Oncology Abstracts

The standard of care for early postmenopausal ERα+ breast cancer patients is adjuvant endocrine therapy, with or without a CDK 4/6 inhibitor in the metastatic setting. However, many patients are resistant or experience recurrence 10 to 15 years after treatment. A subset (10–40%) of ERα+ therapy-resistant breast cancers express somatic ESR1 mutations. The two most common ERα mutations are Y537S and D538G, which confer ERα constitutive activity. Lasofoxifene is a SERM developed to treat vulvovaginal atrophy and osteoporosis. In this study, we tested the hypothesis that lasofoxifene would be an effective inhibitor of MCF7 tumor explants engineered to express Y537S or D538G ERα. We used the mammary intraductal mouse model (MIND) for our studies. Three MCF7 cell variants, MCF7 WT, MCF7 Y537S and MCF7 D538G were injected into the mammary ducts of NSG mice. Cells were labeled with a luciferase reporter to monitor tumor growth by in vivo imaging. Mice were treated with different doses of lasofoxifene, vehicle, or the SERD, fulvestrant. After 70 days of treatment, primary tumor growth, as measured by endpoint tumor weight, of MCF7 WT, D538G and Y537S explants was significantly inhibited versus vehicle by 10 mg/kg lasofoxifene and fulvestrant. Compared to fulvestrant, lasofoxifene was significantly more effective at 5 and 10 mg/kg for the MCF7 Y537S and D538G tumors. Notably, the two MCF7 mutants metastasized to the lung and liver, whereas WT MCF-7 cells were only very weakly metastatic by the end of the study. Lasofoxifene significantly inhibited the metastasis of both MCF7 Y537S and D538G to the lungs and liver at 5 and 10 mg/ml. In contrast, fulvestrant only inhibited metastasis of the MCF7 D538G mutant to both organs. These data suggest that lasofoxifene may be useful as a treatment for ERα+ metastatic breast cancers, including those that express constitutively active ERα mutations.