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Liquid biopsy and minimal residual disease — latest advances and implications for cure

Nature Reviews Clinical Oncology volume 16, pages 409–424 (2019)Cite this article

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Abstract

Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize minimal residual disease (MRD), which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence. This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs and ctDNA in blood samples. In this Review, we discuss the key technologies that can be used to detect and characterize CTCs in surveillance of MRD and provide a brief overview of similar roles of ctDNA analyses. We then focus on the current clinical data on the use of CTCs and ctDNA in the detection and monitoring of MRD and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of individual patients with cancer.

Key points

  • Minimal residual disease (MRD) can be defined as cancer persisting in a patient after treatment that cannot be detected with current medical imaging modalities and is, therefore, an occult stage of cancer progression.

  • Liquid biopsy approaches based on the detection of small numbers of circulating tumour cells (CTCs) or minute amounts of circulating cell-free tumour DNA (ctDNA) now enable MRD detection in patients with various malignancies.

  • CTC detection at primary diagnosis of cancer predicts an unfavourable prognosis and is, therefore, applicable to risk stratification strategies beyond the current approaches to tumour staging.

  • Monitoring of CTCs and ctDNA during post-surgical follow-up assessments can enable the detection of disease relapse many months earlier than is possible with current radiological imaging procedures.

  • Further characterization of CTCs and ctDNA can provide insights into the molecular evolution of MRD during tumour progression, with implications for therapy to delay or even prevent metastatic relapse.

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Fig. 1: Technologies for CTC and ctDNA enrichment, detection and characterization.
Fig. 2: Methods of ctDNA detection.
Fig. 3: Therapeutic targets and resistance mechanisms.
Fig. 4: Therapeutic strategies depending on dynamic changes in tumour burden in patients with cancer.

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Acknowledgements

The authors thank N. Reimers for her assistance in designing figure 4. The authors received support from the German Cancer Aid Fund (Deutsche Krebshilfe); DFG (Deutsche Forschungsgemeinschaft); the French National Institute of Cancer (INCa); CANCER-ID, an Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115749, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions; and the European Liquid Biopsies Academy (ELBA) Innovative Training Networks (ITN) Horizon 2020 project H2020-MSCA-ITN-2017 (Towards widespread clinical application of blood-based diagnostic tools).

Competing interests

K.P. and C.A.-P. have ongoing patent applications related to circulating tumour cells. K.P. has received honoraria from Agena, Novartis, Roche and Sanofi and research funding from European Federation of Pharmaceutical Industries and Associations (EFPIA) partners (Angle, Menarini and Servier) of the CANCER-ID programme of the European Union–EFPIA Innovative Medicines Initiative. C.A.-P. has received honoraria from Janssen.

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Nature Reviews Clinical Oncology thanks J.-Y. Pierga and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Klaus Pantel

  2. Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre and University of Montpellier, Montpellier, France

    Catherine Alix-Panabières

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  1. Klaus Pantel
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ClinicalTrials.gov database: https://clinicaltrials.gov/

ELBA: https://elba.uni-plovdiv.bg/

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Pantel, K., Alix-Panabières, C. Liquid biopsy and minimal residual disease — latest advances and implications for cure. Nat Rev Clin Oncol 16, 409–424 (2019). https://doi.org/10.1038/s41571-019-0187-3

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