Abstract This proposal to continue in the Pancreatic Cancer Detection Consortium will further build and enhance our biospecimen resource that collects longitudinal blood samples on patients at risk of developing pancreatic cancer and unique tissue resources that include rare pancreatic premalignant lesions. We propose to continue and enhance our discovery and validation of blood-based and imaging-based biomarkers that have the potential to detect and differentiate the earliest possible stages of pancreatic lesions that are likely to progress to cancer. This proposal proceeds from an ongoing effort that was initiated 3.5 years ago in which we have enrolled approximately 469 patients with known germline mutations or with significant inherited risk of unknown etiology (more than 2 affected with no defined mutations) for pancreatic cancer. We prospectively collect biological specimens (100 mL blood) and detailed clinical data every six months from an at-risk cohort that represents the target population envisioned for clinical application of biomarkers with potential to detect pancreatic cancer. In addition to patients with inherited risk, we will continue to collect longitudinal samples on groups of patients with increased risk of pancreatic cancer: those with pancreatic cystic neoplasms or chronic pancreatitis, and new onset diabetes (NOD). We also propose three biomarker research specific aims that have grown out of progress during the previous grant award. One aim will build upon our previous results with mucin type biomarkers and related glycoproteins by examining the potential of a set of additional biomarkers to improve detection cancer prior to clinical diagnosis in the earliest stages of disease progression. A second aim will examine the capacity of newly identified antibodies to CEACAM6 to identify earliest lesions in the pancreas by immunohistochemistry and state of the art imaging modalities. A third aim will determine the performance characteristics of a panel of exosome-based biomarkers detecting early pancreatic cancer and differentiating benign cystic lesions from those that progress to cancer.