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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, Sarah Nevitt, Yiwen Liu, Melissa Harden, Claire Khouja, Gary Raine, Rachel Churchill, Sofia Dias
PMCID: PMC11808444  PMID: 39898371

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(including MEDLINE and EMBASE) and trial registers were undertaken in September 2023 to identify published and unpublished studies of multi-cancer early detection tests.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.

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

  1. NHS. NHS Screening. 2021. URL: www.nhs.uk/conditions/nhs-screening/ (accessed 7 September 2023).
  2. NHS. Lung Health Checks. 2023. URL: www.nhs.uk/conditions/lung-health-checks/ (accessed 7 September 2023).
  3. Cancer Research UK. Cancer Incidence for Common Cancers. URL: www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared (accessed 7 September 2023).
  4. GRAIL. About Galleri. A New Way to Screen for More Cancers. URL: www.galleri.com/what-is-galleri (accessed 7 September 2023).
  5. GRAIL. Breakthrough Test Performance. 2023. URL: www.galleri.com/hcp/galleri-test-performance (accessed 21 September 2023).
  6. Lennon AM, Buchanan AH, Kinde I, Warren A, Honushefsky A, Cohain AT, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 2020;369:eabb9601. doi: 10.1126/science.abb9601. [DOI] [PMC free article] [PubMed]
  7. Gao Q, Zeng Q, Wang Z, Li C, Xu Y, Cui P, et al. Circulating cell-free DNA for cancer early detection. Innovation 2022;3:100259. doi: 10.1016/j.xinn.2022.100259. [DOI] [PMC free article] [PubMed]
  8. Nguyen THH, Lu YT, Le VH, Bui VQ, Nguyen LH, Pham NH, et al. Clinical validation of a ctDNA-based assay for multi-cancer detection: an interim report from a Vietnamese longitudinal prospective cohort study of 2795 participants. Cancer Invest 2023;41:232–48. doi: 10.1080/07357907.2023.2173773. [DOI] [PubMed]
  9. Ranade A, Bhatt A, Page R, Limaye S, Crook T, Akolkar D, Patil D. Hallmark circulating tumor-associated cell clusters signify 230 times higher one-year cancer risk. Cancer Prev Res (Phila) 2021;14:11–6. doi: 10.1158/1940-6207.CAPR-20-0322. [DOI] [PubMed]
  10. Xie L, Du X, Wang S, Shi P, Qian Y, Zhang W, et al. Development and evaluation of cancer differentiation analysis technology: a novel biophysics-based cancer screening method. Expert Rev Mol Diagn 2022;22:111–7. doi: 10.1080/14737159.2021.2013201. [DOI] [PubMed]
  11. Mikami H, Kimura O, Yamamoto H, Kikuchi S, Nakamura Y, Ando T, Yamakado M. A multicentre clinical validation of AminoIndex Cancer Screening (AICS). Sci Rep 2019;9:7. doi: 10.1038/s41598-019-50304-y. [DOI] [PMC free article] [PubMed]
  12. Brito-Rocha T, Constancio V, Henrique R, Jeronimo C. Shifting the cancer screening paradigm: the rising potential of blood-based multi-cancer early detection tests. Cells 2023;12:935. doi: 10.3390/cells12060935. [DOI] [PMC free article] [PubMed]
  13. NHS. The NHS Long Term Plan. 2019. URL: www.longtermplan.nhs.uk/publication/nhs-long-term-plan/ (accessed 7 September 2023).
  14. Dhruva SS, Smith-Bindman R, Redberg RF. The need for randomized clinical trials demonstrating reduction in all-cause mortality with blood tests for cancer screening. JAMA Intern Med 2023;183:1051–3. doi: 10.1001/jamainternmed.2023.3610. [DOI] [PubMed]
  15. Lee R, Robbins HA. PATHFINDER: another step on the uncharted path to multicancer screening. Lancet 2023;402:1213–5. doi: 10.1016/S0140-6736(23)02050-0. [DOI] [PubMed]
  16. Etzioni R, Gulati R, Weiss NS. Multicancer early detection: learning from the past to meet the future. J Natl Cancer Inst 2022;114:349–52. doi: 10.1093/jnci/djab168. [DOI] [PMC free article] [PubMed]
  17. Wise J. A blood test for multiple cancers: game changer or overhyped? BMJ 2022;378:o2279. doi: 10.1136/bmj.o2279. [DOI] [PubMed]
  18. Mahase E. Clinicians raise concerns over pilot of blood test for multiple cancers. BMJ 2023;383:2268. doi: 10.1136/bmj.p2268. [DOI] [PubMed]
  19. The Galleri Trial. About the Trial. 2021. URL: www.nhs-galleri.org/about-the-trial (accessed 7 September 2023).
  20. Centre for Reviews and Dissemination. Systematic Reviews. CRD’s Guidance for Undertaking Reviews in Healthcare. York: CRD, University of York; 2009.
  21. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed]
  22. Thomas J, Graziosi S, Brunton J, Ghouze Z, O’Driscoll P, Bond M, et al. EPPI-Reviewer: Advanced Software for Systematic Reviews, Maps and Evidence Synthesis. London: EPPI Centre, UCL Social Research Institute, University College London; 2022.
  23. Stevenson M, Sergeant E, Firestone S. epiR: Tools for the Analysis of Epidemiological Data. R Package Version 2.0.65. 2023. URL: https://CRAN.R-project.org/package=epiR (accessed 24 October 2023).
  24. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2023. URL: www.R-project.org/ (accessed 24 October 2023).
  25. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al.; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011;155:529–36. doi: 10.7326/0003-4819-155-8-201110180-00009. [DOI] [PubMed]
  26. Wickham H. ggplot2: Elegant Graphics for Data Analysis [program]. New York: Springer-Verlag; 2016.
  27. Wade R, Nevitt S, Harden M, Dias S, Raine G, Khouja C, et al. Multi-cancer Early Detection Tests for Screening. PROSPERO 2023 CRD42023467901; 2023. URL: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023467901 (accessed 30 October 2023).
  28. Healthwatch York. URL: www.healthwatchyork.co.uk/ (accessed 22 September 2023).
  29. Hull York Medical School. Transforming Cancer Outcomes in Yorkshire. URL: www.hyms.ac.uk/research/transform (accessed 22 September 2023).
  30. Humber and North Yorkshire Cancer Alliance. About Us. URL: https://hnycanceralliance.org.uk/about-us/ (accessed 22 September 2023).
  31. Schrag D, Beer TM, McDonnell CH 3rd, Nadauld L, Dilaveri CA, Reid R, et al. Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet 2023;402:1251–60. doi: 10.1016/S0140-6736(23)01700-2. [DOI] [PMC free article] [PubMed]
  32. Klein EA, Richards D, Cohn A, Tummala M, Lapham R, Cosgrove D, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol 2021;32:1167–77. doi: 10.1016/j.annonc.2021.05.806. [DOI] [PubMed]
  33. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV; CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol 2020;31:745–59. doi: 10.1016/j.annonc.2020.02.011. [DOI] [PMC free article] [PubMed]
  34. Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 2018;359:926–30. doi: 10.1126/science.aar3247. [DOI] [PMC free article] [PubMed]
  35. Beer TM. Shifting the Paradigm for Early Cancer Detection: A Multi-biomarker Class Approach to MCED Testing. Video of Presentation from the 2023 ASCO Annual Meeting. Exact Sciences; 2023. URL: www.exactsciences.com/Pipeline-and-Data/multi-cancer-early-detection/resources (accessed 19 October 2023).
  36. Gene Solutions. SPOT-MAS Multi Cancer Early Detection. URL: https://genesolutions.vn/en/product/spot-mas/ (accessed 24 October 2023).
  37. Datar Cancer Genetics. Datar Cancer Genetics. Non-invasive Solutions in Cancer. URL: https://datarpgx.com/ (accessed 24 October 2023).
  38. AnPac Bio-Medical Science Company Limited. Anpac Bio. URL: www.anpacbio.com/ (accessed 24 October 2023).
  39. Ajinomoto Group. AminoIndex®. URL: www.ajinomoto.com/innovation/action/aminoindex (accessed 24 October 2023).
  40. Nicholson BD, Oke J, Virdee PS, Harris DA, O’Doherty C, Park JE, et al. Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study. Lancet Oncol 2023;24:733–43. doi: 10.1016/S1470-2045(23)00277-2. [DOI] [PubMed]
  41. Cance W, Lilyestrom W, Johnson T, Winn R, Jemal A. Employer-based Implementation of Galleri® Multi-cancer Early Detection Testing to Address Socioeconomic Disparities in Receipt of Screening. AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, Orlando, FL, September 29–October 2, 2023. p. C108.
