Abstract Background: Gene polymorphisms of HER2 have been identified. Their impact on the risk of breast cancer, the response and the toxicity of anti HER2 treatments have been studied. According to a small report of Beauclair (2007), the polymorphism at codon 655 of the HER2 gene may represent a risk factor for cardiotoxicity induced by Trastuzumab (T). In this study, we evaluated the incidence of the Val655Ile polymorphism in (neo)adjuvant breast cancer patients (pts) with cardiac toxicity and in matched patients without cardiac toxicity. Methods: 40 HER2 positive breast cancer pts treated between 2008 and 2011 by (neo)adjuvant sequential chemotherapy plus T developed a cardiac toxicity. Definition of cardiac toxicity was a 10% absolute decrease in LVEF (Left Ventricular Ejection Fraction) or a decrease in LVEF to a threshold value of <50%. 84 pts without cardiac toxicity were matched according to age, received dose of anthracyclin and T, BMI and cardiac risk factors. Polymorphism of Her2 gene in codon 655 was searched by PCR on lymphocyte DNA from blood samples in this population and in the control group. Genomic DNA was extracted from EDTA blood samples (300ml) on the MagNa Pure Compact instrument. The HER2 Ile655Val (rs1163201) polymorphism was detected by sequencing using a 3730 DNA Analyser. Results: In the cardiac toxicity group 2,5% (1 patient) presented a genotype Val/Val at HER2 codon 655, 40% (16) were heterozygous (Ile) and 57,5% (23) had the wild type. In the control population, the incidence was respectively 3,6% (3 pts), 36,9% (31) and 59,5% (50). No differences were found between the both groups (p = 0,91). Conclusions: The incidence of mutated, heterogeneous and wild type genotype was similar to the literature. We could not confirm the Val allele at HER2 codon 655 as a risk factor of cardiotoxicity. HER2 polymorphism cannot be used in clinical practice to predict the risk of cardiac toxicity of T. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-21.