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02-03-2017 | Liquid biopsy | Review | Article

Integrating liquid biopsies into the management of cancer

Giulia Siravegna, Silvia Marsoni, Salvatore Siena, Alberto Bardelli


During cancer progression and treatment, multiple subclonal populations of tumour cells compete with one another, with selective pressures leading to the emergence of predominant subclones that replicate and spread most proficiently, and are least susceptible to treatment. At present, the molecular landscapes of solid tumours are established using surgical or biopsy tissue samples. Tissue-based tumour profiles are, however, subject to sampling bias, provide only a snapshot of tumour heterogeneity, and cannot be obtained repeatedly. Genomic profiles of circulating cell-free tumour DNA (ctDNA) have been shown to closely match those of the corresponding tumours, with important implications for both molecular pathology and clinical oncology. Analyses of circulating nucleic acids, commonly referred to as 'liquid biopsies', can be used to monitor response to treatment, assess the emergence of drug resistance, and quantify minimal residual disease. In addition to blood, several other body fluids, such as urine, saliva, pleural effusions, and cerebrospinal fluid, can contain tumour-derived genetic information. The molecular profiles gathered from ctDNA can be further complemented with those obtained through analysis of circulating tumour cells (CTCs), as well as RNA, proteins, and lipids contained within vesicles, such as exosomes. In this Review, we examine how different forms of liquid biopsies can be exploited to guide patient care and should ultimately be integrated into clinical practice, focusing on liquid biopsy of ctDNA — arguably the most clinically advanced approach.

Nat Rev Clin Oncol 2017; 14: 531–548. doi: 10.1038/nrclinonc.2017.14

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Cancers arise owing to the accumulation of molecular alterations in genes that control cell survival, growth, proliferation, and differentiation within the nascent tumour. Currently, the molecular profile of cancers is typically assessed using DNA and/or RNA obtained from a fragment of the primary tumour or a single metastatic lesion; therapeutic strategies are subsequently defined according to the molecular profile of the tissue. Importantly, however, the molecular profile of tumours evolves dynamically over time. The ability of tumours to evolve in response to a wide variety of endogenous and exogenous selective pressures has several implications: firstly, the genetic make-up of individual cancers is highly heterogeneous; secondly, within a single patient, distinct metastatic lesions can be molecularly divergent; thirdly, therapeutic stress exerted on tumour cells, particularly by targeted drugs, can dynamically modify the genomic landscape of tumours1,2,3,4,5. Of note, human blood samples contain materials — including cell-free DNA (cfDNA) and RNA (cfRNA); proteins; cells; and vesicles (such as exosomes) — that can originate from different tissues, including cancers. Indeed, the rapid turnover of cancer cells is postulated to result in the constant release of tumour-derived nucleic acids and vesicles into the circulation, and viable tumour cells can also separate from the tumour to enter the bloodstream. Thus, the ability to detect and characterize circulating cell-free tumour DNA (ctDNA) and/or tumour-derived RNA (predominantly microRNAs (miRNAs)), and circulating tumour cells (CTCs), has enabled clinicians to repeatedly and non-invasively interrogate the dynamic evolution of human cancers (Fig. 1). The possibility of probing the molecular landscape of solid tumours via a blood draw, with major implications for research and patient care, has attracted remarkable interest among the oncology community; the term 'liquid biopsy' is often used to describe this approach6.

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