KRAS and TP53 Circulating Tumor DNA are Prognostic in Localized Pancreatic Cancer

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) carries high mortality despite neoadjuvant chemotherapy (NAC) and surgical resection, creating an urgent need for prognostic biomarkers to guide treatment. We aimed to determine whether circulating tumor DNA (ctDNA) detected by next-generation sequencing (NGS) predicts survival in patients with localized PDAC. METHODS: Patients with localized PDAC were prospectively enrolled at an academic institution between October 2020 and November 2024 (NCT04616131). Patients underwent next-generation sequencing (NGS), with blood samples collected at diagnosis, post-NAC, and post-resection. Total, KRAS-specific, and TP53-specific ctDNA detection rates were quantified. Associations with overall survival (OS) were evaluated by using Kaplan-Meier curves and multivariable Cox proportional hazards models adjusting for key clinical covariates. RESULTS: We collected 219 samples from 113 patients across three treatment timepoints. Mutant KRAS ctDNA was detected in 19% at diagnosis, decreased to 4.6% after NAC (19% vs. 4.6%, p = 0.010), and was detected in 8.2% after resection. Total ctDNA detection at diagnosis predicted lower odds of proceeding to resection (adjusted odds ratio [aOR] 0.38, 95% confidence interval [CI] 0.14-0.97, p = 0.049). KRAS and TP53 co-occurrence at diagnosis independently predicted shorter OS (adjusted hazard ratio 5.66, 95% CI 2.43-13.18, p < 0.001). Increases in total ctDNA maximum variant allele frequency over treatment also predicted shorter OS (adjusted hazard ratio 1.14, 95% CI 1.01-1.28, p = 0.028). CONCLUSIONS: In a large prospective cohort, tumor-agnostic NGS-based ctDNA detection demonstrated prognostic value in patients with localized PDAC undergoing NAC and surgery. These findings suggest ctDNA can inform treatment monitoring and risk stratification, supporting further evaluation in larger, multi-center studies to guide clinical decision-making.