Serial ctDNA dynamics predict clinical outcomes in metastatic and locally advanced PDAC: a systematic review

Circulating tumor DNA (ctDNA) is being studied for prognosis and treatment monitoring in pancreatic ductal adenocarcinoma (PDAC). Given the limitations of CA19-9, including non-secretion and confounding by cholestasis, we assessed whether serial ctDNA dynamics predict progression-free survival (PFS) and overall survival (OS) in localized and advanced PDAC, and whether ctDNA adds information to CA19-9.

We conducted a PRISMA-guided systematic review of PubMed, Translational Research, MDPI, and JAMA. Eligible studies included patients with PDAC who had ≥2 ctDNA measurements during perioperative care, treatment, or surveillance and reported associations with OS, PFS, DFS/RFS, recurrence, progression, EMR, molecular progression, or lead-time versus imaging/CA19-9. Two reviewers screened 119 records, of which 17 studies met inclusion criteria. Because of heterogeneity in assays, sampling schedules, and reporting, results were synthesized narratively.

Across studies, ctDNA detectability and clinical utility varied according to disease stage, assay type, and sampling window. In resected PDAC, a CLIA-validated ddPCR KRAS assay study reported preoperative ctDNA detection in 49% of patients (29/59). In the same cohort, ctDNA detected during follow-up predicted recurrence with 90% sensitivity (95% CI, 74%-98%) and 88% specificity (95% CI, 62%-98%) and preceded clinical or radiographic recurrence by a median of 84 days (IQR, 25-146). In advanced PDAC treated with palliative chemotherapy, longitudinal sampling every 4 weeks showed that ctDNA monitoring identified progression before radiology in 20 of 30 patients (67%) with baseline-detectable ctDNA, with a median lead time of 23 days (P = 0.01). In the same cohort, CA19-9 increases, when present, showed a shorter median lead time of 9.5 days (P = 0.03), and ctDNA detected progression in some patients without a corresponding CA19-9 increase during therapy. Across the included studies, baseline ctDNA positivity was generally associated with higher-risk disease, whereas early ctDNA decline or clearance during treatment and postoperative or longitudinal ctDNA negativity were associated with more favorable outcomes.

Serial ctDNA dynamics in PDAC were associated with recurrence, progression, treatment response, and survival across perioperative and systemic therapy settings. ctDNA appears most consistent as a postoperative MRD marker and may complement CA19-9 and imaging during treatment monitoring. Prospective studies are needed to standardize sampling schedules, response thresholds, and ctDNA-guided clinical use.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261321972, identifier CRD420261321972.