Prospective study of prognostic relevance of KRAS-mutant ctDNA detected by NGS or ddPCR in localized PDAC

Pancreatic ductal adenocarcinoma (PDAC) carries high mortality despite multimodal therapy, and improved biomarkers are needed to guide perioperative care. A prospective cohort study (2020-2024) at Northwestern University Chicago (IL) evaluated the prognostic significance of KRAS-mutant circulating tumor DNA (ctDNA) detected by next-generation sequencing (NGS) or digital droplet PCR (ddPCR) in localized PDAC. The cohort included 106 patients undergoing neoadjuvant chemotherapy (NAC). Blood samples for ctDNA assessment were assessed at diagnosis, post-NAC, and post-resection using tumor-agnostic NGS and ddPCR targeting KRAS G12D/V/R mutations. At diagnosis, KRAS-mutant ctDNA was detected in 17.2% by NGS and 64.9% by ddPCR. Detection by both platforms was associated with shorter overall survival (OS), with the higher-sensitivity ddPCR assay providing greater prognostic discrimination by identifying additional patients with poor outcomes not captured by NGS (NGS median OS 11.2 versus 30.5 months; p<0.001; ddPCR median OS 24.7 versus 70.9 months; p=0.004). Stratified by detection method, median OS was shortest in patients with ctDNA detected by both NGS and ddPRC (10.9 months), longest in those not detected by either platform (40.7 months), and intermediated in patients detected only by ddPCR (26.9 months; p<0.001). The authors conclude that in localized PDAC, KRAS-mutant ctDNA detected by NGS or ddPCR was associated with worse survival. ddPCR identified additional patients missed by NGS.xtagstartz/p>