High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

SIMPLE SUMMARY: Tumor mutation burden (TMB) represents the mutational load in the tumor cell genome and serves as a surrogate marker for tumor neoantigen production and potential immunogenicity. TMB has been widely explored as a complementary or alternative biomarker for immune checkpoint inhibitors in various malignancies including lung cancer. However, its clinical implication in the targeted-therapy setting is scarcely investigated. This study demonstrates that high TMB is independently associated with poor progression-free and overall survivals, and a low frequency of secondary T790M mutation in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma that are treated with tyrosine kinase inhibitors (TKIs). To the best of our knowledge, this is the first study demonstrating the significant association between the TMB level and resistance pattern after TKI failure. ABSTRACT: This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients’ subgroup warranting tailored therapeutic approaches.