Circulating Tumor Cells: Liquid Biopsy of Cancer

Abstract

BACKGROUND:The detection and molecular characterization of circulating tumor cells (CTCs) are one of the most active areas of translational cancer research, with Ͼ400 clinical studies having included CTCs as a biomarker. The aims of research on CTCs include (a) estimation of the risk for metastatic relapse or metastatic progression (prognostic information), (b) stratification and real-time monitoring of therapies, (c) identification of therapeutic targets and resistance mechanisms, and (d) understanding metastasis development in cancer patients.CONTENT: This review focuses on the technologies used for the enrichment and detection of CTCs. We outline and discuss the current technologies that are based on exploiting the physical and biological properties of CTCs. A number of innovative technologies to improve methods for CTC detection have recently been developed, including CTC microchips, filtration devices, quantitative reverse-transcription PCR assays, and automated microscopy systems. Molecularcharacterization studies have indicated, however, that CTCs are very heterogeneous, a finding that underscores the need for multiplex approaches to capture all of the relevant CTC subsets. We therefore emphasize the current challenges of increasing the yield and detection of CTCs that have undergone an epithelialmesenchymal transition. Increasing assay analytical sensitivity may lead, however, to a decrease in analytical specificity (e.g., through the detection of circulating normal epithelial cells).

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

“…Single CpG methylation in TS genes even ranged from 2% to >15%. Although we cannot exclude BC dormancy or early‐stage second tumors, circulating tumor cells in these patients occur at very low concentrations of one tumor cell in the background of millions of blood cells and have an average half‐life of only 1–3 h after separation 40, 41. Similarly, cell‐free circulating DNA has a half‐life of approximately 14 h and is rapidly cleared from blood, if not replenished from apoptotic/necrotic cells every few hours 42.…”

Circulating tumor cells

“…In this context, and taking into consideration the frequent genetic discordance between primary tumors and corresponding metastases, the hypothesis of the "liquid biopsy" using CTCs emerged as a minimally invasive alternative to traditional tissue biopsy in determining cancer therapy. 9 To date, the CellSearch system is the only FDA-cleared test for CTCs assessment with prognostic purpose in metastatic breast, prostate, and colorectal cancer. 10 In metastatic colorectal cancer, the CellSearch system received US FDA clearance for routine clinical use with a threshold CTC count ≥3/7.5 mL of blood, to stratify patients into favorable and unfavorable prognostic groups.…”

Liquid Biopsy in Liquid Tumors

“…It is accepted that there might be 1 CTC/10 9 cells in a patient blood sample with a metastatic tumor. The studies on CTCs are aimed to evaluate the risk of relapse in an oncological patient, to select treatment and monitor response to therapy, to identify novel therapeutic targets, to detect driver mutations that might be druggable if known, to evaluate pharmacodynamic effects, to analyze resistance mechanisms or to understand molecular basis of tumor metastasis dissemination [9] [10]. CTCs and ccfDNA, likely provide a mean of the intra-tumour heterogeneity of cancer, since this genetic circulating material may arise from all different tumor sections, being more representative that the information provided by a single tissue biopsy [10].…”