Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives
Abstract
:1. Introduction
2. Diagnosis and Etiology of Pancreatic Cancer
3. Circulating Tumor Cells in Pancreatic Cancer
3.1. Methods of CTC Isolation and Detection
- -
- Physical/biological systems isolate CTCs on the basis of electric charge or cell size. The enrichment relies on the fact that CTCs have a higher density, a different electric charge, a different motility, and a larger size than normal blood components. They can thus be isolated with dedicated devices (microfilters, microfluidic chips, electric separation, etc.).
- -
- Surface antibody–based enrichment can be used as “positive” or “negative” enrichment. Positive selection relies on antibodies directed against the surface markers of the CTCs. Common CTC isolation techniques use the epithelial cell adhesion molecule (EpCAM) for positive selection. To eliminate normal blood components, the negative selection systems deplete leukocytes from the specimens. They use CD45 antibodies to bind the blood components and to isolate the CD45-negative CTCs.
- -
- Morphological examination supported by immunocytological staining for cancer-specific antibodies is the gold standard for CTC detection and definition. This can be performed after physical enrichment but can also be performed in part with surface-antibody based methods, even though the cytological evaluation is not as good as for regular cytological specimens.
- -
- -
- Mutational analysis of the DNA of enriched cells for tumor-specific mutations in PDAC—typically KRAS. This also allows for comparison of the mutational landscape of the CTC with the primary tumor with a high specificity. Our own results showed a heterogeneous picture of the CTC in comparison with the primary tumor; we had about 40% discordant “CTC-primary tumor pairs” [31]. Ankeny et al. found a 100% concordance in five pairs tested [25].
3.2. Clinical Utility of CTCs
3.2.1. Differential Diagnosis and Early Detection
3.2.2. CTC as Prognostic Marker
3.2.3. CTC as Predictive Marker
3.2.4. Advanced Clinical Utility in Other Entities
4. Materials and Methods
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CTC | Circulating tumor cell | OS | Overall survival |
CEC | Circulating epithelial cell | PFS | Progression-free survival |
tCTC | Total CTC | EUS | Endoscopic ultrasound |
mCTC | Mesenchymal/epithelial CTC | FNA | Fine-needle aspiration |
eCTC | Epithelial CTC | CK | Cytokeratin |
PDAC | Pancreatic ductal adenocarcinoma | ZEB1 | Zinc finger homebox 1 |
IPMN | Intraductal papillary mucinous neoplasm | SeFish | Immunostaining-fluorescence in situ hybridization |
EMT | Epithelial-mesenchymal transition | HER2 | Human epidermal growth factor receptor 2 |
MET | Mesenchymal-epithelial transition | TIC | Tumor initiating cell |
References
- Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics. CA Cancer J. Clin. 2010, 60, 277–300. [Google Scholar]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2015, 65, 5–29. [Google Scholar]
- Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the united states. Cancer Res. 2014, 74, 2913–2921. [Google Scholar] [CrossRef] [PubMed]
- Becker, A.E.; Hernandez, Y.G.; Frucht, H.; Lucas, A.L. Pancreatic ductal adenocarcinoma: Risk factors, screening, and early detection. World J. Gastroenterol. 2014, 20, 11182–11198. [Google Scholar] [CrossRef]
