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.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Schneider BP,Li L,Shen F,Miller KD,Radovich M,O'Neill A,Gray RJ,Lane D,Flockhart DA,Jiang G,Wang Z,Lai D,Koller D,Pratt JH,Dang CT,Northfelt D,Perez EA,Shenkier T,Cobleigh M,Smith ML,Railey E,Partridge A,Gralodoi
10.1038/bjc.2014.430subject
Has Abstractpub_date
2014-09-09 00:00:00pages
1241-8issue
6eissn
0007-0920issn
1532-1827pii
bjc2014430journal_volume
111pub_type
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