The human epidermal growth factor receptor (HER2) is overexpressed in 25-30% of human breast cancers [1].  It is a predictive marker for poor prognosis in patients with metastasic breast cancer.  There has been new therapies were developed to target tumour cells with HER2 overexpression by blocking HER2 at the cell surface.  Trastuzumab (Herceptin) is the most widely used a monoclonal antibody against the HER2 receptor [1].

A serious drawback is the cardiotoxicity associated with the use of this medication as a single agent or in combination with chemotherapy.  The incidence of cardiotoxicity in patients were 13% when combined with paclitaxel, 27% when administered with an anthracycline as opposed to 7% with anthracycline alone [2].  HER receptors and ligands are expressed in the heart.  In contrast to cancer, the deletion of HER proteins has been shown to cause abnormal cardiac development.  The HER proteins and ligands play an important role in cardiac development and protection against cardiac failure [1].

Studies have found that 33% of women with heart failure died within 2 years of initial diagnosis.  Cardiotoxicity is a significant adverse drug reaction that can result in morbidity and mortality [1].  It is critical to minimize the effects of this adverse drug reaction in patients taking trastuzumab so that patients do not need to trade one lethal disease for another.

Proposal

I propose that a study be carried out to observe whether there are genetic variants associated with trastuzumab-induced cardiotoxicity.  We would carry out a genome-wide association study on the trastuzumab case-control patient samples.  To characterize the effects of trastuzumab cardiotoxicity, we well measure the left ventricular function using patient echocardiograms.  Determining the shortening fraction of the left ventricle is more useful for detecting cardiotoxic effects [2,3]. Some patients may take longer to develop the cardiotoxicity.  Therefore, we will continue to monitor the patient's echocardiograms long term (5 year follow up) to ensure that we have designated control patients appropriately.  Patient DNA will be extracted and genotyped using a high-throughput genotyping assay.  We will then analyze the results to determine whether there are genetic variants associated with trastuzumab-cardiotoxicity.  The results will then be replicated in a second cohort of patients.

The aim of this study is to determine genetic factors that predispose individuals to this adverse drug reaction prior to therapy.  This will enable the development of a genotype-based safe dosing guideline or alternative treatment to those individuals at high risk of cardiotoxicity.

References:
1. Feldman AM et al. (2000) Circulation 102:272
2.McArthur HL and Chia S (2007) N Engl J Med. 357:94-95.
3.Biancaniello T et al (1980) Journal of Pediatrics. 97:45-50