Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that
-Trastuzumab (Herceptin), currently prescribed for metastatic breast cancer, has recently been shown to be effective as adjuvant therapy in early receptor 2 (HER2)-positive breast cancer. Cardiotoxicity is a serious adverse effect. A decrease in left ventricular ejection fraction (LVEF) occurs in as many as 27% of women treated with trastuzumab when combined with standard chemotherapy. The pathophysiology of this effect, which differs from the cardiotoxicity of anthracyclines, remains poorly understood. While overt heart failure is reversed with standard therapy, the longer-term consequences of asymptomatic declines in LVEF remain unknown. Monitoring 3-monthly for 5-10% changes in LVEF, the criteria for cessation of trastuzumab therapy in the clinical trials, is not possible for the population of women who might benefit from trastuzumab for early breast cancer. Extension of this therapy to an older and less fit population than those enrolled in the trials, with less rigorous cardiac screening, may result in significantly more cardiotoxicity.KEY WORDS: breast cancer, cardiac failure, cardiotoxicity, echocardiography, trastuzumab (Herceptin) Introduction Trastuzumab (Herceptin) was introduced in the late 1990s for use in the treatment of metastatic breast cancer and this is now standard practice in the UK. According to recent evidence, trastuzumab is now indicated as adjuvant therapy during or after chemotherapy, in women with early stage breast cancers whose tumours over express the growth factor receptor (HER-2) protein. 20-25% of breast cancers overexpress HER-2, suggesting that this therapy might be indicated in as many as 3,700 women per year in the UK. Aside from the issues related to the cost of the drug, which have recently brought Herceptin into the spotlight, an important but less publicised aspect concerns its cardiotoxicity. Trastuzumab-associated cardiac dysfunction has been reported with an incidence of between 3% and 27% in phase II/III trials and close monitoring is recommended. This article reviews the evidence regarding the cardiotoxicity of trastuzumab and raises questions concerning cardiac monitoring. The role of trastuzumab in breast cancer therapyHER-2 is a proto-oncogene that codes for the transmembrane receptor tyrosine kinase protein p185HER2. The HER-2 gene is amplified and protein overexpressed in 20-25% of breast cancers. HER-2 mediated signalling has a direct role in the pathogenesis of these cancers, the HER-2 positive phenotype being associated with increased proliferation, angiogenesis and resistance to apoptosis. 1 In patients with tumours demonstrating this alteration prognosis is poor compared to HER-2 negative disease. 2 Trastuzumab is a recombinant humanised monoclonal antibody that selectively binds to the extracellular domain of the HER-2 protein. It shows single agent activity in metastatic disease with response rates of up to 35% depending on the context in which it is used. 3,4 Trastuzumab when added to chemotherapy is superior to chemotherapy alone, improving re...
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