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

B. P. Schneider, L. Li, F. Shen, K. D. Miller, M. Radovich, A. O'Neill, R. J. Gray, D. Lane, D. A. Flockhart, G. Jiang, Z. Wang, D. Lai, D. Koller, J. H. Pratt, C. T. Dang, D. Northfelt, E. A. Perez, T. Shenkier, M. Cobleigh, M. L. Smith & 7 others E. Railey, A. Partridge, J. Gralow, Joseph A. Sparano, N. E. Davidson, T. Foroud, G. W. Sledge

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1241-1248
Number of pages8
JournalBritish Journal of Cancer
Volume111
Issue number6
DOIs
StatePublished - Sep 9 2014

Fingerprint

Hypertension
Blood Pressure
Genome-Wide Association Study
Single Nucleotide Polymorphism
Genome
Validation Studies
Bevacizumab
Genotype
Breast Neoplasms
Phenotype
Neoplasms
Therapeutics

Keywords

  • bevacizumab
  • breast cancer
  • hypertension
  • SNP
  • SV2C

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schneider, B. P., Li, L., Shen, F., Miller, K. D., Radovich, M., O'Neill, A., ... Sledge, G. W. (2014). Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. British Journal of Cancer, 111(6), 1241-1248. https://doi.org/10.1038/bjc.2014.430

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. / 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, Joseph A.; Davidson, N. E.; Foroud, T.; Sledge, G. W.

In: British Journal of Cancer, Vol. 111, No. 6, 09.09.2014, p. 1241-1248.

Research output: Contribution to journalArticle

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, Gralow, J, Sparano, JA, Davidson, NE, Foroud, T & Sledge, GW 2014, 'Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100', British Journal of Cancer, vol. 111, no. 6, pp. 1241-1248. https://doi.org/10.1038/bjc.2014.430
Schneider BP, Li L, Shen F, Miller KD, Radovich M, O'Neill A et al. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. British Journal of Cancer. 2014 Sep 9;111(6):1241-1248. https://doi.org/10.1038/bjc.2014.430
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, Joseph A. ; Davidson, N. E. ; Foroud, T. ; Sledge, G. W. / Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. In: British Journal of Cancer. 2014 ; Vol. 111, No. 6. pp. 1241-1248.
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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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AU - Schneider, B. P.

AU - Li, L.

AU - Shen, F.

AU - Miller, K. D.

AU - Radovich, M.

AU - O'Neill, A.

AU - Gray, R. J.

AU - Lane, D.

AU - Flockhart, D. A.

AU - Jiang, G.

AU - Wang, Z.

AU - Lai, D.

AU - Koller, D.

AU - Pratt, J. H.

AU - Dang, C. T.

AU - Northfelt, D.

AU - Perez, E. A.

AU - Shenkier, T.

AU - Cobleigh, M.

AU - Smith, M. L.

AU - Railey, E.

AU - Partridge, A.

AU - Gralow, J.

AU - Sparano, Joseph A.

AU - Davidson, N. E.

AU - Foroud, T.

AU - Sledge, G. W.

PY - 2014/9/9

Y1 - 2014/9/9

N2 - 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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KW - breast cancer

KW - hypertension

KW - SNP

KW - SV2C

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