nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

24.02.2016 | Original Article – Cancer Research

Transcripts of circulating tumor cells detected by a breast cancer-specific platform correlate with clinical stage in bladder cancer patients

verfasst von: Tilman Todenhöfer, Jörg Hennenlotter, Nathalie Dorner, Ursula Kühs, Stefan Aufderklamm, Steffen Rausch, Simone Bier, Johannes Mischinger, Doreen Schellbach, Siegfried Hauch, Natalie Feniuk, Jens Bedke, Georgios Gakis, Arnulf Stenzl, Christian Schwentner

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

There is increasing interest in circulating tumor cells (CTCs) as a biomarker in bladder cancer (BC). In the present pilot study, we used a platform originally developed for detection of breast cancer CTCs to assess breast cancer-associated transcripts in CTCs of patients with different stages of BC. Moreover, transcripts specific for cancer stem cells and epithelial mesenchymal transition (EMT) were assessed.

Methods

We prospectively enrolled 83 BC patients and 29 controls. The AdnaTest^® system was used to enrich epithelial cells in peripheral blood and to detect breast cancer-associated, stem cell-specific or EMT-specific transcripts. Test results were correlated with clinical and pathological stage.

Results

A positive AdnaTest^® BreastCancerDetect was present in 6.9 % of controls (group A), 6.7, 15.0 and 18.7 % of patients with non-muscle-invasive BC (B), cM0 muscle-invasive BC (C) and metastatic BC (D) (p = 0.13). Stem cell-specific transcripts in group A, B, C and D were detected in 10.3, 10.0, 22.5 and 31.3 % (p = 0.03). EMT-associated transcripts were present in 3.5, 3.3, 15.0 and 18.7 % (p = 0.03). In group C, epithelial and stem-like transcripts correlated with tumor stage (p = 0.01 and 0.04).

Conclusions

CTCs with expression of breast cancer-associated transcripts are present in a considerable proportion of patients with BC. EMT and stem cell-specific transcripts of CTCs correlate with clinical stage and can be detected in patients negative for epithelial transcripts. The prognostic relevance of AdnaTest^® results in BC patients and potential implications for therapy decisions remain to be determined in prospective studies.

Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46. doi:10.1186/bcr2333 CrossRefPubMedPubMedCentral

Alva A, Friedlander T, Clark M, Huebner T, Daignault S, Hussain M, Lee C, Hafez K, Hollenbeck B, Weizer A, Premasekharan G, Tran T, Fu C, Ionescu-Zanetti C, Schwartz M, Fan A, Paris P (2015) Circulating tumor cells as potential biomarkers in bladder cancer. J Urol. doi:10.1016/j.juro.2015.02.2951 PubMed

Andreopoulou E, Yang LY, Rangel KM, Reuben JM, Hsu L, Krishnamurthy S, Valero V, Fritsche HA, Cristofanilli M (2012) Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer select/detect versus veridex cell search system. Int J Cancer 130(7):1590–1597. doi:10.1002/ijc.26111 CrossRefPubMed

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J (2014) AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. New Engl J Med 371(11):1028–1038. doi:10.1056/NEJMoa1315815 CrossRefPubMedPubMedCentral

Choi W, Czerniak B, Ochoa A, Su X, Siefker-Radtke A, Dinney C, McConkey DJ (2014a) Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 11(7):400–410. doi:10.1038/nrurol.2014.129 CrossRefPubMed

Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, Melquist J, Bondaruk J, Majewski T, Zhang S, Pretzsch S, Baggerly K, Siefker-Radtke A, Czerniak B, Dinney CP, McConkey DJ (2014b) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25(2):152–165. doi:10.1016/j.ccr.2014.01.009 CrossRefPubMedPubMedCentral

Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, Yeh JJ, Milowsky MI, Iyer G, Parker JS, Kim WY (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111(8):3110–3115. doi:10.1073/pnas.1318376111 CrossRefPubMedPubMedCentral

