Emphasizing that Evista is only indicated for prevention and treatment of postmenopausal osteoporosis, Dr. Mar-tino, a medical oncologist at John Wayne Cancer Institute, Santa Monica, California, presented the findings at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 1000).
She discussed data from the 4-year CORE (Continuing Outcomes Relevant to Evista) trial, a follow-up with continued observation of women who had already participated for 4 years in the MORE (Multiple Outcomes of Raloxifene) trial, as well as combined results across the 8-year study period.
MORE was a randomized, double-blind, placebo-controlled osteoporosis treatment trial in postmenopausal women without a history of breast cancer, to determine as a secondary endpoint whether postmenopausal women on raloxifene had a lower risk of invasive breast cancer. The 3-year treatment phase was followed by a 1-year extension.
A total of 7,705 women (mean age 66.5 years, 96% Caucasian) taking raloxifene or placebo were followed for a median of 48 months, from 1994 through 1998, at 180 clinical centers in 25 countries, mainly in the United States and Europe. Participants received 120 mg of raloxifene daily (two 60-mg tablets); or 60 mg of raloxifene daily (one 60-mg tablet plus one placebo tablet); or two placebo tablets.
During the MORE study period, treatment with raloxifene reduced the risk of invasive breast cancer by 72% among postmenopausal women with osteoporosis. The MORE investigators determined that, to prevent 1 case of invasive breast cancer, 93 osteoporotic women would need to be treated with raloxifene.
CORE Trial
The CORE trial began on Jan. 1, 1999, as an additional 4-year follow-up to the MORE trial, but with invasive breast cancer reduction as the primary endpoint, Dr. Martino said. The 4,011 participants in MORE who were screened and consented to participate in CORE were not re-randomized; they retained the randomization to which they had originally been assigned in the MORE trial, with two thirds assigned to raloxifene and one third assigned to placebo. However, all CORE patients assigned to raloxifene received the same dose, 60 mg/d. There was a brief period (median 10.6 months) between MORE and CORE during which no patients received treatment.
"An additional 1,217 women at these same sites were completing their MORE trial participation when CORE was being designed," Dr. Martino said. "By study design, their breast cancer data are encompassed in CORE as part of the CORE time period starting in January 1999."
Data on 5,213 women were available for analysis. A total of 52 cases of invasive breast cancer were identified: 28 in the placebo group (n = 1,703) and 24 in the raloxifene group (n = 3,510). The incidence of invasive breast cancer in the raloxifene group was 59% lower than in the placebo group (hazard ratio 0.41, 95% CI 0.24-0.71; P < .001). Estrogen-receptor status was determined for 46 of the women with invasive breast cancer; the incidence of ER-positive invasive breast cancer was reduced by 66% with raloxifene. Use of raloxifene did not affect the incidence of ER-negative breast cancer.
Combined Data
The combined data show that 8 years of raloxifene in the MORE and CORE trials was associated with a 66% reduction in the risk of invasive breast cancer overall and a 76% reduction in the risk of invasive ER-positive breast cancer. The combined data show that 69 women would need to be treated with raloxifene to prevent 1 case of invasive breast cancer during that time span, she said.
"Whether one looks at the MORE trial, or the CORE trial, or the two combined, the same biology is observed—that, yes, this agent does have the ability to reduce the incidence and the risk of breast cancer," she said at a press conference held during the ASCO meeting. "The reduction in breast cancer incidence appears to be specific to ER-positive breast cancer, with no difference noted in ER-negative breast cancer; nor did we see any difference in noninvasive breast cancer."
Safety Data
Safety data were derived from assessment of the 4,011 women who participated in MORE and CORE for the entire 8 years of those studies. Importantly, she said, over the 8 years of treatment, there was no increased risk of vaginal bleeding, endometrial hyperplasia, or endometrial cancer with raloxifene use. Although hot flushes and leg cramps were more common with raloxifene than placebo, these occurred with greater frequency during the MORE trial (years 1-4) in the raloxi-fene group but were equal during years 5-8 between the two groups. Dr. Martino noted that there were no new toxicities identified in the CORE trial.
A twofold increase in risk of venous thromboembolism with raloxifene vs placebo persisted over the 8-year study period, but this increased risk was small and did not reach significance, Dr. Martino said. This is an important issue to consider, particularly in sedentary patients, she noted, but added that "these still are rare events." The increased incidence of pulmonary emboli with raloxifene was significant: 0.2% in the placebo group vs 0.6% in the raloxifene group (P = .048). However, she noted that "overall, the drug is easy to use and quite safe," with no increased incidence of arterial thrombotic events such as stroke or myocardial infarction.
