that requires understanding risks and benefits of the drug. Studies have shown that women are not good at estimating their own risk of breast cancer, so it is important that they have the opportunity to discuss their choice with their health care provider, said Joan James, chemoprevention trial program coordinator at Fox Chase Cancer Center in Philadelphia. But most primary-care doctors don't have the time to spend with patients to adequately explain the risks and benefits of chemoprevention. "Every day, we're given a recommendation of a new screening test or a new behavior intervention or something that we're supposed to be counseling our patient about," said Tracy Battaglia, M.D., professor of medicine and a primary-care physician at Boston University Medical Center. Only so much can be crammed into a routine doctor visit.
Many women who want prevention drugs must approach their doctors themselves, said Joelle Machia, a program director for the breast cancer prevention trial at Fred Hutchinson Cancer Research Center in Seattle. They often hear about chemoprevention options through family members with breast cancer or their own internet research. These women are often at much higher risk because of a family history of the disease or a diagnosis with precancer, and are therefore much more likely to benefit from tamoxifen.
These are the women who are taking tamoxifen in large numbers, said Larry Wickerham, M.D., associate director of the National Surgical Adjuvant Breast and Bowel Project, which has conducted several breast cancer prevention trials. And they're not relying on their primary-care physician. "These women are being frequently seen by breast oncologists or medical oncologists who are familiar with tamoxifen and who understand the risk of these biopsy-proven risk factors, and as a result, discuss and arguably promote the use of tamoxifen. And there is a fair number of people who fall into that category every year."
Wickerham refutes the idea that tamoxifen use is as low as it's portrayed in the media. "I think it's a little naive like most things in life to think that everyone says no to tamoxifen, but it's being portrayed that way," he said. "The data on how often tamoxifen is being used for prevention are at best shaky. There may well be more people taking tamoxifen for prevention than is commonly thought."
There may also be more people taking raloxifene for breast cancer prevention. The results of the Study of Tamoxifen and Raloxifene showed that raloxifene was as effective as tamoxifen at reducing the risk of invasive breast cancer, and among women taking raloxifene, there were fewer cases of uterine cancer and blood clots. Because raloxifene is used to treat and prevent osteoporosis, doctors are already familiar with it and are more willing to prescribe it to patients. Wickerham and others predict that if the FDA approves raloxifene for breast cancer prevention, doctors will be quick to prescribe it to their high-risk patients. "It would occur almost overnight, and, it is hoped, will be the item that results in broad usage for drugs in chemoprevention," Wickerham said. And because raloxifene offers the same benefits as tamoxifen for preventing breast cancer with few side effects, more women may be interested in taking it too.
Supporters of chemoprevention hope that as better prevention drugs come on the market, more women will be willing to take them. Yet for the moment, these future drugs are on hold. The STELLAR trial, for example, was supposed to compare raloxifene and letrozole—another breast cancer drug that some say holds huge promise for chemoprevention. Supporters fear that canceling the trial will leave women with too few chemoprevention options. "Some women will be taking tamoxifen and some will be taking raloxifene, and we'll have to stay at a 50% risk reduction and never make any strides when this new trial has the potential to lower risk by 70%," James said. If their predictions are true and letrozole has greater preventive power with fewer side effects, then chemoprevention could get a huge boost in popularity.
Still others worry that until prevention becomes a priority in health care, chemoprevention drugs won't reach enough women. While the focus on prevention has improved in the last decade, there are not enough incentives for physicians and hospitals to devote time and money to prevention strategies. "They make money for treating cancer. The incentives for the health care system and pharmaceutical companies are not structured to reward investment in cancer prevention," Armstrong said. "It's in nobody's business plan to prevent it."
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