Genome-wide association study for anthracycline-induced congestive heart failure

Bryan P. Schneider, Fei Shen, Laura Gardner, Milan Radovich, Lang Li, Kathy D. Miller, Guanglong Jiang, Dongbing Lai, Anne O'Neill, Joseph A. Sparano, Nancy E. Davidson, David Cameron, Irmina Gradus-Pizlo, Ronald A. Mastouri, Thomas M. Suter, Tatiana Foroud, George W. Sledge

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. Experimental Design: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. Results: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). Conclusions: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.

Original languageEnglish (US)
Pages (from-to)43-51
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2017

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Genome-Wide Association Study
Anthracyclines
Heart Failure
Single Nucleotide Polymorphism
Breast Neoplasms
Stroke Volume
Research Design
Biomarkers
Genotype
Clinical Trials
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Schneider, B. P., Shen, F., Gardner, L., Radovich, M., Li, L., Miller, K. D., ... Sledge, G. W. (2017). Genome-wide association study for anthracycline-induced congestive heart failure. Clinical Cancer Research, 23(1), 43-51. https://doi.org/10.1158/1078-0432.CCR-16-0908

Genome-wide association study for anthracycline-induced congestive heart failure. / Schneider, Bryan P.; Shen, Fei; Gardner, Laura; Radovich, Milan; Li, Lang; Miller, Kathy D.; Jiang, Guanglong; Lai, Dongbing; O'Neill, Anne; Sparano, Joseph A.; Davidson, Nancy E.; Cameron, David; Gradus-Pizlo, Irmina; Mastouri, Ronald A.; Suter, Thomas M.; Foroud, Tatiana; Sledge, George W.

In: Clinical Cancer Research, Vol. 23, No. 1, 01.01.2017, p. 43-51.

Research output: Contribution to journalArticle

Schneider, BP, Shen, F, Gardner, L, Radovich, M, Li, L, Miller, KD, Jiang, G, Lai, D, O'Neill, A, Sparano, JA, Davidson, NE, Cameron, D, Gradus-Pizlo, I, Mastouri, RA, Suter, TM, Foroud, T & Sledge, GW 2017, 'Genome-wide association study for anthracycline-induced congestive heart failure', Clinical Cancer Research, vol. 23, no. 1, pp. 43-51. https://doi.org/10.1158/1078-0432.CCR-16-0908
Schneider, Bryan P. ; Shen, Fei ; Gardner, Laura ; Radovich, Milan ; Li, Lang ; Miller, Kathy D. ; Jiang, Guanglong ; Lai, Dongbing ; O'Neill, Anne ; Sparano, Joseph A. ; Davidson, Nancy E. ; Cameron, David ; Gradus-Pizlo, Irmina ; Mastouri, Ronald A. ; Suter, Thomas M. ; Foroud, Tatiana ; Sledge, George W. / Genome-wide association study for anthracycline-induced congestive heart failure. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 1. pp. 43-51.
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AU - Shen, Fei

AU - Gardner, Laura

AU - Radovich, Milan

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AU - Miller, Kathy D.

AU - Jiang, Guanglong

AU - Lai, Dongbing

AU - O'Neill, Anne

AU - Sparano, Joseph A.

AU - Davidson, Nancy E.

AU - Cameron, David

AU - Gradus-Pizlo, Irmina

AU - Mastouri, Ronald A.

AU - Suter, Thomas M.

AU - Foroud, Tatiana

AU - Sledge, George W.

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N2 - Purpose: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. Experimental Design: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. Results: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). Conclusions: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.

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