  42. Neal RD, Johnson P, Clarke CA, Hamilton SA, Zhang N, Kumar H, et al. Cell-free DNA-based multi-cancer early detection test in an asymptomatic screening population (NHS-Galleri): design of a pragmatic, prospective randomised controlled trial. Cancers (Basel) 2022;14:4818. doi: 10.3390/cancers14194818. [DOI] [PMC free article] [PubMed]
  43. GRAIL LLC. PATHFINDER 2: A Multi-cancer Early Detection Study. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2021. URL: https://classic.clinicaltrials.gov/show/ NCT05155605 (accessed 13 October 2023).
  44. GRAIL LLC. REFLECTION: A Clinical Practice Learning Program for Galleri®. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2022. URL: https://classic.clinicaltrials.gov/show/ NCT05205967 (accessed 13 October 2023).
  45. University College London. The SUMMIT Study: A Cancer Screening Study. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2019. URL: https://classic.clinicaltrials.gov/show/ NCT03934866 (accessed 13 October 2023).
  46. Nguyen VT, Nguyen TH, Doan NN, Pham TM, Nguyen GT, Tran TT, et al. Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization. medRxiv [Preprint]; 1 August 2023 (cited 13 October 2023). https://doi.org/10.1101/2023.04.12.23288460 doi: 10.7554/eLife.89083. [DOI] [PMC free article] [PubMed]
  47. Maeda S, Miyagi E, Yao M, Ichikawa Y, Rino Y. AminoIndexTM Cancer Screening (AICS) follow-up study, interim analysis report. Cancer Sci 2017;109:P-2386.
  48. Suzuki M. Usefulness of AminoIndex Cancer Screening (AICS) for breast cancer screening. Eur J Cancer 2014;50:S64.
  49. Dempsey AA, Tripp JH, Chao S, Stamatiou D, Pilcz T, Ying J, Burakoff R. Aristotle: a single blood test for pancancer screening. J Clin Oncol 2020;38:e15037.
  50. Arber N, Shapira S, Kazanov D, Fokra A, Sally Z, Zigdon S, et al. CD24 predictive levels – a simple novel blood test for early detection of various malignancies. United European Gastroenterol J 2017;5:A765.
  51. Massarwi S, Shapira S, Kazanov D, Asido S, Hay-Levy M, Matatov G, et al. CD 24 for early detection and surveillance of cancer using a universal simple blood test. United European Gastroenterol J 2019;7:407.
  52. Shapira S, Kazanov D, Shimon MB, Levy MH, Mdah F, Asido S, et al. The dark age of single organ screening is over: CD24 is a novel universal simple blood test for early detection of cancer. J Clin Oncol 2020;38:e15591.
  53. Shapira S, Kazanov D, Shimon MB, Mdah F, Levy MH, Galazan L, et al. The dark age of single organ screening is over: CD24 is a novel universal pan-cancer blood test for early detection of cancer. Gastroenterology 2021;160:S-130.
  54. Madah F, Kazanov D, Motlaq M, Argaman L, Shaked M, Shenberg G, et al. The dark age of single organ screening is over: CD24 is a novel universal pan-cancer blood test for early detection of cancer. Cancer Res 2023;83:3342.
  55. Luan Y, Zhong G, Li S, Wu W, Liu X, Zhu D, et al. A panel of seven protein tumour markers for effective and affordable multi-cancer early detection by artificial intelligence: a large-scale and multicentre case-control study. EClinicalMedicine 2023;61:102041. doi: 10.1016/j.eclinm.2023.102041. [DOI] [PMC free article] [PubMed]
  56. Mao M, Luan Y, Zhong G, Li S, Wu W, Liu X, et al. A panel of seven protein tumour markers for effective and affordable multi-cancer early detection by artificial intelligence. JCO Global Oncology 2023;9:155. doi: 10.1016/j.eclinm.2023.102041. [DOI] [PMC free article] [PubMed]
  57. Mao M, Li S, Ren Q, Luan Y, Liang W, Geng S, et al. Integrating multi-omics features for blood-based multi-cancer early detection. JCO Global Oncology 2023;9:156.
  58. Cision. SeekIn Presents New Data Supporting Its Pan-cancer Early Detection Test at the Early Detection of Cancer Conference 2022. Cision; 2022. URL: www.prnewswire.com/news-releases/seekin-presents-new-data-supporting-its-pan-cancer-early-detection-test-at-the-early-detection-of-cancer-conference-2022-301652662.html (accessed 26 October 2023).