- Ferrone, C.R.; Finkelstein, D.M.; Thayer, S.P.; Muzikansky, A.; Fernandez-delCastillo, C.; Warshaw, A.L. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J. Clin. Oncol. 2006, 24, 2897–2902. [Google Scholar] [CrossRef]
- Goggins, M. Molecular markers of early pancreatic cancer. J. Clin. Oncol. 2005, 23, 4524–4531. [Google Scholar] [CrossRef]
- Vincent, A.; Herman, J.; Schulick, R.; Hruban, R.H.; Goggins, M. Pancreatic cancer. Lancet 2011, 378, 607–620. [Google Scholar] [CrossRef]
- Lutz, M.P.; Zalcberg, J.R.; Ducreux, M.; Aust, D.; Bruno, M.J.; Büchler, M.W.; Delpero, J.R.; Gloor, B.; Glynne-Jones, R.; Hartwig, W.; et al. 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. Eur. J. Cancer 2017, 79, 41–49. [Google Scholar] [CrossRef]
- Von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703. [Google Scholar] [CrossRef]
- Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.-L.; Gourgou-Bourgade, S.; de la Fouchardière, C.; et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011, 364, 1817–1825. [Google Scholar] [CrossRef]
- Schwarz, L.; Vernerey, D.; Bachet, J.-B.; Tuech, J.-J.; Portales, F.; Michel, P.; Sa Cunha, A. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy-a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). BMC Cancer 2018, 18, 762. [Google Scholar] [CrossRef] [PubMed]
- Diehl, S.J.; Lehmann, K.J.; Sadick, M.; Lachmann, R.; Georgi, M. Pancreatic cancer: Value of dual-phase helical CT in assessing resectability. Radiology 1998, 206, 373–378. [Google Scholar] [CrossRef] [PubMed]
- Sefrioui, D.; Blanchard, F.; Toure, E.; Basile, P.; Beaussire, L.; Dolfus, C.; Perdrix, A.; Paresy, M.; Antonietti, M.; Iwanicki-Caron, I.; et al. Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours. Br. J. Cancer 2017, 117, 1017–1025. [Google Scholar] [CrossRef] [PubMed]
- Reimers, N.; Pantel, K. Liquid biopsy: Novel technologies and clinical applications. Clin. Chem. Lab. Med. 2019, 57, 312–316. [Google Scholar] [CrossRef]
- Court, C.M.; Ankeny, J.S.; Hou, S.; Tseng, H.-R.; Tomlinson, J.S. Improving pancreatic cancer diagnosis using circulating tumor cells: Prospects for staging and single-cell analysis. Expert Rev. Mol. Diagn. 2015, 15, 1491–1504. [Google Scholar] [CrossRef]
- Kulemann, B.; Liss, A.S.; Warshaw, A.L.; Seifert, S.; Bronsert, P.; Glatz, T.; Pitman, M.-B.; Hoeppner, J. KRAS mutations in pancreatic circulating tumor cells: A pilot study. Tumour Biol. 2016, 37, 7547–7554. [Google Scholar] [CrossRef]
- Koorstra, J.B.; Hustinx, S.R.; Offerhaus, G.J.; Maitra, A. Pancreatic carcinogenesis. Pancreatology 2008, 8, 110–125. [Google Scholar] [CrossRef]
- Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988, 53, 549–554. [Google Scholar] [CrossRef] [Green Version]
- Makohon-Moore, A.; Iacobuzio-Donahue, C.A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 2016, 16, 553–565. [Google Scholar] [CrossRef] [Green Version]
- Nagrath, S.; Jack, R.M.; Sahai, V.; Simeone, D.M. Opportunities and Challenges for Pancreatic Circulating Tumor Cells. Gastroenterology 2016, 151, 412–426. [Google Scholar] [CrossRef] [Green Version]
