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.
OBJECTIVE
No 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.


METHODS
DNA 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.


RESULTS
The 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 = 0.58; 95% CI, 0.36 to 0.93; P = .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 = 0.62; 95% CI, 0.46 to 0.83; P = .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 = .005 and P = .022, respectively).


CONCLUSIONS
Our 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.
Schneider
Bryan P
BP
Indiana University School of Medicine, Indianapolis, IN, USA. bpschnei@iupui.edu
Wang
Molin
M
Radovich
Milan
M
Sledge
George W
GW
Badve
Sunil
S
Thor
Ann
A
Flockhart
David A
DA
Hancock
Bradley
B
Davidson
Nancy
N
Gralow
Julie
J
Dickler
Maura
M
Perez
Edith A
EA
Cobleigh
Melody
M
Shenkier
Tamara
T
Edgerton
Susan
S
Miller
Kathy D
KD
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel