Genetic variants in CCL5 and CCR5 genes and serum VEGF‐A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients

Early VEGF‐A reduction (EVR) by targeting abundant VEGF‐A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF‐A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first‐line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n=48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR‐based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF‐A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression‐free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24‐0.83, P=0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26‐0.95, P=0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF‐A levels at baseline and a greater decrease in VEGF‐A levels at day 14 compared with the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first‐line treatment for mCRC.

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