Focus on ERBB2

Abstract

The ERBB2 (HER2) gene codes for a tyrosine kinase receptor that activates pathways involved in cell division, differentiation and apoptosis. Gene amplification, and as a result protein overexpression, are commonly seen in breast tumors and correlate with poor prognosis. The overexpressed protein is the target of trastuzumab, a monoclonal antibody routinely used in clinical practice. A new tyrosine kinase inhibitor, lapatinib, is already an alternative in women progressing despite treatment with trastuzumab. Using comprehensive tagging approaches, highly-powered association studies concluded that ERBB2 was unlikely to be a breast cancer predisposition gene. ERBB2 pharmacogenomics are of little relevance at present, since we have no knowledge of polymorphisms in the gene that could affect the binding, efficacy or tolerability of trastuzumab or lapatinib. There is minor contribution from hepatic cytochrome CYP2C19 to the metabolism of lapatinib, whereas in vitro studies have shown the drug to be a substrate for the transporter P-glycoprotein. If, and how, the pharmacokinetics of lapatinib would be altered in individuals carrying polymorphisms in CYP2C19 or ABCB1 – the gene that codes for the P-glycoprotein – is yet to be determined.