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Originally published In Press as doi:10.1074/mcp.M700305-MCP200 on November 12, 2007.
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Molecular & Cellular Proteomics 7:424-430, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.


Research

Plasma and Serum Levels of Tissue Inhibitor of Metalloproteinases-1 Are Associated with Prognosis in Node-negative Breast Cancer

A Prospective Study*

Sidse Ørnbjerg Würtz{ddagger},§, Susanne Møller||, Henning Mouridsen**, Pernille Briæmer Hertel**, Esbern Friis{ddagger}{ddagger} and Nils Brünner{ddagger},§

From the {ddagger} Department of Veterinary Pathology, The Faculty of Life Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg C, Denmark, || Danish Breast Cancer Cooperative Group, Rigshospitalet, Strandboulevarden 47, DK-2100 Copenhagen, Denmark, Departments of ** Oncology and {ddagger}{ddagger} Breast and Endocrine Surgery, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, and § Danish Centre for Translational Breast Cancer Research, University of Copenhagen, Grønnegaardsvej 15, 1870 Frederiksberg C, Denmark

The tumor level of TIMP-1 has been suggested as a new prognostic marker in breast cancer. The purpose of this study was to investigate whether TIMP-1 also carries prognostic information when measured in blood as this is a much more preferable material compared with tumor extracts. Using ELISA, TIMP-1 was measured in prospectively collected preoperative plasma and serum samples from 519 patients with primary breast cancer, and the measurements were related to patient outcome. The median age of the patients was 58 years (range, 38–80 years), and the median follow-up time was 1043 days (range, 300–1630 days). Plasma and serum TIMP-1 measurements correlated significantly with each other with a Pearson correlation coefficient of 0.75 (p < 0.0001). For univariate survival analysis, patients were divided into quartiles according to increasing TIMP-1 levels (Q1–Q4). Analysis of all patients showed that high TIMP-1 plasma levels were significantly associated with a shorter disease-free survival. Subgroup analysis showed that plasma TIMP-1 significantly predicted the prognosis of node-negative patients but not of node-positive patients. Importantly plasma TIMP-1 was able to further stratify low risk node-negative patients. High serum TIMP-1 levels were associated with a shorter disease-free survival; however, the association was not statistically significant. In contrast, serum TIMP-1 significantly predicted the prognosis of node-negative and low risk patients. In multivariate survival analysis of node-negative patients including all the classical prognostic parameters, plasma TIMP-1 remained significantly associated with prognosis when comparing Q1 with Q2 and Q4. Serum TIMP-1 remained significant when comparing Q1 with Q4. Taken together, this study is to our knowledge the first large prospective study suggesting that TIMP-1 carries independent prognostic information when measured in blood, especially plasma. This was especially true in the node-negative group of patients and in patients already defined as low risk patients using the currently available prognostic parameters.


To whom correspondence should be addressed: University of Copenhagen, The Faculty of Life Sciences, Dept. of Veterinary Pathology, Ridebanevej 9, 1870 Frederiksberg C, Denmark. Fax: 45-3535-3514; E-mail: suw{at}life.ku.dk


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