Circulating tumor DNA-guided early detection and minimal residual disease monitoring in pancreatic and biliary cancers: evidence, barriers, and opportunities.

Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTCs) are characterized by dismal prognoses, largely because effective strategies for early detection are lacking and post-surgical relapse is common. Liquid biopsy—particularly circulating tumor DNA (ctDNA) analysis—offers a minimally invasive and highly specific approach to reshape the clinical management of these malignancies. In this review, we synthesize recent advances in ctDNA applications across two ctDNA-guided scenarios: early diagnosis/screening and postoperative minimal residual disease (MRD) monitoring. We trace the evolution of ctDNA detection technologies from digital PCR (ddPCR) to next-generation sequencing (NGS)–based tumor-informed and tumor-agnostic assays, and summarize key prospective and retrospective studies in pancreatobiliary tumors. A central feature of our article is the side-by-side comparison of PDAC and BTCs, highlighting shared technical barriers—low ctDNA yield, stromal desmoplasia, clonal hematopoiesis—and their distinct genomic landscapes (PDAC: KRAS, TP53, CDKN2A, SMAD4; BTCs: IDH1/IDH2 mutations, FGFR2 fusions, ERBB2 or BRAF alterations), which together influence assay design and clinical interpretability. Finally, we outline clinical opportunities, including serial ctDNA-based risk stratification, ctDNA-informed adjuvant escalation/de-escalation, and the integration of multi-omics data, standardized reporting, and artificial intelligence (AI)–assisted signal analysis to improve sensitivity in low-shedding tumors. This framework aligns ctDNA technology with real-world clinical decision points in pancreatic and biliary cancers.