Predictive Performance of Cell-Free Nucleic Acid-Based Multi-Cancer Early Detection Tests: A Systematic Review

Abstract Background Cancer-screening tests that can detect multiple cancer types, or multi-cancer early detection (MCED) tests, have emerged recently as a potential new tool in decreasing cancer morbidity and mortality. Most MCED assays are based on detecting cell-free tumor DNA (CF-DNA) in the blood. MCEDs offer the potential for screening for cancer organ sites with high mortality, both with and without recommended screening. However, their clinical utility has not been established. Before clinical utility can be established, the clinical validity of MCEDs, i.e., their ability to predict cancer status, must be demonstrated. In this study we performed a systematic review of the predictive ability for cancer of cell-free-nucleic acid-based MCED tests. Content We searched PubMed for relevant publications from January 2017 to February 2023, using MeSH terms related to multi-cancer detection, circulating DNA, and related concepts. Of 1811 publications assessed, 61 were reviewed in depth and 20 are included in this review. For almost all studies, the cancer cases were assessed at time of diagnosis. Most studies reported specificity (generally 95% or higher) and overall sensitivity (73% median). The median number of cancer types assessed per assay was 5. Many studies also reported sensitivity by stage and/or cancer type. Sensitivity generally increased with stage. Summary To date, relatively few published studies have assessed the clinical validity of MCED tests. Most used cancer cases assessed at diagnosis, with generally high specificity and variable sensitivity depending on cancer type and stage. The next steps should be testing in the intended-use population, i.e., asymptomatic persons.