NCI Launches Second National Breast Cancer Prevention Trial

Women with an increased risk of breast cancer don't have to helplessly wait and wonder if they'll find that dreaded tumor. They have the choice to pursue a preventive course of action. The first national breast cancer prevention trial sponsored by the National Cancer Institute (NCI) proved the drug tamoxifen cut the risk of breast cancer in half for women at high risk.1 Following this finding the Food and Drug Administration (FDA) approved the use of tamoxifen as a preventive measure in October 1998. Now the second national breast cancer prevention study, the Study of Tamoxifen and Raloxifene (STAR), is recruiting 22,000 postmenopausal women at increased risk for breast cancer across the United States, Puerto Rico, and Canada. This constitutes the first large randomized clinical trial comparing the efficacy of raloxifene, an osteoporosis drug, to tamoxifen for the reduction of breast cancer. Tamoxifen is the first clinically available selective estrogen receptor modulator (SERM). SERMs bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as antagonists in others. The antagonistic effect may result from the inability of the SERM to activate the estrogen receptor in certain tissues.2 Women diagnosed with breast cancer have been using tamoxifen for the past two decades as part of therapy. Tamoxifen is a potent antiestrogen in the breast and prevents the growth of estrogen receptor-dependent tumors. It is also associated with a decrease in low-density lipoprotein cholesterol and conservation of bone density in postmenopausal women.3 Unfortunately, tamoxifen therapy increases risk of endometrial (uterine lining) carcinoma and polyp development. In far fewer cases, pulmonary embolism (blood clot in the lung), deep vein thrombosis (blood clots in the major veins), and stroke were observed with tamoxifen use. Clotting and uterine cancer are a greater concern in postmenopausal women. SERMs have tremendous clinical potential if they can be tweaked to produce estrogenlike effects on nonreproductive tissues such as bone and lipid without the proliferative effects on the breast and uterus. In December 1997 the FDA approved raloxifene, a more recent SERM, for osteoporosis prevention in postmenopausal women. Clinical trials designed to study raloxifene's effect on osteoporosis showed that women taking the drug had a lower rate of breast cancer than a control group. They also experienced positive effects on lipid profiles. Interestingly, both preclinical and clinical studies revealed that unlike tamoxifen, raloxifene is a pure antiestrogen in the uterus. Therefore, it should not cause endometrial tumors. This difference in the proliferative activity affecting the uterus may give raloxifene an edge over tamoxifen since the drugs show similar clinical profiles.4 The most common side effects are hot flashes and vaginal discharge. STAR will allow researchers to determine whether raloxifene is as effective as tamoxifen in reducing the risk of breast cancer in postmenopausal women. Since raloxifene has only been studied in postmenopausal women, a separate study is evaluating the safety of raloxifene for premenopausal women. call the National Cancer Institute's Cancer Information Service at (800)4-CANCER (800-422-6237) for information in English or Spanish. The number for callers with TTY equipment is (800)332-8615. In Canada, call the Canadian Cancer Society's Cancer Information Service at (888)939-3333 for information in English or French. Visit the National Cancer Institute's clinical trials Web site at cancertrials.nci.nih.gov. Over the next three years STAR will enroll 22,000 postmenopausal women who are at increased risk for breast cancer. Half the women will receive tamoxifen and the other half will receive raloxifene in the double-blind study; neither the doctor nor the patient will know which drug is being administered. The five-year study will include regular follow-up examinations, mammograms, and gynecologic exams. Worta McCaskill-Stevens, program director for STAR at NCI, doesn't believe this number will be difficult to reach based on the high interest level. The last study enrolled 13,388 volunteers out of 100,000 screened. She comments, "There is a significant effort to make the trial accessible to all ethnic groups so we can have a much more diverse population." Almost all the participants (96.4 percent) were white in the first breast cancer prevention study. Mary Daly, director of family risk assessment at Fox Chase Cancer Center, Philadelphia, was a principal investigator for the first study and will have the same role in STAR. Daly, hopeful that STAR will provide women with another breast cancer prevention choice, says, "The chemical structures are so similar [with tamoxifen and raloxifene], we are anticipating there will be equal effectiveness in breast cancer reduction, but that needs to be scientifically established." She adds, "We expect a decreased risk to the endometrium [with raloxifene use] will be observed in this study, but the magnitude of that risk needs to be quantified." "Completion and results of the first prevention trial have been instrumental in raising awareness of women about breast cancer and breast cancer prevention," says McCaskill-Stevens. Though the preventive approach toward breast cancer is new and exciting, she warns, "We are now helping women to determine their risk because breast cancer prevention is not for everyone, [just those] at high risk. Risk assessment and counseling is relatively new in our society." NCI has a computer disk available that helps a patient and her physician determine her probability of developing breast cancer. Risk factors include a strong family history of breast cancer, breast lumps requiring biopsy, early menstruation, and no children or childbirth after age 30. An established algorithm then determines eligibility for treatment. "Ultimately it is a personal decision that a woman has to make based on all the information that we give her whether or not she wants to [risk experiencing side effects with the preventive approach]," says Daly. B. Fisher et al., "Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel Project P-1 study," Journal of the National Cancer Institute, 90:1371-88, Sept. 16, 1998. S.R. Goldstein, "Selective estrogen modulators: a new category of therapeutic agents for extending the health of postmenopausal women," American Journal of Obstetrics and Gynecology, 179:1479-84, December 1998. C.P. Spencer, "Selective estrogen modulators: women's panacea for the next millennium?" American Journal of Obstetrics and Gynecology, 180:763-70, March 1999. W. Khovidhunkit et al., "Clinical effects of raloxifene hydrochloride in women," Annals of Internal Medicine, 130:431-40, March 2, 1999.

NCI Launches Second National Breast Cancer Prevention Trial

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