Plasma TIMP-1 in patients with metastatic colorectal cancer treated with first-line oxaliplatin-based therapy with or without cetuximab: Results from the Nordic VII study.

Abstract

e14710 Background: Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a biomarker in patients with metastatic colorectal cancer (mCRC). TIMP-1 inhibits matrix metalloproteinases and has tumor promoting functions. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based but not oxaliplatin-based treatment in patients with mCRC. Based on our prior studies, we here tested the hypothesis that high pretreatment plasma TIMP-1 correlate with short overall survival (OS) and short progression-free survival (PFS) but not response rate (RR) in patients with mCRC included in the NORDIC VII Study in which patients received oxaliplatin-based therapy. Methods: In the NORDIC VII Study patients were randomized to: A) Nordic FLOX; B) Nordic FLOX + cetuximab or C) Nordic FLOX intermittently + cetuximab continuously. Plasma samples for TIMP-1 analysis were available from 426 patients. Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic ELISA. Results: The three study populations were comparable and not different from the total intention to treat population. The median pretreatment plasma TIMP-1 was 269 ng/mL (58-1318 ng/mL). KRAS mutated in 149 patients (35%). There was no interaction between treatment arms and pretreatment plasma TIMP-1 either for PFS (p = 0.16) or OS (p = 0.64). High pretreatment plasma TIMP-1 was associated with shorter PFS (HR=1.22, 1.07-1.39, p=0.003) and shorter OS (HR=1.55, 1.36-1.80, p<0.0001). RR did not correlate significantly to pretreatment plasma TIMP-1 (OR=1.16, 0.91-1.49, p=0.22). Multivariate analysis (TIMP-1, Köhne index, KRAS and BRAF status, CRP, CEA, age, gender) demonstrated that high pretreatment plasma TIMP-1 was not an independent biomarker of PFS (HR=1.06, 0.88-1.28, p=0.52) or OS (HR=1.19, 0.96-1.47, p=0.11). Conclusions: Plasma TIMP-1 is a prognostic biomarker in patients with mCRC treated with 1st line oxaliplatin-based therapy +/- cetuximab. A predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment, and no significant treatment by marker interaction was observed.