Body Mass Index Influences the Salutary Effects of Metformin on Survival After Lobectomy for Stage I NSCLC

J Thorac Oncol. 2019 Dec;14(12):2181-2187. doi: 10.1016/j.jtho.2019.07.020. Epub 2019 Aug 6.

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/m2 and ≤25 kg/m2). 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.

Keywords: Diabetes; Lung cancer; Metformin; Survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Body Mass Index*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Female
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Pneumonectomy / methods*
  • Survival Analysis

Substances

  • Hypoglycemic Agents
  • Metformin