Prognostic Value and Longitudinal Dynamics of Multigene Circulating Tumor DNA in Advanced Pancreatic Cancer Treated with 5-Fluorouracil-Based Chemotherapy

Circulating tumor DNA (ctDNA) is a minimally invasive biomarker in pancreatic ductal adenocarcinoma (PDAC), but the prognostic information added by multigene ctDNA metrics beyond KRAS and carbohydrate antigen 19-9 (CA19-9) is uncertain. In this prospective observational pilot study, 51 patients with advanced PDAC receiving 5-fluorouracil-based chemotherapy underwent 118-gene ctDNA profiling at baseline and 4 and 8 weeks after treatment initiation. ctDNA burden was summarized with variant allele frequency (VAF) metrics: Sum VAF and Top4 VAF (KRAS, TP53, CDKN2A, SMAD4). Twelve-month progression-free survival (PFS) areas under the curve were 0.816 for Top4 VAF, 0.812 for Sum VAF, 0.788 for KRAS VAF, and 0.687 for CA19-9; the Top4–KRAS difference was not statistically significant (95% confidence interval, −0.120 to 0.131). Baseline ctDNA detection and high Top4 VAF remained associated with shorter PFS and overall survival after adjustment for clinical covariates. Detectable Top4 VAF at 4 weeks was associated with shorter PFS (hazard ratio, 5.739; p < 0.001). Top4 VAF changes differed across radiologic response categories at 8 but not 4 weeks; CA19-9 showed no significant paired change. These exploratory findings suggest that baseline and early on-treatment multigene ctDNA carries prognostic information in advanced PDAC, although superiority over KRAS or CA19-9 was not established.