TIMP-1 Is Significantly Associated with Objective Response and Survival in Metastatic Colorectal Cancer Patients Receiving Combination of Irinotecan, 5-Fluorouracil, and Folinic Acid

Research output: Contribution to journalJournal articleResearchpeer-review

Nanna M Sørensen, Per Byström, Ib Jarle Christensen, Åke Berglund, Hans Jørgen Nielsen, Nils Brünner, Bengt Glimelius

Purpose: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against
apoptosis.We raisedth e hypothesis that elevatedtu mor tissue levels and thereby plasma levels
of TIMP-1wouldp redict resistance to apoptosis-inducing chemotherapy.
Experimental Design: Ninety patients with metastatic colorectal cancer were included in the
study. PlasmaTIMP-1and serum carcinoembryonic antigen (CEA) were measured in samples
obtainedbef ore 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 plasmaTIMP-1had higher probability of
obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI),
1.4-8.5,P =0.007].CEAtreatedas a continuous variablewas also a statistically significantpredictorof
no response (OR,1.3; 95%CI,1.0-1.7, P = 0.02, areaunder the curve 0.66) butmuchless so.
PlasmaTIMP-1was the only significant covariate in a multivariable analysis of best objective
response (OR, 3.6; 95%CI,1.4-9.5; P = 0.001). PlasmaTIMP-1scoredas a continuous variable on
the log scale (loge) was significantly associatedwith overall survival [OS; hazardr atio (HR), 3.8;
95% CI, 2.4-5.9; P < 0.0001] andw ith time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P =
0.048). Multivariable analysis showedthat plasmaTIMP-1was significant for OS when including
routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P < 0.0001). A multivariable analysis
includingTTP instead of OS showed that only plasmaTIMP-1was retained in the model (HR,1.5).
CEA was not significantly associatedw ith TTP or OS when TIMP-1was included in the model.
Conclusion: This study shows that plasmaTIMP-1 levels are significantly and independently
associatedw ith objective response,TTP, and OS in patients with metastatic colorectal cancer
receiving combination chemotherapy.
Original languageEnglish
JournalClinical Cancer Research
Issue number14
Pages (from-to)4117-22
Number of pages6
Publication statusPublished - 2007

ID: 34089126