Genetic variants in CCL5 and CCR5 genes and serum VEGF‐A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients. Issue 10 (14th December 2018)

• Record Type: Journal Article
• Authors: Suenaga, Mitsukuni; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Okazaki, Satoshi; Berger, Martin D.; Miyamoto, Yuji; Schirripa, Marta; Soni, Shivani; Barzi, Afsaneh; Yamaguchi, Toshiharu; Lenz, Heinz‐Josef
• Is Part Of: International journal of cancer. Volume 144:Issue 10(2019)
• Page Start: 2567
• Page End: 2577
• Publication Date: 2018-12-14
• Subjects: CCL5 -- CCR5 -- VEGF‐A -- bevacizumab -- metastatic colorectal cancer; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31968
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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 to 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. Abstract : What's new? Bevacizumab, the first anti‐angiogenic agent targeting VEGF‐A, has been widely used in several cancer types. However, an efficacy biomarker is still lacking. The CCL5/CCR5 axis modulates VEGF‐A production via endothelial progenitor cells migration, and here the authors tested whether genetic polymorphisms could predict bevacizumab efficacy in patients with metastatic colorectal cancer. Gene polymorphisms in CCL5 and CCR5 genes were found to correlate with serum VEGF‐A levels during bevacizumab treatment. Early VEGF‐A reduction due to bevacizumab was differently observed between the genetic variants. Genetic variants in CCL5 / CCR5 genes were demonstrated to vary sensitivity to bevacizumab due to different circulating VEGF‐A levels.