Abstract
IntroductionCirculating 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.MethodsBlood 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).ResultsFive 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.ConclusionsElevated 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 registrationCurrent Controlled Trials: ISRCTN59722891
Highlights
Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination
In patients with five or more CTCs, serum levels were above the cut-off for Carbonic anhydrase IX (CAIX) in 47% vs. 25% in those with less than five CTCs (p = 0.01)
Whether increased secretion of tissue inhibitor of metalloproteinase 1 (TIMP)-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations
Summary
Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. 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. Circulating tumor cells (CTC) derived from primary tumors and metastatic sites can be detected in the circulation. The CellSearch® system, which combines both automated enrichment and immunostaining, is the only standardized technology that was approved by the Food and Drug Administration for the detection of CTC in patients with metastatic breast, colon, and prostate cancer [3,4,5]. CTC detection and characterization has already improved our understanding of the complex process underlying tumor cell dissemination and metastatic progression in breast cancer. It is widely accepted that the release of tumor cells from solid tumors requires specific mechanisms such as proteolysis and release is enhanced when tumor hypoxia occurs
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