Targeted therapy for breast cancer with Herceptin
Breast cancer has the highest prevalence compared to other types of malignancies in the UK. Approximately 1 in 8 women will be diagnosed with breast cancer within their lifetime.i. It can be non-invasive (found in ducts of the breast) or invasive (develops in cells that line the breast duct).REFERENCE Breast cancer can spread to other parts of the body via the bloodstream or the axillary lymph nodes, this is known as metastatic breast cancer.REFERENCE?? Breast cancer composes of a group of several important tumour subtypes, each requiring different treatment regimes. Between 20-30% REFERENCE of human breast cancer is caused by the amplification of the HER2 (human epidermal growth factor receptor-2) gene, causing overexpression of the HER2 receptor. REFERENCE. The overexpression of HER2 gene makes up one of the subtypes of breast cancer.ii
HER2 is a member of the epidermal growth factor receptor family of the receptor tyrosine kinases. The intracellular domain of HER2 has tyrosine kinase activity that regulates important aspects of the physiology, growth and differentiation of cells. If the HER2 gene mutates this can lead to development of a malignant tumour. HER2 can go from having about 20,000 receptors on a cell to having 2,000,000. This huge change causes an increase in receptor mediated intracellular signalling, bringing about one of the most aggressive forms of breast cancer. HER2 became clinically relevant with the demonstration that HER2-positive breast cancers have worse prognosis than HER2-negative tumours. After amplification the HER2 phenotype is thought to be fixed for the duration of the invasive tumour and so testing for HER2 can be performed. If the patient comes back HER2-positive, they will be offered a monoclonal antibody called trastuzumab, trademarked as Herceptin. An advantage of Herceptin is that it is specific to the HER2 receptor, thus only works on patients who are HER2-positive. Herceptin has an extended half-life allowing for constant exposure to the tumour cell. Herceptin has the ability to bind to both the intracellular and extracellular receptors. The main disadvantage of Herceptin is its side effect profile, primarily affecting the cardiovascular system.
Mechanism of action
Although the mechanism of action is not fully understood there are a number of accepted theories which include an immune-mediated response, direct effects on the HER2 receptor and effects on other enzyme pathways.
Herceptin binds to the HER2-overexpressing cells causing many phenotypic changes. These changes consist of the downmodulation of the HER2 receptor, inhibition of tumour cell growth, reversed cytokine resistance, restored E-cadherin expression levels and reduced vascular endothelial growth factor production. In clinical trials it has demonstrated that Herceptin has not only cytostatic but also cytotoxic properties. This is due to the activation of antibody-dependent cellular cytotoxicity (ADCC). The Fc domain of Herceptin binds to natural killer cells which express the Fc gamma receptor. As a result, the body’s immune system helps destroy the tumour cells.
When HER2 is overexpressed, it undergoes proteolytic cleavage which results in the release of the extracellular domain. Herceptin can block this shedding by inhibiting metalloproteinase activity.
PI3K is activated by survival factors. Once activated it can lead to the activation of AKT which is associated with many malignancies. It has been suggested that Herceptin reduces the signalling from the PI3K pathway, stimulating apoptosis and the inhibition of proliferation (1). Nagata et al (2004) demonstrated how Herceptin can block PI3K signalling by reducing PTEN tyrosine phosphorylation and by increasing PTEN membrane localisation and phosphatase activity. This leads to rapid AKT dephosphorylation ad inhibition of cell proliferation
Side effects
Herceptin prolongs survival in metastatic breast cancer patients. Compared with chemotherapy alone patients receiving both have a significantly longer time to progression, a higher response rate and a longer duration of response. However, with most drugs it does not come without side effects. As Herceptin only targets cells with HER2 receptors it does not cause some of the side effects chemotherapy does for example loss of hair. The most common adverse reactions in patients receiving Herceptin are: fever, nausea, vomiting, infusion reactions, diarrhoea, headache, fatigue, rash and neutropenia. There have been about 2-3% of cases which have led to cardiac dysfunction. This is due to Herceptin downregulating NRG-1 which is essential for the activation of cell survival pathways in cardiomyocytes and maintenance of cardiac function. Therefore, screening of the heart must be done before the drug is administered as approximately 10% of people are unable to tolerate the drug because of pre-existing heart problems. There is also an increased risk of cardiomyopathy when Herceptin is taken with anthracycline chemotherapy. Although this side-effect is rare, monitoring should continue whilst the patient is still taking the drug. Furthermore, there is evidence that Herceptin can cause foetal abnormalities. This means that whilst taking the drug women should use effective contraception to ensure they do not become pregnant.
Clinical process
For Herceptin to be given it is mandatory that the patient is HER2 tested. HER2 levels are scored using validated immunohistochemical techniques and in accordance with published guidelines. Patients with tumours expressing the HER2 scored at level of 3+ are recommended to use Herceptin. The drug can be given to a patient in two ways: by infusion or by subcutaneous injection under the skin of the thigh. If given by infusion, the first round is given for 90 minutes and then reduced to 30 minutes after that if the dose is well tolerated. If being given to a patient with early-stage cancer, the drug is usually administered for one year, but if being given to a patient with metastatic cancer then the drug is continuously given for as long as it helps the patient. The number of times the drug is given depends on the tolerance and severity of the breast cancer. With both metastatic and early-stage breast cancer the recommended dose is 6mg/kg body weight using a three-weekly schedule. Alternatively, if using a once-weekly schedule then the recommended dose is 2mg/kg body weight.
Cost-effectiveness of Herceptin
The average period of survival after diagnosis of metastatic breast cancer is 18-24 months, but this is reduced up to 50% for patients overexpressing HER2. In less than 15years of usage Herceptin has transformed HER2-positive breast cancer from the hardest to cure type of the disease to one of the most responsive to treatment.
In advanced metastatic breast cancer, using Herceptin and paclitaxel together, it is estimated that the gross impact of providing both drugs instead of paclitaxel alone is approximately £17 million per annum. This includes the cost of testing, treatment and cardiac tests.
Net price per 150mg vial is £407.40, assuming an average patient weight of 67kg. A period of 15 months of using Herceptin cost approximately £24,852