© 1998 by Oxford University Press
Tamoxifen moved another step closer to approval for breast cancer prevention when the Oncologic Drugs Advisory Committee of the Food and Drug Administration on Sept. 2 recommended approval of its use to reduce the risk of breast cancer in women at high risk for the disease.
But questions remain about whose risk is high enough to outweigh the risk of potential side effects. So far, physicians appear cautious about prescribing tamoxifen to healthy women. And new findings heralding the preventive potential of a rival drug, raloxifene, complicate the picture.
After release of the Breast Cancer Prevention Trial results, first announced in April and published Sept. 16, showing a 49% reduction in invasive breast cancer incidence among participants who took tamoxifen, the National Cancer Institute said women at increased risk for the disease could now consider taking tamoxifen to lower their risk (see Journal of the National Cancer Institute, Sept. 16, 1998, p. 1371, and News, May 6, 1998). Zeneca Pharmaceuticals of Wilmington, Del., which markets tamoxifen as Nolvadex®, filed a Supplemental New Drug Application with the FDA on April 30, following the dissemination of the BCPT results.
A Woman's Choice
"The ODAC recommendation made it clear that any use of Nolvadex in otherwise healthy women at increased risk of breast cancer is a choice that should be made available to women in consultation with their doctors," said Robert C. Black, president of Zeneca.
"The committee also emphasized that the NCI, the FDA, and Zeneca should work together to provide doctors and women with detailed information on risk assessment," Black added. "Zeneca is committed to meeting this goal."
The FDA must now consider whether to adopt the ODAC recommendation. But the agency remains cautious in its appraisal of tamoxifen.
"You don't expose potentially tens of millions of women to a powerful treatment with the assumption it's going to help them," said FDA Acting Commissioner Michael Friedman, M.D. Tamoxifen "looks very promising, but the question is for which patients, at what cost in toxicity."
At the ODAC hearing, some breast cancer advocates argued that tamoxifen should not be approved for prevention because of concerns about the drug's serious side effects, particularly endometrial cancer and blood clots in the lungs.
"I have great concern for women who come in healthy and die from something they take, thinking it's going to prevent them from dying from something else," said breast cancer survivor Ann Fanfa.
Women who believe their breast cancer risk makes tamoxifen a good bet should not have problems getting their health maintenance organizations to cover the drug, sources said, despite the fact that tamoxifen is still approved only for women already diagnosed with breast cancer.
Donald White, a spokesman for the American Association of Health Plans in Washington, D.C., said he polled about 10 member organizations.
"They all said that the decision about how to use an FDA-approved drug that's on the formulary is made by the clinician, in consultation with his or her peers and with the patient," White reported. "That is a clinical decision that the HMOs don't track." AAHP represents more than 1,000 HMOs, preferred provider organizations, and other network-based plans that provide health care for more than 140 million Americans.
"If a new application is discovered for a drug," White added, "the pharmaceutical department of the HMO might circulate this information to clinicians. But HMOs don't engage in the kind of micromanagement on clinical decisions that would be called for in order to somehow restrict the specific usage of an FDA-approved drug."
Physicians' Decisions
If and when FDA approves tamoxifen for prevention, he said, that action would likely have more impact on individual physicians' decisions about how to use it than on HMO policies.
"If a physician prescribes tamoxifen to a patient, then we cover it," said Patti Embry-Tautenhan, a spokeswoman for Harvard Pilgrim Health Plan in Brookline, Mass. "We've tried to educate our physicians about who are good candidates for this drug. However, physicians have complete license to prescribe as they see fit."
AAHP's White said that among members he polled, none knew of any physicians who were currently prescribing tamoxifen to healthy women.
Meanwhile, at the annual meeting of the American Society of Clinical Oncology in May, researchers at the University of California, San Francisco reported that another drug, raloxifene -- like tamoxifen, a selective estrogen receptor modulator -- reduced breast cancer risk by 70% in postmenopausal women participating in an osteoporosis trial. (Raloxifene was approved by FDA for the prevention of postmenopausal osteoporosis in December 1997.) In that study, after an average of 33 months, 11 women assigned to raloxifene (0.21%) developed breast cancer, compared with 21 women on placebo (0.82%).
Head-on Comparison
"If we continue to see positive results from the study, as we expect, women who are concerned about breast cancer should consult their doctors about whether raloxifene is a treatment they should consider," said Steven Cummings, M.D., professor of medicine and epidemiology at UCSF, and lead author of the study.
A potentially major advantage of raloxifene, Cummings and co-authors said, is that unlike tamoxifen, it appears not to increase risk for endometrial cancer. (Of the 13,388 women in the BCPT, 36 in the tamoxifen group developed invasive endometrial cancer, compared with 15 in the placebo group.) Both drugs may increase a woman's risk of developing blood clots. Cummings said the study will continue for at least four more years to determine the long-term effects of raloxifene.
Sigrid L. Tishler, M.D., assistant professor of medicine at Harvard Medical School in Boston and an oncologist at Harvard Vanguard Medical Associates (a clinician-run group practice affiliated with Harvard Pilgrim), enrolled patients in the BCPT and hopes to participate in a new trial that will compare raloxifene and tamoxifen head-on.
"Most in the oncology community are being cautious about starting widespread use of tamoxifen for chemoprevention," she said. "There are still a number of questions."
"I think it's a matter of informed consent," she added. "For patients who would fit the profile of women on the breast cancer prevention trial, if they -- understanding all the pros and cons -- want to be treated with tamoxifen, I think that's an appropriate thing to consider. But by no means should that be generalized to breast cancer in the general public, because we really don't know how the risks and benefits would weigh out."
As for raloxifene, Tishler cautioned that the UCSF trial was designed to study osteoporosis, not breast cancer, and the follow-up time is still relatively short.
"The risk profiles of the women in that study are not known, so to use raloxifene as a primary breast cancer prevention is something we really don't have information about," she said.
Another difference is that raloxifene is only approved for postmenopausal women, while some BCPT participants were as young as 35. So Tishler said tamoxifen would be a more appropriate choice for a younger woman who was highly motivated to take action to reduce an elevated risk of breast cancer.
"But would I enthusiastically endorse it?" she said. "I'm not so sure."
-- Tom Reynolds
Tamoxifen Debate Hinges on Whose Risk is High Enough
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  R. Taylor and K. Taguchi Tamoxifen For Breast Cancer Chemoprevention: Low Uptake by High-Risk Women After Evaluation of a Breast Lump Ann. Fam. Med, May 1, 2005; 3(3): 242 - 247. [Abstract] [Full Text] [PDF]
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 T. J. Powles Re: Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study J Natl Cancer Inst, April 21, 1999; 91(8): 730 - 730. [Full Text] [PDF]
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