Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective Study

Rink, Michael; Chun, Felix K.; Dahlem, Roland; Soave, Armin; Minner, Sarah; Hansen, Jens; Stoupiec, Malgorzata; Coith, Cornelia; Kluth, Luis A.; Ahyai, Sascha A.; Friedrich, Martin G.; Shariat, Shahrokh F.; Fisch, Margit; Pantel, Klaus; Riethdorf, Sabine

doi:10.1016/j.eururo.2012.01.017

« Previous Next »European Urology
Volume 61, Issue 4 , Pages 810-817, April 2012

Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective Study

Michael Rink
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA
- Corresponding author. Department of Urology, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel. +49 40 74105 3442; Fax: +49 40 74104 2444.
- Both authors contributed equally to the manuscript.
Felix K. Chun
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Corresponding author. Department of Urology, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel. +49 40 74105 3442; Fax: +49 40 74104 2444.
- Both authors contributed equally to the manuscript.
Roland Dahlem
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Armin Soave
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Sarah Minner
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Jens Hansen
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Malgorzata Stoupiec
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Cornelia Coith
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Luis A. Kluth
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Sascha A. Ahyai
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Martin G. Friedrich
- Department of Urology, HELIOS Hospital Krefeld, Krefeld, Germany
Shahrokh F. Shariat
- Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA
- Division of Medical Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA
Margit Fisch
- Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Klaus Pantel
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Sabine Riethdorf
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Accepted 10 January 2012. published online 20 January 2012.

Abstract

Background

Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB).

Objective

Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB.

Design, setting, and participants

Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization.

Intervention

Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy.

Measurements

Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis.

Results and limitations

CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1–100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size.

Conclusions

Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.

Take Home Message

Circulating tumor cells (CTC) are detectable in almost 25% of patients with clinically nonmetastatic bladder cancer prior to radical cystectomy. Presence of precystectomy CTC was a strong independent predictor for disease recurrence and mortality. The molecular profile of CTC may help guide individualized targeted therapy.

Keywords: Bladder cancer, Circulating tumor cells, CTC, Outcome, Survival, CellSearch System, HER2