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  • Review Article
  • Published:

Liquid biopsy: monitoring cancer-genetics in the blood

Abstract

Cancer is associated with mutated genes, and analysis of tumour-linked genetic alterations is increasingly used for diagnostic, prognostic and treatment purposes. The genetic profile of solid tumours is currently obtained from surgical or biopsy specimens; however, the latter procedure cannot always be performed routinely owing to its invasive nature. Information acquired from a single biopsy provides a spatially and temporally limited snap-shot of a tumour and might fail to reflect its heterogeneity. Tumour cells release circulating free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin, and detection of cancer-associated alleles in the blood has long been impossible to achieve. Technological advances have overcome these restrictions, making it possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions (primary and metastases) as well as offering the opportunity to systematically track genomic evolution. This Review will explore how tumour-associated mutations detectable in the blood can be used in the clinic after diagnosis, including the assessment of prognosis, early detection of disease recurrence, and as surrogates for traditional biopsies with the purpose of predicting response to treatments and the development of acquired resistance.

Key Points

  • Under representation of the heterogeneity of a tumour and poor sample availability means tissue biopsies are of limited value for the assessment of tumour dynamics in the advanced stages of disease

  • Extended periods between sampling and clinical application of the results, as well as additional lines of treatment between sampling, might result in an altered genetic composition of the tumour

  • Circulating free DNA can be extracted from the blood and tumour-specific aberrations assessed to provide a genetic landscape of the cancerous lesions in a patient

  • Tracking tumour-associated genetic aberrations in the blood can be used to assess the presence of residual disease, recurrence, relapse and resistance

  • Monitoring the emergence of tumour-associated genetic aberrations in the blood can be used to detect the emergence of resistant cancer cells 5–10 months before conventional methods

  • To implement circulating tumour DNA testing in the clinic, standardization of techniques, assessment of reproducibility and cost-effectiveness is required as well as prospective validation in clinical trials

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Figure 1: Release and extraction of cfDNA from the blood.
Figure 2: Monitoring tumour-specific aberrations to detect recurrence and resistance.

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Acknowledgements

We would like to thank Giulia Siravegna and Elisa Scala (IRCC, Institute for Cancer Research at Candiolo, Italy) for their assistance with technical aspects concerning methods of DNA extraction from blood. Work in the authors' laboratories is supported by 'Fondazione Piemontese per la Ricerca sul Cancro—ONLUS grant 'Liquid Biopsy—5 per mille 2010 Sanità'; AIRC 2010 Special Program Molecular Clinical Oncology 5xMille, Project n. 9970 (A. Bardelli); AIRC, grants MFAG 11349 (F. Di Nicolantonio) and IG 12812 (A. Bardelli); 'Fondazione Piemontese per la Ricerca sul Cancro—ONLUS grant 'Farmacogenomica—5 per mille 2009 MIUR'—(F. Di Nicolantonio); the European Community's Seventh Framework Programme under grant agreement n. 259015 COLTHERES; Intramural Grants Fondazione Piemontese per la Ricerca sul Cancro ONLUS (5 per mille 2008 Ministero dell'Istruzione, dell'Università e della Ricerca) to A. Bardelli and F. Di Nicolantonio. E. Crowley is supported by the Marie-Curie Incoming Fellowship.

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E. Crowley researched the data for the article, and all authors made a substantial contribution to discussion of the content, to writing the article and to reviewing or editing the manuscript before submission.

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Correspondence to Alberto Bardelli.

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Crowley, E., Di Nicolantonio, F., Loupakis, F. et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10, 472–484 (2013). https://doi.org/10.1038/nrclinonc.2013.110

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