The Role of PD-L1 in Treatment Decision-Making for Perioperative EGFR-Mutated Lung Cancer and its Genomic Analysis

BACKGROUND: Epidermal growth factor receptor-mutated (EGFR-M+) non-small-cell lung cancer (NSCLC) represents a substantial proportion of lung cancer and remains associated with a considerable risk of postoperative recurrence despite advances in targeted therapies. The role of programmed death-ligand 1 (PD-L1) expression in the perioperative treatment of EGFR-M+ NSCLC remains controversial. The gene mutation landscape of PD-L1 in EGFR-M+ NSCLC and its relationship with prognosis remain poorly understood. METHODS: We retrospectively included patients with EGFR-M+ NSCLC, including 43 patients with stage IB-IV disease who underwent immunotherapy combined with chemotherapy followed by surgery (NeoGroup) and 499 patients with stage IB-III disease undergoing surgery (AdjGroup). Disease-free survival, radiological response, pathological response, clinicopathological factors, and genomic characteristics were analyzed to evaluate their associations with PD-L1 tumor proportion score (TPS). RESULTS: The NeoGroup had objective response, pathological complete response, and major pathologic response rates of 44.2%, 18.6%, and 41.9%, respectively. A higher frequency of PD-L1 TPS ≥1% at baseline correlated with better radiological responses. Patients who had a major pathologic response also had a greater increase in PD-L1 TPS from baseline after therapy (P = 0.0195). In the AdjGroup (N = 499), PD-L1 TPS ≥50% independently predicted shorter disease-free survival. Patients with PD-L1 ≥1% more frequently harbored TP53 co-mutations and had poorer survival in external cohorts. CONCLUSION: PD-L1 plays a dual role in perioperative EGFR-M+ NSCLC, indicating higher recurrence risk after surgery while predicting improved response to immunochemotherapy. PD-L1 may serve as a biomarker to guide individualized perioperative treatment strategies in EGFR-M+ NSCLC. Prospective validation is still warranted.