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

Germline and somatic alterations in the epidermal growth factor receptor (EGFR) gene contribute to the pathogenesis and therapeutic response of non-small cell lung cancer (NSCLC). This retrospective single-center study analyzed 507 Azerbaijani patients with NSCLC who were genotyped for EGFR mutations between 2009 and 2024. Real-time PCR identified somatic EGFR mutations in 137 cases (27.0%), whereas 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 noncarriers; P = 0.03), and four developed tyrosine kinase inhibitors resistance within 6 to 8 months of treatment. Kaplan-Meier and Cox regression analyses revealed no significant survival difference between hereditary and somatic mutation groups (median overall survival 24.9 vs. 24.0 months; log-rank P = 0.69; hazard ratio = 1.19; 95% confidence interval, 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.

This study underscores the clinical importance of the rare germline EGFR T790M mutation in lung cancer. Detecting carriers with a family history may allow earlier diagnosis and inform targeted prevention, supporting more precise screening for high-risk individuals.