Integrating multi-cancer early detection into cancer screening programs in the United States: A cost-effectiveness modeling study.

10523 Background: In 2021, standard-of-care (SoC) screening for breast, cervical, colorectal, lung, and prostate cancers in the United States cost $43.2 billion to detect 197,773 cancers, with colonoscopy—used as a primary colorectal screening modality—accounting for $23.7 billion, the largest share of expenditures (54.9%). Multi-cancer early detection (MCED) blood tests could complement SoC single-cancer early detection (SCED) screening but may substantially increase overall costs if implemented without concurrent redesign of screening pathways. Methods: A static decision model used 2021 U.S. SoC screening volumes and costs, 2020 Census data, cancer-specific incidence in high- and low-risk groups, and published SCED and MCED performance to simulate 75.6 million unique screened individuals after adjusting for overlap across programs. We evaluated (1) SoC alone, (2) SoC plus either a low-cost two-step MCED assay (OnceSeek followed by SeekInCare; “OncoSeek Duet”, $143/person) or a higher-priced cfDNA methylation-based MCED test (Galleri, $949/person), and (3) a budget-neutral strategy replacing primary colonoscopy with FIT, designated as SCED 2.0, with savings reinvested to fund OncoSeek Duet for all screened individuals. Results: SoC alone detected 197,773 cancers (262 per 100,000) with a PPV of 0.7% at a total cost of $43.2 billion, or $218,276 per cancer detected. Adding OncoSeek Duet increased detections to 398,586 (527 per 100,000; 2.0-fold), PPV to 43.3% (61.9-fold increase) and total cost to $54.0 billion (25.0% increase), reducing cost per cancer to $135,429, while expanding detection to 9 additional cancer types beyond the 5 SoC targets. Adding Galleri yielded 572,223 cancers (757 per 100,000; PPV of 60.7%) at $114.9 billion total cost (2.7-fold increase) and $200,823 per cancer, improving yield but with markedly higher budget impact than OncoSeek Duet. SCED 2.0 cut costs to $20.0 billion (2.2-fold decrease), reduced cost per cancer to $106,876, saved $23.1 billion, and yielded 187,509 detections (5.2% decrease). Reinvesting these savings to provide OncoSeek Duet for all restored and expanded detection to 391,022 cancers (2.1-fold increase), maintained a high PPV of 42.9%, incurred $78,899 per cancer and produced a $12.3 billion surplus without increasing overall screening expenditure. Conclusions: In this U.S. modeling analysis, integrating MCED into SoC screening substantially increased cancers detected and lowered cost per cancer, particularly when using lower-cost OncoSeek Duet. Optimizing high-cost SCED components, such as colonoscopy, can fully finance population-wide MCED while preserving or improving efficiency, supporting a value-based, budget-neutral path for MCED implementation in national screening programs.