The differential prognostic implications of PD-L1 expression in the outcomes of Filipinos with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors

Abstract

Background The tumor immune microenvironment influences tumor evolution in non-small cell lung cancer (NSCLC). Yet, the prognostic value of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor (EGFR)-mutant NSCLC remains controversial. Additionally, prognostic studies in Filipinos with EGFR-mutant NSCLC remain unexplored to this day. Methods We prospectively studied the outcomes of EGFR-mutant NSCLC in Filipino cohort, and retrospectively verified the survival trend using The Cancer Genome Atlas (TCGA) cohort. Kaplan-Meier method and generalized linear regression were used to assess survival. Expression and DNA methylation of cluster of differentiation 274 ( CD274 , gene that codes for PD-L1) were examined from TCGA tumor profiles. Pearson’s correlation was used to correlate PD-L1 expression with outcomes associated with occurrence of EGFR mutations, tyrosine kinase inhibitor (TKI) types, and programmed cell death protein 1 (PD-1) expression. Proteome network analysis was used to examine the correlation between drug resistance and PD-L1. Results PD-L1 positivity was associated with significantly longer progression-free survival (PFS; P=0.0096) but had a significantly contrasting influence in the overall survival (OS; P=0.0011). PD-L1 positivity (in both protein and RNA) was associated with longer median OS (mOS) in exon21 L858R, whereas, negativity was associated with longer mOS in exon19 deletion (exon19del). Stratification (high, low, negative) of PD-L1 expression lacked significant prognostic value (all P>0.05). PD-L1/ CD274 expression (P<0.05) and DNA methylation (P<0.001) vary significantly among NSCLC subtypes and in different disease stages. Erlotinib treatment produced the longest median progression-free survival (mPFS; 874 days) relative to other EGFR-TKIs (137–311 days). PD-L1 lacked a significant correlation with EGFR-TKIs. Consistent with the immune-regulation activities of PD-1, higher expression leads to relatively shorter mOS. PD-1 correlated positively with PD-L1 expression and occurrence of exon21 L858R. Conclusions PD-L1 differentially influenced the outcomes of Filipinos with EGFR-mutant NSCLC. NSCLC subtypes, disease stage, and PD-1 expression may impact the collective outcomes associated with PD-L1 and EGFR-sensitizing mutations.

NKX2‑1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non‑small cell lung cancer

“…The present study was conducted using clinical data from the Clinical Proteomics for Cancer Initiative program described elsewhere (Filipino cohort) ( 13 , 17 , 18 ); lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) data from The Cancer Genome Atlas (TCGA cohort) ( 19 ); and longitudinal lung cancer single-cell RNA-sequencing (scRNA-seq) project data (Bivona cohort) ( 20 ). All participants were confirmed as having NSCLC with either adenocarcinoma or squamous histology.…”

“…SJREB-2020-97). Blood and tissues samples were collected from recruited Filipino patients with NSCLC and were immediately processed for plasma testing, histopathological examination or cryopreservation at −80°C, as previously described ( 18 ). The specimens were tested for the presence of EGFR-sensitizing mutations using PCR, and assayed for PD-L1 and TTF-1 protein expression using IHC.…”