AUTHOR=Cuyàs Elisabet , Buxó Maria , Ferri Iglesias Maria José , Verdura Sara , Pernas Sonia , Dorca Joan , Álvarez Isabel , Martínez Susana , Pérez-Garcia Jose Manuel , Batista-López Norberto , Rodríguez-Sánchez César A. , Amillano Kepa , Domínguez Severina , Luque Maria , Morilla Idoia , Stradella Agostina , Viñas Gemma , Cortés Javier , Joven Jorge , Brunet Joan , López-Bonet Eugeni , Garcia Margarita , Saidani Samiha , Queralt Moles Xavier , Martin-Castillo Begoña , Menendez Javier A. 

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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00193

DOI=10.3389/fonc.2019.00193

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> The minor allele (<italic>C</italic>) of the single-nucleotide polymorphism (SNP) <italic>rs11212617</italic>, located near the <italic>ataxia telangiectasia mutated</italic> (<italic>ATM</italic>) 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).</p><p><bold>Methods:</bold> 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 <italic>rs11212617</italic> genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction.</p><p><bold>Results:</bold> Logistic regression analyses revealed a significant relationship between the <italic>rs11212617</italic> genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]<sub>genotype×arm</sub> = 10.33, 95% confidence interval [CI]: 1.29–82.89, <italic>p</italic> = 0.028). In the metformin-containing arm, patients bearing the <italic>rs11212617 C</italic> allele had a significantly higher probability of pCR (OR<sub><italic>A</italic>/<italic>C,C</italic>/<italic>C</italic></sub> = 7.94, 95%CI: 1.60–39.42, <italic>p</italic> = 0.011). Conversely, no association was found between <italic>rs11212617</italic> and clinical response in the reference arm (OR<sub><italic>A</italic>/<italic>C,C</italic>/<italic>C</italic></sub> = 0.77, 95%CI: 0.20–2.92, <italic>p</italic> = 0.700). After controlling for tumor size and hormone receptor status, the <italic>rs11212617 C</italic> allele remained a significant predictor of pCR solely in the metformin-containing arm.</p><p><bold>Conclusions:</bold> If reproducible, the <italic>rs11212617 C</italic> allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients.</p><p><bold>Trial Registration:</bold> EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, <ext-link ext-link-type="uri" xlink:href="https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES</ext-link>.</p>