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

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

doi:10.3389/fonc.2020.00342

Abstract

Introduction: Mutations in the ESR1 gene (ESR1m) 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 ESR1m 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 ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy.Methods: 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 ESR1m.Results: 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. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET.Discussion: Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m 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.

Highlights

Mutations in the ESR1 gene (ESR1m) 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
Regardless of the extensive research that is being conducted in this field, several questions remain unanswered about ESR1 mutations (ESR1m), such as whether it is associated with endocrine resistance to aromatase inhibitors (AIs) used with a curative intent treatment in theadjuvant setting
Our study reports that differently than in AI-resistant metastatic breast cancer, ESR1m are not a common mechanism of resistance in tumors with primary endocrine resistance in the neoadjuvant setting

Summary

Introduction

Mutations in the ESR1 gene (ESR1m) 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. We evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy. Breast tumors are known to undergo genomic evolution, and ESR1 mutations (ESR1m) have been identified in 9–40% of patients with metastatic ER+ breast cancer resistant to aromatase inhibitors (AIs) [3,4,5,6,7]. Regardless of the extensive research that is being conducted in this field, several questions remain unanswered about ESR1m, such as whether it is associated with endocrine resistance to AIs used with a curative intent treatment in the (neo)adjuvant setting

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