Abstract P6-05-06: Association of HER2/neu single nucleotide polymorphism with trastuzumab-related cardiotoxicity
Authors: Chuang E , Stanton S , Ward MM , Christos P , Sanford R , Lam C , Cobham MV , Donovan D , Scheff R , Cigler T , Moore A , Vahdat LT , Lane ME 
Published: August 2014

Abstract
Background: Treatment with trastuzumab prolongs overall survival when given to patients (pts) with Her2/neu+ breast cancer (BC). The primary toxicity of trastuzumab is cardiotoxicity and the incidence is estimated at 2-4% in the adjuvant setting. The mechanism for trastuzumab-induced cardiotoxicity is not known. Although Her2neu expression is usually not seen on cardiac myocytes, its expression has been shown to be upregulated after chemotherapy. Trastuzumab is a monoclonal antibody that binds to the extracellular domain of Her2/neu. We hypothesized that single nucleotide polymorphisms (SNPs) in the Her2/neu receptor may play a role in trastuzumab associated cardiotoxicity.
Methods: 140 pts with BC who were treated with chemotherapy and trastuzumab were enrolled into an IRB approved protocol at the Weill Cornell Medical College between July 2008 and March 2013. Cardiotoxicity was defined as either symptomatic CHF, or a decline in LVEF of 15% (or if LVEF &lt;55% a decline in LVEF of 10%) that required management with medications and led to temporary or permanent discontinuation of trastuzumab. 11 nonsynonomous human ErbB2 SNPs were identified in the National Center for Biotechnology Information SNP database (rs1136201, rs2172826, rs28933368, rs28933369, rs28933370, rs34602395, rs36085723, rs4252633, rs55943169, rs56366519, rs61552325). Genotyping of SNPs was performed on DNA prepared from blood or buccal washes. The relationship between SNP characteristics and cardiotoxicity status was assessed by the chi-square test and multivariable logistic regression analysis.
Results: 140 subjects (29 with cardiotoxicity and 111 without) had 11 SNPs sequenced. Median age of subjects was 56 years (range: 32-85), mean baseline LVEF was 65% (±6%). 16.4% of subjects had hypertension (HTN). 80% of patients were Caucasian, 10% East Asian, 7.1% African American, 2.9% South Asian. There were two SNPs for which there was variation seen among subjects: rs 1136201 (corresponding to codon 655) and rs61552325 (codon 1170). The frequencies of the codon 655 polymorphisms were: AA (Ile/Ile) 67.9%, AG (Ile/Val) 29.3%, and GG (Val/Val) 2.9%. The frequencies of the codon 1170 polymorphisms were: CC (Pro/Pro) 20.7%, GC (Ala/Pro) 45.7%, and GG (Ala/Ala) 33.6%. There was no association observed between the codon 655 polymorphism and cardiotoxicity (p = 0.96). A significant association between cardiotoxicity and the codon 1170 polymorphism was observed, with subjects having cardiotoxicity being more likely to carry the CC allele compared with subjects without cardiotoxicity (34.5% vs 17.1%, p = 0.04). This association persisted after multivariable adjustment for age, race, and HTN status (adjusted OR = 2.60, 95% CI = 1.02-6.62, p = 0.046).
Conclusion: In this study, the Her2/neu 1170 Pro/Pro polymorphism was associated with trastuzumab cardiotoxicity. If confirmed in a larger series, this polymorphism could be used to identify pts who may be at increased risk for cardiotoxicity and who may benefit from treatments associated with less cardiotoxicity. Furthermore, the Her2/neu 1170 SNP has previously been implicated as a minor histocompatibility antigen, and our findings raise the possibility that immune mediated mechanisms may play a role in trastuzumab related cardiotoxicity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-06.