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Executive Summary

The use of estrogen or hormone replacement therapy in investigative trials in women who previously have been treated for breast cancer was cleared by FDA's Fertility & Maternal Health Drugs Advisory Committee at its Feb. 14 meeting. The committee voted eight to zero in favor with one abstention. The affirmative vote responded to a question posed by FDA on the ethics of conducting "well-designed trials of hormone replacement therapy in women who have been treated for breast cancer when a primary outcome of interest will be to ascertain whether the treatment exacerbates breast cancer recurrence." Committee member Arthur Haney, MD, Duke University Medical Center, voicing the consensus of most of the panel, said: "My reaction is that the risk is low enough and the benefits are potentially great enough that a quality trial needs to be performed and is ethical to do." The only member of the committee to abstain in the vote, James Schlesselman, PhD, Uniformed Services University of the Health Sciences, remarked that he has seen no evidence "with regard to breast cancer groups that [shows] estrogen replacement therapy or hormone replacement therapy is going to be beneficial with regard to breast cancer risk." Schlesselman said that, based on the evidence, he believes "the breast cancer risk is going to be increased." The advisory committee rejected, by a seven-to-two margin, a suggestion that the label warning against the use of estrogens and progestins for women who have been treated for breast cancer be dropped. The committee declined to modify the warning statement until data from the proposed trials have been analysed. The committee heard presentations on studies ranging widely in their conclusions. Some studies supported the idea that hormone replacement therapy actually decreases the risk of developing breast cancer. Other studies showed that hormone replacement therapy could increase the risk of breast cancer several-fold. Of three meta-analyses of studies in the literature presented at the meeting, two found a 30%-50% increase in the risk of breast cancer after 15 years of therapy and one was inconclusive. "We just don't know for sure whether it is going to be detrimental or not [but] we do know that there are other potential benefits" to hormone replacement therapy, Jennifer Niebyl, MD, University of Iowa Medical School, commented. Among the anticipated benefits of hormone replacement therapy are: alleviation of menopausal symptoms such as hot flashes, vaginal dryness, and sleeplessness; prevention and treatment of osteoporosis; and potential cardiovascular protection, although it is still an unapproved indication for estrogens. A commonly used argument for the use of hormone replacement therapy in postmenopausal women who have had breast cancer is that 400,000 women in the U.S. die from cardiovascular disease each year while substantially fewer, 46,000, die from breast cancer. The number of women living following treatment of breast cancer is also increasing. There are currently 1.6 mil. breast cancer survivors in the U.S. and 175,000 new breast cancer cases diagnosed annually. Recommendations on the design of studies with hormone replacement therapy were also made by the committee. Chairperson Barbara Hulka, MD, University of North Carolina School of Public Health, observed that if women with a low risk of recurrent disease are enrolled in a trial, the size of the study would have to be in the range of 6,000-8,000 patients. However, if high-risk women are recruited for a study, only 500-600 subjects would be required. Committee consultant Steven Piantadosi, MD, Johns Hopkins University, suggested that the trials, whether high or low risk, be large enough to accumulate at least 1,000 outcome events. The primary outcomes suggested by the committee were recurrence of breast cancer followed by quality of life. "Taking women with advanced disease who will have a high recurrence will mean that you will get more recurrences [and] you will be able to get statistically significant outcome events much more rapidly," Hulka said. Committee members agreed that drug options offered in the trials should not be "lumped together" under the term of hormone therapy. Women would receive either placebo, estrogen alone (only for women who have had hysterectomies), progestin alone, estrogen plus progestin (continuous or cyclic therapy). Women would not necessarily need to be stratified according to type of breast disease, the committee members concurred; however, studies should use some kind of prognostic indexing system to follow subgroups of patients based on type of disease. FDA has received three protocols from investigators planning hormone replacement trials. One protocol was submitted by Avrum Bluming, MD, University of Southern California, who represents a consortium of oncologists planning a study in 300 women previously treated for breast cancer. The women will receive .625 mg of Wyeth-Ayerst's Premarin plus 2.5 mg medroxyprogesterone in the study, which is scheduled to run for 10 years and look at recurrence rates, bone density, endometrial changes and other parameters. A second, larger study by Alan Wile, MD, University of California at Irvine, which is being conducted in conjunction with Bluming's study, will recruit 5,000 women and follow them for three to four years. Under the Wile protocol, women will receive Premarin plus medroxyprogesterone or placebo. Wulf Utian, MD, Case Western Reserve University, who submitted a protocol for a third study, suggested to the committee that progestin alone might be used to treat menopausal symptoms in women recovered from breast cancer. He is planning a 40-subject pilot study using Bristol-Myers Squibb's Megace (megestrol acetate), a drug already approved for the treatment of breast cancer itself.

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