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Molecular analysis of circulating tumour cells—biology and biomarkers

Nature Reviews Clinical Oncology volume 11, pages 129–144 (2014)Cite this article

Subjects

Key Points

  • Circulating tumour cells (CTCs) can be captured from a simple blood test and their molecular characterization can provide vital insights into tumour heterogeneity

  • Advances in single-cell genomic profiling have enhanced the ability to interrogate CTCs for 'actionable' aberrations and emerging resistant subclones, which will assist in patient treatment stratification

  • Biological processes during CTC invasion and metastasis such as epithelial–mesenchymal transition and circulating tumour microemboli, typically explored in preclinical models are now being examined in the clinical setting

  • CTC and cell-free DNA mutational profiling represent complementary biomarkers for identification of predictive targets and real-time monitoring of disease in clinical practice

  • CTC assay validation and clinical qualification is required if CTCs are to become routine tests in the clinic; collaborative efforts between academia and industry are needed to make this a reality

Abstract

Growing evidence for intratumour heterogeneity informs us that single-site biopsies fall short of revealing the complete genomic landscape of a tumour. With an expanding repertoire of targeted agents entering the clinic, screening tumours for genomic aberrations is increasingly important, as is interrogating the tumours for resistance mechanisms upon disease progression. Multiple biopsies separated spatially and temporally are impractical, uncomfortable for the patient and not without risk. Here, we describe how circulating tumour cells (CTCs), captured from a minimally invasive blood test—and readily amenable to serial sampling—have the potential to inform intratumour heterogeneity and tumour evolution, although it remains to be determined how useful this will be in the clinic. Technologies for detecting and isolating CTCs include the validated CellSearch® system, but other technologies are gaining prominence. We also discuss how recent CTC discoveries map to mechanisms of haematological spread, previously described in preclinical models, including evidence for epithelial–mesenchymal transition, collective cell migration and cells with tumour-initiating capacity within the circulation. Advances in single-cell molecular analysis are enhancing our ability to explore mechanisms of metastasis, and the combination of CTC and cell-free DNA assays are anticipated to provide invaluable blood-borne biomarkers for real-time patient monitoring and treatment stratification.

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Figure 1: Potential of single CTC analysis to evaluate tumour heterogeneity and disease evolution.
Figure 2: Proposed mechanisms of tumour cell dissemination.
Figure 3: Examples of EMT cells isolated by ISET®.

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Acknowledgements

The authors thank Cancer Research UK for research support via core funding to the Cancer Research UK Manchester Institute (C5659/A12328). R. L. Metcalf and L. Carter are supported by an unrestricted educational grant from Cancer Research UK and AstraZeneca.

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  1. Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, 550 Wilmslow Road, Manchester, M20 4BX, UK

    Matthew G. Krebs, Robert L. Metcalf, Louise Carter, Ged Brady, Fiona H. Blackhall & Caroline Dive

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M. G. Krebs, R. L. Metcalf and L. Carter researched the data for the article, and discussed its content with C. Dive and F. H. Blackhall. All authors wrote the manuscript and edited it before submission.

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Correspondence to Caroline Dive.

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Krebs, M., Metcalf, R., Carter, L. et al. Molecular analysis of circulating tumour cells—biology and biomarkers. Nat Rev Clin Oncol 11, 129–144 (2014). https://doi.org/10.1038/nrclinonc.2013.253

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