The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.
Trial registration: ClinicalTrials.gov NCT00088010.