- Kanda, M.; Matthaei, H.; Wu, J.; Hong, S.-M.; Yu, J.; Borges, M.; Hruban, R.H.; Maitra, A.; Kinzler, K.; Vogelstein, B.; et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012, 142, 730–733. [Google Scholar] [CrossRef] [PubMed]
- Ashworth, T. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Aust. Med. J. 1869, 14, 146–149. [Google Scholar]
- Rhim, A.D.; Mirek, E.T.; Aiello, N.M.; Maitra, A.; Bailey, J.M.; McAllister, F.; Reichert, M.; Beatty, G.L.; Rustgi, A.K.; Vonderheide, R.; et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012, 148, 349–361. [Google Scholar] [CrossRef] [PubMed]
- Kulemann, B.; Pitman, M.B.; Liss, A.S.; Valsangkar, N.; Fernández-Del Castillo, C.; Lillemoe, K.D.; Hoeppner, J.; Mino-Kenudson, M.; Warshaw, A.L.; Thayer, S. Circulating tumor cells found in patients with localized and advanced pancreatic cancer. Pancreas 2015, 44, 547–550. [Google Scholar] [CrossRef]
- Ankeny, J.S.; Court, C.M.; Hou, S.; Li, Q.; Song, M.; Wu, D.; Lee, T.; Lin, M.; Sho, S.; Rochefort, M.M.; et al. Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br. J. Cancer 2016, 114, 1367–1375. [Google Scholar] [CrossRef] [Green Version]
- Khoja, L.; Backen, A.; Sloane, R.; Menasce, L.; Ryder, D.; Krebs, M.; Board, R.; Clack, G.; Hughes, A.; Blackhall, F.; et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br. J. Cancer 2012, 106, 508–516. [Google Scholar] [CrossRef]
- Court, C.M.; Ankeny, J.S.; Sho, S.; Winograd, P.; Hou, S.; Song, M.; Wainberg, Z.A.; Girgis, M.; Graeber, T.G.; Agopian, V.; et al. Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer. Ann. Surg. Oncol. 2018, 25, 1000–1008. [Google Scholar] [CrossRef]
- Rosenbaum, M.W.; Cauley, C.E.; Kulemann, B.; Liss, A.S.; Castillo, C.F.-D.; Warshaw, A.L.; Lillemoe, K.D.; Thayer, S.P.; Pitman, M.B. Cytologic characteristics of circulating epithelioid cells in pancreatic disease. Cancer Cytopathol. 2017, 125, 332–340. [Google Scholar] [CrossRef] [Green Version]
- Cauley, C.E.; Pitman, M.B.; Zhou, J.; Perkins, J.; Kuleman, B.; Liss, A.S.; Fernandez-Del Castillo, C.; Warshaw, A.L.; Lillemoe, K.D.; Thayer, S.P.; et al. Circulating Epithelial Cells in Patients with Pancreatic Lesions: Clinical and Pathologic Findings. J. Am. Coll. Surg. 2015, 221, 699–707. [Google Scholar] [CrossRef] [Green Version]
- Bidard, F.C.; Huguet, F.; Louvet, C.; Mineur, L.; Bouché, O.; Chibaudel, B.; Artru, P.; Desseigne, F.; Bachet, J.B.; Mathiot, C.; et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary CirCe 07 study to the LAP 07 trial. Ann. Oncol. 2013, 24, 2057–2061. [Google Scholar] [CrossRef]
- Kulemann, B.; Rösch, S.; Seifert, S.; Timme, S.; Bronsert, P.; Seifert, G.; Martini, V.; Kuvendjiska, J.; Glatz, T.; Hussung, S.; et al. Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations. Sci. Rep. 2017, 7, 4510. [Google Scholar] [CrossRef] [PubMed]
- Brugge, W.R. Endoscopic approach to the diagnosis and treatment of pancreatic disease. Curr. Opin. Gastroenterol. 2013, 29, 559–565. [Google Scholar] [CrossRef] [PubMed]
- Kitano, M.; Yoshida, T.; Itonaga, M.; Tamura, T.; Hatamaru, K.; Yamashita, Y. Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer. J. Gastroenterol. 2019, 54, 19–32. [Google Scholar] [CrossRef] [PubMed]
- Luchini, C.; Veronese, N.; Nottegar, A.; Cappelletti, V.; Daidone, M.G.; Smith, L.; Parris, C.; Brosens, L.A.A.; Caruso, M.G.; Cheng, L.; et al. Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine. Cancers (Basel) 2019, 11, 1152. [Google Scholar] [CrossRef] [PubMed]
