Ultrasensitive plasma ctDNA <i>KRAS</i> 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 <i>KRAS</i> mutations, nominating circulating tumor DNA (ctDNA) <i>KRAS</i> 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 <i>KRAS</i> assay in a large cohort of patients with unresectable PDA (<i>N</i> = 189) recruited to the BIOPAC study between 2008-2015. Baseline and longitudinal serum CA19-9 and plasma ctDNA <i>KRAS</i> were correlated with time to progression (TTP) and overall survival (OS). Baseline ctDNA <i>KRAS</i> detection rate was 93.7% (86.4% in patients with non-elevated CA19-9). ctDNA <i>KRAS</i> and CA19-9 were positively correlated yet independently associated with TTP and OS (ctDNA <i>KRAS p</i> = 0.0018 and 0.0014; CA19-9 <i>p</i> = 0.0294 and 0.0007, respectively). A generated model quantitating longitudinal ctDNA <i>KRAS</i> correctly assessed greater than 80% of patient responses. Quantitative detection of <i>KRAS</i> ctDNA is an informative prognostic biomarker, complementary to CA19-9 in patients with unresectable PDA. Longitudinal ctDNA <i>KRAS</i> may inform therapeutic decision making and provides a kinetically dynamic and quantitative metric of patient response.