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.

Breast Cancer Res 2011 Jul 11;13(4):R71. Epub 2011 Jul 11.

Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20241 Hamburg, Germany.

Introduction: 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.

Trial Registration: Current Controlled Trials: ISRCTN59722891.

Download full-text PDF

Source Listing
July 2011
27 Reads

Publication Analysis

Top Keywords

metastatic breast
timp-1 caix
patients ctcs
tumor cells
breast cancer
serum levels
patients metastatic
cell dissemination
non-elevated levels
levels 001
presence ctcs
tumor cell
pfs months
months elevated
elevated serum


(Supplied by CrossRef)

C Alix-Panabieres et al.
Clin Cancer Res 2008

K Pantel et al.
Nat Rev Clin Oncol 2009

DF Hayes et al.
Clin Cancer Res 2006

S Riethdorf et al.
Clin Cancer Res 2007

FC Bidard et al.
Ann Oncol 2008

M Cristofanilli et al.
N Engl J Med 2004

A Lipton et al.
J Clin Oncol 2008

SO Wurtz et al.
Acta Oncol 2008

A Lipton et al.
Cancer 2007

CM Alexander et al.
J Cell Biol 1996

XW Liu et al.
J Biol Chem 2003

Similar Publications