Abstract
Purpose of Review
Circulating tumor cells represent rare events in the peripheral blood of patients with cancer that can provide insight into tumor biology. CTC enumeration, isolation, and analysis represent liquid biopsy approaches whose role in the management of patients with cancer continues to evolve in the era of precision medicine. This review presents an overview of technologies central to studying CTCs.
Recent Findings
Technologies for CTC isolation can be divided into two categories: label-dependent and label-independent. Label-dependent techniques utilize biological properties such as cell surface proteins, while label-independent techniques utilize distinctive physical properties such as cell size, density, and plasticity. Advances in microfluidics designs as well as hybrid combinations of label-dependent and label-independent techniques have resulted in unprecedented improvements in CTC isolation, permitting not only the detection and enumeration of these rare events but also providing the means for studying them and exploring them as a new dimension of cancer biomarkers.
Summary
With advances in tools for isolating and studying CTCs in hand, questions regarding the clinical utility of CTC enumeration in peripheral blood, detection of CTC-associated biomarkers, and analysis of dynamic changes in CTCs during the course of cancer therapy represent exciting new opportunities for cancer research.
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References
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Plaks V, Koopman CD, Werb Z. Cancer. Circulating tumor cells. Science. 2013;341:1186–8.
Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.
Yu M, Stott S, Toner M, Maheswaran S, Haber DA. Circulating tumor cells: approaches to isolation and characterization. J Cell Biol. 2011;192:373–82.
Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res. 2007;13:920–8.
Krebs MG, Hou JM, Ward TH, Blackhall FH, Dive C. Circulating tumour cells: their utility in cancer management and predicting outcomes. Ther Adv Med Oncol. 2010;2:351–65.
•• de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–9 Landmark paper describing the prognostic utility of circulating tumor cells in patients with metastatic prostate cancer.
Maheswaran S, Haber DA. Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev. 2010;20:96–9.
Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med. 2015;7:1–11.
Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–45.
Parsons DW, Jones S, Zhang X, Lin JCH, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.
Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–21.
Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152:714–26.
Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature. 2011;469:356–61.
Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.
•• Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213–21 Landmark paper describing the prognostic utility of circulating tumor cells in patients with metastatic colorectal cancer.
•• Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91 Landmark paper describing the prognostic utility of circulating tumor cells in patients with metastatic breast cancer.
Toss A, Mu Z, Fernandez S, et al. CTC enumeration and characterization: moving toward personalized medicine. Ann Transl Med. 2014;2:108.
Wang L, Balasubramanian P, Chen AP, Kummar S, Evrard YA, Kinders RJ. Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells. Semin Oncol. 2016;43:464–75.
Andreopoulou E, Yang LY, Rangel KM, Reuben JM, Hsu L, Krishnamurthy S, et al. Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/Detect versus Veridex CellSearch system. Int J Cancer. 2012;130:1590–7.
Muller V, Riethdorf S, Rack B, et al. Prognostic impact of circulating tumor cells assessed with the CellSearch System and AdnaTest Breast in metastatic breast cancer patients: the DETECT study. Breast Cancer Res. 2012;14:R118.
Van der Auwera I, Peeters D, Benoy IH, et al. Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer. Br J Cancer. 2010;102:276–84.
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.
Hyun KA, Koo GB, Han H, Sohn J, Choi W, Kim SI, et al. Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget. 2016;7:24677–87.
Xu L, Mao X, Imrali A, Syed F, Mutsvangwa K, Berney D, et al. Optimization and evaluation of a novel size based circulating tumor cell isolation system. PLoS One. 2015;10:e0138032.
Bidard FC, Weigelt B, Reis-Filho JS. Going with the flow: from circulating tumor cells to DNA. Sci Transl Med. 2013;5:207ps214.
Ma M, Zhu H, Zhang C, et al. “Liquid biopsy”-ctDNA detection with great potential and challenges. Ann Transl Med. 2015;3:235.
Chan F, Goodman O, Fink L, Vogelzang NJ, Pomerantz D, Khoury JD. Dramatically elevated circulating tumor cell numbers in a patient with small cell neuroendocrine carcinoma of the prostate. Arch Pathol Lab Med. 2010;134:120–3.
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Kristofor Yap declares no conflict of interest. Evan Cohen reports grants from ANGLE, Plc. and Hitachi Chemical. James M. Reuben has received research funding from and is a member of the Scientific Advisory Board of ANGLE, Plc. He also reports grants and personal fees from Hitachi Chemical Company. Joseph D. Khoury has received research funding from and is a member of the Scientific Advisory Board of ANGLE, Plc.
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Yap, K., Cohen, E.N., Reuben, J.M. et al. Circulating Tumor Cells: State-of-the-art Update on Technologies and Clinical Applications. Curr Hematol Malig Rep 14, 353–357 (2019). https://doi.org/10.1007/s11899-019-00531-x
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DOI: https://doi.org/10.1007/s11899-019-00531-x