February 2001

From University of Pittsburgh Medical Center

University of Pittsburgh-led study confirms that Raloxifene protects post-menopausal women from invasive breast cancer

Pittsburgh, Feb. 13 -- The drug raloxifene significantly reduces the risk of invasive breast cancer in post-menopausal women, according to results of a large-scale study involving the University of Pittsburgh Graduate School of Public Health (GSPH) and published in the upcoming issue of Breast Cancer Research and Treatment. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial measured the effects of raloxifene, which has been approved by the U.S. Food and Drug Administration for the prevention and treatment of osteoporosis, on breast cancer rates after four years of follow-up. The results confirm the studyís preliminary findings, which where published in the June 1999 issue of the Journal of the American Medical Association.

"The MORE trial showed that raloxifene reduces the risk of invasive breast cancer by 72 percent in women who took this drug daily for four years," said Jane Cauley, Dr.P.H., lead author on the study and associate professor of epidemiology at the GSPH. "Specifically, raloxifene reduced the risk of estrogen-receptor positive invasive breast cancer by 84 percent. This finding indicates that raloxifene is very effective at curbing the development of estrogen-fed breast tumors among older women with an average breast cancer risk."

MORE, a multi-center osteoporosis trial, involved 7,705 post-menopausal women, average age of 66.5 years, with a history of osteoporosis. About 12 percent reported a family history of breast cancer. Participants were randomly assigned to receive 60 mg or 120 mg of raloxifene per day or a placebo. Neither investigator nor participant knew who received placebos and who received raloxifene.

After four years, 22 cases of breast cancer were confirmed among the 5,129 women assigned to either dose of raloxifene, versus 39 cases among the 2,576 women assigned to the placebo. There were no significant differences in outcome between the group taking 60 mg of the drug and those taking 120 mg. Overall, raloxifene was well-tolerated by participants.

The hormone estrogen declines as women pass through menopause. Without it, women suffer problems including hot flashes, bone loss and changes in cholesterol that could predispose them to heart disease. At the same time, however, estrogen is known to fuel the growth of certain breast and endometrial cancers whose cells have estrogen receptors. For these reasons, investigators have been searching for estrogen alternatives, or selective estrogen-receptor modifiers (SERMs), that interact with the cell receptor for estrogen and confer estrogenís beneficial properties, yet curtail its tumor-promoting role. The MORE trial showed that raloxifene blocks the estrogen receptors in estrogen-receptor-positive breast cancers, or those that are fueled by estrogen. The drug showed no effect on estrogen-receptor-negative breast cancers, or those that do not depend on estrogen for growth.

In a separate study, the large-scale Breast Cancer Prevention Trial (BCPT), researchers found that tamoxifen, another SERM, reduced the incidence of invasive breast cancer in women at significantly increased risk of this disease. As in the case of raloxifene, tamoxifen produced its greatest risk reduction in women with estrogen-receptor positive breast cancers.

The Study of Tamoxifen and Raloxifene (STAR), a five-year breast cancer prevention trial that will enroll up to 22,000 high-risk participants, will offer a head-to-head comparison of the two drugs. Completing this trial is very important, according to Dr. Cauley, because it is expected to show whether the two agents are equivalent in reducing breast cancer in women at high risk for this disease and whether one agent produces fewer undesirable side effects.

In the MORE study, raloxifene also was shown to increase bone density and reduce vertebral fractures. Previous studies of tamoxifen also have shown its ability to increase bone density and reduce fractures, but this effect was not statistically significant in the BCPT. Both agents also reduce levels of so-called bad cholesterol, which could reduce heart disease; however, the effects of tamoxifen on reducing heart disease were not statistically significant in the BCPT. The effect of raloxifene on reducing heart disease and breast cancer is currently under study in the Raloxifene Use for the Heart (RUTH) study, which recently completed enrolling more than 10,000 older women at risk of heart disease. Longer-term effects of raloxifene on reducing the incidence of breast cancer in post-menopausal women will be evaluated in the Continuing Outcomes Relevant to Evista (CORE) trial.

Venous thromboembolism, or obstruction of a blood vessel, is a serious, although infrequently reported side effect of raloxifene. Other side effects associated with raloxifene include flu symptoms, hot flashes, leg cramps, endometrial cavity fluid and peripheral edema.

Other authors of the MORE paper include Steven Eckert, Ph.D., Kathryn A. Krueger, M.D., Sheryl L. Silfen, M.D., Erin L. Walls, E.L.S., Douglas B. Muchmore, M.D., and Henry Schmitt, M.D., of Eli Lilly and Co.; Larry Norton, M.D., of Memorial Sloan-Kettering Cancer Center, New York; David W. Purdie, M.D., of the Centre for Metabolic Bone Disease, University of Hull and the Royal Hull Hospitals, England; Jordi Farrerons, M.D., of Hospital Santa Cruz and San Pablo, Spain; Avraham Karasik, M.D., of Chaim Sheba Medical Center, Israel; Dan Mellstrom, M.D., Ph.D., Department of Geriatrics, Sahlgrenska University Hospital, Sweden; Kong Wah Ng, M.D., The University of Melbourne Department of Medicine, Australia; Jan J. Stepan, M.D., D.Sc., Charles University, Third Department of Internal Medicine, Czech Republic; Trevor J. Powles, Ph.D., of the Breast Unit, Royal Marsden NHS Trust Hospital; Monica Morrow, M.D., of the department of surgery, Northwestern University Medical School; Marc E. Lippman, M.D., of the Lombardi Cancer Center, Georgetown University Medical Center; Alberto Costa, M.D., of the European Institute of Oncology, Italy; and V. Craig Jordan, Ph.D., D.Sc., of the Robert H. Lurie Cancer Center, Northwestern University.

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