title: Risk factors for anthracycline-associated cardiotoxicity.
abstract: OBJECTIVE
  Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults.
  
  
  METHODS
  We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated.
  
  
  RESULTS
  We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556).
  
  
  CONCLUSIONS
  This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.
authors.affiliation: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, B421 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA. raquel.reinbolt@osumc.edu.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Reinbolt
authors.affiliation: The Ohio State University College of Medicine, 1470, Highland St., Columbus, OH, 43210, USA.
authors.forename: Roshan
authors.initials: R
authors.lastname: Patel
authors.affiliation: Center for Biostatistics, The Ohio State University Comprehensive Cancer Center, 2012, Kenny Road, Columbus, OH, 43221, USA.
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Cynthia Dawn
authors.initials: CD
authors.lastname: Timmers
authors.affiliation: Division of Human Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Pilarski
authors.affiliation: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, B421 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.affiliation: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, B421 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA.
authors.forename: Maryam B
authors.initials: MB
authors.lastname: Lustberg
mesh_terms: D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D018943:Anthracyclines / Q000009:adverse effects*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics*; D066126:Cardiotoxicity / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000429:Alcohol Oxidoreductases; C531130:CBR3 protein, human
keywords: Anthracycline; CBR; Cardiotoxicity; Single nucleotide polymorphisms; Trastuzumab