Comprehensive Systematic Evidence Review of the Clinical Utility of Polygenic Risk Scores for Hepatocellular Carcinoma and Pancreatic Cancer Risk Assessment

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Project Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-046. Hepatocellular carcinoma (HCC) and pancreatic cancer, as leading causes of cancer-related mortality in the United States, urgently necessitate effective early detection and prevention strategies to transform patient outcomes. The advent of polygenic risk scores (PRS) in genetic research represents a groundbreaking opportunity to refine risk assessment and clinical management for HCC and pancreatic cancer. This project will conduct a state-of-the-science systematic evidence review to critically examine the clinical utility of PRS for these malignancies, providing a solid foundation for informed decision-making in clinical practice. Our multidisciplinary team, boasting extensive expertise in systematic reviews and a diverse array of fields—biomedical informatics, biostatistics, statistical genetics, cancer epidemiology, clinical trials design, oncology, and cancer control—will rigorously apply established knowledge synthesis guidelines to execute the proposed supplement. This meticulous approach will enable us to identify PRS models poised for clinical trials, evaluate their limitations and challenges, and determine their clinical utility. Furthermore, we will assess the potential benefits and harms of PRS implementation in clinical practice, explore innovative strategies to integrate PRS with non-PRS models for enhanced cancer risk prediction and propose optimal study designs and methodologies for evaluating PRS efficacy and effectiveness. Our robust framework for conducting this comprehensive systematic evidence review comprises five essential steps: 1) framing the questions, 2) identifying relevant work, 3) assessing the quality of studies, 4) summarizing the evidence, and 5) interpreting the findings. Our comprehensive search strategy will encompass major biomedical and health sciences electronic databases, the grey literature, and online PRS repositories, ensuring a thorough analysis. Employing the Prediction Model Risk of Bias (ROB) Assessment Tool (PROBAST), we will rigorously assess reviewed studies’ qualities and applicability. Upon completion, this project will generate indispensable evidence on the potential benefits, harms, and clinical utility of PRS implementation for HCC and pancreatic cancer risk assessments. Our findings will inform recommendations for future research directions and contribute to developing evidence-based guidelines for PRS use in cancer prevention, early detection, and management, ultimately leading to improved patient outcomes in a new era of personalized cancer care.