Association of Tumor Mutational Burden With DNA Repair Mutations and Response to Anti–PD-1/PD-L1 Therapy in Non–Small-Cell Lung Cancer

Young Kwang Chae*, Andrew A. Davis, Kirtee Raparia, Sarita Agte, Alan Pan, Nisha Mohindra, Victoria Villaflor, Francis Giles

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Purpose: To examine clinical predictors of tumor mutational burden (TMB), to explore the association between TMB and DNA repair mutations, and to analyze TMB as a biomarker for response to immune checkpoint blockade in non–small-cell lung cancer. Patients and Methods: TMB scores were determined retrospectively for 72 consecutive patients at our institution with next-generation sequencing comprehensive genomic profiling testing by Foundation Medicine. TMB scores were correlated with a number of clinical variables and presence of DNA repair mutations. Thirty-four patients were treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies, and survival analyses based on TMB score were performed. In addition, tissue immunohistochemical analysis was performed for a subset of patients. Results: History of smoking, but not other clinical variables, including prior treatment lines, stage of disease, and number of metastatic sites, predicted higher TMB score. Higher TMB score was significantly associated with greater number of DNA repair mutations. In the subset of patients treated with immune checkpoint blockade, higher TMB score significantly predicted overall survival, but not progression-free survival (hazard ratio = 0.10, P = .003; hazard ratio 1.1, P = .84, respectively). In a small subset of patients, PD-1/PD-L1 staining did not independently predict progression-free survival or overall survival. Conclusion: Tissue TMB was significantly associated with smoking history and number of DNA repair mutations. TMB is a promising biomarker for response to anti–PD-1/PD-L1 therapy, with higher TMB score predicting longer overall survival.

Original languageEnglish (US)
Pages (from-to)88-96.e6
JournalClinical Lung Cancer
Volume20
Issue number2
DOIs
StatePublished - Mar 2019

Keywords

  • Biomarker
  • Immunotherapy
  • NGS
  • NSCLC
  • TMB

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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