Prognostic implications of MDM2 expression in surgically resected epidermal growth factor receptor mutant lung cancer with pathological lymph node metastasis

MDM2 protein regulates p53 protein activity; however, the prognostic impact of MDM2 expression in primary lung cancer on patient prognoses is unknown. This study investigated the prognostic implications of MDM2 protein expression among patients with epidermal growth factor receptor mutant (EGFRm) lung adenocarcinoma with pathologic lymph node metastases after surgery. Immunohistochemical analysis was conducted to determine the MDM2 expression of pN1-N2 EGFRm [exon 19 deletion mutation (Ex19) and exon 21 L858R mutation (Ex21)] lung cancer that were surgically resected between January 2010 and December 2020 (n=124). The postoperative prognosis and cumulative incidence of recurrence were retrospectively analyzed. MDM2 protein expression was positive in 56 patients (45.2%) with EGFRm lung adenocarcinoma. The relapse-free survival (RFS) rate was significantly better among patients with MDM2+ vs. those with MDM2- (5-year RFS: 35.5% vs. 14.8%, P=0.04). Multivariable analysis revealed MDM2+ as an independent favorable prognostic factor for RFS [hazard ratio (HR), 0.64; 95% confidence interval (CI): 0.42-0.98; P=0.04]. Among patients with Ex21 lung cancer (n=63), significantly better RFS and overall survival (OS) were seen in patients with MDM2+ than those with MDM2- (5-year RFS: 36.4% vs. 9.2%, P=0.005; 5-year OS: 81.8% vs. 39.3%, P=0.002). Multivariable analysis revealed that among patients with Ex21 lung cancer, MDM2+ was an independent favorable prognostic factor for RFS (HR, 0.43; 95% CI: 0.23-0.80; P=0.008) and OS (HR, 0.32; 95% CI: 0.15-0.67; P=0.003), and it was also associated with a low cumulative incidence of overall distant recurrence (HR, 0.42; 95% CI: 0.20-0.87; P=0.02) and central nervous system recurrence (HR, 0.23; 95% CI: 0.07-0.80; P=0.02). MDM2 protein expression is a prognostic predictor of RFS and OS in patients with pN1-N2 Ex21 lung cancer after curative surgery. MDM2 can be a novel biomarker for predicting postoperative prognosis and distant metastasis, especially in the central nervous system.