Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100

Abstract

A B S T R A C T PurposeNo biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. Patients and MethodsDNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. ResultsThe VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio ϭ 0.58; 95% CI, 0.36 to 0.93; P ϭ .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio ϭ 0.62; 95% CI, 0.46 to 0.83; P ϭ .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P ϭ .005 and P ϭ .022, respectively). ConclusionOur data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…For example, there is proving to be considerable genetic variability within the VEGF gene, evidenced by multiple single nucleotide polymorphisms (SNPs). Notably, certain VEGF SNPs were shown to predict tumor responses and overall survival of metastatic breast cancer patients receiving combination of chemo‐ and anti‐VEGF therapy (bevacizumab) (Jain et al., 2009; Schneider et al., 2008). These provocative observations, while lacking mechanistic details, may help explaining the puzzling therapeutic heterogeneity of patient's responses to anti‐VEGF therapy, and call for auditing genetic variation and gene expression signatures in vascular cells.…”

La résistance aux traitements antiangiogéniques

“…La présence de ces facteurs en forte concentration dans le plasma ne permet cependant pas de prédire clairement la réponse aux agents antiangiogéniques. En effet, l'hétérogénéité des tumeurs mais aussi le polymorphisme qui existe pour les gènes codant le VEGF et ses récepteurs, constituent une partie importante de la variabilité observée dans les réponses aux traitements [44]. La complexité liée aux processus de l'angiogenèse tumorale et de la résistance aux agents qui l'inhibent, nécessite de développer des modèles précliniques qui incluent non seulement les données obtenues chez les patients mais également le contexte environnemental représentatif de la tumeur.…”

Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice

“…Unlike other targeted therapies, however, no molecular biomarkers clearly predict bevacizumab efficacy. Recent studies have investigated the influence of VEGF gene polymorphisms (VGPs) on the response to bevacizumab in breast and ovarian cancer (Schneider et al, 2008;Schultheis et al, 2008). Formica et al (2011) first reported a predictive value for PFS of VGPs located in the promoter/5′ UTR in bevacizumab-treated mCRC patients.…”