Engilbertsson H, Aaltonen KE, Bjornsson S, Kristmundsson T, Patschan O, Ryden L, Gudjonsson S (2015) Transurethral bladder tumor resection can cause seeding of cancer cells into the bloodstream. J Urol 193(1):53–57. doi:10.1016/j.juro.2014.06.083 CrossRefPubMed

Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579):472–476. doi:10.1038/nature15748 CrossRefPubMed

Flaig TW, Wilson S, van Bokhoven A, Varella-Garcia M, Wolfe P, Maroni P, Genova EE, Morales D, Lucia MS (2011) Detection of circulating tumor cells in metastatic and clinically localized urothelial carcinoma. Urology 78(4):863–867. doi:10.1016/j.urology.2011.05.045 CrossRefPubMedPubMedCentral

Gazzaniga P, Nofroni I, Gandini O, Silvestri I, Frati L, Agliano AM, Gradilone A (2005) Tenascin C and epidermal growth factor receptor as markers of circulating tumoral cells in bladder and colon cancer. Oncol Rep 14(5):1199–1202PubMed

Hayashi T, Seiler R, Oo HZ, Jager W, Moskalev I, Awrey S, Dejima T, Todenhofer T, Li N, Fazli L, Matsubara A, Black PC (2015a) Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over-expressing bladder cancer. J Urol. doi:10.1016/j.juro.2015.05.087 PubMed

Hayashi T, Seiler R, Oo HZ, Jager W, Moskalev I, Awrey S, Dejima T, Todenhofer T, Li N, Fazli L, Matsubara A, Black PC (2015b) Targeting HER2 with T-DM1, an Antibody-cytotoxic Drug Conjugate, is effective in HER2-overexpressing bladder cancer. J Urol. doi:10.1016/j.juro.2015.05.087 PubMed

Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr, Chatta GS, Nanus DM, Glode LM, Trump DL, Chen H, Smith DC, National Cancer I (2007) Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25(16):2218–2224. doi:10.1200/JCO.2006.08.0994 CrossRefPubMed

Karabacak NM, Spuhler PS, Fachin F, Lim EJ, Pai V, Ozkumur E, Martel JM, Kojic N, Smith K, Chen PI, Yang J, Hwang H, Morgan B, Trautwein J, Barber TA, Stott SL, Maheswaran S, Kapur R, Haber DA, Toner M (2014) Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat Protoc 9(3):694–710. doi:10.1038/nprot.2014.044 CrossRefPubMedPubMedCentral

Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T (2012) Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res 14(1):R15. doi:10.1186/bcr3099 CrossRefPubMedPubMedCentral

Liu H, Zhang X, Li J, Sun B, Qian H, Yin Z (2015) The biological and clinical importance of epithelial-mesenchymal transition in circulating tumor cells. J Cancer Res Clin Oncol 141(2):189–201. doi:10.1007/s00432-014-1752-x CrossRefPubMed

Msaouel P, Koutsilieris M (2011) Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. BMC Cancer 11:336CrossRefPubMedPubMedCentral

Muller V, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer E, Aktas B, Kasimir-Bauer S, Pantel K, Fehm T, Group DS (2012) Prognostic impact of circulating tumor cells assessed with the Cell Search System and AdnaTest Breast in metastatic breast cancer patients: the DETECT study. Breast Cancer Res 14(4):R118. doi:10.1186/bcr3243 CrossRefPubMedPubMedCentral

Ning Y, Zhang W, Hanna DL, Mendez A, Yang D, Sunakawa Y, Stremitzer S, Matsusaka S, Okazaki S, Parekh A, El-Khoueiry RE, Flores B, Hauch S, Barzi A, El-Khoueiry AB, Lenz H-J (2015) Circulating tumor cell (CTC) EMT and stem cell biomarker expression predict overall survival (OS) in mCRC by a combined immunomagnetic qRT-PCR approach. ASCO Meeting Abstr 33(15_suppl):11018

Oudard S, Culine S, Vano Y, Goldwasser F, Theodore C, Nguyen T, Voog E, Banu E, Vieillefond A, Priou F, Deplanque G, Gravis G, Ravaud A, Vannetzel JM, Machiels JP, Muracciole X, Pichon MF, Bay JO, Elaidi R, Teghom C, Radvanyi F, Beuzeboc P (2015) Multicentre randomised phase II trial of gemcitabine + platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer 51(1):45–54. doi:10.1016/j.ejca.2014.10.009 CrossRefPubMed

