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. 2025 Jan;29(2):1-105.
doi: 10.3310/DLMT1294.

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

Ros Wade  1 , Sarah Nevitt  1 , Yiwen Liu  1 , Melissa Harden  1 , Claire Khouja  1 , Gary Raine  1 , Rachel Churchill  1 , Sofia Dias  1
Affiliations

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

Ros Wade et al. Health Technol Assess. 2025 Jan.

Abstract

Background: General population cancer screening in the United Kingdom is limited to selected cancers. Blood-based multi-cancer early detection tests aim to detect potential cancer signals from multiple cancers in the blood. The use of a multi-cancer early detection 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 multi-cancer early detection 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(including MEDLINE and EMBASE) and trial registers were undertaken in September 2023 to identify published and unpublished studies of multi-cancer early detection tests. Test manufacturer websites and reference lists of included studies and pertinent reviews were checked for additional studies. The target population was individuals aged 50-79 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, acceptability and satisfaction. The risk of bias was assessed using the quality assessment of diagnostic accuracy studies-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: 1 ongoing randomised controlled trial, 13 completed cohort studies, 17 completed case-control studies and 5 ongoing cohort or case-control studies. Individual tests claimed to detect from 3 to over 50 different types of cancer. Diagnostic accuracy of currently available multi-cancer early detection tests varied substantially: Galleri® (GRAIL, Menlo Park, CA, USA) sensitivity 20.8-66.3%, specificity 98.4-99.5% (three studies); CancerSEEK (Exact Sciences, Madison, WI, USA) sensitivity 27.1-62.3%, specificity 98.9- 99.1% (two studies); SPOT-MAS™ (Gene Solutions, Ho Chi Minh City, Vietnam) sensitivity 72.4-100%, specificity 97.0-99.9% (two studies); Trucheck™ (Datar Cancer Genetics, Bayreuth, Germany) sensitivity 90.0%, specificity 96.4% (one study); Cancer Differentiation Analysis (AnPac Bio, Shanghai, China) sensitivity 40.0%, specificity 97.6% (one study). AICS® (AminoIndex Cancer Screening; Ajinomoto, Tokyo, Japan) screens for individual cancers separately, so no overall test performance statistics are available. Where reported, sensitivity was lower for detecting earlier-stage cancers (stages I-II) compared with later-stage cancers (stages III-IV). Studies of seven other multi-cancer early detection 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 multi-cancer early detection tests. The evidence was limited; there were no completed randomised controlled trials 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 United States of America; however, study results may not be representative of the United Kingdom's general screening population. No meaningful results were reported relating to patient-relevant outcomes, such as mortality, potential harms, health-related quality of life, acceptability or satisfaction.

Conclusions: All currently available multi-cancer early-detection 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 outcomes and consider patient and service impacts.

Study registration: This study is registered as PROSPERO CRD42023467901.

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR161758) and is published in full in Health Technology Assessment; Vol. 29, No. 2. See the NIHR Funding and Awards website for further award information.

Keywords: CANCER SCREENING; EARLY DETECTION OF CANCER; EVIDENCE SYNTHESIS; MCED; MULTI-CANCER DETECTION; SYSTEMATIC LITERATURE REVIEW.

Plain language summary

Cancer screening is only available for some cancers. New tests that look for signs of cancer in blood (blood-based multi-cancer early detection tests) are being developed; they aim to detect multiple different cancers at an early stage, when they are potentially more treatable. Taking account of stakeholder feedback, we reviewed all studies assessing the effectiveness of blood-based multi-cancer early detection tests for cancer screening. We thoroughly searched for relevant studies and found over 8000 records. We included 30 completed studies and 6 ongoing studies of 13 different tests. None of the studies were of good quality, mainly because they did not properly check whether the test result might have been incorrect and whether participants with a negative test result actually had cancer. Most studies included participants who are different from the general United Kingdom population that would likely be invited for this type of cancer screening test. None of the studies reported meaningful results for patient-relevant outcomes, such as death, potential harms, quality of life and acceptability. We found 14 completed studies assessing 6 tests that are currently available: Galleri® (GRAIL, Menlo Park, CA, USA), CancerSEEK (Exact Sciences, Madison, WI, USA), SPOT-MAS™ (Gene Solutions, Ho Chi Minh City, Vietnam), Trucheck™ (Datar Cancer Genetics, Bayreuth, Germany), Cancer Differentiation Analysis (AnPac Bio, Shanghai, China) and AICS® (AminoIndex Cancer Screening; Ajinomoto, Tokyo, Japan). All of the tests were quite good at ruling out cancer, but their accuracy for finding cancer varied a lot, mostly because of differences in the study methods and characteristics of the included participants. The tests were better at finding more advanced cancers, which are potentially less curable than early cancers, so more research is needed to know whether tests would actually save lives. Better-designed studies including participants similar to those who might get the test in the real world, and which report on patient-relevant outcomes and properly consider patient experience and impact on services, are needed. Several new studies are planned or underway.

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References

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    1. GRAIL. About Galleri. A New Way to Screen for More Cancers. URL: www.galleri.com/what-is-galleri (accessed 7 September 2023).
    1. GRAIL. Breakthrough Test Performance. 2023. URL: www.galleri.com/hcp/galleri-test-performance (accessed 21 September 2023).

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