Multi-cancer early detection tests for general population screening: a systematic literature review

Background: General population cancer screening in the UK is limited to selected cancers. Blood-based multi-cancer early detection (MCED) tests aim to detect potential cancer signals from multiple cancers in the blood. The use of an MCED test for population screening requires a high specificity and a reasonable sensitivity to detect early-stage disease, so that the benefits of earlier diagnosis and treatment can be realised. Objective: To undertake a systematic literature review of the clinical effectiveness evidence on blood-based MCED tests for screening. Methods: Comprehensive searches of electronic databases (including MEDLINE and Embase) and trial registers were undertaken in September 2023 to identify published and unpublished studies of MCED tests. Test manufacturer websites and reference lists of included studies and pertinent reviews were checked for additional studies. The target population was individuals aged 50 to 79 years without clinical suspicion of cancer. Outcomes of interest included test accuracy, number and proportion of cancers detected (by site and stage), time to diagnostic resolution, mortality, potential harms, health-related quality of life (HRQoL), acceptability and satisfaction. Risk of bias was assessed using the QUADAS-2 checklist. Results were summarised using narrative synthesis. Stakeholders contributed to protocol development, report drafting, and interpretation of review findings. Results: Over 8000 records were identified. Thirty-six studies met the inclusion criteria: one ongoing randomised controlled trial (RCT), 13 completed cohort studies, 17 completed case-control studies and five ongoing cohort or case-control studies. Individual tests claimed to detect from three to over 50 different types of cancer. Diagnostic accuracy of currently available MCED tests varied substantially: Galleri ® (GRAIL) sensitivity 20.8% to 66.3%, specificity 98.4% to 99.5% (3 studies); CancerSEEK (Exact Sciences) sensitivity 27.1% to 62.3%, specificity 98.9% to 99.1% (2 studies); SPOT-MAS ™ (Gene Solutions) sensitivity 72.4% to 100%, specificity 97.0% to 99.9% (2 studies); TruCheck ™ (Datar Cancer Genetics) sensitivity 90.0%, specificity 96.4% (1 study); CDA (AnPac Bio) sensitivity 40.0%, specificity 97.6% (1 study). AICS ® (Ajinomoto) screens for individual cancers separately, so no overall test performance statistics are available. Where reported, sensitivity was lower for detecting earlier stage cancers (Stage I-II) compared with later stage cancers (Stage III-IV). Studies of seven other MCED tests at an unclear stage of development were also summarised. Limitations: Study selection was complex; it was often difficult to determine the stage of development of MCED tests. The evidence was limited; there were no completed RCTs and most included studies had a high overall risk of bias, primarily owing to limited follow-up of participants with negative test results. Only one study of Galleri recruited asymptomatic individuals aged over 50 in the USA, however, study results may not be representative of the UK general screening population. No meaningful results were reported relating to patient relevant outcomes, such as mortality, potential harms, HRQoL, acceptability or satisfaction. Conclusions: All currently available MCED tests reported high specificity (>96%). Sensitivity was highly variable and influenced by study design, population, reference standard test used and length of follow-up. Future work: Further research should report patient relevant outcome and consider patient and service impacts. ### Competing Interest Statement Churchill: Evidence Synthesis Programme Advisory Group (2016 to 2020). Dias: fees from the Association of the British Pharmaceutical Industry (ABPI) for delivering the NICE/DSU/ABPI Masterclass on evidence synthesis (2021, 2022); NIHR Research for Patient Benefit (RfPB): Under-represented disciplines and specialisms: Methodologists, Research Advisory Committee Member. ### Clinical Protocols ### Funding Statement This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR161758) and will be published in full in the Health Technology Assessment Journal. See the NIHR Journals Library website for further project information. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This study did not generate any new data as it used existing sources, and all data is contained within the manuscript. Any queries should be addressed to the corresponding author.