Abstract P1-09-01: ESR1 mutations confer radiation resistance in breast cancer

Background: Acquired mutations in oncogenic drivers in response to systemic therapies is a common mechanism of treatment resistance. How such mutations alter response to radiation therapy is poorly understood. The increasing adoption of radiation therapy in the treatment of oligometastatic disease further amplifies the need to define the role of such mutations in modifying response to radiation therapy. Over 70% of breast cancers are Estrogen Receptor (ER)-positive. Endocrine therapies, which block ER signaling, are the mainstay in the treatment of such cancers. Acquired mutations in the gene encoding for ER (ESR1) are a common mechanism of acquired resistance to endocrine therapies in metastatic breast cancer. 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. Methods: To test if ESR1 mutations influence response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knockin two of the most common ESR1 mutations found in breast cancer patients (Y537S and D538G). Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. γ-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. Results: 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. Mice harboring ESR1 mutant xenografts showed remarkable resistance to radiation therapy. Conclusion: ESR1 mutations, which confer resistance to endocrine therapies, also confer profound resistance to radiation therapy. ESR1 mutations have been primarily reported in metastatic ER-positive breast cancer patients with prior history of treatment with endocrine therapies. 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. Finally, 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: Nashir Udden, Qian Wang, Prasanna G Alluri. ESR1 mutations confer radiation resistance in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-09-01.