Analysis of tumor mutational burden and mutational landscape comparing whole-exome sequencing and comprehensive genomic profiling in patients with resectable early-stage non-small-cell lung cancer

Background: Identifying actionable driver mutations via tissue-based comprehensive genomic profiling (CGP) is paramount in treatment decisions for metastatic non-squamous, non-small-cell lung cancer (NSCLC). However, the role of CGP remains elusive in resectable NSCLC. Here, we elucidate the feasibility of CGP in early-stage NSCLC Korean patients and compare the tumor mutational burden (TMB) and mutation landscape using three different platforms.

Methods: All surgically resected NSCLC samples (N = 96) were analyzed to assess the concordance in TMB calculation and targetable mutations using whole-exome sequencing (WES) and TruSight Oncology 500 (TSO500). In all, 26 samples were analyzed with Foundation One CDx Assay (F1CDx). Programmed death-ligand 1 (PD-L1) expression was evaluated using Vectra Polaris.

Results: Stage distribution post-surgery was 80% I (N = 77) and 20% II (N = 19). Ninety-nine percent (N = 95) were adenocarcinoma. The median TMB with WES and TSO500 was 1.6 and 4.7 mut/Mb, respectively (p < 0.05). Using all three platforms, the median TMB was 1.9, 5.5, and 4 mut/Mb for WES, TSO500, and F1CDx, respectively (p = 0.0048). Linear regression analysis of TMB values calculated between WES and TSO500 resulted in a concordance correlation coefficient of 0.83. For the PD-L1 tumor proportion score of <1% (negative, N = 18), 1-49% (low, N = 68), and ⩾50% (high, N = 10), the R² values were 0.075, 0.79, and 0.95, respectively. The R² values for TMB concordance were variable between the three platforms. Mutation landscape revealed EGFR mutation (51%, N = 49) as the most common actionable driver mutation, comprising L858R (N = 22), E19del (N = 20), and other non-common EGFR mutations (N = 7).

Conclusion: TSO500 and F1CDx showed robust analytical performance for TMB assessment with TSO500 showing stronger concordance of TMB with high PD-L1 expression. As the paradigm for the management of early-resected NSCLC continues to evolve, understanding TMB and the mutation landscape may help advance clinical outcomes for this subset of patients.