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Originally published as JCO Early Release 10.1200/JCO.2008.20.6359 on February 2 2009 © 2009 American Society of Clinical Oncology.
Race to Report: Are Vascular Endothelial Growth Factor Genetic Polymorphisms Associated With Outcome in Advanced Breast Cancer Patients Treated With Paclitaxel Plus Bevacizumab?Department of Medical Oncology, National Cancer Centre Singapore; and Centre for Molecular Epidemiology, Faculty of Medicine, National University of Singapore, Singapore
Centre for Molecular Epidemiology, Faculty of Medicine, National University of Singapore, Singapore To the Editor: In the October 1, 2008, issue of Journal of Clinical Oncology, Schneider et al1 reported a positive association between the VEGF-2578 AA genotype and overall survival in patients with metastatic breast cancer receiving paclitaxel and bevacizumab. In addition, an association between the VEGF-1154 A allele and superior median overall survival was also reported in patients in the same arm, with each active allele having an additive effect. The authors are to be commended for their novel exploratory analysis of a difficult pharmacogenomic question, in the context of a large prospective randomized trial. Nevertheless, we would like to raise epidemiologic and statistical concerns with regard to the way in which the study was conducted. First, a more conservative formal test of interaction would have been preferred to study the association of the reported vascular endothelial growth factor polymorphisms with the relevant outcomes. This would have been a single test to demonstrate that there was an association with the relevant outcome (overall survival) in the experimental arm but no such association in the control arm. The authors presented data for the experimental arm only, reporting that there was no statistically significant result in the control arm. Second, with the selection of paraffin-embedded tumor blocks for genotyping, the benefits of randomization in eliminating bias are diminished, even if the numbers in each arm are equal. Hence, particularly in this exploratory analysis, controlling for any additional clinically relevant confounders after the univariate analysis would be important. In particular, we note that both polymorphisms predicting for better outcomes were more common in the white population in comparison with the African American population. As reported by the authors, the VEGF 2578 A allele and the VEGF-1154 A allele have respective frequencies of 49% and 33% in the white population, and 24% and 10% in the African American population. The disparity of breast cancer survival between whites and African Americans is well known,2 and is multifactorial in nature. Ethnic variation and admixture are major concerns in any association study, and thus, a breakdown of the patient genotypes by ethnicity would be useful in assessing the validity of this study. We hope that clarifications of these concerns will strengthen the conclusions of the study. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Schneider BP, Wang M, Radovich M, et al: 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. J Clin Oncol 26:4672–4678, 2008. 2. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71–96, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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