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OPINION

Early stage NSCLC — challenges to implementing ctDNA-based screening and MRD detection

Abstract

Circulating tumour DNA (ctDNA) refers to the fraction of cell-free DNA in a patient’s blood that originates from a tumour. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumours have resulted in increased interest in exploiting ctDNA as a tool to facilitate earlier detection of cancer and thereby improve therapeutic outcomes by enabling early intervention. ctDNA analysis might also have utility in the adjuvant therapeutic setting by enabling the identification of patients at a high risk of disease recurrence on the basis of the detection of post-surgical minimal (or molecular) residual disease (MRD). This approach could provide the capability to adapt clinical trials in the adjuvant setting in order to optimize risk stratification, and we argue that this objective is achievable with current technologies. Herein, we evaluate contemporary next-generation sequencing (NGS) approaches to ctDNA detection with a focus on non-small-cell lung cancer. We explain the technical and analytical challenges to low-frequency mutation detection using NGS-based ctDNA profiling and evaluate the feasibility of ctDNA profiling in both screening and MRD assessment contexts.

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Fig. 1: Detection of ctDNA in patients with NSCLC.
Fig. 2: Circulating cell-free DNA concentrations detected in patients with early stage (stage I–III) NSCLC and associated probabilities of detecting mutations in ctDNA.
Fig. 3: The correlation between the abundance of ctDNA, tumour volume, tumour diameter, and T stage.

Figure adapted from ref.8, Macmillan Publishers Limited.

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Acknowledgements

The work of C.A. is supported by a Stand Up To Cancer–LUNGevity–American Lung Association Lung Cancer Interception Dream Team translational research grant and the Rosetrees Trust. The work of C.S. has been supported by the Breast Cancer Research Foundation, Cancer Research UK (CRUK; Tracking Cancer Evolution Through Therapy (TRACERx) and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, the CRUK University College London Experimental Cancer Medicine Centre, a Stand Up To Cancer–LUNGevity–American Lung Association Lung Cancer Interception Dream Team Translational Research Grant, the European Research Council (THESEUS project), the Medical Research Council, the UK National Institute for Health Research, the Novo Nordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Rosetrees Trust, the University College London Hospitals Biomedical Research Centre, and the Wellcome Trust.

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Nature Reviews Clinical Oncology thanks B. Li, C. Rolfo, and Y.-L. Wu for their contribution to the peer review of this work.

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C.A. and N.J.B. researched the data for the article, and C.A. and C.S. wrote the manuscript. All authors contributed to discussions of content and reviewed and/or edited the manuscript.

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Correspondence to Charles Swanton.

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Competing interests

C.A. and C.S. submitted a patent with University College London (UCL) business PLC (provisional patent number 1618485.5) based on a phylogenetic approach to analysis of circulating tumour DNA. C.S. has received grant support from AstraZeneca; personal fees from Boehringer Ingelheim, Celgene, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and Roche; has stock options in Achilles Therapeutics, ApoGen Biotechnologies, EPIC Bioscience, and GRAIL; and is a co-founder of Achilles Therapeutics. N.J.B. declares no competing interests.

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Abbosh, C., Birkbak, N.J. & Swanton, C. Early stage NSCLC — challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol 15, 577–586 (2018). https://doi.org/10.1038/s41571-018-0058-3

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