title: Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.
abstract: BACKGROUND
  Variations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case-control study.
  
  
  METHODS
  140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF <55%, a decline in LVEF of 10%) that resulted in at least temporary discontinuation of trastuzumab, whereas controls had no decline in their LVEF. Eleven ErbB2 single gene SNPs that resulted in an alteration in the HER2-neu protein amino acid sequence were studied. Single gene SNP analysis was carried out using SNP genotyping assays from genomic DNA obtained from peripheral blood or buccal swab.
  
  
  RESULTS
  Only two of the ErbB2 SNPs (Ile 655 Val and Pro 1170 Ala) were found to have variation. There was no association between codon 665 and cardiotoxicity; however the proline variant of amino acid 1170 was more likely than the alanine variant to be found in cases with trastuzumab cardiotoxicity (35% of case patients as compared to 17% of controls, p = 0.04). This association remained significant in multivariable analysis taking into account age, race, and history of hypertension (adjusted OR = 2.60, 95% CI = 1.02, 6.62, p = 0.046).
  
  
  CONCLUSIONS
  The Her2/neu Pro 1170 Ala polymorphism can be used to identify a subset of patients who are at increased risk of cardiotoxicity from trastuzumab therapy. Her2/neu single nucleotide polymorphisms may be useful in conjunction with other biomarkers to risk stratify patients in order to optimize clinical management.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. sestant2@uw.edu.|Current address: Tumor Vaccine Group, University of Washington, 850 Republican Street Box 358050, Seattle, WA, 98102, USA. sestant2@uw.edu.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Stanton
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. mmw2003@med.cornell.edu.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Ward
authors.affiliation: Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY, 10065, USA. pac2001@med.cornell.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Christos
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. rachelsanford28@gmail.com.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sanford
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. christinalam@gmail.com.
authors.forename: Christina
authors.initials: C
authors.lastname: Lam
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. mac2034@med.cornell.edu.
authors.forename: Marta V
authors.initials: MV
authors.lastname: Cobham
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. dianadonovannp@gmail.com.
authors.forename: Diana
authors.initials: D
authors.lastname: Donovan
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. rjs2002@med.cornell.edu.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Scheff
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. tec9002@med.cornell.edu.
authors.forename: Tessa
authors.initials: T
authors.lastname: Cigler
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. almoore@med.cornell.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Moore
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. ltv2001@med.cornell.edu.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. mel2009@med.cornell.edu.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Lane
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 425 E 61st St. 8th floor, New York, NY, 10065, USA. elc2007@med.cornell.edu.
authors.forename: Ellen
authors.initials: E
authors.lastname: Chuang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D066126:Cardiotoxicity / Q000209:etiology / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D012307:Risk Factors; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human