Comprehensive Analysis of TP53 and KEAP1 Mutations and Their Impact on Survival in Localized- and Advanced-Stage NSCLC.

ABSTRACT

INTRODUCTION: TP53 and KEAP1 are frequently mutated in NSCLC, but their prognostic value is ambiguous, particularly in localized stage tumors. METHODS: This retrospective cohort study included a total of 6297 patients with NSCLC who were diagnosed between November 1998 and February 2020. The primary end point was overall survival. Patients were diagnosed in a central pathology laboratory as part of the Network Genomic Medicine collaboration, encompassing more than 300 lung cancer-treating oncology centers in Germany. All patients underwent molecular testing, including targeted next-generation panel sequencing and in situ hybridization. RESULTS: A total of 6297 patients with NSCLC were analyzed. In 1518 surgically treated patients (Union for International Cancer Control [UICC] I-IIIA), truncating TP53 mutations and KEAP1 mutations were independent negative prognostic markers in multivariable analysis (hazard ratio [HR]TP53truncating = 1.43, 95% confidence interval [CI] 1.07-1.91, p = 0.015; HRKEAP1mut = 1.68, 95% CI1.24-2.26, p = 0.001). Consistently, these mutations were associated with shorter disease-free survival. In 4779 patients with advanced-stage (UICC IIIB-IV) tumors, TP53 mutations did not predict outcome in univariable analysis. In contrast, KEAP1 mutations remained a negative prognostic factor (HRKEAP1mut = 1.40, 95% CI 1.23-1.61, p < 0.001) in patients with advanced-stage tumors. Furthermore, those with KEAP1-mutant tumors with co-occurring TP53 missense mutations had longer overall survival than those with KEAP1-mutant tumors with wild-type or truncating TP53 mutations. CONCLUSIONS: This study found that TP53 and KEAP1 mutations were prognostic for localized and advanced-stage NSCLC. The increased relative hazard of harboring TP53 or KEAP1 mutations was comparable to an increase in one UICC stage. Our data suggest that molecular stratification on the basis of TP53 and KEAP1 mutation status should be implemented for localized and advanced-stage NSCLC to optimize and modify clinical decision-making.