Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma with Lead-Time Trajectory in Pre-Diagnostic Samples

Background & Aims: Early detection biomarkers for pancreatic ductal adenocarcinoma (PDAC) are needed since the clinically validated biomarker, CA19-9, has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers. Methods: Whole transcriptome assay interrogated 2,083 miRNAs in 15 µl of plasma from multicenter diagnostic cohorts (N=203: controls, n=82; diagnosed PDAC cases: n=121) and a pre-diagnostic PLCO cohort (N=96; controls, n=48; pre-diagnosed cases, n=48). A three-miRNA biomarker signature was developed for early detection of PDAC. Results: The three-miRNA signature detected PDAC from healthy controls independently (AUC = 0.974) and in combination with CA19-9 (AUC = 0.995). It also discriminated from pancreatitis (AUC = 0.931), improving performance of CA19-9 alone (AUC = 0.749) in combination (AUC = 0.954). Blinded validation in pre-diagnostic PLCO cohort revealed lead-time trajectory increase in AUC to 0.702 tat twelve-months before PDAC diagnosis. Conclusions: Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers, with model performance progressively increasing approximately twelve months before diagnosis. Overall design: Whole transcriptome assay interrogated 2,083 miRNAs in 15 µl of plasma from multicenter age-matched cohorts (N=203: controls, n=82; diagnosed PDAC cases: n=121) and a pre-diagnostic PLCO age- and gender-matched cohort (N=96; controls, n=48; pre-diagnosed cases, n=48).