Abstract 769: Evaluating the diagnostic burden of tumor localization strategies for multi-cancer early detection tests
Authors: Tyson Christopher , O'Donnell Elizabeth K. , Fishman Elliot , Parthasarathy Vijay , Beer Tomasz M. 
Published: April 2023

Abstract
Introduction: Blood-based multi-cancer early detection (MCED) tests in development may substantially expand the number of “screenable” cancers. Defining an optimal approach for tissue of origin (TOO) localization in individuals with cancer-suspected MCED results is critical. Two recent prospective trials employed differing and distinct approaches for conducting TOO evaluation. The PATHFINDER study conducted molecular TOO testing for localization and DETECT-A used upfront neck-to-thigh imaging-first to rule-in or rule-out and then to localize the cancer. Using mathematical modeling, we examined the diagnostic burden of each approach.
Methods: Building upon a published quantitative framework, a mathematical expression for diagnostic burden was derived as a function of positive predictive value (PPV) of the detection module, TOO accuracy of the localization module, and number of procedures associated with each diagnostic outcome; the latter were estimated from established clinical guidelines with diagnostic procedures narrowly selected for molecular TOO calls. We then explored the relationship between PPV, TOO accuracy, and diagnostic burden. Imaging and molecular TOO strategies were compared by estimating absolute difference in diagnostic burden across a range of performance levels.
Results: With a molecular TOO strategy we estimate 2.1 procedures to reach diagnostic resolution for correctly-localized true positives, 4.4 for incorrectly-localized true positives, and 4 for false positives; with imaging TOO, 2.75 procedures for true positives and 2.4 for false positives. Across the entire spectrum of performance for both detection and localization, a strategy with molecular TOO resulted in a mean diagnostic burden of 3.6 (Var 0.198); with imaging TOO, 2.6 (Var 0.010). The breakeven curve defined by zero absolute difference between strategies shows that molecular TOO has lower burden for only 4.5% of all possible PPV and TOO accuracy combinations and that 79% PPV is required for a 90% accurate molecular TOO strategy to be less burdensome than imaging TOO.
Conclusions: This analysis demonstrates that imaging TOO is more efficient than molecular TOO across 95.5% of all possible PPV and TOO accuracy combinations. Molecular TOO can reduce diagnostic burden when localization accuracy is very high or overall test PPV is very high. This analysis highlights the need for ongoing innovation in cancer detection and cancer localization as separable parts of the MCED test. In summary, the use of advanced imaging first to determine TOO as part of an MCED screening approach is likely less burdensome than a broad molecular TOO approach, although a nuanced approach to molecular TOO based on probability and type of cancer may contribute to diagnostic efficiency.
Citation Format: Christopher Tyson, Elizabeth K. O'Donnell, Elliot Fishman, Vijay Parthasarathy, Tomasz M. Beer. Evaluating the diagnostic burden of tumor localization strategies for multi-cancer early detection tests [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 769.