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 .

Impact of Metformin on Cancer Biomarkers in Non-Diabetic Cancer Patients: A Systematic Review and Meta-Analysis of Clinical Trials

“…Table 1 indicates the characteristics of the included studies. The selected studies were performed in Italy [ 10 , 19 ], USA [ 20 , 21 ], Great Britain [ 22 , 23 ], Canada [ 13 , 24 ], and Spain [ 25 ]. The sample size was 1047 participants in metformin treatment and control groups, and their age ranged from 42 to 77 years.…”

“…Seven studies assessed the impact of metformin compared to placebo prescribed to breast cancer, and two studies evaluated the impact of metformin in a patient with endometrial cancer. Eight studies indicated the effect of metformin on the insulin levels [ 10 , 13 , 20 , 21 , 22 , 23 , 24 , 25 ], six studies on FBS [ 10 , 20 , 21 , 23 , 24 , 25 ], five on HOMA-IR [ 19 , 20 , 23 , 24 , 25 ], eight on BMI [ 10 , 13 , 19 , 20 , 21 , 22 , 23 , 24 ], and seven on Ki-67 [ 10 , 13 , 19 , 20 , 22 , 23 , 24 ].…”

“…The quality of the evaluation of the articles has been shown in Table 2 . Five RCTs reported information on the generation of random sequence with low bias [ 10 , 13 , 19 , 20 , 22 , 24 , 25 ]. Four studies did not show any concealment of the assignment [ 21 , 22 , 23 , 24 ].…”

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients

“…Nevertheless, the ever-growing number of individual clinical trials (>300) investigating metformin in the treatment of various types of cancer has highlighted a need for more rigorous planning to focus on potential predictive biomarkers [65]. Along this line, we have recently proposed that the minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated gene, might warrant consideration as a predictive clinical biomarker to inform the personalized used of metformin in breast cancer patients [66]. In contrast to predictive biomarkers, which attempt to a priori predict the likelihood to respond to a particular treatment from the properties of the tumor, pharmacodynamic biomarkers provide a post-treatment measure of whether a given drug has reached its target, exerted a pharmacological response, and the degree of such response [67].…”

Association between ABC family variants rs1800977, rs4149313, and rs1128503 and susceptibility to type 2 diabetes in a Chinese Han population

“…Single nucleotide polymorphisms (SNP) are one of the most common human genetic variations, accounting for more than 90% of all known polymorphisms, and hundreds have been found to be associated with T2DM. 4 , 5 However, reported studies only explain some of the causes of T2DM, and further investigation is needed to fully understand the relationship between SNPs and T2DM.…”