Abstract
Cancer screening is an essential public health intervention for diagnosing cancers at an early stage that can enable earlier treatment — ideally with curative intent — and thus lead to improved outcomes. Over the past decade, liquid biopsy-based tests have emerged as a promising, minimally invasive and broadly applicable screening approach by combining multi-cancer early detection (MCED) with tumour tissue-of-origin identification. Large-scale randomized clinical trials evaluating liquid biopsy-based MCED approaches are now under way, although whether the diagnostic performance of this first generation of MCED tests is sufficient to translate into clinical benefits remains to be determined. In this Review, we discuss the promises and pitfalls of current MCED tests and highlight possible trajectories for the field of early cancer detection.
Key points
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Cancer screening programmes have led to clinical benefits across a number of tumour types, although a universal cancer screening test does not yet exist. Multi-cancer early detection (MCED) via a single test requires sampling or imaging of all sites in the body.
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Liquid biopsies enable minimally invasive detection of circulating nucleic acids, proteins and/or cancer cells. As these technologies have matured and technical performance improved, investigators are exploring the potential for liquid biopsy-based screening.
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The analytical sensitivity of liquid biopsy-based MCED tests is a function of both the volume of plasma sampled and the number of markers targeted. This concept is well-established in the field of personalized monitoring of cancer using liquid biopsy assays based on mutations; here, we appraise the performance of MCED tests through this same lens.
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Methylation-based MCED tests have rapidly gained traction and are being tested in randomized controlled trials, which reflects their high sensitivity and specificity. Competing technologies might emerge over time, particularly as sequencing costs decrease further.
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Ongoing clinical trials should not only assess whether screening with liquid biopsy-based MCED tests detects cancers earlier but also determine whether this translates into real clinical benefit on a population level.
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Outcomes from upcoming randomized controlled trials will be crucial for guiding the development of the next generation of MCED assays, bringing the field a step closer to the implementation of blood test-based cancer screening.
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Acknowledgements
This Review was not explicitly funded from any grant. The authors acknowledge funding from Cancer Research UK (CTUQQR-Dec22/100005, awarded to P.S. for the Cancer Prevention Trials Unit, and C1287/A26886, EDDRPG-May24/100002, C36857/A27548, EDDCPGM\100001, A20240, C9545/A29580, SEBINT-2024/100003, C7893/A26233 and CTRQQR-2021\100004 to N.R.). Cancer Research UK did not have a role in the design of this Review, the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. The work of N.R. is supported by the European Union and the UK Research & Innovation (UKRI) under the UK government’s Horizon Europe funding guarantee (EU PANCAID 101096309, UKRI 10070284). Views and opinions expressed in this manuscript are, however, those of the authors only and do not necessarily reflect those of the European Union, the European Health and Digital Executive Agency (HADEA) or the UKRI; neither the European Union nor the granting authorities can be held responsible for them. The authors acknowledge feedback on figures from R. Lam.
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J.C.M.W. and N.R. are inventors on patents for methods of circulating tumour DNA detection. J.C.M.W. is a consultant for, co-founder and shareholder of Prima Mente and has been a consultant for Cleary Gottlieb, Delfi Diagnostics and Rostrum. P.S. is compensated by Grail for time spent on their advisory board and is also Director of the Cancer Prevention Trials Unit at Queen Mary University of London, which is contracted by GRAIL to act as the clinical trials unit for the NHS-Galleri trial.
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Wan, J.C.M., Sasieni, P. & Rosenfeld, N. Promises and pitfalls of multi-cancer early detection using liquid biopsy tests. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01033-x
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DOI: https://doi.org/10.1038/s41571-025-01033-x
