Germline EGFR T790M in Lung Cancer: Prevalence, Clinical Impact, and Implications for Hereditary Risk

Germline and somatic alterations in the EGFR gene contribute to the pathogenesis and therapeutic response of non–small cell lung cancer (NSCLC). This retrospective single-center study analyzed 507 Azerbaijani NSCLC patients genotyped for EGFR mutations between 2009 and 2024. Real-time PCR identified somatic EGFR mutations in 137 cases (27.0%), while next-generation sequencing confirmed germline EGFR T790M variants in 11 patients (2.1%). Among these, nine carried concurrent somatic EGFR alterations and two harbored only germline variants; the latter are excluded from the present analysis and will be reported separately. All germline carriers had a positive family history of lung cancer. Germline carriers were more often diagnosed at early stages (I–II, 45.5% vs. 18.2% in non-carriers; p = 0.03), and four developed tyrosine kinase inhibitor (TKI) resistance within 6–8 months of treatment. Kaplan–Meier and Cox regression analyses revealed no significant survival difference between hereditary and somatic mutation groups (median OS 24.9 vs. 24.0 months; log-rank p = 0.69; HR = 1.19; 95% CI, 0.52–2.73). These findings indicate that germline EGFR T790M represents a measurable hereditary variant within the South Caucasus population and emphasize the need to integrate germline testing into diagnostic workflows and familial risk assessment strategies for EGFR-driven NSCLC.