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The term liquid biopsy is used in contraposition to the traditional “solid” tissue biopsy. In the oncology field it has opened a new plethora of clinical opportunities as tumor-derived material is shedded into the different biofluids from where it can be isolated and analyzed. Common biofluids include blood, urine, saliva, cerebrospinal fluid (CSF), pleural effusion or bile. Starting from these biological specimens several analytes can be isolated, among which we will review the most widely used: circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), proteins, metabolites, and exosomes. Regarding the nature of the biomarkers it will depend on the analyte, the type of tumor and the clinical application of the liquid biopsy and it includes, somatic point mutations, deletions, amplifications, gene-fusions, DNA-methylated marks, tumor-specific miRNAs, proteins or metabolites. Here we review the characteristics of the analytes and the methodologies used for their isolation. We also describe the applications of the liquid biopsy in the management of patients with cancer, from the early detection of cancers to treatment guidance in patients with advanced tumors. Finally, we also discuss some current limitations and still open questions.

Liquid biopsy is a convenient, fast, non-invasive and reproducible sampling method that can dynamically reflect the changes in tumor gene expression profile, and provide a robust basis for individualized therapy and early diagnosis of cancer. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the currently approved diagnostic biomarkers for screening cancer patients. In addition, tumor-derived extracellular vesicles (tdEVs), circulating tumor-derived proteins, circulating tumor RNA (ctRNA) and tumor-bearing platelets (TEPs) are other components of liquid biopsies with diagnostic potential. In this review, we have discussed the clinical applications of these biomarkers, and the factors that limit their implementation in routine clinical practice. In addition, the most recent developments in the isolation and analysis of circulating tumor biomarkers have been summarized, and the potential of non-blood liquid biopsies in tumor diagnostics has also been discussed.