1. Introduction Patients and Methods Results Conclusion Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. Colorectal cancer (CRC) is generally characterized by aberrant Wnt signaling. The Wnt signaling pathway was found to be deregulated in 93% of colorectal cancer. Wnt signaling pathway genes AXIN2 and TCF7L2 complex control the proliferation and differentiation of intestinal epithelial cells. Our previous study showed polymorphisms in TCF7L2 and AXIN2 were associated with increase risk of colon cancer. Hence, we tested the hypothesis whether single nucleotide polymorphisms (SNPs) in TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) will predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. DNA was extracted from 424 patients’ blood or tissue treated with first-line FOLFIRI+BV and prospectively enrolled in a prospective pharmacogenomic translational study. Median follow up is 45.1 months and median PFS and OS were 10.4 and 27.3 months, respectively. Three functionally significant SNPs: TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with tumor response rate (RR), progression free survival (PFS), and overall survival (OS). The associations between genetic variants and clinical outcome were examined using χ 2 test, log-rank test, and Cox regression models whenever appropriate. All tests were 2-sided and p values were not adjusted for multiple testing. Table 1. Baseline characteristics of the 424 patients included in the biomarker analysis. Genetic variants in Wnt signaling pathway predict gender and tumor location dependent survival in metastatic colorectal cancer (mCRC) patients(pts) treated with first-line FOLFIRI and Bevacizumab(FOLFIRI/BEV) Yan Ning 1, Wu Zhang 1, Dongyun Yang 1, Fotios Loupakis 2, Takeru Wakatsuki 1, Sebastian Stintzing 1, Nico B Volz 1, Rita E El-Khoueiry 1, Joseph E Li 1, Melissa LaBonte 1, Federica Marmorino 2, Chiara Cremolini 2, Afsaneh Barzi 1, Anthony El-Khoueiry 1, Heinz-Josef Lenz 1 1 USC/Norris Comprehensive Cancer Center, Los Angeles, CA; 2 U.O. Oncologia Medica 2 – Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy Patient Characteristics Abstract ID: 3568 Results Our data show for the first time Wnt signaling pathway gene polymorphisms TCF7L2 rs7903146 and AXIN2 rs2240308 may predict PFS and OS in mCRC pts treated with first-line FOLFIRI/BEV. More importantly, this predictive value is dependent on gender and tumor location, suggesting a different role of Wnt signaling in female vs male and in right vs left side tumor. Our preliminary data warrants clinical trial validation. Figure 1. In male, pts with any T allele of TCF7L2 rs7903146 had worse OS (p=0.029) and PFS (p=0.014) in right-sided tumors compared to those carrying C/C genotype (P for interaction = 0.047) (OS). Table 2. Significant TCF7L2 rs7903146 and AXIN rs 2240308 polymorphisms and clinical outcome in first-line FOLFIRI+BV therapy. Figure 2. In female, TCF7L2 rs7903146 concluded pts with any T (CT/TT) allele were significantly associated with better OS and PFS compared to those with CC genotypes by tumor location. Pts with C/C genotype in left-side tumor had worse OS (p=0.037); Pts with C/C genotype in right-side tumor had worse PFS (p=0.022). Figure 3. Tumor response of TCF7L2 rs7903146 and AXIN rs 2240308 in male pts.