Introduction

1. Genetic variants predict clinical outcome clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV) Harpreet Singh, Alexandra Pohl, Anthony El-Khoueiry, Georg Lurje, Wu Zhang, Dongyun Yang, Yan Ning, Jabi Shriki, Syma Iqbal, Heinz-Josef Lenz University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA Introduction Results PFS by MMP-9 -1562C>T Recent studies have suggested that germline polymorphisms involved in angiogenesis were associated with clinical outcome in patients treated with the VEGF-inhibitor bevacizumab. (Schneider et al. JCO 2008, Manegold et al ASCO 2008). We tested whether functional polymorphisms involved in genes in angiogenesis- (VEGF, KDR, IL-6, CXCR1 and-2), apoptosis (p53) and cell-proliferation (MMP2,-7 and-9, ICAM)-related pathways in an expanded patient cohort of 79 patients with mCRC, treated with FOLFOX or Xelox and BV predict progression-free survival (PFS) or response (RR). 79 patients (47 men, 32 women) with a median age of 56 years (range 29-81) were treated with with either FOLFOX/BV (33 patients) or XELOX/BV (46 patients). Radiologic response: 2/79 pts (3%) CR, 41/77 pts (52%) PR, 32/77 pts (41%) SD and 3/79 pts (4%) DP. At a median follow-up of 32.0 months (range: 1.4- 47.8 months), the median time to progression was 10.8 months (95% CI: 8.1-14.9), whereas median overall survival hasn’t been reached yet. We found IL-6 G-174C (p=0.025, Fisher’s exact test) and p53 codon 72 (p=0.029, Fisher’s exact test) polymorphisms associated with response to BV -therapy. The multivariate logistic regression of IL6 -174G>C and p53 codon 72 showed a borderline significance for IL6 -174G>C (p=0.065) and a significant assocation with RR for p53 (p=0 .023), respectively. Furthermore, there were statistically significant associations between MMP-9 -1572C>T, CXCR-1 2607G>C and PFS (p=0.023 and p=0.014, respectively, log-rank test). In multivariate analysis, MMP-9 1572C>T demonstrated to be an independent prognostic factor for PFS (adjusted p=0.002); whereas CXCR-1 2607G>C showed only borderline significance (adjusted p=0.055). Material and Methods PFS by CXCR-1 2607G>C Whole blood samples were obtained from 79 patients, who received first-line treatment for mCRC with FOLFOX ( or XELOX and BV at University of Southern California medical facilities. All patients signed informed consent; patient information was collected through prospective database and chart review. Statistical endpoints of this study were Progression Free Survival (PFS) and Response Rate (RR). Genomic DNA was extracted from white blood cells using the QiaAmp kit (Qiagen, Valencia, CA). Genotyping was performed using PCR-RFLP technique, direct sequencing and 5’-end [ϒ-33P] labeled PCR-protocols. Conclusions These are the first data to predict clinical outcome in mCRC patients treated with FOLFOX/BV or XELOX/BV. Our data demonstrate that functional polymorphisms in MMP-9 and CXCR-1, leading to alteration of transcription, predict PFS in patients treated with the angiogenesis-inhibitor BV. Furthermore, polymorphisms in IL6 and p53 have demonstrated to predict response to BV-treatment. However, confirmation of these findings in larger, prospective genotype-guided clinical trials is warranted. References • genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008;26:4672-8. • Schneider BP, Wang M, Radovich M, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 • Manegold P, El-Khoueiry A, Lurje G, Singh H, Yang D, Zhang WC, H; Shriki, J; Pohl, A; Iqbal, S; Lenz, HJ ICAM-1, GRP-78, and NFkB gene polymorphisms and clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV). In: ASCO annual meeting Chicago, IL, USA: J Clin Oncol 2008.