  59. Gao Q, Lin YP, Li BS, Wang GQ, Dong LQ, Shen BY, et al. Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies. Ann Oncol 2023;34:486–95. doi: 10.1016/j.annonc.2023.02.010. [DOI] [PubMed]
  60. Gao Q, Li B, Xu J, Fang S, Qiu F, Su J, et al. Analysis of epigenomic signatures in cell-free DNA (cfDNA) from cancer patients and high-risk controls: a blinded test cohort of THUNDER-II study. J Clin Oncol 2021;39:e22518.
  61. Guangzhou Burning Rock Dx Co., Ltd. Multi-cancer Early-detection Test in Asymptomatic Individuals (PREVENT). ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2022. URL: https://classic.clinicaltrials.gov/show/ NCT05227534 (accessed 28 September 2023).
  62. Shanghai Zhongshan Hospital. Pan-canceR Early DetectIon projeCT (PREDICT). ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2021. URL: https://classic.clinicaltrials.gov/show/ NCT04817306 (accessed 17 October 2023).
  63. Salat A, Voigt W, von und zu Zwerger B. Prospective and single-blinded evaluation of the multi-cancer Carcimun-test. Precis Cancer Med 2022;5:12. https://doi.org/10.21037/ pcm-21-35
  64. Ma Y, Zhao G, Wang K, Song L, Xiong S, Li H, et al. Clinical performance of a liquid biopsy test based on the detection of multiple DNA methylation biomarkers for early detection of gastrointestinal cancers. J Clin Oncol 2022;40:e16096.
  65. Schrag D, McDonnell CH, Nadauld L, Dilaveri CA, Klein EA, Reid R, et al. A prospective study of a multi-cancer early detection blood test. Ann Oncol 2022;33:S961.
  66. Beer TM, McDonnell CH, Nadauld L, Liu MC, Klein EA, Reid RL, et al. A prespecified interim analysis of the PATHFINDER study: performance of a multicancer early detection test in support of clinical implementation. J Clin Oncol 2021;39:3070.
  67. Beer TM, McDonnell CH, Nadauld L, Liu MC, Klein EA, Reid RL, et al. Interim results of PATHFINDER, a clinical use study using a methylation-based multi-cancer early detection test. J Clin Oncol 2021;39:3010.
  68. Klein E, Beer T. Assessing implementation of a multi-cancer early detection blood test for population screening in a clinical practice setting: prospective PATHFINDER cohort study. Cancer Prev Res (Phila) 2023;16:IA022.
  69. Nadauld L, McDonnell CH, Liu MC, Klein E, Beer TM, Schrag D, et al. The PATHFINDER study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancer Res 2020;80:CT291. doi: 10.3390/cancers13143501. [DOI] [PMC free article] [PubMed]
  70. Nadauld LD, McDonnell CH 3rd, Beer TM, Liu MC, Klein EA, Hudnut A, et al. The PATHFINDER study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancers (Basel) 2021;13:3501. doi: 10.3390/cancers13143501. [DOI] [PMC free article] [PubMed]
  71. GRAIL LLC. Assessment of the Implementation of an Investigational Multi-cancer Early Detection Test into Clinical Practice. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2020. URL: https://classic.clinicaltrials.gov/show/ NCT04241796 (accessed 28 September 2023).
  72. University of Oxford. SYMPLIFY – Assessing a Multi-cancer Early Detection Test in Individuals Referred with Signs and Symptoms of Cancer. ISCRTN Registry, BioMed Central Ltd; 2021. URL: www.isrctn.com/ISRCTN10226380 (accessed 28 September 2023).
  73. Tang WHW, Yimer H, Tummala M, Shao S, Chung G, Clement J, et al. Performance of a targeted methylation-based multi-cancer early detection test by race and ethnicity. Prev Med 2023;167:107384. doi: 10.1016/j.ypmed.2022.107384. [DOI] [PubMed]
  74. Bryce AH, Thiel DD, Seiden MV, Richards D, Luan Y, Coignet M, et al. Performance of a cell-free DNA-based multi-cancer detection test in individuals presenting with symptoms suspicious for cancers. JCO Precis Oncol 2023;7:e2200679. doi: 10.1200/PO.22.00679. [DOI] [PMC free article] [PubMed]
  75. Shao SH, Allen B, Clement J, Chung G, Gao J, Hubbell E, et al. Multi-cancer early detection test sensitivity for cancers with and without current population-level screening options. Tumori 2023;109:335–41. doi: 10.1177/03008916221133136. [DOI] [PMC free article] [PubMed]
  76. Rossi SH, Stewart GD. Re: Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Eur Urol 2022;82:442–3. doi: 10.1016/j.eururo.2022.06.012. [DOI] [PubMed]
  77. Klein EA, Richards D, Cohn A, Tummala M, Lapham R, Cosgrove D, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test. Cancer Res 2021;81:LB013. doi: 10.1016/j.annonc.2021.05.806. [DOI] [PubMed]
  78. Klein EA, Richards D, Cohn A, Tummala M, Lapham R, Cosgrove D, et al. Detecting Cancer Signal Across Multiple Cancers with One Blood Draw: Validating a Multi‑Cancer Early Detection (MCED) Yest. American Academy of Family Physicians (AAFP) Family Medicine Experience (FMX), Anaheim, CA, September 28–October 2, 2021.
