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High Preoperative Plasma Tissue Inhibitor of Metalloproteinase-1 Levels Are Associated with Short Survival of Patients with Colorectal Cancer¹

Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen, Denmark [M. N. H-A., R. W. S., I. J. C., N. B.]; Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, DK-2650 Denmark [H. J. N.]; School of Biological Sciences, University of East Anglia, Norwich, NR4 7T3 United Kingdom [G. M.]; and Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892-1500 [W. S-S.]

ABSTRACT

The objective of the present study was to measure preoperative plasma tissue inhibitor of metalloproteinase (TIMP)-1 levels in colorectal cancer patients and relate these values to clinical and biochemical patient characteristics. TIMP-1 levels were determined by ELISA in EDTA plasma samples collected preoperatively from 588 colorectal cancer patients. Plasma TIMP-1 levels were distributed with a median value of 141.1 µg/liter (range, 53.7–788.7 µg/liter). Whereas no significant differences were found in the median plasma TIMP-1 levels among patients with Dukes’ stage A, B, and C disease, patients with Dukes’ stage D disease had significantly higher plasma TIMP-1 levels (P < 0.0001); however, high plasma TIMP-1 levels were not restricted to advanced disease. A relatively weak correlation between plasma TIMP-1 level and age was found (r = 0.35; P < 0.0001). There was no significant difference in TIMP-1 levels between males and females (P = 0.97). Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels [scored as the log_e(TIMP-1); hazard ratio = 3.3; 95% confidence interval, 2.6–4.2; P < 0.0001]. Including covariates (Dukes’ stage, primary tumor location, gender, age, plasminogen activator inhibitor type 1, and soluble urokinase plasminogen activator receptor) in a multivariate analysis, TIMP-1 was retained in the final model (hazard ratio = 2.5; 95% confidence interval, 1.7–3.7; P < 0.0001). This study showed a highly significant association between preoperative plasma TIMP-1 levels and survival in colorectal cancer patients, with higher plasma TIMP-1 levels being associated with poor outcome. Independent of clinical parameters including Dukes’ stage, plasma TIMP-1 levels were found to strongly predict prognosis of colorectal cancer patients. Additional studies are needed to validate the clinical usefulness of plasma TIMP-1 measurements.

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