Role of the HER2 [lle655Val] genetic polymorphism in tumorogenesis and in the risk of-trastuzumab-related cardiotoxicity

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. Results: Experimental study: HER2-expressing cells acquired the characteristics of tumor cells. The Val isoform-expressing cells showed the highest growth capacity and developed aggressive tumors sensitive to trastuzumab. Clinical study: There was no link between tumor response or survival and HER2 genotype. All cases of treatment- related cardiotoxicity were found in the Ile/Val group and there was no cardiac toxicity in the Val/Val and Ile/Ile patients. 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.