  79. Venn O, Bredno J, Thornton A, Chang C, Hubbell E, Kurtzman K, et al. Robustness of a Targeted Methylation-based Multi-cancer Early Detection (MCED) Test to Population Differences in Self-reported Ethnicity. AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, Orlando, FL, September 29–October 2, 2023.
  80. Tang WHW, Yimer H, Tummala M, Shao S, Chung G, Clement J, et al. Performance of a targeted methylation-based multi-cancer early detection test by race/ethnicity. J Clin Oncol 2021;39:3071. doi: 10.1016/j.ypmed.2022.107384. [DOI] [PubMed]
  81. Yimer HA, Tang WHW, Tummala MK, Shao S, Chung GG, Couch F, et al. Detection of cancer signal for over 50 AJCC cancer types with a multi-cancer early-detection test. J Clin Oncol 2021;39:3072.
  82. Papadopoulos N. A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer. Cancer Res 2020;80:CT022.
  83. Suzuki M. Breast cancer screening by evaluating amino acid levels in the blood. Breast 2015;24:S69.
  84. Schrag D, Beer TM, McDonnell CH, Nadauld L, Dilaveri CA, Klein EA, et al. Evaluation of anxiety, distress and satisfaction with a multi-cancer early detection test. Ann Oncol 2022;33:S963.
  85. Klein EA, McDonnell CH, Nadauld L, Dilaveri CA, Reid R, Marinac CR, et al. Clinical Evaluation of Cancer Signal Origin (CSO) Prediction and Diagnostic Resolution Following Multi-cancer Early Detection Testing. Chicago, IL: American Society of Clinical Oncology (ASCO); 2–6 June 2023.
  86. Westgate C, Kingsbury D, Poliak M, Lipton J, McMillin M, Malinow LB, et al. Early Real-world Experience with a Multi-cancer Early Detection Test. Chicago, IL: American Society of Clinical Oncology (ASCO); 2–6 June 2023.
  87. McDonnell CH, Hudnut AG, Behl D, Ang R, Spinelli B, Jacobs D, et al. Diagnostic workup following a multicancer early detection test with a cancer signal origin prediction. J Clin Oncol 2022;40:e15037.
  88. Buchanan AH, Lennon AM, Rego SP, Choudhry OA, Elias PZ, Sadler JR, et al. Long-term clinical outcomes of cancers diagnosed following detection by a blood-based multi-cancer early detection (MCED) test. J Clin Oncol 2023;41:3037.
  89. Lennon AM, Buchanan AH, Rego SP, Choudhry OA, Elias PZ, Sadler JR, et al. Outcomes in participants with a false positive multi-cancer early detection (MCED) test: results from >4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study. J Clin Oncol 2023;41:3039. doi: 10.1158/1940-6207.CAPR-23-0451. [DOI] [PMC free article] [PubMed]
  90. McGuinness LA. robvis: an R Package and Web Application for Visualising Risk-of-Bias Assessments. 2019. URL: https://CRAN.R-project.org/package=robvis (accessed 27 November 2023).
  91. GRAIL. Written Evidence Submitted by GRAIL (FCR0024) to the Health and Social Care Committee Future Cancer Inquiry. UK Parliament Health and Social Care Committee; 2023. URL: https://committees.parliament.uk/writtenevidence/120627/pdf/ (accessed 30 October 2023).
  92. Johnson P. An Update on the Ongoing NHS-Galleri Trial. NHS England; 2024. URL: www.england.nhs.uk/blog/an-update-on-the-ongoing-nhs-galleri-trial/ (accessed 31 July 2024).
