Insuline like growth factor receptor-1 (IGFR-1), MET, and BRAF and primary resistance to cetuximab therapy in colorectal cancer patients.

4135 Background: Mechanisms for intrinsic resistance to cetuximab, a monoclonal antibody against EGFR, are not fully elucidated. KRAS mutations cannot account for all resistant cases. Preclinical data suggested that MET could interfere with anti-EGFR strategies and IGF1R mediate resistance to anti-EGFR therapies through continued activation of PI3K-Akt pathway. This study investigated molecular predictors for intrinsic resistance to cetuximab therapy in colorectal cancer patients.,The study was conducted in a cohort of 85 metastatic colorectal cancer patients (mCRC) treated with cetuximab-based therapy in whom EGFR and KRAS status was known. We analyzed MET (fluorescence in situ hybridization-FISH), IGF1R (FISH and immunohistochemistry-IHC), BRAF (mutation) and PI3KCA (mutation).,In 76 cases successful for MET FISH analysis, increased copy numbers (mean ≥ 5) was observed in 7 patients (9.2%), including 2 (2.6%) with gene amplification and 5 (6.6%) with high polysomy. MET status was not associated with clinical characteristics nor response to cetuximab. IGF1R was successfully evaluated in 77 and 70 cases by FISH and IHC, respectively. No IGF1R amplification or high polysomy was observed. Using a cut off of 95 for IHC, determined by ROC analysis, no association with response or time to progression was observed. IGF1R IHC+ (N=52) had significantly longer survival (OS) than IHC- (16.1 versus 6.7 months, p=0.006). BRAF and PI3KCA mutation analyses were performed in 79 cases. BRAF was mutated in 4 (5.0%) and although not significantly associated with clinical end-points, individuals harboring such mutation did not respond to the therapy, with time to progression (TTP) and OS shorter than in BRAF wildtype (TTP: 1.2 versus 4.6 months, p=0.09; OS: 5.4 versus 9.8 months, p=0.3). No difference in response, TTP, and OS was observed in 14 patients (17.7%) harboring PI3KCA mutation versus wild type individuals.,The rarity of MET and IGF1R gene amplification suggests a marginal role in intrinsic resistance to anti-EGFR therapy in mCRC. The role of BRAF mutations as responsible for cetuximab failure and the potential prognostic implication of IGF1R expression merits further evaluation. No significant financial relationships to disclose.