title: Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.
abstract: BACKGROUND
  Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.
  
  
  METHODS
  A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100.
  
  
  RESULTS
  When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4).
  
  
  CONCLUSIONS
  A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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authors.lastname: Li
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.affiliation: Department of General Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.lastname: Radovich
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
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authors.lastname: Gray
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.affiliation: Indiana Institute for Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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authors.lastname: Lai
authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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authors.lastname: Koller
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Pratt
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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authors.initials: CT
authors.lastname: Dang
authors.affiliation: Department of Medicine, Mayo Clinic, Scottsdale, AZ 85054, USA.
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authors.affiliation: Mayo Clinic, Jacksonville, FL 32224, USA.
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authors.affiliation: BCCA - Vancouver Cancer Center, Vancouver, BC, V5Z 4E6, USA.
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authors.affiliation: Department of Internal Medicine , Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
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authors.affiliation: Research Advocacy Network, Plano, TX 75093, USA.
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authors.affiliation: Research Advocacy Network, Plano, TX 75093, USA.
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authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D000068258:Bevacizumab; D015415:Biomarkers; D001794:Blood Pressure; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C585899:SV2C protein, human; D000068258:Bevacizumab