Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | 2021
Comprehensive Analysis of TP53 and KEAP1 Mutations and their Impact on Survival in Localized and Advanced Stage Non-Small Cell Lung Cancer.
Abstract
INTRODUCTION\nTP53 and KEAP1 are frequently mutated in non-small cell lung cancer (NSCLC) but their prognostic value is ambiguous, particularly in localized stage tumours.\n\n\nPATIENTS AND METHODS\nThis retrospective cohort study included 6297 NSCLC patients, who were diagnosed between November 1998 and February 2020. The primary endpoint was overall survival (OS). Patients were diagnosed in a central pathology laboratory as part of the Network Genomic Medicine (NGM) collaboration, encompassing more than 300 lung cancer treating oncology centres in Germany. All patients underwent molecular testing including targeted NGS panel sequencing and in-situ hybridization.\n\n\nRESULTS\n6297 NSCLC patients were analysed. In 1518 surgically treated patients (UICC I-IIIA), truncating TP53 mutations and KEAP1 mutations were independent negative prognostic markers in multivariable analysis (HRTP53truncating 1.43 [95% CI 1.07 to 1.91]; P=0.015, HRKEAP1mut 1.68 [95% CI 1.24 to 2.26]; P=0.001). Consistently, these mutations were associated with shorter disease-free survival (DFS). In 4779 advanced stage (UICC IIIB-IV) patients, 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 to 1.61], P<0.001) in patients with advanced stage tumours. Further, KEAP1 mutant tumours with co-occurring TP53 missense mutations revealed longer OS than KEAP1 mutant tumours with wildtype or truncating TP53 mutations.\n\n\nCONCLUSIONS\nThis study found that TP53 and KEAP1 mutations were prognostic for localized and advanced NSCLC. The increased relative hazard of harbouring TP53 or KEAP1 mutations was comparable to an increase in one UICC stage. Our data suggests that molecular stratification based on TP53 and KEAP1 mutation status should be implemented for localized and advanced stage NSCLC to optimize and modify clinical-decision making.