Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy

Abstract

Considerable interest surrounds the use of immune-checkpoint inhibitors in patients with solid tumours following the demonstration of the impressive clinical efficacy of anti-programmed cell death protein 1 and anti-programmed cell death 1 ligand 1 antibodies in several tumour types. However, the emergence of unexpected tumour response patterns, such as pseudoprogression or hyperprogression, might complicate the management of patients receiving these agents. Analysis of circulating tumour DNA (ctDNA) has been shown to have prognostic value by enabling the detection of residual proliferating disease in the adjuvant setting and estimation of tumour burden in the metastatic setting, which are key stratification biomarkers for use of immune-checkpoint inhibition (ICI). Furthermore, examinations of ctDNA for genetic predictors of responsiveness to immunotherapy, such as mutations, tumour mutational load, and microsatellite instability provide a noninvasive surrogate for tumour biopsy sampling. Proof-of-concept reports have also demonstrated that quantitative changes in ctDNA levels early in the course of disease are a promising tool for the assessment of responsiveness to ICI that might complement standard imaging approaches. Other applications of this technology are also currently under investigation, such as early detection of resistance to immunotherapy and characterization of mechanisms of resistance. The aim of this Review is to summarize available data on the application of ctDNA in patients receiving immunotherapy and to discuss the most promising future directions.

Key points

  • Analysis of circulating tumour DNA (ctDNA) can enable the detection of residual disease, which corresponds to a minimal tumour burden, thus enabling use of immune-checkpoint inhibition (ICI) when it is most likely to be effective.

  • Analysis of ctDNA enables the noninvasive detection of mismatch repair deficiencies and assessment of tumour mutational burden, two predictive biomarkers of responsiveness to ICI.

  • Monitoring ctDNA levels in patients with metastatic cancer receiving ICI enables the efficacy of therapy to be determined early in the course of treatment and might avoid the prolonged administration of ineffective treatments.

  • Mutations that are likely to be predictive of either efficacy or resistance to ICI can be detected in ctDNA.

  • Further clinical studies are needed to comprehensively demonstrate the clinical utility of ctDNA as a biomarker of ICI in clinical practice.

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Fig. 1: Analysis of ctDNA.
Fig. 2: Potential clinical applications of ctDNA in patients receiving immune-checkpoint inhibition.
Fig. 3: Assessment of tumour mutational burden in blood.
Fig. 4: Approaches for detecting microsatellite instability.

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Acknowledgements

The authors thank A. Valcarcel (Instutit Curie) for her comments on the manuscript. This work was supported by the Institut Curie SIRIC2 (grant INCa-DGOS-INSERM_12554).

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L.C., O.L., J.-Y.P., and F.-C.B. researched data for this article; all authors made a substantial contribution to discussions of content, writing the manuscript, and reviewing and/or editing the manuscript before submission.

Correspondence to François-Clément Bidard.

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Competing interests

C.P., M.-H.S., and F.-C.B. have ongoing patent applications relating to circulating tumour DNA analysis. The other authors declare no competing interests.

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