Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy

• Published in: Nature reviews. Clinical oncology 2018-10, Vol.15 (10), p.639-650
• Main Authors: Cabel, Luc, Proudhon, Charlotte, Romano, Emanuela, Girard, Nicolas, Lantz, Olivier, Stern, Marc-Henri, Pierga, Jean-Yves, Bidard, François-Clément
• Format: Article
• Language: English
• Subjects: 631/1647/2017; 692/4028/67/1059/2325; 692/700/139; 692/700/1750; Apoptosis; Biomarkers; Biopsy; Cancer; Care and treatment; Cell death; Data processing; Deoxyribonucleic acid; DNA; Enzymes; Health aspects; Immune checkpoint inhibitors; Immunotherapy; Medicine; Medicine & Public Health; Metastases; Metastasis; Methods; Microsatellite instability; Mismatch repair; Mutation; Oncogenes; Oncology; Oncology, Experimental; Patients; PD-1 protein; Regulation; Review Article; Solid tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-018-0074-3

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. The majority of patients receiving immunotherapy do not respond to treatment but might still have adverse events. Furthermore, some patients with an initial response will develop acquired resistance to treatment. In this Review, the authors describe the role of circulating tumour DNA in the management of patients receiving immunotherapy. 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 o