Defining the role of raloxifene for the prevention of breast cancer.

Over the last 5 years, the results of several breast cancer prevention trials have demonstrated the usefulness of antiestrogen selective estrogen receptor modulators (SERMs) for the prevention of breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 breast cancer prevention trial was the first trial to show a major benefit of a SERM: The anti-estrogen SERM tamoxifen reduced the risk of breast cancer in women who were at high risk of the disease by 49% (1). The results of several other breast cancer prevention trials confirmed the cancer-preventive benefit of tamoxifen [reviewed in Cuzick et al. (2)], although the magnitudes of benefit reported in these other trials were lower than that reported by the P-1 trial. Together, these results provide strong support for the use of tamoxifen to reduce the risk of breast cancer in women at high risk of this disease. However, since 1998, tamoxifen has not been widely used for this purpose largely because of concerns over its side effects, which include the induction of hot flashes as well as increased risks of thromboembolic events and uterine cancer. These potentially serious side effects have caused physicians to carefully weigh the risks and benefits of tamoxifen before prescribing it for women at high risk of breast cancer. Other agents currently being tested for breast cancer prevention include other SERMS (e.g., raloxifene and arzoxifene) as well as aromatase inhibitors (e.g., anastrazole). Raloxifene is an anti-estrogen SERM that blocks the effects of estrogen in the breast and stimulates calcium uptake in the bone (3,4). Both tamoxifen and raloxifene increase the risk of thromboembolic events (1,3,4). However, unlike tamoxifen, raloxifene does not appear to increase the risk of uterine cancer (3,4). Thus, raloxifene may be safer than tamoxifen. In this issue of the Journal, Martino et al. (5) present results from the Continuing Outcomes Relevant to Evista (CORE) trial, a breast cancer prevention trial designed to determine whether treatment with raloxifene reduced the incidence of breast cancer among women who were previously enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a multicenter, double-blind trial designed to examine the reduction in risk of vertebral fractures among approximately 7700 postmenopausal women with osteoporosis who were randomly assigned to receive either placebo or raloxifene at 60 mg/day or 120 mg/day (3,4). This trial demonstrated that raloxifene reduced vertebral bone fractures in women with osteoporosis by 35% (60-mg dose) to 47% (120-mg dose) (3). Analysis of a secondary endpoint of the MORE study demonstrated a 72% reduction in invasive breast cancer incidence after 4 years of raloxifene (4). The results from the CORE study indicate that continued treatment with raloxifene reduces breast cancer incidence in postmenopausal women with osteoporosis. However, the results from this study do not answer several other important questions concerning preventive therapy, including: 1) what is the most effective drug to use for breast cancer prevention? 2) which agent is safest? 3) who should be treated with preventive therapy? 4) how are the risks and benefits of preventive therapy best assessed? and 5) what is the optimal duration of preventive therapy? Because breast cancer incidence was a secondary endpoint in the MORE trial, investigators developed the CORE trial as an extension of the MORE trial to evaluate the effect of 4 additional years of raloxifene treatment on the incidence of invasive breast cancer in postmenopausal women with osteoporosis. Women who agreed to participate in the CORE study were assigned to continue raloxifene at 60 mg/day or placebo for 4 more years according to their initial randomization assignment in the MORE trial. The primary endpoint was the incidence of invasive breast cancer. A secondary endpoint was the incidence of invasive estrogen receptor (ER)–positive breast cancer. Martino et al. (5) report that, among patients treated with up to 4 additional years of raloxifene, the annual incidence of invasive breast cancer was reduced by 59% and the annual incidence of ER-positive breast cancer was reduced by 66%.