Clinicopathological and molecular parameters of lung adenocarcinomas (ADC) associated with programmed cell death ligand 1 (PD-L1) protein expression.

Abstract

7555 Background: Recent efforts in targeting the PD-1/PD-L1 pathway in solid tumors have resulted in durable responses in early phase clinical trials. Additionally, it has been reported that PD-L1 overexpression by immunohistochemistry (IHC) could serve as a predictor of patient response to anti-PD-1/PD-L1 therapies. However, the association of clinicopathological and molecular features with PD-L1 expression in ADC is not well-defined. Methods: PD-L1 (E1L3N, Cell Signaling Technology) and CD8 IHC were performed on tissue microarrays of 242 resected ADC that underwent detailed histological analysis. Clinical molecular testing had been performed in a subset (n = 128). Membranous expression of PD-L1 (any intensity) in 5% or more tumor cells was defined as positive. CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). PD-L1 expression was correlated with clinicopathological and molecular features as well as prognosis. Results: Pathologic stage was 0 in 1, I in 188, II in 37, III in 9, and IV in 7. Of the 242 cases, 38 (15.7%) exhibited PD-L1 expression which was significantly associated with smoking history (p = 0.008), large tumor size (p = 0.007), solid or acinar predominant pattern (p < 0.001), high nuclear grade (grade 3, p < 0.001), vascular invasion (p = 0.012), increased CD8+ TILs (grade 2-3, p < 0.001), and KRAS mutations (p = 0.001). By multivariate analysis high nuclear grade (p = 0.011), KRASmutations (p = 0.004), and increased CD8+ TILs (p = 0.005) remained significant. In addition, advanced stage (II or higher vs. I, p = 0.056) had a borderline significance of PD-L1 expression. There was no difference in 5 year progression-free survival (PFS) for PD-L1 positive (65%) and negative (69%) patients, while advanced stage correlated with shorter PFS (p = 0.039) in a cox proportional-hazards regression model. Conclusions: PD-L1 overexpression is significantly associated with increased CD8+ TILs and KRAS mutations in resected ADC. The latter suggests that targeting the PD-1/PD-L1 pathway may be a viable treatment option for patients with KRAS mutated ADC in which there are currently no effective targeted therapies available.