Ultrasensitive plasma ctDNA assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma.

Precision oncology requires sensitive and specific clinical biomarkers. Carbohydrate Antigen 19-9 (CA19-9) is widely used in pancreatic ductal adenocarcinoma (PDA) but lacks sensitivity and specificity. Nearly all PDAs harbor somatic mutations, nominating circulating tumor DNA (ctDNA) as an alternative disease biomarker, however, variable clinical performance has limited its clinical utility. We applied an ultrasensitive, PCR mutation enrichment, next generation sequencing ctDNA assay in a large cohort of patients with unresectable PDA ( = 189) recruited to the BIOPAC study between 2008-2015. Baseline and longitudinal serum CA19-9 and plasma ctDNA were correlated with time to progression (TTP) and overall survival (OS). Baseline ctDNA detection rate was 93.7% (86.4% in patients with non-elevated CA19-9). ctDNA and CA19-9 were positively correlated yet independently associated with TTP and OS (ctDNA = 0.0018 and 0.0014; CA19-9 = 0.0294 and 0.0007, respectively). A generated model quantitating longitudinal ctDNA correctly assessed greater than 80% of patient responses. Quantitative detection of ctDNA is an informative prognostic biomarker, complementary to CA19-9 in patients with unresectable PDA. Longitudinal ctDNA may inform therapeutic decision making and provides a kinetically dynamic and quantitative metric of patient response.