Tumor localization strategies of multi-cancer early detection tests: a quantitative assessment

Background: Multi-cancer early detection (MCED) tests may expand cancer screening. Characterizing diagnostic resolution approaches following positive MCED tests is critical. Two trials employed distinct resolution approaches: a molecular signal to predict tissue of origin (TOO) and an imaging-based diagnostic strategy. This modeling study characterizes diagnostic journeys and impact in a hypothetical population of average risk MCED eligible patients.

Methods: A mathematical expression for diagnostic burden was derived using positive predictive value (PPV), molecular TOO localization accuracy, and numbers of procedures associated with each diagnostic outcome. Imaging-based and molecular TOO-informed strategies were compared. Excess lifetime cancer risk due to futile radiation exposure was estimated using organ-specific diagnostic imaging radiation doses.

Results: Across all PPVs and localization performances, a molecular TOO strategy resulted in a higher diagnostic burden: 3.6 procedures [SD 0.445] vs 2.6 procedures [SD 0.100] for the imaging strategy. Estimated diagnostic burden was higher for molecular TOO in 95.5% of all PPV and TOO accuracy combinations; ≥79% PPV and 90% accuracy would be required for a molecular TOO-informed strategy to be less burdensome than imaging. The maximum rate of excess cancer incidence from radiation exposure for MCED false positive results (individuals aged 50-84) was 64.6/100,000 (annual testing, 99% specificity), 48.5/100,000 (biennial testing, 98.5% specificity), and 64.6/100,000 (biennial testing, 98% specificity).

Conclusions: An imaging-based diagnostic strategy is more efficient than a molecular TOO-informed approach across almost all PPV and TOO accuracy combinations. The use of an imaging-based approach for cancer localization can be efficient and low-risk compared to a molecular-informed approach.