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

Introduction Blood-based multi-cancer early detection (MCED) tests may expand the number of screenable cancers. Defining an optimal approach to diagnostic resolution for individuals with positive MCED test results is critical. Two prospective trials employed distinct diagnostic resolution approaches; one employed a molecular signal to predict tissue of origin (TOO) and the other used an imaging-based diagnostic strategy. Using mathematical modeling, we compared the diagnostic burden of each approach and characterized the risk of excess cancer incidence that may be attributable to radiation exposure associated with a false positive (FP) MCED test result and an imaging-based diagnostic strategy. Methods A mathematical expression for diagnostic burden was derived using MCED test positive predictive value (PPV), molecular TOO localization accuracy, and the expected number of imaging procedures associated with each diagnostic outcome. Imaging and molecular TOO strategies were compared by estimating diagnostic burden across a wide range of MCED PPVs and TOO accuracies. Organ-specific radiation dose for diagnostic imaging was extracted from the literature and used as input to National Cancer Institute RADRat tool for estimating excess lifetime cancer risk due to radiation exposure. Results For the molecular TOO diagnostic approach, an average of 2.1 procedures are required to reach diagnostic resolution for correctly-localized TPs, 4.4 procedures for incorrectly-localized TPs, and 4 procedures for FPs, vs. an average of 2.75 procedures for TPs and 2.4 for FPs with an imaging-based diagnostic strategy. Across the entire range of possible PPV and localization performance, a molecular TOO strategy resulted in a higher mean diagnostic burden: 3.6 procedures (SD 0.445) vs. 2.6 procedures (SD 0.1) for the imaging strategy. Predicted diagnostic burden was higher for molecular TOO in 95.5% of all possible PPV and TOO accuracy combinations; 79% or higher PPV would be required for a 90% accurate molecular TOO strategy to be less burdensome than imaging. The maximum rate of excess cancer incidence from radiation exposure for FP results from MCED screening between the ages of 50-84 was estimated at 64.6 per 100,000 (annual testing, 99% specificity), 48.5 per 100,000 (biennial testing, 98.5% specificity), and 64.6 per 100,000 (biennial testing, 98% specificity). Conclusions This analysis demonstrates that an imaging-based diagnostic strategy is more efficient than a molecular TOO-informed approach across 95.5% of all possible MCED 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-based approach.