AUTHOR=Reinert Tomás , Ramalho Susana , de Vasconcelos Vivian Castro Antunes , Silva Leonardo Roberto , da Silva Ana Elisa Ribeiro , de Andrade Camila Annicchino , Kraft Maria Beatriz de Paula Leite , Coelho Guilherme Portela , Mandelli Jovana , Binotto Monique , Cabello Cesar , Paiva Silva Geisilene Russano de , Bines José , Barrios Carlos H. , Ellis Matthew J. , Graudenz Marcia Silveira 

TITLE=ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor–Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00342

DOI=10.3389/fonc.2020.00342

ISSN=2234-943X

ABSTRACT=<p><bold>Introduction:</bold> Mutations in the <italic>ESR1</italic> gene (<italic>ESR1</italic>m) are important mechanisms of resistance to endocrine therapy in estrogen receptor–positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of <italic>ESR1</italic>m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of <italic>ESR1</italic>m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy.</p><p><bold>Methods:</bold> We followed a prospective cohort of patients with ER+ HER2– stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of <italic>ESR1</italic>m.</p><p><bold>Results:</bold> One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. <italic>ESR1</italic> mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET.</p><p><bold>Discussion:</bold> Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that <italic>ESR1</italic> mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, <italic>ESR1</italic>m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET.</p>