Abstract
BACKGROUND: This systematic review and meta-analysis synthesised current evidence on circulating tumour DNA (ctDNA) for predicting clinical outcomes in patients with non-resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: PubMed, Embase, and Cochrane databases were searched up to 31/01/2025. Eligible studies reported prognostic value of ctDNA in patients with non-resectable PDAC. Meta-analyses evaluated associations between baseline ctDNA and changes in ctDNA during treatment (ctDNA kinetics) and survival outcomes. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: Sixty-four studies involving 5652 patients with non-resectable PDAC were included, with 24 studies contributing to meta-analyses. High baseline ctDNA level implied shorter overall survival (OS; HR = 2.3, 95 % CI 1.9-2.8; n = 1883) and progression-free survival (PFS; HR = 2.1, 95 % CI 1.8-2.4; n = 1196). Unfavourable ctDNA kinetics were associated with shorter OS (HR = 3.1, 95 % CI 2.3-4.3; n = 269) and PFS (HR = 4.3, 95 % CI 2.6-7.2; n = 244). Thirty-three studies had high risk of bias in at least one QUIPS domain. CONCLUSION: Baseline ctDNA and ctDNA kinetics demonstrate strong prognostic value in non-resectable PDAC. However, clinical translation is limited by methodological heterogeneity, notably the use of study-specific, non-validated thresholds. Standardised, externally validated thresholds for interpreting ctDNA changes are needed to support clinical implementation. PROSPERO: CRD42023438774.