title: Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study.
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.
  
  
  METHODS
  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.
  
  
  METHODS
  Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy.
  
  
  METHODS
  Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. mrink@uke.uni-hamburg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Rink
authors.forename: Felix K
authors.initials: FK
authors.lastname: Chun
authors.forename: Roland
authors.initials: R
authors.lastname: Dahlem
authors.forename: Armin
authors.initials: A
authors.lastname: Soave
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.forename: Jens
authors.initials: J
authors.lastname: Hansen
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Stoupiec
authors.forename: Cornelia
authors.initials: C
authors.lastname: Coith
authors.forename: Luis A
authors.initials: LA
authors.lastname: Kluth
authors.forename: Sascha A
authors.initials: SA
authors.lastname: Ahyai
authors.forename: Martin G
authors.initials: MG
authors.lastname: Friedrich
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Margit
authors.initials: M
authors.lastname: Fisch
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D015653:Cystectomy; D018572:Disease-Free Survival; D005260:Female; D005858:Germany; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009360:Neoplastic Cells, Circulating / Q000737:chemistry* / Q000473:pathology; D018579:Patient Selection; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood* / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human