SAN ANTONIO — Raloxifene continued to markedly reduce breast cancer incidence in postmenopausal osteoporotic women over the course of 8 years in an extension of the landmark Multiple Outcomes of Raloxifene Evaluation trial, according to Silvana Martino, D.O., of the John Wayne Cancer Institute, Santa Monica, Calif.
An attempt to learn in the extended MORE study whether a single baseline serum estradiol measurement might identify subgroups of osteoporotic women who are particularly likely or unlikely to benefit from long-term raloxifene in terms of breast cancer risk reduction proved largely unsuccessful. The magnitude of reduction in invasive breast cancer with raloxifene turned out to be independent of estradiol level, although the absolute benefit was greater in women with a level of at least 5 pmol/L, Dr. Martino said at a breast cancer symposium sponsored by the Cancer Therapy and Research Center.
MORE was a 4-year randomized double-blind trial in roughly 7,700 women that led to marketing approval of raloxifene (Evista), which is a selective estrogen-receptor modifier (SERM) for prevention and treatment of postmenopausal osteoporosis. Among the predefined secondary end points in MORE was the incidence of invasive breast cancer, which was 72% less with raloxifene, compared with placebo.
Because breast cancer incidence was a secondary end point in MORE, however, an extension trial—the Continuing Outcomes Relevant to Evista (CORE) study—was undertaken to evaluate the safety and efficacy of an additional 4 years of raloxifene use, this time with invasive breast cancer prevention as the primary outcome measure. A total of 3,510 postmenopausal osteoporotic women randomized to raloxifene in MORE were assigned to an additional 4 years of the SERM at 60 mg per day. In addition, 1,703 women from the MORE placebo arm continued on placebo.
MORE and CORE were sponsored by Eli Lilly & Co. Dr. Martino serves as a consultant to the company.
During the 4 years of the extended trial, the incidence of invasive breast cancer was reduced 59% in the raloxifene group, compared with the placebo group. Estrogen receptor-positive invasive breast cancer was reduced 66% with raloxifene as well. Thus, the magnitude of risk reduction during the second 4 years of raloxifene therapy was similar to that noted during the initial 4 years.
This is significant because raloxifene for osteoporosis is essentially lifelong therapy. Moreover, the maximal recommended duration for the use of tamoxifen to reduce the incidence of breast cancer in high-risk women is 5 years.
During the 8 years of the combined MORE and CORE studies, the incidence of invasive breast cancer was reduced 66% with raloxifene, compared with placebo, while the rate of estrogen receptor-positive invasive breast cancer was 76% less in the raloxifene arm than the placebo arm.
There was no difference between the two study arms in the incidence of estrogen receptor-negative invasive breast cancer or noninvasive breast cancer in CORE, nor in the full 8-year combined experience.
In CORE, the incidence of thromboembolism in raloxifene-treated women was 2.9 events per 1,000 woman-years, two times greater than with placebo. The rates in MORE were similar to those in CORE. No new safety concerns emerged with the use of raloxifene during years 4–8 of treatment.
The baseline serum estradiol data suggested the existence of a threshold effect, with women having an estradiol of at least 5 pmol/L—half of all study participants—deriving greater benefit in terms of reduction in invasive breast cancer. (See chart.)
Audience members noted that CORE didn't address the important issue of whether raloxifene is beneficial for prevention of breast cancer in at-risk women who don't have osteoporosis. That issue is being studied in two randomized clinical trials: the Raloxifene Use for the Heart (RUTH) trial in postmenopausal women at elevated cardiovascular risk, and the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) trial, a head-to-head comparison.