Introduction

1. Genesinvolved in EGFR-degradation are predictive for efficacy in metastatic colorectal cancer patients treated with cetuximab Sebastian Stintzing1, Wu Zhang1, Takeru Wakatsuki1, Yan Ning1, Dongyun Yang1, Nico Volz1, Joseph E. Li1, Melissa J. LaBonte2, Peter M. Wilson1, Adel Kardosh1, FotiosLoupakis3, Lisa Salvatore3, Martha Schirripa3 and Heinz-Josef Lenz1 1USC/Norris Comprehensive Cancer Center, Los Angeles, CA, 2Azusa Pacific University, Azusa, CA; 3Ospedaliero-Universitaria Pisana, IstitutoToscanoTumori, Pisa, Italy Abstract ID: 3557 Introduction Patient baseline characteristics 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. Kaplan-Meier curves of PFS and OS by UBC12 rs895374 polymorphism • EGFR turnover: • The process of EGFR turnover can be divided into three different stages: • receptor endocytosis • neddylation or ubiquitation • recycling or degradation Results Resultsof multivariate analysis on SNPs of genes involved in theprocess EGFR turnover 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: • Are germline single nucleotide polymorphisms (SNPs) in genes involved in EGFR turnover capable of predictive value in cetuximab treated patients with mCRC. Conclusion References 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. supported by Schmidt M.H., Dicic I. Sci. STKE 2006, pe50 (2006). Oved S., Mosesson Y., Santonico E. et al J BiolChem (2006)281:31 2164-21651 Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Nature416, 183-187 (2002) Legend: PFS = progressionfreesurvival; OS = overallsurvival; HR = Hazardratio; p = logrank´s p; na: not applicable due tosmallnumber, # indicatessignificantvalue