Journal of ISSN: 2373-633X JCPCR

Cancer Prevention & Current Research
Editorial
Volume 5 Issue 2 - 2016
Mutation Analyses of Circulating Tumor Cells, A Real-Time “Liquid Biopsy” Molecular Study for Patients with Cancer
Sandra V Fernandez*
Temple University, USA
Received: June 29, 2016 | Published: July 21, 2016
*Corresponding author: Sandra V. Fernandez, Ph.D, Assistant Research Professor, Protocol Support Laboratory, Fox Chase Cancer Center, Temple University, Philadelphia, PA 19111, USA, Tel: (215) 214-1634; Email:
Citation: Fernandez SV (2016) Mutation Analyses of Circulating Tumor Cells, A Real-Time “Liquid Biopsy” Molecular Study for Patients with Cancer. J Cancer Prev Curr Res 5(3): 00160. DOI: 10.15406/jcpcr.2016.05.00160

Editorial

In cancer management, biomarkers are used for numerous purposes, such as predicting patient survival, identifying patients who are more likely to benefit from a treatment, and monitoring disease progression or therapeutic efficacy.  The identification of biomarkers helps to ensure that patients receive the best therapeutic strategies, thereby avoiding unnecessary treatments and associated toxicities. At present, treatment decisions in the metastatic setting are based on analysis of earlier primary tumor samples or metastatic sites. However, biopsies from primary tumors or metastatic sites are not always feasible, and most important, mutation status of the primary and metastatic lesions can change during the course of disease and therapy. The natural evolution of the tumor itself and the specific therapies to which the patient has been exposed contribute to these changes. Circulating tumor cells (CTCs) isolated from the blood of patients with metastatic carcinoma provide a source of tumor cells and can be potential replacements for such repeatable tumor biopsies.

CTCs have been detected in a majority of epithelial cancers, including those from prostate, colorectal, and breast. CTCs are tumor cells shed from either the primary tumor or its metastases and can thus be regarded as “liquid biopsies” of metastasizing cells. Little is known about the timing of CTC release from primary tumors, their heterogeneity, or their functional properties. Although their exact composition is unknown, a fraction of these cells are thought to be viable metastatic precursors capable of initiating a clonal metastatic lesion. Several studies suggest that the characterization of the mutation status of CTCs could serve as a marker of micrometastatic tumor loads associated with a patient's prognosis and accurately predict the effectiveness of therapy in several cancers [1-3]. Thus, CTC detection and mutational analysis has enormous potential for metastases prediction, monitoring response of patients to therapy, and early prediction of relapse.

For example, in colorectal cancer, mutations in driver genes (APC, KRAS, or PIK3CA) found in the primary tumor and metastasis were also detected in matched CTCs from patients, and interestingly, some CTCs showed amplification of CDK8, a potential new therapeutic target for CDK inhibitors [4]. Recently, the analysis of hundreds of CTCs obtained from patients with colorectal cancer revealed high intra-patient and inter-patient heterogeneity of KRAS [5,6]. CTCs with mutated KRAS will escape anti-EGFR therapy, and their early detection may help to guide therapy in individual patients. In breast cancer, resistance to HER2-targeting therapies is a key issue, and activation of the PI3K pathway by mutations in the PIK3CA gene plays a key role in this process; studies on pools of CTCs showed that 15.9% of patients with metastatic breast cancer had mutations in the PIK3CA gene [7]. More information about the occurrence of these activating mutations in the context of therapeutic interventions is needed.

Establishing the role of a diagnostic test in the medical setting is not straightforward, and for CTCs, the situation is complicated by the broad range of devices currently in use for their isolation. CTCs are found in frequencies on the order of 1-10 CTC per mL of whole blood in patients with metastatic disease, which contains a few million white blood cells and a billion red blood cells. Because of their low frequency, enrichment is needed to increase sensitivity to an acceptable level. CTC assays usually start with an enrichment step that increases the concentration of CTCs by several log units and enables an easier detection of single tumor cells. Furthermore, the only FDA-approved CTC enumeration test, CellSearch, relies on the detection of the surface epithelial cell adhesion molecule, EpCAM, but it is unclear whether all CTCs from epithelial tumors express EpCAM. It is well known that during the epithelial to mesenchymal transition, the expression of epithelial markers on CTCs, such as EpCAM and cytokeratin (CK), may be down-regulated and become undetectable. Although EpCAM might be down-regulated during EMT, the current view is that tumor cells with a partial EMT (or “intermediate phenotype” between epithelial and mesenchymal) are the most aggressive subclones [8]. However, CTCs, when detected, may represent a genomic snapshot of the current disease, and therefore can be used as “liquid tumor biopsies” to study mutations and monitor disease progression or therapeutic efficacy.

The need for improved CTC isolation and characterization methods to enable clinical applications is a current limitation in the analysis of CTCs. However, it was demonstrated that the analysis of cancer-related mutations in CTCs is feasible in a hospital-based clinical laboratory. Future clinical trials focused on interventional studies are needed in order to demonstrate the clinical utility of CTCs.

References

  1. Sastre J, Maestro ML, Gomez-Espana A, Rivera F, Valladares M, et al. (2012). Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study. Oncologist  17 (7): 947-955.
  2. Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, et al. (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J clin oncol 29 (12): 1556-1563.
  3. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, et al. (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12 (14 Pt 1): 4218-4224.
  4. Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, et al. (2013) Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res 73(10): 2965-2975.
  5. Gasch C, Bauernhofer T, Pichler M, Langer-Freitag S, Reeh M, et al. (2013) Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem 59(1): 252-260.
  6. Mostert B, Jiang Y, Sieuwerts AM, Wang H, Bolt-de Vries J, et al. (2013) KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue. Int J Cancer 133(1): 130-141.
  7. Schneck H, Blassl C, Meier-Stiegen F, Neves RP, Janni W et al. (2013) Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients. Mol Oncol 7(5): 976-986.
  8. Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19(11): 1438-1449.
© 2014-2017 MedCrave Group, All rights reserved. No part of this content may be reproduced or transmitted in any form or by any means as per the standard guidelines of fair use.
Creative Commons License Open Access by MedCrave Group is licensed under a Creative Commons Attribution 4.0 International License.
Based on a work at http://medcraveonline.com
Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version | Opera |Privacy Policy