- Aktas, B.; Tewes, M.; Fehm, T.; Hauch, S.; Kimmig, R.; Kasimir-Bauer, S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009, 11, 46. [Google Scholar] [CrossRef] [PubMed]
- Königsberg, R.; Obermayr, E.; Bises, G.; Pfeiler, G.; Gneist, M.; Wrba, F.; de Santis, M.; Zeillinger, R.; Hudec, M.; Dittrich, C. Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol. 2011, 50, 700–710. [Google Scholar] [CrossRef]
- Pailler, E.; Faugeroux, V.; Oulhen, M.; Mezquita, L.; Laporte, M.; Honore, A.; Lecluse, Y.; Queffelec, P.; Ngo-Camus, M.; Nicotra, C.; et al. Acquired Resistance Mutations to ALK-Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non-Small-Cell Lung Cancer. Clin. Cancer Res. 2019. [Google Scholar] [CrossRef]
- Kalluri, R.; Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Investig. 2003, 112, 1776–1784. [Google Scholar] [CrossRef]
- Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [Green Version]
- Cheng, Y.-H.; Chen, Y.-C.; Lin, E.; Brien, R.; Jung, S.; Chen, Y.-T.; Lee, W.; Hao, Z.; Sahoo, S.; Kang, H.M.; et al. Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells. Nat. Commun. 2019, 10, 2163. [Google Scholar] [CrossRef]
- Hoffmann, K.; Kerner, C.; Wilfert, W.; Mueller, M.; Thiery, J.; Hauss, J.; Witzigmann, H. Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients. World J. Gastroenterol. 2007, 13, 257–263. [Google Scholar] [CrossRef] [PubMed]
- Sergeant, G.; Roskams, T.; van Pelt, J.; Houtmeyers, F.; Aerts, R.; Topal, B. Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma. BMC Cancer 2011, 11, 47. [Google Scholar] [CrossRef] [PubMed]
- Soeth, E.; Grigoleit, U.; Moellmann, B.; Röder, C.; Schniewind, B.; Kremer, B.; Kalthoff, H.; Vogel, I. Detection of tumor cell dissemination in pancreatic ductal carcinoma patients by CK 20 RT-PCR indicates poor survival. J. Cancer Res. Clin. Oncol. 2005, 131, 669–676. [Google Scholar] [CrossRef] [PubMed]
- Lin, H.K.; Zheng, S.; Williams, A.J.; Balic, M.; Groshen, S.; Scher, H.I.; Fleisher, M.; Stadler, W.; Datar, R.H.; Tai, Y.-C.; et al. Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin. Cancer Res. 2010, 16, 5011–5018. [Google Scholar] [CrossRef] [PubMed]
- Yadav, D.K.; Bai, X.; Yadav, R.K.; Singh, A.; Li, G.; Ma, T.; Chen, W.; Liang, T. Liquid biopsy in pancreatic cancer: The beginning of a new era. Oncotarget 2018, 9, 26900–26933. [Google Scholar] [CrossRef] [PubMed]
- Gorges, T.M.; Tinhofer, I.; Drosch, M.; Röse, L.; Zollner, T.M.; Krahn, T.; von Ahsen, O. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer 2012, 12, 178. [Google Scholar] [CrossRef]
- Punnoose, E.A.; Atwal, S.K.; Spoerke, J.M.; Savage, H.; Pandita, A.; Yeh, R.-F.; Pirzkall, A.; Fine, B.M.; Amler, L.C.; Chen, D.S.; et al. Molecular biomarker analyses using circulating tumor cells. PLoS ONE 2010, 5, e12517. [Google Scholar] [CrossRef]
- Szczerba, B.M.; Castro-Giner, F.; Vetter, M.; Krol, I.; Gkountela, S.; Landin, J.; Scheidmann, M.C.; Donato, C.; Scherrer, R.; Singer, J.; et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 2019, 566, 553–557. [Google Scholar] [CrossRef]
