Quantitative KRAS ctDNA Dynamics Predict Early Recurrence After Neoadjuvant Therapy and Surgery in Pancreatic Cancer

Early recurrence remains prevalent in pancreatic ductal adenocarcinoma (PDAC) despite multimodality treatment. Circulating tumor DNA (ctDNA) is an emerging prognostic biomarker showing promise in detecting minimal residual disease (MRD). Using a high-sensitivity digital droplet PCR (ddPCR) assay, we evaluated KRAS- mutant ctDNA as a marker of MRD associated with early recurrence (< 12 months) in patients with localized PDAC receiving neoadjuvant chemotherapy (NAC), surgery, and adjuvant chemotherapy (AC). KRAS G12D, G12V, and G12R mutations found in cell-free DNA were detected and quantified with maximum variant allele frequency (mVAF). Of 130 enrolled patients, 55 completed NAC and resection. ctDNA was detected a median of 7.6 months before imaging-confirmed recurrence. Postoperative detection KRAS ctDNA was independently associated with worse recurrence-free survival (RFS) (aHR 3.30, 95% CI 1.33–8.21, p = 0.010), and ctDNA clearance after NAC and surgery was independently associated with improved RFS (aHR 0.23, 95% CI 0.06–0.90, p = 0.035). Median cohort mVAF was 0.03%; patients with mVAF above the median had shorter RFS (12.8 vs. 26.3 months) and more frequent early recurrence (p = 0.027). ctDNA-positive patients who received AC remained with worse outcomes than ctDNA-negative patients, suggesting persistent chemotherapy resistance. These data indicated that persistent KRAS ctDNA after NAC and surgery reflects MRD and support sensitive postoperative ctDNA testing to stratify high risk patients for early recurrence, guiding quantitative, longitudinal monitoring. Future studies in adaptive treatment settings may further extend these findings toward ctDNA-guided clinical decision-making.