Abstract 4370: Lasofoxifene alone or in combination with palbociclib as an effective treatment for therapy-resistant ER-positive metastatic breast cancer

Patients with Estrogen Receptor positive (ER+) metastatic breast cancer (MBC) are currently treated with fulvestrant, a selective estrogen receptor degrader (SERD), or a combination of fulvestrant and palbociclib, a CDK4/6 inhibitor. Approximately 25-40% of patients with MBC have activating mutations in the ERα ligand-binding domain. The two most common mutations are Y537S and D538G, which confer constitutive activity to ERα, resulting in AI/tamoxifen/fulvestrant resistance. Lasofoxifene, a selective estrogen receptor modulator (SERM), was developed for the treatment of vaginal atrophy and osteoporosis. Previous studies from this lab, performed in a mutant ERα MCF-7 xenograph MBC mouse model, showed that lasofoxifene was significantly more effective than fulvestrant at inhibiting tumor growth, as well as metastasis to the lung and liver. In the current dose/response study, we compared the efficacy of lasofoxifene + palbociclib combinations to fulvestrant + palbociclib combinations. Engineered and luciferase-GFP tagged MCF-7 Y537S cells were injected into the mammary ducts of NSG mice (MIND model) and tumor progression was monitored by live luminescence imaging of primary tumors as well as ex vivo imaging of metastatic sites at study endpoint. Our results showed that all dose combinations of lasofoxifene + palbociclib were more effective than fulvestrant + palbociclib at inhibiting primary tumor growth as well as bone, lung, liver and brain metastasis. These data strongly suggest that patients with ERα+ MBC would benefit from orally delivered lasofoxifene + palbociclib therapy and that this combination could be superior to fulvestrant + palbociclib. Citation Format: Muriel Laine, Justyna D. Kurleto, Marianne E. Greene, Linda Phung, Barry S. Komm, Geoffrey L. Greene. Lasofoxifene alone or in combination with palbociclib as an effective treatment for therapy-resistant ER-positive metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4370.