Abstract ES10-1: Recurrent ESR1 mutations activating mutations in breast cancer

Abstract

Abstract Endocrine treatments are the cornerstone treatments in estrogen receptor positive (ER+) breast cancer. Despite their efficacy, resistance to endocrine treatments remains an important clinical challenge. A number of years ago, recurrent estrogen receptor ligand binding domain (LBD) mutations were identified as the most common genomic mechanism of acquired resistance to endocrine treatment in metastatic breast cancer. These mutations were found in about 20% of ER+ metastatic tissue specimens and in more than 30% of patients with metastatic ER+ breast cancer when testing circulating tumor DNA. Pre-clinical studies showed that these mutations lead to constitutional ligand independent transcriptional activity and tumor growth. Recently, we showed that the ER mutations have neomorphic properties that promote metastases. Clinical data, derived mainly from retrospective analyses of clinical trials, indicate that the ER mutations confer resistance to aromatase inhibitors and fulvestrant, and decreased overall survival. A recent study also showed that the Y537S LBD ER mutation is acquired during fulvestrant and palbociclib treatment. Collectively, the ER mutations are important drivers of resistance standard endocrine treatments and confer worse outcomes in ER+ metastatic breast cancer. Clinical trials stratifying patients by ER mutant status or dedicated to patients with the ER mutations are needed to identify therapeutic strategies to target these mutations. Citation Format: Jeselsohn R. Recurrent ESR1 mutations activating mutations in 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 ES10-1.