Molecular and clinical disparity of EGFR-mutant non-small cell lung cancer (NSCLC) based on histopathological stage and EGFR molecular subtypes.

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a cornerstone of therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC), resistance remains a major clinical challenge. The genomic landscape of early-stage (ES) EGFR-mutant NSCLC and its evolution to advanced-stage (AS) disease is not fully understood. This study aimed to characterize the molecular disparities between ES and AS EGFR-mutant NSCLC and to identify genomic alterations associated with EGFR-TKI treatment outcomes. We have collected and profiled the complex genomes of 121 ES and 74 AS NSCLCs to determine their molecular and clinical disparities. Furthermore, we analyzed 84 EGFR-mutant NSCLC patients who were treated with EGFR-TKIs to identify potential molecular correlates that could predict the treatment response within the clinic. Patients were stratified by progression-free survival (PFS) and overall response rate (ORR), and hazard ratio analyses were performed. In the study, significant enrichment of mutations in MTOR, ATRX, STAG2, ABL1, and SPEN was observed in AS tumors, whereas ES tumors predominantly exhibited mutations activating JAK2, ERBB2, and FGFR4. In the EGFR-TKI cohort, poor responders harbored frequent mutations in TP53, KIT, and ALK, and these were associated with worse clinical outcomes. Conversely, favorable responders showed enrichment of MTOR, ATM, EP300, and PIK3R1 mutations. ALK and FANCA were linked to increased hazard, while EP300 and PIK3R1 mutations correlated with improved prognosis. Given the growing importance of biomarker-driven treatment in the field of oncology, our results collectively open up new therapeutic opportunities for ES NSCLC patients.