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  • Review Article
  • Published:

Circulating tumour DNA — looking beyond the blood

Nature Reviews Clinical Oncology volume 19, pages 600–612 (2022)Cite this article

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This article has been updated

Abstract

Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate ‘biopsies’ offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.

Key points

  • Plasma-based circulating tumour DNA (ctDNA) assays can provide invaluable information on the status of a patient’s cancer; however, numerous alternative sources of ctDNA are available that might offer unique advantages in certain settings.

  • Non-blood sources of ctDNA include urine, cerebrospinal fluid, pleural or peritoneal fluid, saliva, stool, and seminal fluid, among others.

  • Analysing ctDNA from non-blood sources might provide a more sensitive method than plasma-based ctDNA assays for particular tumour types or anatomical locations.

  • Non-blood ctDNA assays might be complementary to plasma assays when used for the detection of driver alterations or mechanisms of resistance.

  • Challenges to the clinical implementation of non-blood-based ctDNA assays include difficulties relating to standardization of pre-analytical factors, lack of commercially available assays and the invasive procedures required to obtain certain sample types.

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Fig. 1: Examples of different cancers that can be investigated using non-blood sources of ctDNA.

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Change history

  • 16 December 2022

    In the version of this article initially published, the peer reviewer name Y. Nakamura was misspelled and is now amended in the HTML and PDF versions of the article.

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Acknowledgements

The work of A.T. is supported by an NIHR Academic Clinical Fellowship. The work of D.R. and C.D. is funded by Cancer Research UK (CRUK) via core funding to the CRUK Manchester Institute (grant A27412) and the CRUK Manchester Centre (grant A25254). Support was received by the NIHR Manchester Biomedical Research Centre and the Manchester Experimental Cancer Medicine Centre.

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Authors and Affiliations

  1. Division of Cancer Sciences, The University of Manchester, Manchester, UK

    Ann Tivey, Dominic Rothwell, Caroline Dive & Natalie Cook

  2. The Christie NHS Foundation Trust, Manchester, UK

    Ann Tivey, Matt Church & Natalie Cook

  3. Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Manchester, UK

    Dominic Rothwell & Caroline Dive

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A.T., M.C. and N.C. researched data for article and wrote the manuscript. All authors contributed to discussions of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Natalie Cook.

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Competing interests

C.D. has acted as a consultant and/or adviser of AstraZeneca, Boehringer Ingelheim, Biocartis, GRAIL and Merck, and has received research funding from Angle, Amgen, Astex Pharmaceuticals, AstraZeneca, Bayer, Bioven, Bristol Myers Squibb, Boehringer Ingelheim, Carrick Therapeutics, Celgene, Clearbridge Biomedics, Epigene Therapeutics, GlaxoSmithKline, Menarini, Merck AG, Neomed Therapeutics, Novartis, Roche, Taiho Oncology and Thermo Fisher Scientific. N.C. has received research funding from AstraZeneca, Avacta, Bayer, Boehringer, Eisai, Merck, Orion, Pfizer, RedX, Roche, Starpharma, Stemline Tarveda, Taiho Oncology and UCB. The other authors declare no competing interests.

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Tivey, A., Church, M., Rothwell, D. et al. Circulating tumour DNA — looking beyond the blood. Nat Rev Clin Oncol 19, 600–612 (2022). https://doi.org/10.1038/s41571-022-00660-y

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