Family history enrichment in Non-Small cell Lung Cancer: A cross-sectional − prospective study to inform referral for germline testing

Background: Family history of cancer (FHC) is a recognized proxy of inherited cancer susceptibility. In NSCLC, however, the clinical relevance of FHC remains poorly defined, and standardized approaches to identify patients enriched for pathogenic germline variants (PGVs) are lacking. Methods: FAHIC-Lung (NCT06196424) is a multicenter, cross-sectional/prospective observational study conducted in Italy. Consecutive patients with NSCLC were enrolled, detailed FHC data were collected using a dedicated questionnaire covering cancer type, age at diagnosis, degree of relatedness, smoking exposure, and other risk factors among relatives. A weighted FHC score integrating cancer burden across first-, second-, and third-degree relatives and accounting for family structure and degree of genetic relatedness was developed. Percentile-based thresholds (≥90th percentile, or ≥ 75th percentile with additional risk factors) were used to identify patients with enriched familial cancer profiles. Results: Among 336 evaluable patients, median age at diagnosis was 67 years, 49.7% were female, and 25.9% were never smokers. Cancer in at least one parent was reported in 63.1% of cases, while 27.7% of patients had a personal history of multiple primary malignancies. The median total FHC score was 0.40 (interquartile range 0.12–0.67). Thirty-three patients (9.5%) exceeded the 90th percentile threshold, and 22 patients (6.5%) met the 75th percentile threshold in association with clinical enrichment criteria. Overall, 55 patients (16.4%) were identified as having enriched familial cancer risk and were selected as a target population for systematic genetic counseling and planned germline testing. Conclusions: In this prospective observational study, a standardized and weighted assessment of family history identified a clinically meaningful subset of patients with NSCLC enriched for familial cancer patterns. This framework provides a pragmatic approach to optimize referral to genetic counseling and supports targeted germline screening strategies beyond traditional smoking-based risk models. Prospective validation in the planned translational phase will clarify the clinical utility of this approach.