Pantel K, Alix-Panabieres C (2012) The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. Cancer Discov 2(11):974–975. doi:10.1158/2159-8290.CD-12-0432 CrossRefPubMed

Ribal MJ, Mengual L, Marin M, Algaba F, Ars E, Fernandez PL, Oliva R, Villavicencio H, Alcaraz A (2006) Molecular staging of bladder cancer with RT-PCR assay for CK20 in peripheral blood, bone marrow and lymph nodes: comparison with standard histological staging. Anticancer Res 26(1A):411–419PubMed

Ricardo S, Vieira AF, Gerhard R, Leitao D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J (2011) Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol 64(11):937–946. doi:10.1136/jcp.2011.090456 CrossRefPubMed

Rink M, Chun FK, Minner S, Friedrich M, Mauermann O, Heinzer H, Huland H, Fisch M, Pantel K, Riethdorf S (2011) Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladder cancer. BJU Int 107(10):1668–1675. doi:10.1111/j.1464-410X.2010.09562.x CrossRefPubMed

Rink M, Chun FK, Dahlem R, Soave A, Minner S, Hansen J, Stoupiec M, Coith C, Kluth LA, Ahyai SA, Friedrich MG, Shariat SF, Fisch M, Pantel K, Riethdorf S (2012) Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol 61(4):810–817. doi:10.1016/j.eururo.2012.01.017 CrossRefPubMed

Stojnev S, Ristic-Petrovic A, Velickovic LJ, Krstic M, Bogdanovic D, Khanh do T, Ristic A, Conic I, Stefanovic V (2014) Prognostic significance of mucin expression in urothelial bladder cancer. Int J Clinical Exp Pathol 7(8):4945–4958

Tewes M, Aktas B, Welt A, Mueller S, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat 115(3):581–590. doi:10.1007/s10549-008-0143-x CrossRefPubMed

Tinhofer I, Saki M, Niehr F, Keilholz U, Budach V (2014) Cancer stem cell characteristics of circulating tumor cells. Int J Radiat Biol 90(8):622–627. doi:10.3109/09553002.2014.886798 CrossRefPubMed

Todenhofer T, Hennenlotter J, Feyerabend S, Aufderklamm S, Mischinger J, Kuhs U, Gerber V, Fetisch J, Schilling D, Hauch S, Stenzl A, Schwentner C (2012) Preliminary experience on the use of the Adnatest(R) system for detection of circulating tumor cells in prostate cancer patients. Anticancer Res 32(8):3507–3513PubMed

Tvrdik D, Stanek L, Skalova H, Dundr P, Velenska Z, Povysil C (2012) Comparison of the IHC, FISH, SISH and qPCR methods for the molecular diagnosis of breast cancer. Mol Med Rep 6(2):439–443. doi:10.3892/mmr.2012.919 PubMed

Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z, Wittner BS, Stojanov P, Brachtel E, Sgroi D, Kapur R, Shioda T, Ting DT, Ramaswamy S, Getz G, Iafrate AJ, Benes C, Toner M, Maheswaran S, Haber DA (2014) Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345(6193):216–220. doi:10.1126/science.1253533

Titel: Transcripts of circulating tumor cells detected by a breast cancer-specific platform correlate with clinical stage in bladder cancer patients
verfasst von: Tilman Todenhöfer
Jörg Hennenlotter
Nathalie Dorner
Ursula Kühs
Stefan Aufderklamm
Steffen Rausch
Simone Bier
Johannes Mischinger
Doreen Schellbach
Siegfried Hauch
Natalie Feniuk
Jens Bedke
Georgios Gakis
Arnulf Stenzl
Christian Schwentner
Publikationsdatum: 24.02.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2016
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-016-2129-0

Springer Medizin

Transcripts of circulating tumor cells detected by a breast cancer-specific platform correlate with clinical stage in bladder cancer patients