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(including MEDLINE and Embase) and trial registers were undertaken in September 2023 to identify published and unpublished studies of MCED tests.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.