Genomic characterization of DNA damage response pathway mutations reveals their adverse impact on EGFR-TKI efficacy in non-small cell lung cancer.

Although tyrosine kinase inhibitors (TKIs) significantly improve survival outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), tumor clonal evolution under drug pressure inevitably leads to acquired resistance. DNA damage response (DDR) mutations lead to elevated genome instability, but the frequency and impact of DDR gene/pathway mutations on EGFR-TKI treatment efficacy remain unclear. A total of 790 NSCLC patients who received high-throughput targeted sequencing at Daping Hospital were retrospectively enrolled to analyze the mutation landscape of DDR genes in NSCLC. Next, 202 EGFR-mutant patients from Daping Hospital and 126 patients from the GENIE database who received first-line EGFR-TKI treatment were further enrolled to explore the association between DDR mutations and clinical outcomes. DDR genes including ATM, MSH3, BRCA2 (> 5%), and pathways including the Fanconi anemia (FA), homologous recombination repair (HRR), and mismatch repair (MMR) exhibited substantial mutation rates (15%). In the Daping cohort, patients with DDR mutations had inferior outcomes when receiving EGFR-TKI treatment (median PFS: 14.9 vs. 10.8 months, P = 0.001) and higher mutation burden. Specifically, FA (HR = 2.314, 95% CI: 1.547-3.549, P < 0.001) or HRR (HR = 2.686, 95% CI: 1.786-4.039, P < 0.001) pathway mutations were independent risk factors for disease progression. Notably, patients with co-occurring TP53 and DDR mutations had the worst outcomes compared to those with either single mutations or wild-type TP53/DDR, and similar findings were validated in the GENIE cohort. Our study demonstrates a substantial prevalence of DDR mutations and their association with inferior EGFR-TKI efficacy, highlighting the importance of genomic profiling of DDR mutations to identify this high-risk subpopulation in EGFR-mutant NSCLC.