  93. Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 2019;570:385–9. doi: 10.1038/s41586-019-1272-6. [DOI] [PMC free article] [PubMed]
  94. Annapragada AV, Medina JE, Lof P, Mathios D, Foda ZH, Noe M, et al. Early detection of ovarian cancer using cell-free DNA fragmentomes. Cancer Res 2023;83:773. doi: 10.1158/2159-8290.CD-24-0393. [DOI] [PMC free article] [PubMed]
  95. Xu L, Wang J, Yang T, Tao J, Liu X, Ye Z, et al. Toward the development of a $100 screening test for 6 major cancer types. Cancer Res 2020;80:4601.
  96. Xu L, Wang J, Ma W, Liu X, Li S, Chen S, et al. Validation of a high performing blood test for multiple major cancer screenings. J Clin Oncol 2021;39:10561.
  97. Sun Yat-sen University Cancer Center. PanTum Technique for the Detection of Peripheral Blood APO10 and TKTL1 in the Diagnosis of High Incidence of Malignant Tumors in Chinese Population. Chinese Clinical Trial Registry; 2020. URL: www.chictr.org.cn/showproj.aspx?proj=64757 (accessed 28 September 2023).
  98. Millennium Oncology India Private Limited. A Trial for Confirming the Accuracy of PanTum Test for Solid Tumor Detection. Clinical Trials Registry India; 2022. URL: www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=73694 (accessed 28 September 2023).
  99. Guardant Health Inc. Screening for High Frequency Malignant Disease. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2021. URL: https://classic.clinicaltrials.gov/show/ NCT05117840 (accessed 13 October 2023).
  100. Nguyen H, Raymond VM, Vento-Gaudens E, Marino E, Lang K, Eagle C. Screening for high frequency malignant disease (SHIELD). J Clin Oncol 2022;40:TPS1602.
  101. Raymond V, Nguyen H, Cotton L, Vento-Gaudens E, Eagle C. PP01.20 Trial in progress: screening for high frequency malignant disease (SHIELD). J Thorac Oncol 2023;18:e19.
  102. Harbinger Health. Development and Validation of Harbinger Health Test for Early Cancer Detection. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2022. URL: https://classic.clinicaltrials.gov/show/ NCT05435066 (accessed 17 October 2023).
  103. Adela Inc. cfDNA Assay Prospective Observational Validation for Early Cancer Detection and Minimal Residual Disease. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2022. URL: https://classic.clinicaltrials.gov/show/ NCT05366881 (accessed 29 September 2023).
  104. Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548–54. doi: 10.1038/nm.3519. [DOI] [PMC free article] [PubMed]
  105. Mazzone PJ, Wong KK, Tsay JCJ, Pass HI, Vachani A, Ryan A, et al. Prospective evaluation of cell-free DNA fragmentomes for lung cancer detection. Cancer Res 2023;83:5766.
  106. Delfi Diagnostics Inc. CASCADE-LUNG: Cancer Screening Assay Using DELFI; A Clinical Validation Study in Lung. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); URL: https://classic.clinicaltrials.gov/show/ NCT05306288 (accessed 15 September 2023).
  107. Rigshospitalet, Denmark. Early Detection of de novo Cancer in Liver Transplant Recipients. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); URL: https://classic.clinicaltrials.gov/show/ NCT05492617 (accessed 15 September 2023).
  108. Cameron JM, Sala A, Antoniou G, Brennan PM, Butler HJ, Conn JJA, et al. A spectroscopic liquid biopsy for the earlier detection of multiple cancer types. Br J Cancer 2023;129:1658–66. https://doi.org/10.1038/s41416-023-02423-7 doi: 10.1038/s41416-023-02423-7. [DOI] [PMC free article] [PubMed]
  109. Vincere Cancer Centre. Multi-Cancer Early Detection (MCED) of Firefighters. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2023. URL: https://classic.clinicaltrials.gov/show/ NCT05780957 (accessed 28 September 2023).
  110. Harbinger Health. Press Release – Harbinger Health Raises $140 Million in Series B Funding to Accelerate Advancement of Its Screening Platform for Early-stage Cancers. Harbinger Health; 2023. URL: www.harbinger-health.com/news/harbinger-health-raises-140-million-in-series-b-funding-to-accelerate-advancement-of-its-screening-platform-for-early-stage-cancers (accessed 26 October 2023).
