The landscape of tumor mutational burden and its clinical significance in patients with lung cancer: a Multi-omics study with a meta-analysis

Abstract

Background: Current research on tumor mutational burden (TMB) has focused on tumor immunotherapy responsiveness, but the role of TMB in non-immunotherapy patients is unclear. The purpose of this study is to explore the effect of TMB on lung cancer patients in order to clarify and expand the clinical significance of TMB in lung cancer.Methods: We download mutation data of lung cancer cases from The Cancer Genome Atlas (TCGA) database to analyze TMB and its composition, and study the relationship between TMB and clinicopathological characteristics of lung cancer patients. We then systematically retrieved and analyzed studies on the relationship between TMB and survival outcomes. The hazard ratio (HR) and its 95% confidence interval (CI) were used as an effective size to assess the survival outcomes. The subgroup analyses based on the pathological type, treatment method, TMB detection method and detection materials were also performed to explore the factors that might affect the interpretation of TMB results.Results: TMB in lung squamous cell carcinoma is lower than those in lung adenocarcinoma. In lung adenocarcinoma, patients with EGFR mutation have lower TMB than patients with EGFR wild-type. The summary analysis found that TMB is a better prognostic factor in small cell lung cancer, and more evident in small cell lung cancer receiving immunotherapy. TMB is a neutral or poor prognostic indicator in non-small cell lung cancer, but a better prognostic factor in non-small cell lung cancer receiving immunotherapy. In patients with lung adenocarcinoma, including those with EGFR mutation and receiving EGFR-targeted therapies, high TMB means worse survival. TMB detected by blood specimens is inconsistent and unstable compared to TMB detected by tissue. The clinical significance of TMB from blood specimens needs further study on extensive sample data.Conclusions: The pooled results indicated that TMB is a good prognostic factor in lung cancer patients receiving immunotherapy. But high TMB is connected with worse survival in non-small cell lung cancer without receiving immunotherapy, especially in lung adenocarcinoma. For lung adenocarcinoma patients with both EGFR mutation and high TMB, how to make a choice between EGFR-targeted therapy and immunotherapy is still a problem that requires further research.