Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.
Adult
Aged
Alleles
Antineoplastic Agents
/ therapeutic use
Bevacizumab
/ therapeutic use
Biomarkers, Tumor
/ blood
Chemokine CCL5
/ genetics
Cohort Studies
Colorectal Neoplasms
/ blood
Disease-Free Survival
Female
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
/ genetics
Receptors, CCR5
/ genetics
Vascular Endothelial Growth Factor A
/ blood
CCL5
CCR5
VEGF-A
bevacizumab
metastatic colorectal cancer
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 05 2019
15 05 2019
Historique:
received:
22
05
2018
revised:
23
10
2018
accepted:
29
10
2018
pubmed:
10
11
2018
medline:
7
8
2019
entrez:
10
11
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30411783
doi: 10.1002/ijc.31968
pmc: PMC7497849
mid: NIHMS1623924
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
CCL5 protein, human
0
CCR5 protein, human
0
Chemokine CCL5
0
Receptors, CCR5
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Bevacizumab
2S9ZZM9Q9V
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
2567-2577Subventions
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA014089
Pays : United States
Informations de copyright
© 2018 UICC.
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