- Rhim, A.D.; Thege, F.I.; Santana, S.M.; Lannin, T.B.; Saha, T.N.; Tsai, S.; Maggs, L.R.; . Kochman, M.L.; Ginsberg, G.G.; Lieb, J.G.; et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 2014, 146, 647–651. [Google Scholar] [CrossRef]
- Cohen, J.D.; Javed, A.A.; Thoburn, C.; Wong, F.; Tie, J.; Gibbs, P.; Schmidt, C.; Yip-Schneider, M.T.; Allen, P.; Schattner, M.; et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc. Natl. Acad. Sci. USA 2017, 114, 10202–10207. [Google Scholar] [CrossRef] [Green Version]
- Han, L.; Chen, W.; Zhao, Q. Prognostic value of circulating tumor cells in patients with pancreatic cancer: A meta-analysis. Tumour Biol. 2014, 35, 2473–2480. [Google Scholar] [CrossRef] [PubMed]
- Okubo, K.; Uenosono, Y.; Arigami, T.; Mataki, Y.; Matsushita, D.; Yanagita, S.; Kurahara, H.; Sakoda, M.; Kijima, Y.; Maemura, K.; et al. Clinical impact of circulating tumor cells and therapy response in pancreatic cancer. Eur. J. Surg. Oncol. 2017, 43, 1050–1055. [Google Scholar] [CrossRef] [PubMed]
- Gao, Y.; Zhu, Y.; Zhang, Z.; Zhang, C.; Huang, X.; Yuan, Z. Clinical significance of pancreatic circulating tumor cells using combined negative enrichment and immunostaining-fluorescence in situ hybridization. J. Exp. Clin. Cancer Res. 2016, 35, 66. [Google Scholar] [CrossRef] [PubMed]
- Poruk, K.E.; Valero, V.; Saunders, T.; Blackford, A.L.; Griffin, J.F.; Poling, J.; Hruban, R.H.; Anders, R.A.; Herman, J.; Zheng, L.; et al. Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma. Ann. Surg. 2016, 264, 1073–1081. [Google Scholar] [CrossRef] [Green Version]
- Poruk, K.E.; Blackford, A.L.; Weiss, M.J.; Cameron, J.L.; He, J.; Goggins, M.; Rasheed, Z.A.; Wolfgang, C.L.; Wood, L.D. Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma. Clin. Cancer Res. 2017, 23, 2681–2690. [Google Scholar] [CrossRef]
- Kurihara, T.; Itoi, T.; Sofuni, A.; Itokawa, F.; Tsuchiya, T.; Tsuji, S.; Ishii, K.; Ikeuchi, N.; Tsuchida, A.; Kasuya, K.; et al. Detection of circulating tumor cells in patients with pancreatic cancer: A preliminary result. J. Hepatobiliary Pancreat Surg. 2008, 15, 189–195. [Google Scholar] [CrossRef]
- de Albuquerque, A.; Kubisch, I.; Ernst, D.; Breier, G.; Stamminger, G.; Fersis, N.; Stölzel, U.; Boese-Landgraf, J.; Eichler, A.; Kaul, S. Development of a molecular multimarker assay for the analysis of circulating tumor cells in adenocarcinoma patients. Clin. Lab. 2012, 58, 373–384. [Google Scholar]
- Bissolati, M.; Sandri, M.T.; Burtulo, G.; Zorzino, L.; Balzano, G.; Braga, M. Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer. Tumour Biol. 2015, 36, 991–996. [Google Scholar] [CrossRef]
- Zhang, Y.; Wang, F.; Ning, N.; Chen, Q.; Yang, Z.; Guo, Y.; Xu, D.; Zhang, D.; Zhan, T.; Cui, W. Patterns of circulating tumor cells identified by CEP8, CK and CD45 in pancreatic cancer. Int. J. Cancer 2015, 136, 1228–1233. [Google Scholar] [CrossRef]
- Earl, J.; Garcia-Nieto, S.; Martinez-Avila, J.C.; Montans, J.; Sanjuanbenito, A.; Rodríguez-Garrote, M.; Lisa, E.; Mendía, E.; Lobo, E.; Malats, N.; et al. Circulating tumor cells (Ctc) and kras mutant circulating free Dna (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. BMC Cancer 2015, 15, 797. [Google Scholar] [CrossRef]
