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

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 (OR _A/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 (OR _A/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.

SUBMITTER: Cuyas E

PROVIDER: S-EPMC6447648 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Cuyàs Elisabet E Buxó Maria M Ferri Iglesias Maria José MJ Verdura Sara S Pernas Sonia S Dorca Joan J Álvarez Isabel I Martínez Susana S Pérez-Garcia Jose Manuel JM Batista-López Norberto N Rodríguez-Sánchez César A CA Amillano Kepa K Domínguez Severina S Luque Maria M Morilla Idoia I Stradella Agostina A Viñas Gemma G Cortés Javier J Joven Jorge J Brunet Joan J López-Bonet Eugeni E Garcia Margarita M Saidani Samiha S Queralt Moles Xavier X Martin-Castillo Begoña B Menendez Javier A JA

Frontiers in oncology 20190328

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 inte ...[more]

PMID: 30984619

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Project description:BackgroundTo summarize the chemo-radio effect of metformin in rectal cancers with neoadjuvant chemoradiotherapy on pathological response, tumor regression grade (TRG), and T/N downstaging.MethodsPubMed, MEDLINE, Embase, and Cochrane Database of collected reviews were searched up to June 30, 2022. This study conducted systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sheet. Odds ratios (ORs) and confidence intervals (CIs) which calculated by random-effects models were displayed in forest plots. Newcastle-Ottawa scale was used to assess the risk of bias of the observational cohort studies.ResultsThis systematic review and meta-analysis comprised eight cohorts out of seven studies, with 2294 patients in total. We performed two-way comparison for metformin in diabetic patients vs (1) non-metformin drugs in diabetic patients and (2) nondiabetic patients. In diabetes patient studies, the metformin group had a significantly increased pathological response on TRG (OR: 3.28, CI: 2.01-5.35, I2 = 0%, p < 0.001) and T downstaging (OR: 2.14, CI: 1.24-3.67, I2 = 14%, p = 0.006) in comparison with a non-metformin group. When compared with nondiabetic patients, the pathological response on TRG (OR: 2.67, CI: 1.65-4.32, I2 = 43%, p < 0.001) and T downstaging (OR: 1.96, CI: 1.04-3.71, I2 = 66%, p = 0.04) were also higher in metformin group. The limitation was that no randomized controlled trials were available based on current literature review. Small sample sizes for diabetic metformin or non-metformin users in rectal cancer patients reduced the power of the study.ConclusionsFor patients with rectal cancer and treated with neoadjuvant chemoradiotherapy, metformin administration in diabetic patients increased the pathological response on tumor-regression grade and T downstaging. Further well-designed, high-quality randomized controlled trials are required to reveal the actual effect of metformin.

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

Publications

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

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