Benefit of EGFR-inhibition therapy for metastatic colorectal cancer patients with KRAS-mutated tumors and high plasma TIMP-1 level: Results from the NORDIC VII study

Background: RAS status is the only biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with an epidermal growth factor receptor (EGFR) inhibitor. However, not all KRASwild-type tumors respond to EGFR-inhibition, and some patients with mutated tumors may still benefit from therapy. To improve selection of patients for treatment with EGFR inhibitors, new biomarkers are needed. Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) induces intracellular signalling activating the Akt-survival pathway, and we hypothesize that high TIMP-1 levels interact with the signalling of EGFR and thereby with the anti-tumor effects of EGFR inhibitors. The present study tests the above hypothesis in patients included in the NORDIC VII Study. Methods: mCRC patients were randomized to Nordic FLOX +/- cetuximab (Tveit et al., JCO, 2012). Pre-treatment plasma samples (n=426) were analysed for TIMP-1 using the MAC15 antibody kinetic ELISA. Results: Univariate Cox analyses including all patients showed that high pre-treatment plasma TIMP-1 was significantly associated with shorter PFS (P = .003), and OS (P < .0001). Multivariate analysis (not including treatment) demonstrated that high plasma TIMP-1 was an independent biomarker of OS (P = .016). A significant interaction between plasma TIMP-1, KRAS status and treatment (+/- cetuximab) was demonstrated for OS (P = .002). Patients with KRAS mutated tumors and high TIMP-1 level (> 3rdquartile) had a significantly longer OS if treated with cetuximab (HR, .48; 95% CI, .25 to .93) compared to patients not treated with cetuximab. Conclusions: Patients with KRAS mutated tumors and a high plasma TIMP-1 level seem to benefit from EGFR-inhibition therapy. Based on these results we propose a novel hypothesis on the interaction between EGFR-1 signalling and TIMP-1.