Clinical performance and utility: A microsimulation model to inform the design of screening trials for a multi-cancer early detection test.

Objectives: Designing cancer screening trials for multi-cancer early detection (MCED) tests presents a significant methodology challenge, as natural histories of cell-free DNA-shedding cancers are not yet known. A microsimulation model was developed to project the performance and utility of an MCED test in cancer screening trials.

Methods: Individual natural history of preclinical progression through cancer stages for 23 cancer classes was simulated by a stage-transition model under a broad range of cancer latency parameters. Cancer incidences and stage distributions at clinical presentation in simulated trials were set to match the data from Surveillance, Epidemiology, and End Results program. One or multiple rounds of annual screening using a targeted methylation-based MCED test (Galleri^Ⓡ) was conducted to detect preclinical cancers. Mortality benefit of early detection was simulated by a stage-shift model.

Results: In simulated trials, accounting for healthy volunteer effect and varying test sensitivity, positive predictive value in the prevalence screening round reached 48% to 61% in 6 natural history scenarios. After 3 rounds of annual screening, the cumulative proportions of stage I/II cancers increased by approximately 9% to 14%, the incidence of stage IV cancers was reduced by 37% to 46%, the reduction of stages III and IV cancer incidences was 9% to 24%, and the reduction of mortality reached 13% to 16%. Greater reductions of late-stage cancers and cancer mortality were achieved by five rounds of MCED screening.

Conclusions: Simulation results guide trial design and suggest that adding this MCED test to routine screening in the United States may shift cancer detection to earlier stages, and potentially save lives.