Liquid biopsies come of age: towards implementation of circulating tumour DNA

• Published in: Nature reviews. Cancer Vol. 17; no. 4; pp. 223 - 238
• Main Authors: Wan, Jonathan C. M., Massie, Charles, Garcia-Corbacho, Javier, Mouliere, Florent, Brenton, James D., Caldas, Carlos, Pacey, Simon, Baird, Richard, Rosenfeld, Nitzan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 631/45/147; 631/61/212/2166; 631/67/1059/2326; 631/67/2322; 631/67/69; Biomarkers, Tumor - blood; Biomedicine; Biopsy; Cancer; Cancer Research; Clonal Evolution; Deoxyribonucleic acid; DNA; DNA, Neoplasm - blood; Early Detection of Cancer; ErbB Receptors - genetics; Forecasts and trends; Humans; Identification and classification; Medical research; Molecular diagnostic techniques; Mutation; Neoplasm Staging; Neoplasms - genetics; Neoplasms - pathology; Oncogenes; Precision Medicine; review-article; Tumors
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc.2017.7

Key Points Cell-free DNA (cfDNA) is released predominantly by cell death into the bloodstream, although active secretion may have a role. Since the discovery of fetal cfDNA in the maternal circulation, cfDNA analysis has been rapidly implemented in clinical practice for noninvasive prenatal testing. Mutations were first detected in cfDNA more than two decades ago, and interest in circulating tumour DNA (ctDNA) as a noninvasive cancer diagnostic has increased considerably with the development of molecular methods that permit the sensitive detection and monitoring of multiple classes of mutation. ctDNA may have utility at almost every stage of the management of patients with cancer, including diagnosis, minimally invasive molecular profiling, treatment monitoring, the detection of residual disease and the identification of resistance mutations. ctDNA analysis may be broadly considered as a tool both for quantitative analysis of disease burden and for genomic analysis. The identification of ctDNA in individuals before a cancer diagnosis, and in presymptomatic individuals, suggests the possibility of ctDNA analysis as a tool for earlier detection and screening. Noninvasive cancer classification or subtyping has also emerged as a possibility, although for early detection, both technical and biological factors introduce challenges to the detection of mutant DNA in plasma and its interpretation. Monitoring multiple mutations in parallel can enhance the sensitivity of ctDNA detection, can be used to assess the clonal evolution of patients' disease and may identify resistance mutations before clinical progression is observed. ctDNA analysis is beginning to transition from the research setting into the clinic. The US Food and Drug Administration and the European Medicines Agency have approved ctDNA tests for specific indications in the absence of evaluable tumour tissue. Analysis of gene panels in plasma has now become available as a potential clinical tool. Large studies are under way to establish the overall performance and clinical utility of such assays when a tumour biopsy is not available for analysis. Potential applications of ctDNA have been demonstrated by a number of proof-of-principle studies. Prospective clinical trials are beginning to assess the clinical utility of ctDNA analysis for molecular profiling and disease monitoring. The increasing acceptance of ctDNA is enabling the field to move from exploratory ctDNA studies towards clinical trials in which ctDNA guides decision-making. In order to fully exploit the potential utility of liquid biopsies, it is essential that the biology of cfDNA and ctDNA is explored further. The mechanisms of release and degradation, and the factors that affect the representation of ctDNA in plasma, are poorly understood. The nature of ctDNA will be clarified through both large, well-annotated clinical studies and in vivo studies in which variables can be controlled. Circulating tumour DNA (ctDNA) analysis has the potential to improve prognostication, molecular profiling and disease monitoring in patients with cancer. This Review summarizes recent advances, potential applications in cancer research and personalized oncology, and the introduction of ctDNA into clinical use. Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.