Cost-effective colorectal cancer screening in the United States: Comparative analyses of four molecular tests.

10525 Background: Colorectal cancer (CRC) screening in the United States is costly, largely driven by expensive colonoscopy procedures. In 2021, 22. 3 million screening tests were performed, costing 27. 5 billion; colonoscopy alone accounted for 9. 2 million tests and 23. 7 billion in expenditure (54. 8% of the 43. 2 billion spent on five major cancers). This study compared available molecular tests to identify an approach that balances performance and cost as a primary alternative to colonoscopy. Methods: Four molecular tests were evaluated: two FDA-approved stool-based (fecal immunochemical tests FIT and multitarget stool DNA test Cologuard) and two blood-based (the FDA-approved cfDNA-based Shield and the multiomics-based SimpleScreen). Performance data came from published literature and clinical trials (NCT04136002, NCT01397747, NCTO4369053). Cost analyses used 2021 U. S. screening volumes: FIT, Cologuard, and colonoscopy costs were based on 2021 fee schedules, Shield pricing on Medicare rates; SimpleScreen was excluded due to cost unavailability. Results: For CRC, Cologuard had the highest sensitivity (92. 3%) but lower specificity (84. 4%), whereas FIT showed lower sensitivity (73. 8%) but the highest specificity (93. 4%). Shield and SimpleScreen showed intermediate sensitivities (83. 1%, 79. 2%) and specificities (89. 2%, 91. 1%). For advanced precancerous lesions, blood-based tests showed minimal detection power, with post-test probabilities (equal to PPV) close to pre-test prevalence (Shield 17. 4% vs 14. 3%; SimpleScreen 13. 5% vs 9. 5%; post/pre ratios 1. 2 and 1. 5). In contrast, stool-based tests modestly increased post-test probabilities: Cologuard 20. 7% vs 7. 6%, post/pre ratios 4. 0; and FIT 27. 6% vs 7. 6%, post/pre ratios 4. 4, indicating preventive potential and supporting their use as alternatives to colonoscopy. Cost analysis further identified FIT as the most cost-effective alternative, with the lowest per-case cost of 57, compared to 651 for Cologuard, 2, 571 for colonoscopy, and 1, 495 for Shield. Replacing colonoscopy with FIT for the 9. 2 million current colonoscopy screenings in 2021 would reduce CRC screening expenditures from 27. 5 billion to 4. 3 billion (84. 2% reduction). Comparatively, Cologuard lower costs to 9. 8 billion (64. 3% reduction) and Shield to 17. 6 billion (36. 0% reduction). Nationally, the overall cost for the five major cancers was reduced to 20. 0 billion, resulting in a saving of 23. 2 billion, which could be reallocated to future multi-cancer screening programs to expand population coverage. Conclusions: FIT provides the best balance of performance, preventive potential, and cost-effectiveness. By reducing colonoscopy demand and national screening costs while maintaining adequate detection, it supports sustainable population-wide screening and warrants consideration in guidelines and reimbursement policies.