3557 Background: As many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (response, PFS and OS) in 108 patients with metastatic colorectal cancer enrolled in clinical trials and treated with cetuximab. Methods: Genomic DNA was isolated from blood from 108 patients treated with cetuximab enrolled in one of two clinical trials. All patients were KRAS and BRAF wildtyp. 20 SNPs were selected based on the involvement in receptor endocytosis (CBL, CIN85, endophilin) ubiquitation/neddylation, recycling and degradation (CBL, EPS15, Ubc12, UbcH7). Minor allele frequency had to by higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. Results: In univariate analysis, rs895374 (HR: 1.69; p= 0.03), which is located in the exome of UbcH7, was able to separate patient cohorts significantly in perspective of progression free survival (CC = 5.7mo, CA= 3.6mo, AA= 3.4mo). Using multivariate analysis, rs895375 stayed to be a significant predictor of progression free survival with a Hazard ratio of 2.08 (95% CI 1.24 – 3.48) and a p value of 0.005. UbcH7 plays a pivotal role in the process of neddylation (adding NEDD8 to the EGFR), which switch the balance between recycling and degradation of the EGFR towards degradation. Conclusions: The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. Anti-EGFR antibody like Sym004 might overcome this resistance mechanism by preventing EGFR recycling.