  111. Bao H, Wang Z, Ma X, Guo W, Zhang X, Tang W, et al. Letter to the Editor: an ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection. Mol Cancer 2022;21:129. doi: 10.1186/s12943-022-01594-w. [DOI] [PMC free article] [PubMed]
  112. Nanjing Shihejiyin Technology, Inc. The Jinling Cohort. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2023. URL: https://classic.clinicaltrials.gov/show/ NCT06011694 (accessed 13 October 2023).
  113. Zhang H, Zhao L, Jiang J, Zheng J, Yang L, Li Y, et al. Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification. Nat Commun 2022;13:617. doi: 10.1038/s41467-021-26642-9. [DOI] [PMC free article] [PubMed]
  114. Fudan University Taizhou Institute of Health Sciences. A Prospective, Multicenter Cohort Study of Pan-cancer Screening in Chinese Population. Chinese Clinical Trial Registry; 2021. URL: www.chictr.org.cn/showproj.aspx?proj=141068 (accessed 30 September 2023).
  115. Singlera Genomics Inc. The FuSion Program: A Prospective and Multicenter Cohort Study of Pan-cancer Screening in Chinese Population. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US); 2021. URL: https://classic.clinicaltrials.gov/show/ NCT05159544 (accessed 13 October 2023).
  116. Suo C, Zhao R, Jiang Y, Zhang Y, He Q, Su Z, et al. The FuSion Project of pan-cancer early screening in Chinese – an integrative study by Fudan University and Singlera. Cancer Res 2023;83:4194.
  117. PanTum Detect. PanTum Detect; 2023. URL: www.pantumdetect.com/ (accessed 26 October 2023).
  118. Saman S, Stagno MJ, Warmann SW, Malek NP, Plentz RR, Schmid E. Biomarkers Apo10 and TKTL1: epitope-detection in monocytes (EDIM) as a new diagnostic approach for cholangiocellular, pancreatic and colorectal carcinoma. Cancer Biomark 2020;27:129–37. doi: 10.3233/CBM-190414. [DOI] [PMC free article] [PubMed]
  119. Epigeneres Biotech Pvt Ltd. A Simple Blood Test to Understand Presence or Absence of Cancer. Clinical Trials Registry India; 2023. URL: www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=87700 (accessed 24 October 2023).
  120. Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 2017;9:eaan2415. doi: 10.1126/scitranslmed.aan2415. [DOI] [PMC free article] [PubMed]
  121. Peking University Shenzhen Hospital. SZ-PILOT Study: Prospective Observational Study of the YiDiXueTM Multi-cancer Early Detection Kit in Multi-cancer Early Screening in Normal People. Chinese Clinical Trial Registry; 2022. URL: www.chictr.org.cn/showproj.html?proj=187882 (accessed 30 September 2023).
  122. Staniszewska S, Brett J, Simera I, Seers K, Mockford C, Goodlad S, et al. GRIPP2 reporting checklists: tools to improve reporting of patient and public involvement in research. BMJ 2017;358:j3453. doi: 10.1136/bmj.j3453. [DOI] [PMC free article] [PubMed]
  123. Baker D, Middleton E. Cervical screening and health inequality in England in the 1990s. J Epidemiol Community Health 2003;57:417–23. doi: 10.1136/jech.57.6.417. [DOI] [PMC free article] [PubMed]
  124. Chancellor M, Modi J, Muhammad R, Batioja K, Garrett E, Waters P, Vassar M. Health inequities in mammography: a scoping review. Eur J Radiol 2023;160:110693. doi: 10.1016/j.ejrad.2023.110693. [DOI] [PubMed]
  125. Mosquera I, Mendizabal N, Martín U, Bacigalupe A, Aldasoro E, Portillo I; from the Desberdinak Group. Inequalities in participation in colorectal cancer screening programmes: a systematic review. Eur J Public Health 2020;30:416–25. doi: 10.1093/eurpub/ckz236. [DOI] [PubMed]
  126. McLeod M, Kvizhinadze G, Boyd M, Barendregt J, Sarfati D, Wilson N, Blakely T. Colorectal cancer screening: how health gains and cost-effectiveness vary by ethnic group, the impact on health inequalities, and the optimal age range to screen. Cancer Epidemiol Biomarkers Prev 2017;26:1391–400. doi: 10.1158/1055-9965.EPI-17-0150. [DOI] [PubMed]
  127. Sarfati D, Shaw C, Simmonds S. Commentary: inequalities in cancer screening programmes. Int J Epidemiol 2010;39:766–8. doi: 10.1093/ije/dyq039. [DOI] [PubMed]
  128. Alam Z, Cairns JM, Scott M, Dean JA, Janda M. Interventions to increase cervical screening uptake among immigrant women: a systematic review and meta-analysis. PLOS ONE 2023;18:e0281976. doi: 10.1371/journal.pone.0281976. [DOI] [PMC free article] [PubMed]
  129. Cairns JM, Greenley S, Bamidele O, Weller D. A scoping review of risk-stratified bowel screening: current evidence, future directions. Cancer Causes Control 2022;33:653–85. doi: 10.1007/s10552-022-01568-9. [DOI] [PMC free article] [PubMed]
  130. De Mil R, Guillaume E, Launay L, Guittet L, Dejardin O, Bouvier V, et al. Cost-effectiveness analysis of a mobile mammography unit for breast cancer screening to reduce geographic and social health inequalities. Value Health 2019;22:1111–8. doi: 10.1016/j.jval.2019.06.001. [DOI] [PubMed]
  131. National Cancer Institute Division of Cancer Prevention. Multi-Cancer Detection (MCD) Research. National Cancer Institute, U.S. National Institutes of Health. URL: https://prevention.cancer.gov/major-programs/multi-cancer-detection-mcd-research (accessed 30 October 2023).
