PD‐L1 Expression in Non‐Small Cell Lung Cancer Specimens: Association with Clinicopathological Factors and Molecular Alterations

Immune checkpoint inhibitors (ICI) targeting programmed cell death‐1 or its ligand (PD‐ L1) have improved outcomes in non‐small cell lung cancer (NSCLC). High tumor PD‐L1 expression, detected by immunohistochemistry (IHC) typically on formalin‐fixed paraffin‐embedded (FFPE) histological specimens, is linked to better response. Following our previous investigation on PD‐L1 in cytological samples, the aim of this study was to further explore the potential impacts of various clinicopathological and molecular factors on PD‐L1 expression. Two retrospective NSCLC cohorts of 1131 and 651 specimens, respectively, were investigated for PD‐L1 expression (<1%/1– 49%/≥50%), sample type, sample site, histological type, and oncogenic driver status. In both cohorts, PD‐L1 was positive (≥1%) in 55% of the cases. Adenocarcinomas exhibited lower PD‐L1 expression than squamous cell carcinomas (p < 0.0001), while there was no difference between sample types, tumor locations, or between the two cohorts in multivariate analysis (all p ≥ 0.28). Mutational status correlated significantly with PD‐L1 expression (p < 0.0001), with the highest expression for KRASmutated cases, the lowest for EGFR‐mutated, and the KRAS/EGFR wild‐type cases in between. There was no difference in PD‐L1 levels between different prevalent KRAS mutations (all p ≥ 0.44), while mucinous KRAS‐mutated adenocarcinomas exhibited much lower PD‐L1 expression than non‐mucinous (p < 0.0001). Our data indicate that cytological and histological specimens are comparable for PD‐L1 evaluation. Given the impact of KRAS mutations and the mucinous growth pattern on PD‐L1 expression, these factors should be further investigated in studies on ICI response.