Germline Testing Finds More Mutations in Select Patients With Lung Cancer

Universal germline testing in lung cancer may cast too wide a net, but testing nobody misses a meaningful share of hereditary cancer risk, according to a systematic review of 49 studies published in the journal Lung Cancer.¹

A Question Oncology Has Not Settled

Germline testing is increasingly woven into routine oncology practice for cancers with well-established hereditary syndromes, but its role in lung cancer has remained far less defined. Lung cancer is driven primarily by environmental exposures such as tobacco smoke, and pathogenic germline variants (PGVs) are detected less frequently than in cancers like breast or ovarian cancer. That lower baseline prevalence has fueled debate over whether broad, unselected germline testing in lung cancer is worthwhile or whether a more targeted strategy would yield better results.²

To address that uncertainty, researchers conducted a systematic review of studies reporting PGVs and likely pathogenic germline variants (LPGVs) in patients with lung cancer, categorizing studies according to how patients were selected for testing.¹

The review identified 49 eligible studies: 10 that tested across multiple cancer types (pan-cancer), 21 that tested unselected lung cancer populations, and 18 that applied some form of patient selection before testing. Data were synthesized descriptively rather than through formal comparative statistical testing, reflecting the substantial heterogeneity expected across study populations, testing panels, and selection criteria.

Selection Strategies Lifted Detection, but Inconsistently

PGV and LPGV prevalence varied considerably across the 49 studies. Median prevalence was approximately 6% among unselected lung cancer cohorts (range, 0.03%-33%), climbing to roughly 27% in cohorts where patients had been selected for testing based on clinical criteria (range, 2.65%-94.29%); pan-cancer cohorts fell in between, with a median prevalence of approximately 10% (range, 0.13%-35.1%). A similar pattern emerged in analyses restricted specifically to non–small cell lung cancer, where median prevalence reached approximately 22% in selected cohorts vs about 6% in unselected ones. Selection strategies themselves were highly heterogeneous, with no standardized approach used consistently across studies. Family history was inconsistently collected and rarely applied as a formal selection criterion: only 3 of the 24 studies that collected family history data used it formally to select patients for testing. Exploratory analyses also found higher germline variant prevalence in non-Asian cohorts than in Asian cohorts, though the authors cautioned this gap may partly reflect differences in testing panels and variant-annotation practices rather than true biological variation.

“Germline variants are detectable in LC, although their prevalence appears relatively low in unselected populations, limiting the potential yield of universal testing strategies,” the authors concluded.

Descriptive Synthesis, Not a Head-to-Head Comparison

Because the review synthesized findings descriptively rather than through formal meta-analytic pooling, the reported prevalence figures should be interpreted as directional rather than precise estimates. Variation in testing panels, variant classification criteria, and population ancestry across the 49 included studies further complicates direct comparisons.

The inconsistent collection of family history data across studies also limited the authors' ability to assess how much that single factor, independent of other selection criteria, might improve testing yield.

For oncologists and payers weighing the cost-effectiveness of germline testing panels, the findings suggest that a standardized, criteria-based selection approach (rather than testing either everyone or no one) could be the most efficient path forward, with implications for targeted prevention and familial risk counseling in patients' relatives.

References

1. Citarella F, Ferrara R, Di Maio M, et al. Germline testing in lung cancer: evidence of enrichment without a standardized selection strategy - a systematic review. Lung Cancer. 2026;219:109534. doi:10.1016/j.lungcan.2026.109534
2. The ASCO Post. Is germline testing warranted for all patients with lung cancer? Published September 25, 2022. Accessed October 1, 2026. https://ascopost.com/issues/september-25-2022/is-germline-testing-warranted-for-all-patients-with-lung-cancer/