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Br J Cancer. 2014 Sep 9;111(6):1241-8. doi: 10.1038/bjc.2014.430. Epub 2014 Aug 12.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

Author information

1
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
2
Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
3
Department of General Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4
Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
5
Indiana Institute for Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Medicine, Mayo Clinic, Scottsdale, AZ 85054, USA.
8
Mayo Clinic, Jacksonville, FL 32224, USA.
9
BCCA - Vancouver Cancer Center, Vancouver, BC, V5Z 4E6, USA.
10
Department of Internal Medicine , Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
11
Research Advocacy Network, Plano, TX 75093, USA.
12
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
13
University of Washington, Seattle, WA 98195, USA.
14
Department of Oncology, Montefiore Hospital and Medical Center, Bronx, NY 10467, USA.
15
Cancer Institute and University of Pittsburgh Cancer Center, Pittsburgh, PA 15232, USA.
16
Department of Medicine, Stanford University, Stanford, CA 94305, USA.

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.

PMID:
25117820
PMCID:
PMC4453857
DOI:
10.1038/bjc.2014.430
[Indexed for MEDLINE]
Free PMC Article

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