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.

The PATHFINDER Study: Assessment of the Implementation of an Investigational Multi-Cancer Early Detection Test into Clinical Practice.

To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer "signal") and a cancer signal origin (i.e., tissue of origin). Participants with a "signal detected" will undergo further diagnostic evaluation per guiding physician discretion; those with a "signal not detected" will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a "signal detected" result is expected to be 106 (87-128). Subsequent diagnostic evaluation is expected to detect 52 (39-67) cancers. The positive predictive value of the MCED test is expected to be 49% (39-58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.