Postmenopausal women with high estradiol levels are at highest risk for breast cancer. Tamoxifen, an estrogen inhibitor, has been shown to decrease the risk of contralateral breast cancer in women with estrogen receptor–positive breast cancer. However, evidence of its efficacy in primary prevention among this population is conflicting. The most compelling data were presented in the Breast Cancer Prevention Trial, which suggested that tamoxifen therapy reduced the risk of breast cancer by 50 percent in high-risk women. Tamoxifen is also associated with an increased risk of thromboembolism and endometrial cancer. Raloxifene is a selective estrogen-receptor modulator that has been shown to inhibit cancer growth in animals. Cummings and colleagues evaluated the effectiveness of raloxifene in reducing the risk of breast cancer in postmenopausal women as part of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.
Postmenopausal women up to 80 years of age were eligible for the study if they had osteoporosis (bone density of at least 2.5 standard deviations below normal for young women) or had at least one moderate (or two mild) vertebral compression fracture. Breast examinations and mammography or ultrasonography were conducted at baseline. Exclusion criteria included a history of breast or any other type of cancer other than skin cancer, stroke, venous thromboembolic disease, bone disease or secondary causes of osteoporosis. Patients received 500 mg of calcium daily and up to 600 IU of cholecalciferol daily. Those who met the study criteria were randomized to receive two placebo tablets daily, one placebo tablet and one 60-mg tablet of raloxifene daily, or two 60-mg tablets of raloxifene daily.
Patients returned for follow-up visits every six months. At each visit, they were asked whether they had been diagnosed with breast cancer; if they had, the diagnosis was confirmed by an oncology review board. Repeat mammography was offered after one year and mandatory after two and three years of treatment. Adverse events and current medication regimens were reviewed at each follow-up visit. In patients with possible deep venous thrombosis or pulmonary embolism, results of imaging studies were reviewed.
A total of 7,705 women were included in the MORE trial. Of these, 5,129 received some amount of raloxifene, and 2,576 received placebo. The mean age was 66.5 years, and 12.3 percent of patients reported a family history of breast cancer. Mammography was performed in 91 percent of women who continued the study at two years; breast sonography was performed in 3 percent. After three years, 88 percent had mammography and 3 percent had breast sonography. About 75 percent of all women completed the three-year study. Median follow-up was approximately 40 months.
Breast cancer was diagnosed in 27 women in the placebo group and in 13 women in the raloxifene group. The dosage of raloxifene was not statistically significant because the relative risk of cancer was 0.22 in women taking 60 mg of the drug and 0.26 in women taking 120 mg. Raloxifene also reduced the risk of estrogen receptor–positive breast cancer by 90 percent compared with placebo. The risk of estrogen receptor–negative breast cancer was not affected. Adverse events were more common in the raloxifene groups, and the risk of venous thromboembolic disease was more than three times higher in the raloxifene groups than in the placebo group. Mortality rates did not differ between the treatment groups and the placebo group.
The authors conclude that raloxifene reduced the risk of newly diagnosed invasive breast cancer by 76 percent in postmenopausal women when treatment continued for a median of 40 months. This overall effect is attributed to a 90-percent reduction in estrogen receptor–positive breast cancer. Thus, raloxifene can join tamoxifen as a potentially useful preventive agent in women who are at increased risk of estrogen receptor–positive breast cancer.
editor's note: In an accompanying editorial, Franks and Steinberg compare the benefits of raloxifene with those of other selective estrogen receptor modulators (Franks AL, Steinberg KK. Encouraging news from the SERM frontier. JAMA June 16, 1999;281: 2243–4). Raloxifene has been shown to improve bone density, but it does not increase the risk of endometrial cancer. A study directly comparing the effectiveness of raloxifene and tamoxifen in protecting women against breast cancer is planned. Long-term studies that track the safety and effectiveness of raloxifene are also needed.—g.b.h.