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

Abstract

<b>Background:</b> The minor allele (<i>C</i>) of the single-nucleotide polymorphism (SNP) <i>rs11212617</i>, located near the <i>ataxia telangiectasia mutated</i> (<i>ATM</i>) 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). <b>Methods:</b> 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 <i>rs11212617</i> genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction. <b>Results:</b> Logistic regression analyses revealed a significant relationship between the <i>rs11212617</i> 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, <i>p</i> = 0.028). In the metformin-containing arm, patients bearing the <i>rs11212617 C</i> allele had a significantly higher probability of pCR (OR _{<i>A</i>/<i>C,C</i>/<i>C</i>} = 7.94, 95%CI: 1.60-39.42, <i>p</i> = 0.011). Conversely, no association was found between <i>rs11212617</i> and clinical response in the reference arm (OR _{<i>A</i>/<i>C,C</i>/<i>C</i>} = 0.77, 95%CI: 0.20-2.92, <i>p</i> = 0.700). After controlling for tumor size and hormone receptor status, the <i>rs11212617 C</i> allele remained a significant predictor of pCR solely in the metformin-containing arm. <b>Conclusions:</b> If reproducible, the <i>rs11212617 C</i> allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients. <b>Trial Registration:</b> EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.