Germline Mutation Analysis and Real-World Impact in a Selected Cohort of Patients with Non-Small Cell Lung Cancer: INHERITY LC Study.

[PURPOSE] Hereditary predisposition has not traditionally been considered a significant risk factor for non-small-cell lung cancer (NSCLC), and germline testing is not routinely established. INHERITY LC is a prospective multicenter study designed to explore the prevalence of germline variants in a selected cohort of patients with NSCLC and to assess the clinical impact of germline testing in NSCLC.

[METHODS] Germline genetic testing was conducted using next-generation sequencing (NGS) using a 72-gene panel. 145 patients with NSCLC who met one of the following criteria were selected: 1) family history of NSCLC; 2) young age and negative/low tobacco exposure; or 3) presence of somatic actionable mutations.

[RESULTS] Pathogenic germline variants (PGVs) were identified in 15 patients (10.3%; 95% CI, 5.9-16.3), involving the following genes: BRCA2 (1), CHEK2 (2), ATM (2), PALB2 (1), BARD1 (1), XRCC2 (1), MRE11 (1), NBN (3), FAN1 (1), MLH1 (1), and TP53 (1). A notably higher prevalence of PGVs (22%) was observed among patients who met all three selection criteria. After 1 year of prospective follow-up, cascade testing was performed in PGV-positive families, leading to the identification of 12 healthy relatives carrying PGVs.

[CONCLUSION] The INHERITY LC study identified a PGV prevalence of 10.3% in a selected NSCLC cohort, with most variants affecting genes involved in the DNA damage repair (DDR) pathway. The application of specific selection criteria may enhance the yield of germline testing in this setting. Larger confirmatory studies are warranted to demonstrate that germline testing and genetic counseling for NSCLC may have implications for prevention, early detection, and treatment.