A federal panels review of research on the ability of tamoxifen to prevent the development of breast cancer suggests that the biggest limitation on the use of the drug for this purpose is that primary care physicians are not talking with their patients about whether the agent is right for them.
When used in high-risk patients, two selective estrogen receptor modulators (tamoxifen and raloxifene) can cut the risk of invasive estrogen receptor-positive breast cancer in half, said the U.S. Preventive Services Task Force (USPSTF) in their July 2 Annals of Internal Medicine report and associated clinical guidelines.
But that is only if the drugsand specifically tamoxifen, which is FDA approved for prevention of breast cancerare actually used. The task force report, underscoring an apparent reluctance of primary care physicians to prescribe tamoxifen, is recommending that women and their physicians start talking about breast cancer risk and whether the drug might be an option to consider.
"Women at high risk may not have been approached about taking the drug, but now that we have come out with national guidelines, we hope women will be empowered to get good information and that their physicians will offer it," said Janet Allan, Ph.D., R.N., vice chair of the task force. "We are not saying women should take tamoxifen if they are at high risk for developing breast cancer; we are recommending that they talk to their physicians about it."
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It appears that tamoxifen has not caught on with the public as chemoprevention, said Linda Kinsinger, M.D., assistant professor of medicine at the University of North Carolina, Chapel Hill, who led the independent panel of experts, which was sponsored by the Agency for Healthcare Research and Quality. "In my experience, I havent seen a lot of women asking about it, and I suspect part of the problem may be that not a lot of physicians are bringing the subject up."
Validating Chemoprevention
The USPSTF reviewed three published studies on tamoxifen and one that used raloxifene, which is approved for treatment and prevention of osteoporosis but which some clinicians prescribe off-label to reduce breast cancer risk. The largest tamoxifen clinical trial, the 13,000-plus patient federal Breast Cancer Prevention Trial (BCPT), showed almost a 50% reduction in the risk of breast cancer among high-risk womenan absolute risk reduction of about 20 cases per 1,000 women. Two smaller European studies did not reveal a statistically significant benefit, but Allan said that may have resulted from both the study design of those trials and the relatively short time women took the agents.
The one available clinical trial of raloxifene, the Multiple Outcomes of Raloxifene Evaluation (MORE), which focused on postmenopausal women with osteoporosis, showed a 76% reduction in the relative risk of breast cancer compared with placebo. That resulted in an absolute risk reduction of 8 cases of breast cancer per 1,000 women. (Women in this trial were not at as high a risk of developing breast cancer as those in the BCPT, resulting in a lower absolute risk reduction than in high-risk women.)
Taken together, the studies show that tamoxifen and raloxifene reduced the risk of invasive estrogen receptor-positive breast cancer by approximately 50% in women who had a 1.66% or greater risk for developing the disease in the next 5 years. Even so, a relatively small proportion of women are considered to be at high risk, and only a portion of them can benefit.
And, consistent with previous research and physician guidelines, the USPSTF recommended that women with low or average risk of developing breast cancer should not use the drugs because of associated side effects, some of which are life-threatening. Both tamoxifen and raloxifene can produce hot flashes and increase a womans risk of blood clots, but, more worrisome, tamoxifen use can increase the risk for stroke and uterine cancer.
The USPSTF guidelines found that the balance of benefits over harmful side effects is more favorable for high-risk women in their 40s who have no predisposition toward blood clots, and for women in their 50s who also are not predisposed to blood clots, and who have no uterus. But any use of tamoxifen has to be considered in the context of a number of variables, such as a family history of breast cancer and a history of atypical cells in a breast biopsy, said Allan, adding, "This is a difficult decision for women to make, but at this point, we dont have a great deal to offer yet in preventing breast cancer."
Such decision-making presupposes that primary care physicians are discussing breast cancer risks with their patients, and that does not generally appear to be the case, said Therese Bevers, M.D., medical director of the Cancer Prevention Center at the University of Texas M. D. Anderson Cancer Center, Houston.
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"Many of these physicians dont feel they have the time or the ability to determine a patients risk quotient, and even if they do, they dont want to deal with a cancer drug some think needs constant monitoring for serious side effects," she said. Bevers said she tries to help them build risk assessments tools into their practice, and educate them on the reality of the drugs use.
"The vast majority of women have no idea of their risks and options, and we suspect tamoxifen is being underutilized, that many women at high risk are not using it," Bevers said. "It is, of course, a womans choice not to use the agent, but she needs to know about her risk and options first."
Bevers said she is "thrilled" with the USPSTF recommendation because she sees it as a "driver" to clinicians to start assessing breast cancer risk and offering the tamoxifen option to appropriate women.
Tamoxifen pioneer Craig Jordan, Ph.D., D.Sc., of Northwestern University, Chicago, views the USPSTF report as endorsement of the new concept of chemoprevention of cancer. "It is an important function of government to inform the general population that there may be a health care option now available that may not have been adequately discussed with them," he said.
Preventive Medicine
But the USPSTF recommendations present serious challenges to primary care clinicians who care for women of all ages and varying cancer risks, said primary care physician Albert Mulley Jr., M.D., chief of the General Medicine Division at Massachusetts General Hospital, Boston. Clinicians are increasingly being asked to involve patients in decisions that "have no clear best choice," and in which the medical science is imperfect, leaving many questions unanswered, he said in an editorial that accompanied the task forces guidelines.
And using a risk assessment tool to judge every female patients risk of breast cancer plays into an outsized fear of the cancer, while neglecting other, more beneficial disease-avoidance measures, he said in an interview. For example, women who smoke are nearly twice as likely as nonsmokers to express interest in chemoprevention of breast cancer, when they are far more likely to die of heart attacks, lung cancer, and stroke. "Its human nature to coalesce all your anxiety about mortality into one condition, and for many women, that is breast cancer," he said. "We need to put risk of breast cancer into a broader perspective."
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