PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC), has an overall survival rate of 9%, and detection of PDAC is a high priority area for the NCI. Only 10-20% of patients with PDAC have a primarily resectable disease, while 50- 60% of patients are diagnosed with irresectable disease. Neoadjuvant chemotherapy maybe beneficial to these patients. Disease monitoring of PDAC patients in the neoadjuvant setting is by Computed tomography (CT) or detection of CA19-9 levels. These approaches can be imprecise and not predictive of tumor burden. Thus, there is a need to develop sensitive and specific biomarkers to assess disease burden and monitor patients with PDAC undergoing neoadjuvant therapy. Recently we showed that aberrant DNA methylation analysis in cell-free DNA may be an attractive liquid biopsy approach for the detection of PDAC. The objective of this proposal is to validate our liquid biopsy approach and demonstrate its utility. In Aim 1, we will validate our Methyl 10 biomarkers for the detection of early-stage PDAC. In Aim, 2, we investigate whether our Methyl 10 biomarkers can detect minimal residual disease in pancreatic cancer patients. At the completion of these studies, we will have validated and developed a novel DNA methylation biomarker set that is highly robust in the detection of PDAC and highlight its clinical significance for monitoring treatment strategies in PDAC patients.