Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel

Abstract

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.

Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer

“…Our finding of a positive association between variant rs699947 genotypes and high-grade tumors is in opposite direction of that reported by Jin et al, 23 who found an association between variant homozygous AA and low-grade tumors, whereas other authors reported no association between rs699947 and tumor grade. 37,45,46 Likewise, the results indicating positive association of variant genotypes of rs833061 with high histological grade and lymph node metastases at diagnosis also appear to contradict those of Sa-Nguanraksa et al, 44 who reported lower lymphovascular invasion of breast tumors with the variant homozygous genotype CC. The impact of rs833061 in breast cancer has also been studied by Rahoui et al, 37 who found no significant associations with histopathological features.…”

Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma

“…DNA was extracted from peripheral blood samples corresponding to the 60 patients under study, with a standard desalting method (34). Genotyping for the selected SNPs of VEGFA, EDNRA, FAS and NBS1 was performed with Sanger sequencing, as previously described (35).…”

“…Upon histological evaluation, available tumors were transferred into lowdensity TMAs, whereby three cores (0.6 mm in diameter) were obtained from appropriate regions of each tumor with the use of a manual arrayer (Model I, Beecher Instruments, San Prairie, WI) and included in the TMA block. Subsequently, EBER detection was performed on 4 μm sections from the TMA block with the use of a Bond Max autostainer (Leica Microsystems, Wetzlar, Germany), according to the provider's specifications, as previously described (34)(35)(36)(37). Tumor cells containing EBER transcripts were considered positive when an intense, brown, predominantly nuclear staining was present in >1% of tumor cells (38).…”

Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors

“…A trial involving two arms has found that the AA genotype of the VEGF polymorphism −2578C > A (rs699947) and −1154G > A (rs1570360) in the 5′untranslated promoter region (5′UTR) was related with higher overall survival (OS) in patients receiving combined paclitaxel/bevacizumab [36].…”