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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

Bryan P. Schneider, Molin Wang, Milan Radovich, George W. Sledge, Sunil Badve, Ann Thor, David A. Flockhart, Bradley Hancock, Nancy Davidson, Julie Gralow, Maura Dickler, Edith A. Perez, Melody Cobleigh, Tamara Shenkier, Susan Edgerton, Kathy D. Miller

From the Indiana University School of Medicine, Indianapolis, IN; Harvard School of Public Health and Dana-Farber Cancer Institute, Boston, MA; University of Colorado Health Sciences Center, Denver, CO; Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Memorial Sloan-Kettering Cancer Center, New York, NY; Mayo Clinic, Jacksonville, FL; Rush University Medical Center, Chicago, IL; and British Columbia Cancer Agency, Vancouver Cancer Center, Vancouver, British Columbia, Canada

Corresponding author: Bryan P. Schneider, MD, Indiana Cancer Pavilion, 535 Barnhill Dr, Rm 473, Indianapolis, IN 46202; e-mail: bpschnei{at}iupui.edu

Purpose 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.

Patients and 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).

Conclusion 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.

Supported by an American Society of Clinical Oncology Career Development Award, the Breast Cancer Research Foundation, and a grant from Genentech; also supported by funding for the Consortium on Breast Cancer Pharmacogenomics from the National Institute of General Medical Sciences Pharmacogenetics Research Network (Grant No. U01GM061373; D.A.F.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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