Concomitant Genetic Alterations are Associated with Worse Clinical Outcome in EGFR Mutant NSCLC Patients Treated with Tyrosine Kinase Inhibitors

Abstract

Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKI) are recommended first-line therapy for advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. It is of clinical interest to identify concurrent genetic mutations in NSCLC patients with EGFR mutations in the hopes of discovering predictive biomarkers towards EGFR-TKI treatment. We retrospectively analyzed a cohort of patients with advanced EGFR mutant NSCLC who underwent treatment with first generation TKIs at our hospital by a multi-gene panel via next generation sequencing. A total of 33 patients with mutant EGFR were enrolled. Up to 26 (78.8%) patients had at least one concomitant genetic alteration coexisting with mutant EGFR. Among the concomitant genetic alterations discovered, TP53 mutation was most common (n = 10,30.3%), followed by CDK4 (n = 8, 24.2%) and CDKN2A (n = 7, 21.2%)copy number variation (CNV). Progression-free survival was shorter in patients with concomitant FGFR3 mutation (1.6 vs. 12.6 months, P = .003) and CDKN2A CNV loss (6.5 vs. 13.4months, P = .019). Patients with any concomitant genetic alterations also had significant worse overall survival (24.1 vs. 40.8 months, P = .029). In summary, our study revealed an unfavorable association between concomitant genetic mutations and treatment response towards EGFR-TKI. FGFR3 mutation and CDKN2A CNV loss may be potential predictive markers for treatment outcome and warrant further investigation.