Johns Hopkins University

Principal Investigator (contact): Michael G. Goggins, M.D.
Institution: Johns Hopkins University

Synopsis of Research and Network Resources

Title of the PCDC Project

USING MARKERS TO IMPROVE PANCREATIC CANCER SCREENING AND SURVEILLANCE

Introduction

Since most patients with pancreatic cancer present with advanced disease, pancreatic screening is needed to detect asymptomatic early-stage potentially curable lesions. In our CAncer of the Pancreas Screening (CAPS) clinical studies we have screened ~600 individuals at increased risk of developing pancreatic cancer using family history or gene mutation criteria. Screening can identify precancerous lesions and pancreatic cancers, but better circulating and pancreatic juice markers are needed to aid in pancreatic evaluation. Pancreatic juice collected from the duodenum during routine endoscopic ultrasound reveals that this sample is a rich source of biomarkers of pancreatic neoplasia and the analysis of pancreatic juice could be a useful diagnostic test. Thus, GNAS mutations are highly specific for IPMNs are specifically detected in the juice samples of patients with IPMNs. KRAS mutations are commonly found not only in the pancreatic juice of patients with pancreatic cancer, but in patients undergoing pancreatic screening even when they do not have evidence of pancreatic neoplasia by imaging. Many of these mutations are thought to arise in PanIN, which are not detected by pancreatic imaging tests because these lesions are very small and do not form masses. Thus, pancreatic juice analysis has the potential to indicate the presence of PanIN. More valuable would be a test that would indicate the grade of pancreatic neoplasia since in the absence of cancer, this is usually not possible to determine without analyzing the resected pancreas. We know that TP53 and SMAD4 mutations emerge in high-grade dysplasia and invasive pancreatic cancer tumors and can find TP53 and SMAD4 mutations in pancreatic juice samples in patients with pancreatic cancer and high-grade dysplasia, not in disease controls or those with low- grade dysplasia.

Description of the Project

Our project, which helps support the CAPS screening program, is a joint collaboration between Johns Hopkins University, University of Pittsburgh, University of Pennsylvania, Dana Farber Cancer Institute and Case Western Medical Reserve. Our goals is to develop and follow our CAPS screening cohort, to evaluate biomarkers of pancreatic cancer, and to perform PROBE-based analysis of our best biomarkers of cases within our cohort that progress to pancreatic cancer or high-grade dysplasia during follow-up vs those who do not progress. The main biomarkers we are evaluating are pancreatic juice mutations determined by digital next-generation sequencing and circulating biomarkers, primarily ctDNA.

Specifically, we propose: Aim #1: To determine the diagnostic accuracy of mutations detected in pancreatic fluid as markers of pancreatic cancer and precancerous lesions. We will use novel nextgen sequencing methods to detect mutations in patients with pancreatic cancer, IPMNs, chronic pancreatitis, or normal pancreata. Aim #2: To evaluate circulating markers as diagnostic tests for the early detection of pancreatic cancer. We will evaluate ctDNA and exosomal markers. Aim #3: To evaluate pancreatic fluid and serum markers as tests to detect PanIN-3 and/or pre-clinical pancreatic cancer among high-risk individuals undergoing pancreatic screening and surveillance. We will develop a tissue repository of precious samples to aid in the evaluation of candidate pancreatic cancer markers, including samples from high-risk subjects and PanIN-3 lesions.

Resources for Sharing (e.g., description of cohorts, technologies)

The CAPS sites are primarily following high-risk individuals, but we are also enrolling patients with incidentally identified pancreatic cysts and patients who are undergoing pancreatic evaluation routinely for non-pancreatic indications (such as those who undergo endoscopic ultrasound for other upper GI indications). The Johns Hopkins group also has an extensive biobank of tissues and blood samples from patients who have undergone pancreatic reseection. Technologies such as digital next-generation sequencing developed in the Goggins lab will be used to detect low-abundance mutations.

Opportunities for Collaboration

There are a number of other CAPS sites who are ongoing collaborators with the CAPS program including Dr. James Farrell at Yale University and Dr. Fay Kastrinos at Columbia University. Several other sites have approached us and are interested in collaborating as part of the CAPS program. In addition, screening centers across the world have joined the International CAPS registry to share data and experience.