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Clinical Trial
. 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

B P Schneider  1 , L Li  2 , F Shen  1 , K D Miller  1 , M Radovich  3 , A O'Neill  4 , R J Gray  4 , D Lane  1 , D A Flockhart  5 , G Jiang  2 , Z Wang  2 , D Lai  2 , D Koller  2 , J H Pratt  1 , C T Dang  6 , D Northfelt  7 , E A Perez  8 , T Shenkier  9 , M Cobleigh  10 , M L Smith  11 , E Railey  11 , A Partridge  12 , J Gralow  13 , J Sparano  14 , N E Davidson  15 , T Foroud  2 , G W Sledge  16
Affiliations
Clinical Trial

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

B P Schneider et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
Trial schemas for (A) ECOG-5103 and (B) ECOG-2100.
Figure 2
Figure 2
Consort diagram for (A) ECOG-5103 and (B) ECOG-2100.
Figure 3
Figure 3
Manhattan plot (left) and quantile-quantile plot (right) of genome-wide association results in E5103 under different models of hypertension. X-axis indicates the chromosomal position of each SNP analysed; Y-axis denotes magnitude of the evidence for association, shown as –log10(P-value). (A). Binary model for systolic blood pressure >160 mm Hg. (B). Cumulative dose model for the systolic blood pressure >160 mm Hg.
Figure 4
Figure 4
Association results in the SVC2 region for models of hypertension defined as systolic blood pressure>160 mm Hg. Results for all genotyped and imputed SNPs that passed quality-control parameters are shown. X-axis denotes position of the SNP in the region on chromosome 5; Y-axis denotes magnitude of the evidence for association, shown as −log10(P-value). The most significantly associated SNP is denoted with a purple diamond. The extent of linkage disequilibrium (as measured by r2) between each SNP and the most significantly associated SNP is indicated by the colour scale at top left. Larger values of r2 indicate greater linkage disequilibrium with the most significant SNP. (A) Binary model. (B) Cumulative dose model.
See this image and copyright information in PMC

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