The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin.

Elisabet Cuyàs,Norberto Batista-López,Idoia Morilla,Samiha Saidani,Sara Verdura,Joan Brunet,Gemma Viñas,Eugeni López-Bonet,Jorge Joven,Javier A Menendez,Severina Domínguez,Isabel Álvarez,Joan Dorca,Javier Cortés,Susana Martínez,Agostina Stradella,Kepa Amillano,Begoña Martin-Castilló ,César Augusto Rodríguez-Sánchez ,María Buxó ,María José Ferri ,Margarita García ,Xavier Queralt Molés ,M Luque ,Sònia Pernas ,José Manuel Pérez-García

doi:10.3389/fonc.2019.00193

Abstract

Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC).Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction.Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29–82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (ORA/C,C/C = 7.94, 95%CI: 1.60–39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (ORA/C,C/C = 0.77, 95%CI: 0.20–2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm.Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients.Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.

Highlights

The minor allele C of the noncoding single nucleotide polymorphism (SNP) rs11212617, which is located near the ataxia telangiectasia mutated (ATM) gene, was found to be associated with the metabolic response to the biguanide metformin in the first genome-wide association study (GWAS) carried out in 3,912 Europeans with type 2 diabetes (T2D) [1]
This is the first prospective study evaluating the relationship between the ATM SNP rs11212617 C allele, which has been associated with an increased likelihood of metformin treatment success in T2D [1, 3, 5], and the clinical benefit of adding metformin to well-established neoadjuvant treatment regimens in breast cancer patients
Because greater benefits from HER2-targeted neoadjuvant treatment in breast cancer are achieved in patients with small hormone receptor (HR)-negative tumors compared with patients with large HRpositive tumors [25], it is noteworthy that the capacity of the ATM rs11212617 C allele to predict a higher chance of achieving a pathological complete response (pCR) in patients treated with neoadjuvant metformin was not altered after accounting for factors like tumor size and HR status

Summary

Introduction

The minor allele C of the noncoding single nucleotide polymorphism (SNP) rs11212617, which is located near the ataxia telangiectasia mutated (ATM) gene, was found to be associated with the metabolic response to the biguanide metformin in the first genome-wide association study (GWAS) carried out in 3,912 Europeans with type 2 diabetes (T2D) [1]. Rs11212617 remained a top signal with no other genome-significant hits in a more recent GWAS of 13,123 participants of different ancestries, but failed to associate with glycemic response to metformin in a systematic threestage replication study [4]. The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC)

Methods

Results

Discussion

Conclusion