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Background  Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be.    Methods  The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65–0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40–60 years), end age (70–85 years), and interval (1–20 years).    Results  With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40–80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation.    Conclusions  Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening.

Cost-Effectiveness of Risk-Stratified Colorectal Cancer Screening Based on Polygenic Risk: Current Status and Future Potential