Study of Herceptin on breast cancer

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All women diagnosed with breast cancer should receive Herceptin

During the twenty first century breast cancer has become one of the leading causes of death amongst women in the United Kingdom. More than forty-five thousand women were diagnosed in two-thousand and seven (Office for National Statistics, 2010) with breast cancer and fifty percent of those with early stage cancer will progress to advanced disease (Lewis et al. 2002). Many factors affect the prognosis of advanced breast cancer including age, extent of disease, oestrogen receptor status, and previous chemotherapy treatment (Lewis et al. 2002). However, studies have found that the human epidermal growth factor receptor 2 gene (HER 2) acts as an important prognostic factor since it is over expressed in a proportion of patients with breast cancer, leading to a more aggressive disease with rapid progression and shortened survival time (Goldenburg & Marvin, 1999). The characteristics of HER 2 prove it to be an important target for breast cancer treatment, for example the levels of HER 2 correlate with the level of carcinogenesis, there is less sensitivity to the toxicity of anti-HER2 therapy since there is a higher level of expression found in cancerous cells than in normal cells, and HER 2-targetting drugs may be effective at various disease stages since the over expression of HER 2 has been found in primary and metastatic tumours (Valabrega et al. 2007). From such investigations innovative anti-cancer drugs targeting the HER2 receptor have been developed, the first being Trastuzumab (Herceptin®), in an attempt to treat and improve the quality of life of breast cancer patients. However, clinical trials and further research have revealed certain concerns about the use of Trastuzumab in patients and have consequently resulted in massive deliberation amongst physicians in order provide the greatest benefit to patients.

Trastuzumab is a humanised monoclonal antibody of the immunoglobulin type G1 derived from recombinant DNA which is designed to target, with high specificity, the extracellular domain of the human epidermal growth factor receptor 2 protein (HER 2) that is over expressed in around thirty percent of breast carcinomas (Goldenburg & Marvin, 1999). Antibodies are specific proteins that are produced by B cells within the host's immune system, on response to an antigen, in order to rid of the infection and protect the host. By being humanised Trastuzumab is made up of a hybrid or chimerae of human antibodies but possesses specific murine antigen determining regions (Goldenburg & Marvin, 1999), which provides the specificity to the HER 2 receptor and is less immunogenic to the host (see figure 1).

The HER 2 receptor is a transmembrane tyrosine kinase receptor and is distinctive of the epidermal growth factor receptor family by the absence of a known ligand (Valabrega et al. 2007). The HER 2 receptor itself is encoded by the HER2 (or neu) gene found on chromosome 17 (Burnstein, 2005). It functions by regulating important properties of the cell, including cell growth and differentiation (Burnstein, 2005). The excessive amplification of the HER2 gene causes an over expression of HER2 receptors on the extracellular surface. This results in abnormal signals being produced by the cell and gives rise to the characteristics of breast cancer. Trastuzumab functions by binding to the IV domain on the HER2 receptor and inducing effects on the tumour (see fig.2). Primarily the anti-cancer drug inhibits the receptor signalling cascade (Oakman et al. 2010) of the cancerous cell that is induced by the other members of the EGFR family interacting with their receptors, forming heterodimers or homodimers, (Valabrega et al. 2007) essentially down regulating the amount of HER2 expression. The binding also negatively regulates the P13K pathway in order to mediate transcription factors, through phosphorylation, to trigger apoptosis within the cell and inactivating protein synthesis which contributes to Trastuzumab triggering cell arrest in the G1 phase (Valabrega et al. 2007).

Figure 2. The effects of Trastuzumab binding to the HER2 receptor expressed on breast cancer cells. (Braunstein, 2005).

Trastuzumab has also been found to inhibit metalloproteinase in order to block the shedding of the extracellular domain of HER 2 shedding. In addition, the production of angiogenic vascular endothelial growth factor (VEGF) by the tumour cells (usually in response to hypoxia) is suppressed (Burnstein, 2005) reducing the blood supply, and therefore oxygen concentration, available to the tumour cell thusly limiting its size. Furthermore, the binding of the drug to the receptor activates humoral responses of the host's immune system. Mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells help the immune system identify the tumour and eliminate it from the host. It has also shown to decrease the tumours resistance to both chemotherapy and endocrine therapy (Taylor, 2006). Trastuzumab therefore has a beneficial effect on breast cancer through intracellular and extracellular mechanisms to ultimately reduce the size and aggressiveness of the tumour.

