Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.
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.
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
A K
AK
Koutras
Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
V
V
Kotoula
Department of Clinical Therapeutics, 'Alexandra' Hospital, University of Athens School of Medicine, Athens, Greece.
C
C
Papadimitriou
Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
D
D
Dionysopoulos
Department of Clinical Therapeutics, 'Alexandra' Hospital, University of Athens School of Medicine, Athens, Greece.
F
F
Zagouri
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
H P
HP
Kalofonos
Department of Pathology, University Hospital of Patras, Patras, Greece.
H P
HP
Kourea
Second Department of Medical Oncology, 'Metropolitan' Hospital, Piraeus, Greece.
D V
DV
Skarlos
Third Department of Medical Oncology, 'Agii Anargiri' Cancer Hospital, Athens, Greece.
E
E
Samantas
Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
K
K
Papadopoulou
Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece.
P
P
Kosmidis
Oncology Section, Second Department of Internal Medicine, 'Hippokration' Hospital, Athens, Greece.
D
D
Pectasides
Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
G
G
Fountzilas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D000970:Antineoplastic Agents; D017931:DNA Primers; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel