Abstract
INTRODUCTION: Metformin, a common medication used in the treatment of diabetes mellitus is known to have anticancer effects. We hypothesized that the salutary effect of metformin on the survival of patients with stage I NSCLC is influenced by body mass index (BMI). METHODS: Patients undergoing lobectomy for stage I NSCLC without neoadjuvant therapy were included. Univariate and multivariate survival analyses to examine the association between metformin use and overall survival (OS), disease-specific survival (DSS), and recurrence-free survival were performed, stratified by BMI (>25 kg/m(2) and ≤25 kg/m(2)). Expression of immune checkpoints in patients on metformin and not was performed in a separate cohort of 205 patients with advanced disease. RESULTS: Four hundred thirty-four stage I patients (including 74 metformin users) were deemed eligible for analysis. Univariate and multivariate analysis revealed an association between metformin use and OS (hazard ratio [HR] = 0.52; p = 0.04) as well as DSS (HR = 0.21; p = 0.04) but not recurrence-free survival (HR = 0.67; p = 0.33) in high-BMI patients only. In a separate cohort of 205 patients with tumors of all stages (including 35 metformin users), downregulation of immune checkpoint gene expression (programmed cell death 1, cytotoxic T-lymphocyte associated protein 4, B and T lymphocyte associated, CD27 molecule, lymphocyte activating 3, and inducible T cell costimulator) in metformin users was seen only in high-BMI patients, with upregulation of these genes seen in low-BMI patients with metformin use. CONCLUSIONS: Metformin use may be associated with better OS and DSS only in high-BMI patients. This hypothesis is supported by gene expression data of immune checkpoint genes in metformin users using a separate cohort of advanced-stage tumors. Further studies examining the interaction of BMI with metformin in NSCLC are worthwhile.