Toward Scalable Early Cancer Detection: Evaluating EHR-Based Predictive Models Against Traditional Screening Criteria.

Current cancer screening guidelines cover only a few cancer types and rely on narrowly defined criteria such as age or a single risk factor like smoking history, to identify high-risk individuals. Predictive models using electronic health records (EHRs), which capture large-scale longitudinal patient-level health information, may provide a more effective tool for identifying high-risk groups by detecting subtle prediagnostic signals of cancer. Recent advances in large language and foundation models have further expanded this potential, yet evidence remains limited on how useful EHR-based models are compared with traditional risk factors currently used in screening guidelines. We systematically evaluated the clinical utility of EHR-based predictive models against traditional risk factors, including gene mutations and family history of cancer, for identifying high-risk individuals across eight major cancers (breast, lung, colorectal, prostate, ovarian, liver, pancreatic, and stomach), using data from the All of Us Research Program, which integrates EHR, genomic, and survey data from over 865,000 participants. Even with a baseline modeling approach, EHR-based models achieved a 3- to 6-fold higher enrichment of true cancer cases among individuals identified as high risk compared with traditional risk factors alone, whether used as a standalone or complementary tool. The EHR foundation model, a state-of-the-art approach trained on comprehensive patient trajectories, further improved predictive performance across 26 cancer types, demonstrating the clinical potential of EHR-based predictive modeling to support more precise and scalable early detection strategies.