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  • Perspective
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Liquid biopsy enters the clinic — implementation issues and future challenges

Nature Reviews Clinical Oncology volume 18, pages 297–312 (2021)Cite this article

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Abstract

Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with ‘ctDNA relapse’, a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.

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Fig. 1: Various clinical applications of liquid biopsy using CTCs, circulating nucleic acids or other tumour-derived materials in the bloodstream.
Fig. 2: Roadmap for integration of a liquid biopsy assay into clinical practice.
Fig. 3: Possible designs of clinical studies of treatments to improve the outcomes in patients with ctDNA relapse after treatment of early stage disease.

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Acknowledgements

The work of M.I. is supported by Les Amis de Bordet and Fondation Contre le Cancer. The work of G.W.S. is supported in part by the Susan G. Komen Foundation. The work of S.S.J. is supported in part by the John and Marva Warnock Research Fund, Natalie and Vladimir Ermakoff, and the Stanford Catalyst for Collaborative Solutions, Stanford School of Engineering.

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  1. Department of Medical Oncology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium

    Michail Ignatiadis

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    George W. Sledge

  3. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Stefanie S. Jeffrey

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Correspondence to Michail Ignatiadis or Stefanie S. Jeffrey.

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Competing interests

M.I. has received consultancy fees from Celgene, Novartis, Pfizer, Seattle Genetics and Tesaro, and travel grants from Amgen and Pfizer. The institution of M.I. has received research grants from Menarini Silicon Biosystems and Natera. G.W.S. is a member of the Board of Directors of Tessa Therapeutics and of the Scientific Advisory Boards of Syndax and Verseau Therapeutics. S.S.J. serves as a scientific advisor for Quantumcyte and Ravel Biotechnology.

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Nature Reviews Clinical Oncology thanks R. Rosell; F.-C. Bidard, who co-reviewed with L. Cabel; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Blood Profiling Atlas in Cancer (BloodPAC): https://www.bloodpac.org/

CANCER-ID: https://www.cancer-id.eu/

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European Liquid Biopsy Society (ELBS): http://www.elbs.eu

OncoKB: https://www.oncokb.org/

OncoPrint: https://bioc.ism.ac.jp/packages/3.2/bioc/vignettes/ComplexHeatmap/inst/doc/s8.oncoprint.html#toc_0

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Ignatiadis, M., Sledge, G.W. & Jeffrey, S.S. Liquid biopsy enters the clinic — implementation issues and future challenges. Nat Rev Clin Oncol 18, 297–312 (2021). https://doi.org/10.1038/s41571-020-00457-x

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