Genomic alteration correlates with programmed cell death ligand 1 (PD-L1) expression in 2750 Chinese non-small-cell lung cancer patients.

Abstract

Background: This study sought to identify new biomarkers by examining genomic profiling and PD-L1 expression. While the PD-L1 and tumor mutational burden (TMB) are currently the main clinically available biomarkers for predicting immunotherapy response in non-small-cell lung cancer (NSCLC), the factors that affect PD-L1 expression remain unclear.

Materials and methods: This retrospective study included tumor and blood samples from 2750 Chinese patients with NSCLC who had successful PD-L1 assessments and targeted next-generation sequencing. Clinicopathological characteristics and genomics profile were analyzed. TMB was categorized as high (TMB-H) if there were ≥ 10 mutations per megabase. PD-L1 expression was classified into three groups: PD-L1-negative, PD-L1-low, and PD-L1-high. In addition, genomic data, and immune checkpoint inhibitor (ICI) outcomes for 197 NSCLC patients were obtained from the MSK2020 cohort.

Results: This study included a total of 2750 NSCLC cases. Tumors with high PD-L1 expression were more commonly observed in males and exhibited a higher median TMB. Significant differences in gene mutation frequencies were observed among the different PD-L1 expression groups. Significant differences in mutation frequencies were observed in PD-L1 expression subgroups for the EGFR, TP53, LRP1B, KRAS, SPTA1, and PTPRD genes. Notably, TP53 and KRAS alterations were significantly enriched in PD-L1-high subgroup, while EGFR mutations were associated with PD-L1 negativity. Patients in the PD-L1-high group showed notably improved progression-free survival (PFS) and overall survival (OS) compared to those in the PD-L1-low and negative groups. Further analysis of the combined impact of PD-L1 expression and TMB revealed that the PD-L1-negative/TMB-low subgroup had significantly shorter PFS and OS compared to the other subgroups. This indicates that a composite biomarker combining PD-L1 expression and TMB provides superior predictive value for favorable ICI outcomes.

Conclusions: This study indicates that PD-L1 expression levels are significantly associated with specific genomic alterations and clinical outcomes in patients with NSCLC. Particularly in evaluating the efficacy of ICI therapy, the combined biomarker of PD-L1 and TMB shows important clinical application value.