Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100 Journal Article
| Authors: | Schneider, B. P.; Li, L.; Shen, F.; Miller, K. D.; Radovich, M.; O'neill, A.; Gray, R. J.; Lane, D.; Flockhart, D. A.; Jiang, G.; Wang, Z.; Lai, D.; Koller, D.; Pratt, J. H.; Dang, C. T.; Northfelt, D.; Perez, E. A.; Shenkier, T.; Cobleigh, M.; Smith, M. L.; Railey, E.; Partridge, A.; Gralow, J.; Sparano, J.; Davidson, N. E.; Foroud, T.; Sledge, G. W. |
| Article Title: | Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100 |
| Abstract: | Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. 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. 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). A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials. |
| Keywords: | controlled study; single nucleotide polymorphism; genetics; polymorphism, single nucleotide; angiogenesis inhibitor; bevacizumab; hypertension; biological marker; biological markers; controlled clinical trial; randomized controlled trial; nerve tissue proteins; genetic association; genotype; genome-wide association study; validation study; breast neoplasms; monoclonal antibody; membrane glycoproteins; chemically induced disorder; breast tumor; membrane protein; blood pressure; phase 3 clinical trial; angiogenesis inhibitors; nerve protein; antibodies, monoclonal, humanized; humans; human; female; article; sv2c protein, human |
| Journal Title: | British Journal of Cancer |
| Volume: | 111 |
| Issue: | 6 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-09-09 |
| Start Page: | 1241 |
| End Page: | 1248 |
| Language: | English |
| DOI: | 10.1038/bjc.2014.430 |
| PUBMED: | 25117820 |
| PROVIDER: | scopus |
| PMCID: | PMC4453857 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
