4070 Background: Recent studies suggested polymorphisms involved in angiogenesis related genes associated with clinical outcome in pts treated with the VEGF-inhibitor bevacizumab. (Schneider et al. JCO 2008, Manegold et al ASCO 2008). We evaluated functional polymorphisms involved 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 for their potential prognostic or predictive role in clinical outcome. Methods: Genomic DNA was extracted from 79 mCRC pts (treated with first-line FOLFOX/BV or XELOX/BV at USC) from peripheral blood. Genotyping was performed using PCR-RFLP assays or direct sequencing. Results: 79 pts (47 men, 32 women) with a median age of 56 years (range 29–81), were treated with either FOLFOX/BV (33 pts) or XELOX/BV (46 pts). Radiologic response: 2/79 pts (3%) CR, 41/79 pts (52%) PR, 32/79 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). 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. Furthermore, there were statistically significant associations between genomic polymorphisms in MMP-9, CXCR-1 and PFS (p=0.023 and p=0.014, respectively, log-rank test). Pts with 2 G- alleles in CXCR-1 G+2607C (median PFS=13.7 months, 95% CI:8.4–16.4) and pts homozygous for the C-allele in MMP-9 C-1562T (median PFS= 13.9 months, 95% CI: 10.1–15.8) had longer PFS compared to pts with any C-allele in CXCR-1 G+2607C (median PFS = 7.9 months, 95% CI: 6.9–10.2) and pts with any T-allele in MMP-9 C-1562T (median PFS 7.2 months, 95% CI: 5.3–11.0), respectively. Conclusions: These are the first data to predict clinical outcome in mCRC pts treated with FOLFOX/BV or XELOX/BV. Our data demonstrate that functional polymorphisms in angiogenesis related genes predict response and PFS in pts treated with the angiogenesis- inhibitor BV. However, confirmation of these findings in larger, prospective genotype-guided clinical trials is warranted. [Table: see text]