A Cost-Effective Two-Step Approach for Multi-Cancer Early Detection in High-Risk Populations.

abstractIn population-wide cancer screening, three key issues need to be focused on: the number of cancer cases identified, the number of false positives, and the cost. OncoSeek is a multi-cancer early detection (MCED) test using seven protein tumor markers and artificial intelligence. SeekInCare is an MCED test that integrates the seven protein tumor markers and four cancer genomic features from cell-free DNA by shallow whole-genome sequencing. In a two-step approach, the initial screening is conducted using OncoSeek, and SeekInCare is then used as the secondary test for individuals who tested positive by OncoSeek. We simulated a screening in five million adults ages ≥50 years with a cancer incidence rate of 1.9%. Whereas at 91.0% specificity OncoSeek had 441,450 false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although SeekInCare and Galleri identified more cancer cases (32,015 and 27,455, respectively) than the two-step MCED (21,280), their total costs reached $3,750 million and $4,745 million, respectively. As the positive predictive value of two-step MCED (38.3%) was comparable with SeekInCare (27.7%) and Galleri (38.3%), it reduced the cost by 5.3-fold and 6.6-fold, respectively, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected was $117,133 for SeekInCare and $172,828 for Galleri, which were 3.5-fold and 5.2-fold higher, respectively, than the two-step MCED ($33,534). The two-step approach not only significantly reduces false positives but also cuts down the screening cost substantially, making it a cost-effective strategy for population-wide cancer screening. SIGNIFICANCE: Large-scale screening inevitably leads to significant financial burdens on the healthcare system, which is a key factor constraining nationwide screenings. The two-step MCED approach not only maintains comparable performance but also substantially alleviates financial strains compared with the direct use of next-generation sequencing-based MCED tests for massive screenings.