- Gemenetzis, G.; Groot, V.P.; Yu, J.; Ding, D.; Teinor, J.A.; Javed, A.A.; Wood, L.D.; Burkhart, R.A.; Cameron, J.L.; Makary, M.A.; et al. Circulating Tumor Cells Dynamics in Pancreatic Adenocarcinoma Correlate with Disease Status: Results of the Prospective CLUSTER Study. Ann. Surg. 2018, 268, 408–420. [Google Scholar] [CrossRef] [PubMed]
- Thibodeau, S.; Voutsadakis, I.A. Folfirinox Chemotherapy in Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis of Retrospective and Phase II Studies. J. Clin. Med. 2018, 7, 7. [Google Scholar] [CrossRef] [PubMed]
- Yu, K.H.; Ricigliano, M.; Hidalgo, M.; Abou-Alfa, G.K.; Lowery, M.A.; Saltz, L.B.; Crotty, J.F.; Gary, K.; Cooper, B.; Lapidus, R.; et al. Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer. Clin. Cancer Res. 2014, 20, 5281–5289. [Google Scholar] [CrossRef] [PubMed]
- Miller, M.C.; Doyle, G.V.; Terstappen, L.W.M.M. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J. Oncol. 2010, 2010, 617421. [Google Scholar] [CrossRef] [PubMed]
- Fujii, T.; Reuben, J.M.; Huo, L.; Espinosa Fernandez, J.R.; Gong, Y.; Krupa, R.; Suranenin, M.V.; Graf, R.P.; Lee, J.; Greene, S.; et al. Androgen receptor expression on circulating tumor cells in metastatic breast cancer. PLoS ONE 2017, 12, e0185231. [Google Scholar] [CrossRef] [PubMed]
- Broncy, L.; Paterlini-Bréchot, P. Clinical Impact of Circulating Tumor Cells in Patients with Localized Prostate Cancer. Cells 2019, 8, 676. [Google Scholar] [CrossRef] [PubMed]
- Cristofanilli, M.; Budd, G.T.; Ellis, M.J.; Stopeck, A.; Matera, J.; Miller, M.C.; Reuben, J.M.; Doyle, G.V.; Allard, W.J.; Terstappen, L.W.M.M.; et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 2004, 351, 781–791. [Google Scholar] [CrossRef]
- Brierley, J.D.; Gospodarowicz, M.K.; Wittekind, C. TNM Classification of Malignant Tumours, 8th ed.; John Wiley & Sons, Ltd.: Chichester West Sussex, UK, 2016; ISBN 978-1-119-26357-9. [Google Scholar]
- Trapp, E.; Janni, W.; Schindlbeck, C.; Jückstock, J.; Andergassen, U.; de Gregorio, A.; Alunni-Fabbroni, M.; Tzschaschel, M.; Polasik, A.; Koch, J.; et al. Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer During Follow-Up and Prognosis. J. Natl. Cancer Inst. 2019, 111, 380–387. [Google Scholar] [CrossRef]
- Ignatiadis, M.; Rothé, F.; Chaboteaux, C.; Durbecq, V.; Rouas, G.; Criscitiello, C.; Metallo, J.; Kheddoumi, N.; Singhal, S.K.; Michiels, S.; et al. HER2-positive circulating tumor cells in breast cancer. PLoS ONE 2011, 6, e15624. [Google Scholar] [CrossRef]
- Jakabova, A.; Bielcikova, Z.; Pospisilova, E.; Matkowski, R.; Szynglarewicz, B.; Staszek-Szewczyk, U.; Zemanova, M.; Petruzelka, L.; Eliasova, P.; Kolostova, K.; et al. Molecular characterization and heterogeneity of circulating tumor cells in breast cancer. Breast Cancer Res. Treat. 2017, 166, 695–700. [Google Scholar] [CrossRef] [Green Version]
- Ignatiadis, M.; Litière, S.; Rothe, F.; Riethdorf, S.; Proudhon, C.; Fehm, T.; Aalders, K.; Forstbauer, H.; Fasching, P.A.; Brain, E.; et al. Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091–10093, BIG 1–12, Treat CTC): A randomized phase II trial. Ann. Oncol. 2018, 29, 1777–1783. [Google Scholar] [CrossRef] [PubMed]
Study | Country | n | Tumor Stage | Methodology | CTC Detection Rate * | Outcome | Finding |
---|---|---|---|---|---|---|---|
Soeth et al., 2005 [43] | Germany | 172 | All stages, mostly IV | Density gradient separation | 34% | OS | CTC+: poor OS |
