Genomic profile associated with clinical outcome of EGFR-expressing metastatic colorectal cancer patients treated with epidermal growth factor receptor (EGFR) inhibitor cetuximab

Abstract

3557 Background: Cetuximab is a chimeric anti-EGFR monoclonal antibody with efficacy against EGFR-expressing metastatic colorectal cancer and it was recently approved for use to treat irinotecan refractory metastatic colorectal cancer. Our group has reported association between germline polymorphisms in genes involved in EGFR signaling pathway and overall survival of metastatic colorectal cancer patients treated with Cetuximab at ASCO 2004. This year, we updated this genomic profile and moreover, we studied the correlation between these gene polymorphisms and gene expression levels. Methods: we tested gene polymorphisms and gene expression levels of following important genes involved in EGFR signaling pathway (EGFR,VEGF,COX-2,CyclinD1,IL-8, EGF and E-cadherin) using PCR-RFLP method in genomic DNA extracted from peripheral blood and quantitative realtime RT-PCR in microdissected paraffin-embedded tumor tissue from 39 EGFR-expressing metastatic colorectal cancer patients enrolled in a phase II single agent Cetuximab treatment clinical trial(IMCL-0144). Results: We found a trend of association between EGF A61G polymorphism and overall survival of patients treated with Cetuximab. With median follow-up 7.1 months (95%C.I 2.5, 21.6) and median survival time 5.5 months (95%C.I 2.7, 8.7), Patients with AA homozygous genotype survived a median time of 15.0 months (95%C.I 2.3, 15.9) compared with those have homozygous GG genotype 2.3 months (95%C.I 1.8, 7.3) or heterozygous AG genotype 5.7 months (95%C.I 2.7, 10.7), respectively (p=0.07, logrank test). Also, there is a trend of association between CylinD1 A870G polymorphism and intratumor gene expression levels (p=0.12, Kruskal-Wallis test), no association found between other gene polymorphism and gene expression levels. Conclusions: These data suggest that genomic profile of genes in the EGFR signaling pathway may be potential molecular markers for clinical outcome of the EGFR-expressing refractory metastatic colorectal caner patients treated with single agent EGFR inhibitor Cetuximab. Prospective studies are needed to confirm these preliminary findings. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron, Genentech, Response Genetics Lilly Oncology, Pfizer, Roche, Sanofi National Cancer Institute, National Institutes of Health