Prognostic significance of circulating tumor DNA as a baseline or dynamic factor in advanced NSCLC without oncogenic drivers: A systematic review and meta-analysis

Prognostic biomarkers for advanced non-oncogene-addicted non-small cell lung cancer (NSCLC) remain limited. This PRISMA-compliant systematic review assessed the prognostic value of plasma circulating tumor DNA (ctDNA) at baseline and its dynamics during treatment. Cochrane, EMBASE, and MEDLINE were searched to February 27, 2025, identifying studies reporting hazard ratios (HRs) for overall survival (OS). Bias was evaluated using the Quality in Prognostic Studies tool, and publication bias with funnel plots and Egger’s regression. Among 7,118 records, 43 studies were included, spanning diverse designs, ctDNA assays, quantification units, and definitions of dynamic change. Detectable or elevated baseline ctDNA was associated with worse OS (HR 1.62; 95% CI 1.40-1.87) with substantial heterogeneity and possible small-study bias. Increasing or persistent ctDNA during treatment was strongly prognostic for poor survival (HR 2.69; 95% CI 2.35-3.09). Overall study quality was moderate to high. Plasma ctDNA shows consistent prognostic value, though clinical implementation is limited by methodological variability. • ctDNA predicts overall survival in advanced non-oncogene-addicted NSCLC. • Elevated baseline ctDNA is consistently associated with poorer prognosis. • Increasing or persistent ctDNA during therapy indicates worse survival. • Substantial heterogeneity exists in ctDNA methods and reporting practices. • ctDNA shows promise as a prognostic biomarker but lacks clinical standardization.