TY - JOUR
TI - Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel
AU - Koutras, A.K.
AU - Kotoula, V.
AU - Papadimitriou, C.
AU - Dionysopoulos, D.
AU - Zagouri, F.
AU - Kalofonos, H.P.
AU - Kourea, H.P.
AU - Skarlos, D.V.
AU - Samantas, E.
AU - Papadopoulou, K.
AU - Kosmidis, P.
AU - Pectasides, D.
AU - Fountzilas, G.
JO - The Pharmacogenomics Journal
PY - 2014
VL - 14
TODO - 3
SP - 248-255
PB - Nature Publishing Group
SN - 1470-269X, 1473-1150
TODO - 10.1038/tpj.2013.36
TODO - docetaxel;  vasculotropin;  antineoplastic agent;  docetaxel;  primer DNA;  taxoid;  vasculotropin A, adult;  article;  breast metastasis;  controlled study;  disease association;  drug efficacy;  drug response;  female;  gene deletion;  gene insertion;  genotype;  homozygote;  human;  major clinical study;  multiple cycle treatment;  overall survival;  phase 2 clinical trial;  priority journal;  progression free survival;  single nucleotide polymorphism;  treatment outcome;  VEGF gene;  aged;  Breast Neoplasms;  drug administration;  genetic polymorphism;  genetics;  metastasis;  middle aged;  nucleotide sequence;  pathology;  very elderly, Animalia, Adult;  Aged;  Aged, 80 and over;  Antineoplastic Agents;  Base Sequence;  Breast Neoplasms;  DNA Primers;  Drug Administration Schedule;  Female;  Humans;  Middle Aged;  Neoplasm Metastasis;  Polymorphism, Genetic;  Taxoids;  Vascular Endothelial Growth Factor A
TODO - The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts. © 2014 Macmillan Publishers Limited.
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