Abstract 5145: Project Survival®: Discovery of a molecular-clinical phenome biomarker panel to detect pancreatic ductal adenocarcinoma among at risk populations using high-fidelity longitudinal phenotypic and multi-omic analysis
Authors: Grund Eric M. , Moser A. James , DeCicco Corinne L. , Chand Nischal M. , Perez-Melara Genesis L. , Miller Gregory M. , Shah Punit , Bussberg Valarie , Tolstikov Vladimir , Sarangarajan Rangaprasad , Granger Elder , Narian Niven , Kiebish Michael A. 
Published: June 2022

Abstract
Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for pancreatic ductal adenocarcinoma (PDAC). PDAC is expected to be the second leading cause of cancer death and has a dismal 5 year survival rate of 10%. There is an urgent unmet need to detect the disease at an early stage and stratify patients into more effective treatment regimens within clinically meaningful timeframes. To accomplish this, robust quality controlled OMIC molecular profiling platforms and analytic solutions need to be deployed into precision medicine protocols to discover actionable biomarkers. Project Survival® is a multicenter (n=6), prospective biomarker study (NCT 02781012) of PDAC and relevant controls combining high-fidelity longitudinal phenotypic characterization, multi-omic profiling (proteomics, signaling lipidomics, structural lipidomics, and metabolomics), and agnostic Bayesian artificial intelligence network inference (bAIcis®) to discover biomarkers with diagnostic and therapeutic utility. This study utilizes a systems medicine approach for translational biomarker discovery by performing analysis of matched subject sera, plasma, buffy coat, saliva, urine, and tumor/adjacent normal tissues and integrating them with the respective full clinical annotation using the BERG Interrogative Biology® platform. Multiple longitudinal time points were taken over the course of the six-year timeline enabling dynamic modeling. Utilizing the Project Survival® molecular and clinical data, we have analyzed and integrated baseline samples from 121 at risk patients and 279 patients with PDAC. Samples were randomized and analyzed over the course of recruitment allowing for agnostic discovery and integration to determine diagnostic utility. Discovery analysis identified 123 potential molecular markers, of which, four demonstrated a combined AUC of 0.85, PPV 0.83, NPV 0.72, and OR 13.1. In parallel, 4 non-canonical clinical measurements were assessed for diagnostic utility providing an AUC 0.79, PPV 0.84, NPV 0.72 and OR 13.2. Combining molecular and clinical features demonstrated an AUC of 0.9, PPV 0.9, NPV 0.77, OR 29.2, and p-value 1.4 E-40. Molecular markers revealed no treatment associated expression effects. Taken together, these marker panels demonstrate diagnostic utility to detect PDAC and will be further validated using robust bioanalysis methods as well as in an independent cohort of samples to provide enhanced insight into their positioning in the diagnostic landscape for PDAC.
Citation Format: Eric M. Grund, A. James Moser, Corinne L. DeCicco, Nischal M. Chand, Genesis L. Perez-Melara, Gregory M. Miller, Punit Shah, Valarie Bussberg, Vladimir Tolstikov, Rangaprasad Sarangarajan, Elder Granger, Niven Narian, Michael A. Kiebish. Project Survival®: Discovery of a molecular-clinical phenome biomarker panel to detect pancreatic ductal adenocarcinoma among at risk populations using high-fidelity longitudinal phenotypic and multi-omic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5145.