Abstract 797: Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation

Abstract

Abstract Acquired mutations in ESR1 gene that encodes for Estrogen Receptor (ER) are a common mechanism of acquired resistance to endocrine therapies in breast cancer. However, the role of such mutations in modulation of cell’s response to radiation therapy is poorly understood. In this study, we define the role of ESR1 mutations in altering response to radiation therapy in pre-clinical models of ER-positive breast cancer. To investigate whether ESR1 mutations influence cell’s response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knock-in two of the most common ESR1 mutations, such as Y537S and D538G, found in breast cancer patients. Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. g-H2AX and Comet assays were employed to study the differences in residual unrepaired DNA damage following radiation in these cell lines. MCF7 cell line-derived xenografts harboring the wild type or mutant ESR1 were employed to study differences in radiation resistance of these tumors in vivo. We found that ER-positive cell lines harboring ESR1 mutations exhibited profound resistance to radiation therapy compared to cell lines harboring the wild type ESR1. These radioresistant cell lines also demonstrated significantly less unrepaired DNA damage following radiation therapy. We observed that mice harboring ESR1 mutant xenografts showed remarkable resistance to radiation therapy. We also observed that ESR1 mutations, which confer resistance to endocrine therapies, also confer profound resistance to radiation therapy. Our findings suggest that oligometastatic ER-positive breast cancer patients who are being treated with radiation therapy (such as those enrolled in NRG BR002 trial) may show significant differences in response to radiation therapy based on their ESR1 mutation status. Recent studies are also exploring the use of neo-adjuvant endocrine therapy in non-metastatic ER-positive breast cancer patients. It is conceivable that some of these patients may acquire ESR1 mutations under selective pressure of neoadjuvant endocrine therapy and may respond poorly to subsequent adjuvant radiation therapy. Overall, our findings support potential personalization of radiation treatments in breast cancer patients based on ESR1 mutation status, heralding an era of precision radiation oncology. Citation Format: S. M. Nashir Udden, Prasanna G. Alluri. Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 797.