Molecular Cancer Signal Localization in MCED Testing Minimizes Radiation and Imaging Burden Compared with Whole-body Imaging Approaches

Efficient strategies for diagnostic evaluation of multi-cancer early detection (MCED) tests are needed to distinguish true-positive from apparent false-positive (FP) test results. Extending a previously published model, we compared two post-positive MCED test diagnostic evaluation strategies: a cancer signal origin (CSO)-guided approach with repeat MCED testing to resolve FPs (CSO-Retest strategy) vs a Whole-body imaging (WBI)-Only strategy employing whole-body computed tomography (WBCT) followed by positron emission tomography (PET)/CT scans to resolve FPs. Analyses evaluated 2 scenarios with different test performance characteristics and specificities, with number of imaging procedures required and radiation exposure for each strategy as outcomes measures. The CSO-Retest strategy resulted in 10- to 20-fold reduction in use of WBCT/PET/CT vs the WBI-Only strategy across both scenarios. A 1% reduction in WBI-Only test specificity from 99.5% to 98.5% led to a >3-fold increase in FPs, and more than doubled WBI requirements. Estimated radiation exposure for initial diagnostic evaluations for the CSO-Retest strategy were 0-26.1 mSv, while all initial diagnostic evaluations for the WBI-Only strategy carried an obligatory exposure of 28 mSv. For the 50% of CSO predictions requiring initial imaging, dose exposure ranged from 0.28 mSv (mammography) to 26.1 mSv (triple-phase renal CT), or 1% to 93% of the dose required for the WBI-Only strategy. The results suggest CSO-guided diagnostic strategies incorporating targeted workups and MCED retesting markedly reduces radiation exposure compared to a WBI-only approach, and small changes in MCED test specificity lead to significantly more unnecessary workups.