Prognostic Impact of Baseline Circulating Tumor DNA (ctDNA) in Pancreatic Ductal Adenocarcinoma: A Systematic Review...

Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, with a 5-year overall survival of only 11% across all stages. Serum CA 19-9, the standard clinical biomarker, is limited by inadequate sensitivity in early stage disease and poor specificity. Circulating tumor DNA (ctDNA), which reflects the real-time genomic landscape of the tumor and frequently detects KRAS alterations present in over 90% of PDAC cases, has emerged as a promising prognostic biomarker. However, prior meta-analyses have been limited by smaller cohort sizes and substantial heterogeneity. This systematic review and meta-analysis aimed to evaluate the prognostic impact of detectable baseline ctDNA status in PDAC, irrespective of disease stage. Methods: A systematic search of Scopus, PubMed, and Embase was conducted for studies published up to January 2026, following PRISMA guidelines. Studies were eligible if they enrolled adults with PDAC, assessed ctDNA status (positive vs. negative) at baseline, and reported overall survival (OS) or progression-free survival (PFS). Case reports, reviews, studies focusing on specific mutations, or studies without extractable survival data were excluded. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model (DerSimonian-Laird method). Heterogeneity was assessed using the I² statistic and Cochran's Q test. Subgroup analyses were performed by disease stage (localized vs. advanced PDAC). Results: 14 studies encompassing 1032 patients were included; 487 (47.2%) had detectable baseline ctDNA. Overall, 482 patients (46.7%) had localized disease and 550 (53.3%) had advanced disease. Detectable baseline ctDNA was significantly associated with inferior OS across all 14 studies (pooled HR 2.33, 95% CI 1.98-2.75; p < 0.0001; I² = 7.9%) and with shorter PFS across eight studies (pooled HR 2.16, 95% CI 1.76-2.67; p < 0.0001; I² = 15.7%). In stage-stratified subgroup analyses, ctDNA positivity was independently associated with worse OS in both advanced PDAC (HR 2.21, 95% CI 1.77-2.75; I² = 5%) and localized PDAC (HR 2.54, 95% CI 1.97-3.28; I² = 14.6%), with no statistically significant difference between subgroups (p = 0.412). Similarly, ctDNA positivity predicted worse PFS in advanced (HR 2.19, 95% CI 1.69-2.82; I² = 35.4%) and localized disease (HR 2.15, 95% CI 1.40-3.31; I² = 0%), with no significant between-subgroup differences (p = 0.941). Heterogeneity was consistently low to moderate across analyses. Conclusions: Detectable baseline ctDNA is a potent, independent prognostic biomarker in PDAC, associated with more than a two-fold increased risk of death and disease progression irrespective of disease stage, with consistent findings across studies and ctDNA detection platforms. These findings support further prospective evaluation of baseline ctDNA for prognostic stratification, treatment personalization, and clinical trial enrichment before routine clinical implementation. Standardized assay methodologies and prospective validation are needed to facilitate its future integration into clinical practice.