HER-2: genetic polymorphism and breast cancer

There is a single nucleotide polymorphism in the HER-2 gene, which occurs in the transmembrane domain of the receptor (655 Val/lle). Our group's clinical study of breast cancer patients (N = 57) treated with trastuzumab shows 56% lle/lle, 37% lle/Val and 7% Val/Val. Of note, all cardiac toxicities (N = 5) were found in patients carrying the Val allele in the heterozygous state. Inactivation by mutation of the tumour suppressor gene PTEN constitutes a somatic polymorphism indirectly influencing the HER-2 signalling pathway. Recent experimental and clinical studies suggest that the absence of PTEN may be detrimental to the antitumour efficacy of the monoclonal antibody targeting HER-2, trastuzumab. In contrast, the clinical activity of lapatinib (anti-tyrosine kinase) should be not influenced by PTEN. Both germinal and somatic genetic polymorphisms impacting directly or indirectly HER-2 gene functioning should be investigated in larger groups of patients receiving targeted therapeutics in order to draw conclusions about their clinical appropriateness in follow-up treatment.