Assessment of impending pancreatic cancer in a cohort of new onset diabetes on basis of biomarker trajectory

PURPOSE: To assess the predictive performance of panel protein biomarkers as well as an established algorithm that considers repeat biomarker testing for risk prediction of PDAC among a prospective cohort of patients with New-onset diabetes. PATIENTS AND METHODS: A panel of protein biomarkers (CA19-9, CA125, CEA, LRG1, REG3A and TIMP1) were assayed in 6,516 serially collected pre-diagnostic plasma samples from 2,121 NOD patients from the Consortium of Chronic Pancreatitis Diabetes and Pancreatic Cancer (CPDPC)-initiated NOD study who completed the 3-year study follow-up period. The specimen set included 25 pre-diagnostic samples from the 12 PDAC cases diagnosed during study follow-up. We applied a single threshold (ST) method, which considers biomarker levels at a single time point, as well as a previously established parametrical empirical Bayes (PEB) algorithm, which considers prior biomarker measurements, with case calls made based on pre-specified cutoffs corresponding to 1% 1-year risk. Resultant biomarker data as well as case calls were provided to the EDRN Data Management and Coordinating Center as part of a Prospective-sample-collection-Retrospective-Blinded-Evaluation (ProBE)-compliant Phase 3 biomarker validation study. Area under the Receiver Operating Characteristic Curves (AUC), sensitivity, specificity, population-level positive predictive value (PPV), and negative predictive value (NPV) are reported. RESULTS: The 3-year incidence of PDAC in the NOD cohort was 0.57%. When considering PDAC vs non-cancer controls, respective AUCs of individual protein biomarkers ranged from 0.52-0.94, with CA19-9 achieving the highest overall performance of 0.94 (95% CI: 0.86-1.00). At the pre-defined 1% 1-year risk threshold, CA19-9 yielded sensitivity of 83.3% at 97.2% specificity. Additional markers CEA, CA125, and TIMP1 demonstrated sensitivity of 33.3%, 41.7%, and 8.3%, respectively. In a subset of patients, CA19-9 first tested positive at a median (interquartile range [IQR]) of 7 months (4 to 14 months) prior to clinical PDAC diagnosis. Of the two PDAC cases missed by CA19-9 using the ST method, one (diagnosed with stage III PDAC) was detected using the PEBCA19-9 algorithm. CONCLUSION: In the setting of adult new onset diabetes, CA19-9 is a readily available and promising biomarker that can be leveraged for earlier detection of an underlying pancreatic cancer. Additional protein biomarkers may improve sensitivity for earlier detection of PDAC among cases with low CA19-9.