Circulating Tumor DNA and Neoadjuvant Therapy in Localized Pancreatic Ductal Adenocarcinoma – A Systematic Review and Meta-Analysis

Abstract Background ctDNA is increasingly investigated as a biomarker in pancreatic ductal adenocarcinoma (PDAC), but its role in guiding treatment decisions before, during, and after neoadjuvant treatment (NAT) remains unclear. Aims This study aims to synthesize the current evidence on the predictive value of ctDNA in localized pancreatic ductal adenocarcinoma PDAC, with a particular focus on its potential to guide clinical decision-making before, during, and after NAT. Methods A systematic review and meta-analysis (Prospero: CRD420251013013) of studies evaluating ctDNA in patients with localized PDAC treated with NAT was conducted. Meta-analyses were performed for OS and PFS when ≥2 studies reported outcomes. Results 15 studies, representing 926 patients, met the inclusion criteria. Five studies measured ctDNA using a PCR-only assay, five using only NGS, and four studies used both methods. All studies targeted KRAS mutations for ctDNA assessment, with substantial heterogeneity in assay platforms, thresholds, and sampling timing. Baseline ctDNA detection ranged from 11-73% across resectability categories. Baseline ctDNA positivity was associated with worse PFS (2 studies, pooled HR 2.34, 95% CI 1.21-4.54), but association with OS could not be demonstrated (3 studies, pooled HR 1.50, 95% CI 0.96-2.37). An association between post-NAT ctDNA status and PFS or OS could not be quantitatively investigated. Postoperative ctDNA positivity was associated with inferior OS (2 studies, pooled HR 6.39, 95% CI 1.94-21.01). Conclusion Evidence supporting ctDNA as a biomarker to guide NAT in localized PDAC is limited and inconsistent. Postoperative ctDNA was strongly associated with poor OS, whereas larger studies are needed to assess baseline and post-NAT ctDNA.