Srivastava, Sudhir

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

Abstract Objective: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded EDRN defined phase 2 Biomarker Bakeoff study of eight promising biomarker panels using pancreatic cancer ductal adenocarcinoma (PDAC) case and general population healthy control samples from three institutions. The scientific questions were to determine whether panels could discriminate PDAC cases from controls with Receiver Operating Characteristic Area Under the Curve (AUC) > 0.8, compare panel performance head-to-head via 95% confidence intervals (CI), and determine whether the panel improved upon serum CA19-9 alone. A secondary goal was to perform modeling to discover a new panel consisting of individual biomarkers. Methods: Eligible biomarkers were required to have had a prior EDRN defined phase 2 validation study published and be ready for validation in a sample set from multiple institutions. Three institutions submitted a total of 140 cases and 140 controls frequency matched to cases on age and sex. Four consortium member institutions submitted for validation eight panels consisting of ten plasma, serum and DNA genotyping biomarkers in addition to CA19-9. Locked panel formulas were submitted prior to specimen distribution. The primary metric was AUC with bootstrapped 95% CIs. LASSO penalized regression was used for exploratory panel building. Nested cross validation and internal-external validation were performed, and optimism-corrected performance estimates were computed. Results: The overall sample (N=280) was 51% female, median age of 67 years, and 94% were of non-Hispanic white race and ethnicity. Controls had median BMI 27.3, 56% never smokers, and 12% type II diabetes mellitus (DM2); cases (staged I to IV) had median BMI 26.6, 42% never smokers, and 26% DM2. Overall panel AUC estimates ranged from 89.9 to 96.3 and all were significantly larger than the null hypothesis value of 0.8 (p<0.05). The apparent serum CA19-9 AUC was 91.7 (87.8, 95.6). Two panels were significantly different from serum CA19-9, a panel with FUT2/3 genotype with serum CA19-9 (p=0.002) and a panel containing tissue factor pathway inhibitor (TFPI), tenascin C (TNC), and plasma CA19-9 (p=0.01). In subset analyses by PDAC stage, no panel improved upon the null hypothesis value of 0.8 in stage I (p>0.05), all panels improved upon the null hypothesis value of 0.8 in stage II and III (p<0.05), and only serum CA19-9 did not improve upon the null hypothesis value of 0.8 in stage IV. All biomarkers but two microRNAs were retained in a LASSO model that had optimism corrected AUC=96.4 (95% CI: 94.0, 98.9). Conclusions: All submitted panels performed well overall in this blinded study, with the panel containing FUT2/3 genotype performing the best. Panel discovery improved upon serum CA19-9, though optimism corrected AUC 95% CIs overlap with those of apparent CA19-9 performance. Further work is needed to prioritize promising biomarkers and to improve detection of early stage PDAC. Citation Format: Ann L. Oberg, William R. Bamlet, Grant Izmirlian, Seetharaman Balasenthil, Surinder K. Batra, Masataka Hayashi, Daniel Herman, Michael A. Hollingsworth, Maneesh Jain, Ann M. Killary, Brianna M. Krusen, Suyu Liu, Gopalakrishnan Natarajan, Subrata Sen, Lynette M. Smith, Sudhir Srivastava, Brian M. Wolpin, Kenneth S. Zaret, Michael G. Goggins. Pancreatic Cancer Detection Consortium biomarker bake-off: A consortium Phase 2 blinded biomarker validation and panel discovery study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B070.

Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case‐control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.

Abstract High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

Abstract Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP—controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.

Abstract The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to ( a ) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD ( define ), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients ( enrich ), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms ( find ). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

Abstract Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, “Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study,” that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.