IntroductionPatient baseline characteristics Conclusion 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. The pathways involved in EGFR turnover may be new targets in the treatment of colorectal cancer. Patients and Methods Genomic DNA was isolated from blood from 108 patients treated with cetuximab of two clinical trials. All patients were KRAS and BRAF wildtype. 20 SNPs were selected based on the involvement in receptor endocytosis, ubiquitation/neddylation, recycling and degradation. Minor allele frequency had to be 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. After logistic regression analyses, baseline characteristics showing a p of <0.1 were included in the multivariate analysis. Kaplan-Meier estimation with log-rank testing for differences were carried out. This study tested: 1.Are germline single nucleotide polymorphisms (SNPs) in genes involved in EGFR turnover capable of predictive value in cetuximab treated patients with mCRC. Abstract ID: 3557 References Results 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 (PFS and OS) in 108 patients with metastatic colorectal cancer (mCRC) enrolled in two clinical trials and treated with cetuximab. 1.Schmidt M.H., Dicic I. Sci. STKE 2006, pe50 (2006). 2.Oved S., Mosesson Y., Santonico E. et al J Biol Chem (2006)281: Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Nature 416, (2002) Kaplan-Meier curves of PFS and OS by UBC12 rs polymorphism Results Genes involved in EGFR-degradation are predictive for efficacy in metastatic colorectal cancer patients treated with cetuximab Sebastian Stintzing 1, Wu Zhang 1, Takeru Wakatsuki 1, Yan Ning 1, Dongyun Yang 1, Nico Volz 1, Joseph E. Li 1, Melissa J. LaBonte 2, Peter M. Wilson 1, Adel Kardosh 1, Fotios Loupakis 3, Lisa Salvatore 3, Martha Schirripa 3 and Heinz-Josef Lenz 1 1 USC/Norris Comprehensive Cancer Center, Los Angeles, CA, 2 Azusa Pacific University, Azusa, CA; 3 Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy supported by EGFR turnover: The process of EGFR turnover can be divided into three different stages: -receptor endocytosis -neddylation or ubiquitation -recycling or degradation Baseline characteristics (N= 108) Age: median (range) 64 years (35 – 110) Gendermale: 60% female: 40% Primary outcome data (N = 108) Overall response rate (ORR)20.0 %Progression free survival (PFS)3.7 months (2.8 – 4.6) Disease control rate (DCR)62.9 %Overall survival (OS)10.5 months (7.7 – 13.3) PFSOSPFSOS nHRp*HRp*nHRp*HRp* CBL rs GG AG AA CIN85 rs CC CG GG na na 0.54 CBL rs GG AG AA na na 0.97 CIN85 rs TT CT CC CBL rs AA AG GG CIN85 rs GG AG AA na na 0.81 CBL rs CC CT TT CIN85 rs AA AG GG EPS15 rs17567 TT CT CC na na 0.38 Endophilin rs GG AG AA na na 0.82 EPS15 rs7308 TT CT CC na na 0.47 Endophilin rs GG AG AA EPS15 rs TT CT CC Endophilin rs AA AG GG na na 0.56 NEDD8 rs TT TA AA UBC12 rs CC AC AA # NEDD8 rs AA AG GG na na 0.34 UBC12 rs TT CT CC na na 0.49 NEDD8 rs GG AG AA UBCH7 rs GG GT TT na na 0.25 Results of multivariate analysis on SNPs of genes involved in the process EGFR turnover Legend: PFS = progression free survival; OS = overall survival; HR = Hazard ratio; p = logrank´s p; na: not applicable due to small number, # indicates significant value