Germline testing in lung cancer: evidence of enrichment without a standardized selection strategy - a systematic...

Germline testing (GT) is increasingly integrated into oncology practice, yet its role in lung cancer (LC) remains undefined. While germline predisposition has clinical implications in several malignancies, LC is primarily driven by environmental factors and characterized by a relatively low prevalence of pathogenic germline variants (PGVs). Whether patient selection strategies may improve the detection of germline alterations remains an open question.

We conducted a systematic review of studies reporting PGVs and likely PGVs (LPGVs) in LC. Studies were categorized according to patient selection. Data were synthesized descriptively, without formal comparative testing, given the expected heterogeneity.

49 studies were included: 10 pan-cancer, 21 unselected LC, and 18 selected LC cohorts. PGVs/LPGVs prevalence showed substantial variability across studies. Median prevalence was approximately 6% in unselected and 27% in selected cohorts. A similar pattern was observed in Non-Small Cell LC-specific analyses, where selected populations showed higher prevalence. Selection strategies were highly heterogeneous with no standardized approach across studies. Family history was inconsistently collected and rarely used as a formal selection criterion. Exploratory analyses suggested potential geographic variability.

Germline variants are detectable in LC, although their prevalence appears relatively low in unselected populations, limiting the potential yield of universal testing strategies. Patient selection may increase detection rates, but current approaches are heterogeneous and not standardized. Enrichment strategies could improve the efficiency of GT. Defining reproducible selection frameworks may represent a key step toward integrating GT into LC care, with potential implications for targeted prevention and familial risk assessment.