Hoffmann et al., 2007 [41] | Germany | 37 | All stages | Density gradient separation | 40% | OS | CTC+: Trend for worse OS |
Kurihara et al., 2008 [56] | Japan | 26 | Stage III and IV | CellSearch® | 42% | OS | CTC+: sig. worse OS |
Sergeant et al., 2011 [42] | Belgium | 48 | All stages, 40 resectable | RT-PCR (EpCAM) | 25% preoperative 65% postoperative | OS | No correlation between CTC and survival |
Khoja et al., 2012 [26] | United Kingdom | 54 | 54% non-resectable | ISET®; CellSearch® | 46%/40% | OS; PFS | ISET® detects more CTCs, trend towards decreased OS |
De Albuquerque et al., 2012 [57] | Germany | 34 | All stages (II–IV) | Immunomagnetic (EPCAM) | 47% | PFS | CTC + worse PFS |
Bidard et al., 2013 [30] | France | 79 | Non resectable | CellSearch® | 11% | OS | CTC+ worse OS |
Bissolati et al., 2015 [58] | Italy | 20 | Resectable Stage IIa and b | CellSearch® | 45% | OS; PFS | No correlation to OS or PFS but slightly higher liver metastasis rate in CTC+ |
Zhang et al., 2015 [59] | China | 22 | Stage I–IV, all resectable | Immunomagnetic (CEP 8/ CD45) | 15% | OS | CTC+: worse OS |
Earl et al., 2015 [60] | Spain | 35 | Stage II–IV | CellSearch® | 20% | OS | CTC*: worse OS, almost only metastatic disease |
Poruk et al., 2016 [54] | USA | 60 | All stages | ISET® | 90% | OS, PFS | Epithelial CTC+: worse OS Epithelial CTC+: earlier recurrence |
Gao et al., 2016 [53] | China | 25 | All stages | CD45 depletion and SE-FISH | I+II: 92.3% III + IV: 83.3% | OS | Patients with lower CTC count better OS than patients with high numbers of CTC |
Kulemann et al., 2017 [31] | Germany | 58 | All stages | ScreenCell® | 68% | OS | CTC+: Trend to worse OS |
Okubo et al., 2017 [52] | Japan | 65 | III–IV | CellSearch® | 21% | OS | CTC+ worse OS, more CTC+ in pat. Liver metastases, CTC+ after treatment neg. prong. Factor. |
Poruk et al., 2017 [55] | USA | 60 | All stages mainly I and II | ISET® | 78% | OS, PFS | CTC labeled with TIC (tumor initiating cell) are predictive of decreased OS and PFS |
Gemenetzis et al., 2018 [61] | USA | 165 | All stages | ISET® | 95% of resectable patients (n = 136) | Identification of mesenchymal-mal and epithelial CTC OS; PFS | Higher CTC counts correlate with earlier recurrence Increase of CTC numbers after neoadjuvant treatment CTC+ correlates with early recurrence and OS in the pretreated group. |
Court et al., 2018 [27] | USA | 100 | All stages 71 localized, 29 metastatic | Nano Velcro Chip enumeration | 78% | Identification of occult metastasis; OS | CTC counts correlated with stage and worse OS |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Martini, V.; Timme-Bronsert, S.; Fichtner-Feigl, S.; Hoeppner, J.; Kulemann, B. Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers 2019, 11, 1659. https://doi.org/10.3390/cancers11111659
Martini V, Timme-Bronsert S, Fichtner-Feigl S, Hoeppner J, Kulemann B. Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers. 2019; 11(11):1659. https://doi.org/10.3390/cancers11111659
Chicago/Turabian StyleMartini, Verena, Sylvia Timme-Bronsert, Stefan Fichtner-Feigl, Jens Hoeppner, and Birte Kulemann. 2019. "Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives" Cancers 11, no. 11: 1659. https://doi.org/10.3390/cancers11111659