635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.
KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy
