The International Association for the Study of Lung Cancer Staging Project: The Impact of Common Molecular Alterations on Overall Survival in NSCLC in Initial Analyses of the IASLC Ninth Edition Staging Database

Introduction: TNM staging systems create prognostic categories by anatomic extent of disease. Whether therapeutically important molecular alterations in NSCLC augment the prognostic information of TNM staging is unclear. To study this, we analyzed molecular data from the ninth edition of the lung cancer staging system. Methods: Eligible patients were diagnosed between 2011 and 2019. Analysis was restricted to the following three genes for reliable statistical analyses: EGFR mutations (L858R, exon 19 deletion), ALK fusions, and KRAS mutations (codons 12, 13, or 61). Overall survival (OS) was calculated by the Kaplan-Meier method, and differences in OS were assessed by Cox proportional hazard regression models. Results: A total of 20,580 patients had tumors with molecular data (EGFR = 16,497, ALK = 11,546, KRAS = 2909 patients). EGFR mutations were found in 5428 (32.9%), ALK fusions in 723 (6.3%), and KRAS mutations in 890 (30.6%) tumors. OS was significantly better across all TNM stages among patients with EGFR-mutated tumors and patients with stage IV ALK fusion-positive tumors, whereas patients with stage I KRAS-mutated tumors had significantly worse OS. Multivariable analyses confirmed the OS associations with EGFR-mutated tumors (stage I hazard ratio [HR] = 0.79, stage II HR = 0.71, stage III HR = 0.67, stage IV HR = 0.49) and stage IV ALK fusion-positive tumors (HR = 0.56). Conclusions: Patients with EGFR-mutated tumors had improved OS regardless of stage, whereas an OS benefit was found in stage IV patients with ALK-positive tumors. In the tenth edition, we will evaluate the systematic integration of molecular biomarkers and treatment to refine prognostication for molecular subsets of NSCLC.