Pancreatic Cancer Detection Consortium: Research Units

Pancreatic cystic neoplasm (PCN) represents a common incidental finding in the population. Branch-duct intraductal papillary mucinous neoplasms (IPMN), the most common incidentally discovered PCN, have a risk of malignancy approaching 15%within 15 years of diagnosis. The performance of existing guidelines for identifying early cancer is poor, and results in both surgical overtreatment and missed opportunities for early diagnosis. Effective screening biomarkers are needed to accurately differentiate high-risk PCN that require close surveillance from low risk lesions with little chance to progress. In this proposal, we will test and validate of three novel blood-based biomarkers and one cyst fluid biomarker for the detection of early PDAC in patients with PCN. The proposed markers, developed in both academic and industry settings, show promise in preliminary studies, with sensitivity and specificity sufficiently high to warrant further evaluation. We will incorporate prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) standards to rigorously test the performance of these biomarkers with samples collected from three cohorts: 1) stage I/II PDAC and controls; 2) Patients with PCN who undergo surgical resection; 3) Patients with PCN ≥ 2.5 cm or main pancreatic duct ≥ 5 mm under surveillance with serial imaging and sample collection. We will test performance of the biomarkers individually, and as part of multi-variable models in combination with each other, with the added information of germline testing and clinical laboratory values (CA19 -9, HbA1c), and with specific PDAC risk factors (smoking status, alcohol consumption, diabetes, pancreatitis history). Key components of our research strategy to tackle this recalcitrant problem include: 1) rigorous testing of several promising blood-based biomarkers, individually and in combination, through a unique collaboration between industry and academic partners; 2) testing of a novel platform for advanced cyst fluid analysis for early detection of PDAC and comparison of its performance to blood-based biomarkers; 3) a large number of retrospective and prospective samples interrogated using the PRoBE design, with statistical rigor for biomarker validation; 4) resources leveraged from the established Pancreatic Cancer Early Detection (PRECEDE) Consortium including standardized collection of germline genetic testing, clinical, and laboratory data with blood and cyst fluid biosampling in accordance with PCDC protocols; 6) collection of a large set of de-identified partnering pancreatic images (MRI/MRCP, CT and EUS) and digitized pathology slides on a funded cloud-based platform for collaborative opportunities using artificial intelligence and machine learning strategies, and 7) multimodal data integration for model development. Longitudinal biospecimens will be shared with the PCDC to support the Signature Cohorts, and de-identified stored images (MRI, EUS, digitized pathology) will be available for collaborative consortium efforts.

To diagnose pancreatic ductal adenocarcinoma (PDAC) in its precursor or early stages, novel screening tools must apply liquid biomarkers with localization using novel imaging strategies in high-risk populations. The OHSU PCDC Research Unit proposes three aims highlighting its multidisciplinary strengths in cancer biology, imaging, and implementation science. The overarching theme of the proposed research focuses on sensitivity, feasibility, and patient acceptability. Our sensitive blood-based screening test can be applied with minimal quantities of blood and is easily modifiable based on further discoveries. If positive, this would prompt application of a feasible, non-contrast, and robust magnetic resonance imaging (MRI) protocol that augments MRI and magnetic resonance chlangiopancreatography (MRCP) of the pancreas with quantitatively rigorous MR Fingerprinting (MRF). MRF can simultaneously quantify parameters that are associated with fibrosis and inflammation (T1, T2, and T1p). We hypothesize that these parameters are upregulated in high-grade dysplasia (e.g., high-risk intraductal papillary mucinous neoplasms (IPMNs) and grade 2-3 pancreatic intraepithelial neoplasia (PanIN)) and early-stage pancreatic ductal adenocarcinoma (PDAC). Further, quantitative MRI will reduce the high interobserver variability of MR interpretation and requirement for time consuming and technically complex MR protocols that can be challenging to implement outside of pancreas referral centers. If successful, MRF may obviate the need for Gadolinium based contrast agents in screening populations undergoing frequent MRI and MRCP. Finally, we will increase enrollment of high-risk individuals into PCDC Signature Cohorts, through leveraging an existing large, statewide cohort, Healthy Oregon Project. Further, we will work collaboratively with our Community Outreach, Research & Engagement team to understand and address barriers to engagement in PDAC surveillance among members of minoritized communities, particularly those who suffer disproportionally from PDAC. These efforts will ensure participation among underrepresented populations who are least likely to take part in cancer screening while contributing to the consortium mission of expanding PCDC Signature Cohorts. The OHSU Research Unit is prepared to meaningfully collaborate with the PCDC Consortium by sharing existing resources from the Oregon Pancreas Tissue Registry (> 3,700 patients enrolled), OHSU PRECEDE consortium subjects (> 100 high-risk individuals enrolled to date) and potential expansion to other PRECEDE centers, and the OHSU High Risk Pancreatic Cancer Screening clinic (> 750 unique patients who have completed at least one screening test). In addition, our team includes experts in implementation science who have designed and activated the Healthy Oregon Project, an app-based platform that allows at-home acquisition of genetic data through mail-in kits and population-based interaction to find and interact with high-risk individuals.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with an overall 5-year survival of 11%. Due to its asymptomatic nature and lack of methods for early detection, the majority of PDAC patients (> 85%) present with non-localized tumors. This highlights the need to detect PDAC at an earlier, localized stage. Intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) offer a unique opportunity to identify premalignant lesions to serve as targets for early detection strategies. Dr. Randall Brand and others proposed a two-step surveillance approach for early detection of PDAC: 1) identification of high-risk populations through clinical evaluation with an elevated PDAC prevalence close to or above 1% and 2) development of serum biomarker(s), for repeated testing at intervals to detect subjects in surveillance with a rising risk of PDAC (prevalence ~ 10%) for additional imaging. The goal of this proposal is to identify serum biomarkers and develop in vitro diagnostic multivariate index assays (IVDMIAs) and incorporate them into an “early detection through surveillance” workflow for the detection of early-stage PDAC and its precursor lesions. The intended use of these IVDMIAs are 1) to assist in the clinical evaluation of high-risk subjects to be included in surveillance for the early detection of PDAC, and 2) to detect rising risk of PDAC or high-risk IPMN in the longitudinal evaluation of subjects in surveillance. The project has five specific aims: 1. To discover and develop serum-based PDAC early detection biomarkers through integrated proteomic analysis of serum/tissue samples from early-stage PDAC, IPMN, and benign and healthy controls using a multimodal and phased approach with corroborative supporting evidence from tissue-based proteomic analysis and immunohistochemical (IHC) verification. 2. To use a by-design approach driven by predefined intended uses that are both clinically meaningful and practically feasible to develop and evaluate serum biomarkers for IVDMIAs. 3. To develop and optimize multiplex analytical assays for selected biomarkers and apply them to generate high-quality biomarker data for IVDMIA development and clinical evaluation. 4. To collect and assemble large clinical specimen sample sets for both IVDMIA algorithm development and independent validation. 5. To participate in collaborative activities with other PCDC-RUs. To be successful, the proposed project requires a multi-disciplinary, systems approach and the support of critical technology, data science, and clinical specimen resources. Our team is a unique ensemble of experts in PDAC and IPMN pathology for early detection, clinical chemistry/assay development, clinical proteogenomics, and statistical/machine learning for IVDMIA development. Most importantly, the team members individually and collectively all have a long-standing history of active research with accomplishments in biomarker development and translation into clinical tests, including the first proteomic IVDMIA test cleared by the FDA. We believe with these innovative yet practical approaches, our RU offers the best opportunity to make significant contributions to the PCDC network and address critical clinical unmet needs.