  132. Kaiser J. ‘The complexities are staggering’. U.S. plans huge trial of blood tests for multiple cancers. Science, 22 June 2022. https://doi.org/10.1126/science.add6151
  133. Duffy MJ, Diamandis EP, Crown J. Circulating tumor DNA (ctDNA) as a pan-cancer screening test: is it finally on the horizon? Clin Chem Lab Med 2021;59:1353–61. doi: 10.1515/cclm-2021-0171. [DOI] [PubMed]
  134. Callister MEJ, Crosbie EJ, Crosbie PAJ, Robbins HA. Evaluating multi-cancer early detection tests: an argument for the outcome of recurrence-updated stage. Br J Cancer 2023;129:1209–11. doi: 10.1038/s41416-023-02434-4. [DOI] [PMC free article] [PubMed]
  135. Menon U, Gentry-Maharaj A, Burnell M, Singh N, Ryan A, Karpinskyj C, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2021;397:2182–93. doi: 10.1016/S0140-6736(21)00731-5. [DOI] [PMC free article] [PubMed]
  136. Martin RM, Donovan JL, Turner EL, Metcalfe C, Young GJ, Walsh EI, et al.; CAP Trial Group. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA 2018;319:883–95. doi: 10.1001/jama.2018.0154. [DOI] [PMC free article] [PubMed]
  137. Feng X, Zahed H, Onwuka J, Callister MEJ, Johansson M, Etzioni R, Robbins HA. Cancer stage compared with mortality as end points in randomized clinical trials of cancer screening: a systematic review and meta-analysis. JAMA 2024;331:1910–7. doi: 10.1001/jama.2024.5814. [DOI] [PMC free article] [PubMed]
  138. McCartney M, Cohen D. Galleri promises to detect multiple cancers – but new evidence casts doubt on this much hyped blood test. BMJ 2024;386:q1706. doi: 10.1136/bmj.q1706. [DOI] [PubMed]
  139. LeeVan E, Pinsky P. Predictive performance of cell-free nucleic acid-based multi-cancer early detection tests: a systematic review. Clin Chem 2023;70:90–101. doi: 10.1093/clinchem/hvad134. [DOI] [PubMed]
  140. Pons-Belda OD, Fernandez-Uriarte A, Diamandis EP. Can circulating tumor DNA support a successful screening test for early cancer detection? The Grail paradigm. Diagnostics (Basel) 2021;11:2171. doi: 10.3390/diagnostics11122171. [DOI] [PMC free article] [PubMed]
  141. Brentnall AR, Mathews C, Beare S, Ching J, Sleeth M, Sasieni P. Dynamic data-enabled stratified sampling for trial invitations with application in NHS-Galleri. Clin Trials 2023;20:425–33. doi: 10.1177/17407745231167369. [DOI] [PMC free article] [PubMed]
  142. Marlow LAV, Schmeising-Barnes N, Warwick J, Waller J. Psychological impact of the Galleri test (sIG(n)al): protocol for a longitudinal evaluation of the psychological impact of receiving a cancer signal in the NHS-Galleri trial. BMJ Open 2023;13:e072657. doi: 10.1136/bmjopen-2023-072657. [DOI] [PMC free article] [PubMed]

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