期刊
CLINICAL COLORECTAL CANCER
卷 17, 期 2, 页码 E395-E414出版社
CIG MEDIA GROUP, LP
DOI: 10.1016/j.clcc.2018.02.010
关键词
CCL5/CCR5 signaling; Colorectal cancer; Ethnic difference; Hand-foot skin reaction; Regorafenib
类别
资金
- National Cancer Institute [P30CA014089]
- Gloria Borges Wunderglo Project
- Dhont Family Foundation
- Dave Butler Research Fund
- Call to Cure Research Fund
- Takashi Tsuruo Memorial Fund
- JSPS KAKENHI [15K06860]
- Swiss Cancer League [BIL KLS-3334-02-2014]
- Werner and Hedy Berger-Janser Foundation for cancer research
- Japan Society for the Promotion of Science [S2606]
- NATIONAL CANCER INSTITUTE [P30CA014089] Funding Source: NIH RePORTER
Regorafenib confers the benefit of longer survival in metastatic colorectal cancer patients. The CCL5/CCR5 pathway modulates endothelial progenitor cell migration and vascular endothelial growth factor A production. Genetic variants of CCL4 and CCL3 may predict outcomes, and the different frequencies of CCL5 homozygote may explain ethnic differences in the development of severe hand-foot skin reactions. Background: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. Patients and Methods: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. Results: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Conclusion: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. (C) 2018 Elsevier Inc. All rights reserved.
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