The standard of care for early postmenopausal ERα+ breast cancer patients is adjuvant endocrine therapy, typically an aromatase inhibitor or tamoxifen, and endocrine therapy with or without a CDK 4/6 inhibitor in the metastatic setting. However, a number of these patients are not sensitive to endocrine therapy or experience breast cancer recurrence 10 to 15 years after endocrine treatment, and all eventually progress in the metastatic setting. Metastasis of ER+ therapy-resistant breast cancer correlates with the acquisition of ESR1 activating mutations in up to 40% or more of affected patients. The two most common ERα mutations are Y537S and D538G, both of which confer ERα constitutive activity. Lasofoxifene is a SERM originally developed to treat vulvovaginal atrophy and osteoporosis. In this study, we analyzed the efficacy of lasofoxifene in the treatment of MCF7 tumor explant models that were engineered with CRISPR/Cas9 to express Y537S or D538G ERα. To better mimic the natural micro-environment of infiltrating ductal breast cancer, we used the mammary intraductal mouse model (MIND), in which tumor cells are introduced into the ducts via the nipple. Three MCF7 cell variants, MCF7 WT, MCF7 Y537S and MCF7 D538G were injected into the mammary ducts of NSG mice. Prior to injection, cells were labeled with a luciferase reporter to monitor tumor growth in vivo using a Xenogen IVIS imager. Mice were treated with three different doses of lasofoxifene (1, 5 and 10mg/kg; 5days/wk SQ), vehicle, or the SERD, fulvestrant, (5 mg SQ once per week = 250 mg/kg). 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. In a follow-up combination therapy study of MCF-7 WT and Y537S tumor explants, in which mice were co-treated with either fulvestrant and palbociclib or lasofoxifene and palbociclib, lasofoxifene plus palbociclib demonstrated a better outcome than fulvestrant and palbociclib in terms of primary tumor weight inhibition. Results for lung and liver metastasis inhibition are forthcoming. In conclusion, these data suggest that lasofoxifene may have the potential to be utilized as a treatment for metastatic breast cancers, including those that express constitutively active ERα mutations, including D538G and Y537S, and warrants further study.

Citation Format: Laine M, Greene M, Chang Y-F, Phung L, Hiipakka R, Komm B, Greene GL. Lasofoxifene decreases breast cancer lung and liver metastasis in a mammary intraductal (MIND) xenograft model of mutant ERα+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-09.