Since Trastuzumab targets the HER 2 receptors expressed on the outside of cancerous cell, it is only beneficial to those patients who are diagnosed with HER 2 positive cancer. Therefore all patients with breast cancer will be tested for the over expression of HER 2 using the immunohistochemical (IHC) analysis as recommended by the UK HER2 guidelines (Ellis et al., 2000). The semi-quantitative results range from no expression (0+) to high expression (3+). If the results of the test are borderline (HER2 2+) then a technique known as fluorescent in-situ hybridisation (FISH), which measures the amplification of genes, will be performed to confirm the diagnosis (Ellis et al., 2000) and allow the patient to receive Trastuzumab treatment. FISH has also been proven through clinical trials to give a more accurate prediction to patients' responses to Trastuzumab than other forms of diagnostic test, like IHC (Valabrega et al. 2007). The trial showed that patients who expressed HER 2 in the absence of gene amplification were much less likely to respond to Trastuzumab and therefore aided physicians in providing the most beneficial form of treatment.

The treatments available for metastatic HER2 breast cancer after surgery are not curative but aim to improve the patient's symptoms and quality of life. The treatments available include combination therapy, in which Trastuzumab is used with chemotherapy (cyclophosphamide plus anthracylcine or paclitaxel), chemotherapy alone and monotherapy of Trastuzumab (Ellis et al., 2000). Several randomised clinical trials have been set up to measure the effectiveness of each form of metastatic treatment in order to provide the best treatment for patients whilst identifying and minimising potential risks.

There are only non-comparative studies available for the use of Trastuzumab as monotherapy treatment and therefore is not conclusive. However, use as a single agent in phase II and III randomised trials showed an overall response rate ranging from fifteen to thirty percent (Valabrega et al. 2007). However, the studies did show that the addition of Trastuzumab monotherapy as second-line treatment for patients with MBC overexpressing HER2 at 3+ did have some anti-tumour effects (Slamon et al. 2001).

In phase II and phase III trials Trastuzumab used as combination therapy with chemotherapy proved to be significantly more effective than chemotherapy alone with an improved response rate ranging from fifty to eighty percent (Valabrega et al. 2007). The trial showed an increase in the duration of progression-free survival of seven point eight months compared to four point six with chemotherapy alone (Slamon et al. 2001). There was also a greater overall tumour response with fifty percent versus thirty two perecent (Slamon et al. 2001). The trials showed additionally that Trastuzumab reduced the disease progression and treatment failure rate. However, the occurrence of congestive heart failure due to cardiac dysfunction was high amongst those receiving combination therapy compared to those on chemotherapy alone, the highest being Trastuzumab with anthrocycline-based chemotherapy (Valabrega et al. 2007). Around twenty-five percent of patients on the clinical trials presented with chills, fever or both within the initial infusions of Trastuzumab and within forty-seven percent of patients they acquired a mild-moderate infection, typically of the upper respiratory tract or catheter. There was an increase in the incidence of leukopenia and anaemia but these were only mild cases and sepsis was low amongst the patients (Slamon et al. 2001).

The success of the metastatic breast cancer randomised trials led onto investigations of the drugs efficaciousness in early stage HER 2-positive breast cancer patients. The results of the trials presented that when Trastuzumab is used in combination with chemotherapy in early stage cancer the possibility of relapse is halved and prolongs survival and so a treatment of one year of Trastuzumab is recommended (Slamon et al. 2005).

To conclude, the discovery of the relationship between the overexpression of HER 2 receptors and the carcinogenesis of breast cancer was a revolutionary breakthrough in treating metastatic and, more recently, early stage cancer. Trastuzumab was developed to target the HER 2 receptor to essentially inhibit the tumours growth and the characteristics it promotes. However, not all patients with breast cancer can be treated with Trastuzumab due to its specificity to the HER 2 receptors that are only expressed in around thirty percent of patients (ref). Therefore certain diagnostic tests, like IHC analysis and the FISH analysis, are performed on samples in order to predict if Trastuzumab will have a response on the tumour. Although the theory of Trastuzumab comes across as a success as a stable form of treatment for HER2-postive breast cancer, underneath there are some serious concerns. The randomised clinical trials found Trastuzumab to have a significant increase in the incidences of heart failure indicating a serious risk to patients. Additionally, it has been found to cause some mild to moderate infections and other adverse symptoms. The evidence shows that Trastuzumab has indeed been proven to be effective in prolonging the life of breast cancer patients and improving regression but the question lies as to what extent and if it will be beneficial to the patient in the long run. Therefore physicians must weigh up the advantages and disadvantages of prescribing the drug and use the information available to them regarding the patient in order to provide the best treatment. Personally, I believe that even though Trastuzumab has not been a complete success it provides a combined effective treatment for HER 2 positive breast cancer and has laid the fundamental foundations towards developing a more effective and less harmful drug in the future.

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