Abstract 657: ESR1 mutations abundance in local recurrence of endocrine-treated breast cancer
Authors: Zundelevich Adi , Dadiani Maya , Kahana-Edwin Smadar , Gadot Moran , Sela Tal , Marin Irina , Necula Daniela , Pavlovsky Anya , Barshack Iris , Kaufman Bella , Gal-Yam Einav N. 
Published: August 2018

Abstract
Emerging mutations in the ESR1 gene that encodes for estrogen receptor (ER) have been recently associated with resistance to endocrine therapy in ER positive metastatic breast cancer patients. These mutations promote the active conformation of the receptor, conferring resistance to endocrine therapy, and were associated with shorter progression free survival. ESR1 mutations were found to rarely exist in primary tumors (~1%) but are relatively common in metastatic, endocrine therapy-resistant lesions, with an estimated prevalence of ~10-50%. Nevertheless, not much is known about the incidence of these mutations in local recurrence (breast and adjacent lymph nodes) and its clinical significance. The objective of this study is to determine the prevalence of ESR1 mutations in local recurrence of endocrine-treated breast cancer patients. To this end, we collected a cohort of breast cancer patients that had at least one local or loco-regional recurrence during or after adjuvant endocrine treatment for primary breast cancer. We analyzed the 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) using droplet digital PCR technology in 44 samples from 34 patients (some of the patients had more than one recurrence). ESR1 mutations were identified in 10/34 (29%) patients. Specifically, mutations were distributed between D538G (5/34), Y537S+ D538G (4/34) and L536R (1/34). ESR1 Mutations developed after or on Tamoxifen only treatment in 50% of the positive patients (5/10 patients) and after or on Tamoxifen + Aromatase Inhibitor (AI) treatment in the other 50% (5/10 patients). Notably, one patient developed ESR1 mutation while on neoadjuvant endocrine therapy. ESR1 mutations persisted in local recurrence samples of mutation positive patients that had more than one local recurrence and the chance of detecting a mutation in patients that had more than one recurrence was higher than in those with a single recurrence. This study demonstrates that ESR1 mutations are common in local recurrence of hormone receptor positive breast cancer. Further studies to establish the clinical significance of these mutations and their impact on survival are underway. Since local recurrences are amenable to curative therapy, the identified unexpected high prevalence of ESR1 mutations at this stage of the disease may have important consequences for choosing the optimal adjuvant treatment option for these patients.
Citation Format: Adi Zundelevich, Maya Dadiani, Smadar Kahana-Edwin, Moran Gadot, Tal Sela, Irina Marin, Daniela Necula, Anya Pavlovsky, Iris Barshack, Bella Kaufman, Einav N. Gal-Yam. ESR1 mutations abundance in local recurrence of endocrine-treated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 657.