TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid.
OBJECTIVE
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.


METHODS
Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.


RESULTS
Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.


CONCLUSIONS
This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.
Sørensen
Nanna M
NM
Section of Biomedicine, Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.
Byström
Per
P
Christensen
Ib J
IJ
Berglund
Ake
A
Nielsen
Hans Jørgen
HJ
Brünner
Nils
N
Glimelius
Bengt
B
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002272:Carcinoembryonic Antigen / Q000097:blood*; D003110:Colonic Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D009362:Neoplasm Metastasis; D016017:Odds Ratio; D012004:Rectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin