1. 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)281:31 2164-21651 3.Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Nature 416, 183-187 (2002) Kaplan-Meier curves of PFS and OS by UBC12 rs895374 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 rs7105971 GG AG AA 52 32 14 1.54 1.39 0.271.54 1.20 0.42 CIN85 rs7051590 CC CG GG 79 10 8 1.14 na 0.661.24 na 0.54 CBL rs4938637 GG AG AA 74 24 2 0.96 na 0.881.01 na 0.97 CIN85 rs5955820 TT CT CC 70 13 14 1.06 1.01 0.990.98 1.39 0.71 CBL rs4938638 AA AG GG 45 41 16 0.91 0.66 0.450.95 0.77 0.76 CIN85 rs1017874 GG AG AA 76 9 0.80 na 0.461.09 na 0.81 CBL rs251837 CC CT TT 31 52 17 0.72 0.70 0.401.09 0.92 0.89 CIN85 rs11795873 AA AG GG 35 16 36 1.09 1.01 0.961.23 1.05 0.87 EPS15 rs17567 TT CT CC 65 35 5 0.69 na 0.070.79 na 0.38 Endophilin rs604737 GG AG AA 70 21 5 1.13 na 0.670.93 na 0.82 EPS15 rs7308 TT CT CC 64 31 6 0.70 na 0.090.82 na 0.47 Endophilin rs6570808 GG AG AA 30 52 11 0.83 0.59 0.410.73 0.41 0.14 EPS15 rs1065754 TT CT CC 43 48 14 0.99 1.22 0.760.98 1.17 0.89 Endophilin rs7526812 AA AG GG 71 21 3 0.69 na 0.190.83 na 0.56 NEDD8 rs363169 TT TA AA 26 51 18 1.18 1.07 0.640.89 1.21 0.68 UBC12 rs895374 CC AC AA 26 52 21 2.07 2.11 0.02 # 1.43 1.60 0.41 NEDD8 rs363170 AA AG GG 71 22 0 1.34 na 0.321.38 na 0.34 UBC12 rs895374 TT CT CC 60 35 4 0.97 na 0.900.83 na 0.49 NEDD8 rs363172 GG AG AA 31 52 13 0.82 0.94 0.730.60 0.91 0.21 UBCH7 rs5754216 GG GT TT 71 21 3 0.70 na 0.250.63 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