Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity

Abstract

Background:To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab.Patients and methods: Experimental study: The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice. The effect of trastuzumab was determined in both experimental models. Clinical study: 61 patients with advanced breast cancers and treated by trastuzumab were genotyped for HER2 by PCR-RFLP. The influence of HER2 genotype on the trastuzumab treatment was examined. Conclusions: This study establishes a clear-cut difference between the two HER2 isoforms regarding their tumorogenic potential with an advantage for the Val/HER2 isoform. In breast cancer patients treated with trastuzumab, the presence of a Val allele may constitute a risk factor for cardiac toxicity.

Trastuzumab

“…Most reported polymorphisms affecting the efficacy of anticancer treatment are single nucleotide polymorphisms (SNPs) [17]. Several SNPs in the extracellular, transmembrane, and intracellular regions of HER-2 have been studied; however, their reported influence on trastuzumab efficacy remains controversial [18,19]. Currently, there are no arguments to determine the pharmacogenetic status of HER-2 to individualize trastuzumab treatment.…”

Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors

“…These prediction models would ideally have the ability to include some of the new very sensitive indicators of left ventricular function (Fallah-Rad et al 2011 ), in addition to weighted factor scores for age, BMI, a measure of physical activity or cardiorespiratory fi tness, hypertension, diabetes, dyslipidemia, and any prior cardiac event. Ideally the models could also be adapted to include provision for genetic polymorphisms predisposing to cardiac risk such as the common HER-2 Ile655Val allele in the HER-2 gene (Beauclair et al 2007 ), and polymorphisms in NADPH oxidase, MDR 1, MDR 2, catalase, superoxide dismutase, NADPH:quinone oxidoreductase, carbonyl reductase 3, and glutathione s-transferase (Wojnowski et al 2005 ;Deng and Wojnowski 2007 ).…”

Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy

“…The downside to this discussion is that there is variable risk of trastuzumab-induced cardiotoxicity that depends mainly on the concomitant medication [107]. A recent report indicates that this cardiotoxicity may also be significantly associated to a polymorphism-generating valine instead of isoleucine at position 655 in the HER2 gene [108]. However, even though (1) it would be easy to genotype patients prior to starting trastuzamab therapy and (2) the adverse effect ADR is serious enough to justify the screening, the great antineoplastic efficacy shown by trastuzamab makes it difficult to predict whether these genetic tests will routinely be applied in the near future.…”