Skip to main content

Advertisement

Log in

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

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):1199–1202

    CAS  PubMed  Google Scholar 

  • 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  Google Scholar 

  • 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  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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):411–419

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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):3507–3513

    PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tilman Todenhöfer.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of the University of Tuebingen (Approval Number 295/2015BO2).

Conflict of interest

DS, NF and SH are employees of Qiagen Hannover.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Todenhöfer, T., Hennenlotter, J., Dorner, N. et al. Transcripts of circulating tumor cells detected by a breast cancer-specific platform correlate with clinical stage in bladder cancer patients. J Cancer Res Clin Oncol 142, 1013–1020 (2016). https://doi.org/10.1007/s00432-016-2129-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-016-2129-0

Keywords

Navigation