Liquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis

Liquid biopsies are emerging as a favorable alternative to conventional tissue biopsies, providing a noninvasive approach for the detection and monitoring of cancer biomarkers. The FDA approval of a companion diagnostic test for lung cancer and a screening test for colorectal cancer based on the analysis of ctDNA were important milestones in the clinical implementation of liquid biopsies. CTC enumeration using the CellSearch® CTC test is FDA approved for the prognosis of breast, colorectal, and prostate cancers. Circulating EVs, RNAs, and TEPs are promising new constituents of liquid biopsies. Recent technological developments in the field have the potential to address current limitations of liquid biopsies and enhance the sensitivity of cancer biomarker detection. Liquid biopsies, comprising the noninvasive analysis of circulating tumor-derived material (the ‘tumor circulome’), represent an innovative tool in precision oncology to overcome current limitations associated with tissue biopsies. Within the tumor circulome, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the only components the clinical application of which is approved by the US Food and Drug Administration (FDA). Extracellular vesicles (EVs), circulating tumor RNA (ctRNA), and tumor-educated platelets (TEPs) are relatively new tumor circulome constituents with promising potential at each stage of cancer management. Here, we discuss the clinical applications of each element of the tumor circulome and the prevailing factors that currently limit their implementation in clinical practice. We also detail the most recent technological developments in the field, which demonstrate potential in improving the clinical value of liquid biopsies. Liquid biopsies, comprising the noninvasive analysis of circulating tumor-derived material (the ‘tumor circulome’), represent an innovative tool in precision oncology to overcome current limitations associated with tissue biopsies. Within the tumor circulome, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the only components the clinical application of which is approved by the US Food and Drug Administration (FDA). Extracellular vesicles (EVs), circulating tumor RNA (ctRNA), and tumor-educated platelets (TEPs) are relatively new tumor circulome constituents with promising potential at each stage of cancer management. Here, we discuss the clinical applications of each element of the tumor circulome and the prevailing factors that currently limit their implementation in clinical practice. We also detail the most recent technological developments in the field, which demonstrate potential in improving the clinical value of liquid biopsies. a fluorescent dye that binds to AT-rich regions on DNA and is used to stain nuclei. programmed cell death; can be induced by external stimuli and is a tightly regulated process. highly sensitive dPCR method that combines emulsion PCR and flow cytometry to identify and quantify DNA mutations. a portion of the Sialyl-Lewis A antigen. Its presence is highly correlated with advanced epithelial cancers. a sensitive method of analysis comprising the sequencing of cancer-specific (personalized) panels of genes to identify cancer-specific mutations. the condition in which a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Clonal hematopoiesis has been linked to a greater than tenfold increased risk of developing a hematological cancer. medical device, often an in vitro test, providing information that is essential and required for the safe and effective use of a corresponding drug. It is often developed simultaneously with the corresponding drug. The cobas® EGFR Mutation Test v2 described in the main text, for example, comprises a PCR-based analysis of a set of mutations, insertions, and deletions on the EGFR gene and is used to inform the use of erlotinib and osimertinib in NSCLC. a quantitative PCR method that is used for the absolute quantification of DNA, without the need for a calibration curve with samples of known quantities. The initial sample mix (which is prepared as in a common qPCR) is split into several individual wells before the amplification step. Following PCR amplification, the absolute quantification of the target is calculated using Poisson statistics, based on the number of positive and negative wells for the target sequence. a variation of dPCR in which the sample is partitioned in a large number of tiny water-oil emulsion droplets, containing on average one fragment of starting material each, before the analysis. The partition of the sample in small droplets in emulsion has the advantage, compared with dPCR, of increasing the number of partitions analyzed and, therefore, the resolution of the analysis. a process in which epithelial cells lose their polarization and adhesion properties, gaining migratory properties and, thus, differentiate into mesenchymal cells. the presence of different genetic clones within the same tumor. the time needed for half the amount of a substance to be removed from circulation by biological processes. the process by which cancer cells invade blood or lymphatic vessels through the basal membrane. a device that integrates multiple sequential laboratory functions on a very small device (chip). a type of in vitro diagnostic test that is designed, manufactured, and used within a single laboratory. repeated observations of the same parameter (e.g., the serum concentration of a protein) in the same patient over a period of time. the presence of a small number of tumor cells remaining after surgery, chemo- or radiotherapy (residual) when the patient is considered to be in remission. traumatic cell death resulting from acute cellular injury. small lymph nodal metastases that may be undetected histologically in tissue biopsies. a population-based stochastic optimization technique that shares many similarities with genetic algorithms. an enzyme, the physiological function of which is to liquefy semen in the ejaculate. It is produced by the prostate gland and its blood concentration is elevated in prostate cancer. in a binary classification test (positive/negative; healthy/diseased) the sensitivity measures the proportion of actual positives that are correctly identified as positive by the test. It is also called the ‘true positive rate’ (TPR). in a binary classification test, the specificity measures the proportion of actual negatives that are correctly identified as negative by the test. It is also called the ‘ true negative rate’ (TNR) an enzyme that catalyzes the transfer of phosphate groups from ATP to tyrosine residues of proteins. a genomic technique used for sequencing all the protein-coding genes in a genome (exome).