title: Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer.
abstract: BACKGROUND
  Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. The tissue inhibitor of metalloproteinase 1 (TIMP-1) plays a role in tissue invasion and is also involved in angiogenesis, abrogation of apoptosis and in chemoresistance. Carbonic anhydrase IX (CAIX) is a metalloenzyme involved in cell adhesion, growth and survival of tumor cells. The aim of the study was to investigate whether serum concentrations of TIMP-1 and CAIX are associated with the detection of CTC in metastatic breast cancer.
  
  
  METHODS
  Blood was obtained in a prospective multicenter setting from 253 patients with metastatic breast cancer at the time of disease progression. Serum TIMP-1 and CAIX were determined using commercial ELISA-kits (Oncogene Science). CTC were detected with the CellSearch system (Veridex).
  
  
  RESULTS
  Five or more CTCs were detected in 122 patients out of 245 evaluable patients (49.8%). Out of 253 metastatic patients 70 (28%) had serum TIMP-1 levels above 454 ng/mL. Serum CAIX was elevated above 506 ng/mL in 90 (35%) patients. Both serum markers had prognostic significance. Median progression free survival (PFS) was 7.2 months with elevated TIMP-1 vs. 11.4 months with non-elevated levels (p < 0.01). OS was 11.5 vs. 19.1 months (p < 0.01). Median PFS was 7.5 months with elevated CAIX vs. 11.7 months with non-elevated levels (p < 0.01), overall survival (OS) was 13.4 months vs. 19.1 months (p < 0.01). In patients with five or more CTCs, serum levels were above the cut-off for CAIX in 47% vs. 25% in those with less than five CTCs (p = 0.01). For TIMP-1, 37% patients with five or more CTCs had elevated serum levels and 17% of patients with less than five CTCs (p = 0.01). Including TIMP-1, CAIX, CTC and established prognostic factors in the multivariate analysis, the presence of CTCs, the therapy line and elevated CAIX remained independent predictors of OS.
  
  
  CONCLUSIONS
  Elevated serum levels of the invasion markers TIMP-1 and CAIX in metastatic breast cancer are prognostic markers and are associated with the presence of CTCs. Whether increased secretion of TIMP-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations.
  
  
  BACKGROUND
  Current Controlled Trials: ISRCTN59722891.
authors: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20241 Hamburg, Germany.
authors: Volkmar
authors: V
authors: Müller
authors: Sabine
authors: S
authors: Riethdorf
authors: Brigitte
authors: B
authors: Rack
authors: Wolfgang
authors: W
authors: Janni
authors: Peter A
authors: PA
authors: Fasching
authors: Erich
authors: E
authors: Solomayer
authors: Bahriye
authors: B
authors: Aktas
authors: Sabine
authors: S
authors: Kasimir-Bauer
authors: Julia
authors: J
authors: Zeitz
authors: Klaus
authors: K
authors: Pantel
authors: Tanja
authors: T
authors: Fehm
mesh_terms: D000951:Antigens, Neoplasm / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000097:blood*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015999:Multivariate Analysis; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases