Liquid Biopsy in Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Distinct liquid biopsy modalities are emerging as promising tumor-specific biomarkers to monitor treatment response and predict survival in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) may reflect underlying systemic disease burden and complement conventional imaging or CA19-9 assessment. This systematic review and meta-analysis evaluated the prognostic significance of liquid biopsy biomarkers in patients with resected PDAC. METHODS: A systematic review and meta-analysis was performed in accordance with PRISMA guidelines. Studies published until 1 July 2025 evaluating ctDNA, CTCs, or EVs in patients with resected PDAC, with or without neoadjuvant therapy, were evaluated. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Study quality was assessed using the QUADAS-2 tool. RESULTS: The meta-analysis included 44 studies (26 ctDNA, 12 CTC, and 6 EV studies; >2,500 patients). Preoperative ctDNA positivity was associated with worse OS (pooled hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.86-3.44) and RFS (HR, 2.28; 95% CI, 1.67-3.11), with low-to-moderate heterogeneity. Postoperative ctDNA positivity demonstrated stronger associations with worse OS (HR, 5.15; 95% CI, 1.57-16.88) and RFS (HR, 3.12; 95% CI, 2.01-4.82), with moderate-to-substantial heterogeneity. Preoperative CTC positivity was associated with inferior RFS (HR, 2.70; 95% CI, 1.32-5.52), with substantial heterogeneity. In individual studies, EV-based biomarkers demonstrated consistent adverse outcomes. However, quantitative pooling was not feasible due to marked heterogeneity. CONCLUSION: In resected PDAC, preoperative ctDNA is a robust predictor of recurrence and survival. Both CTCs and EVs show biologically compelling but assay-dependent prognostic signals.