Epidermal Growth factor Receptor Status in Gastric Malignancies

Selva Seetha Raman, S (2007) Epidermal Growth factor Receptor Status in Gastric Malignancies. Masters thesis, Kilpauk Medical College, Chennai.


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INTRODUCTION: Cells are constantly exposed to a variety of external stimuli, ranging from soluble endocrine and paracrine factors to signaling molecules on neighboring cells. Thus, it is extremely important that the cell correctly interprets these extracellular signals to create an appropriate developmental or proliferative response. Beatson's original observation on breast cancer regression after ovariectomy published in 1896 provided the first insight into the hormone dependent nature of the tumours. In the 1950s Ludwig Gross first showed the clear evidence of tumor specific immunogenicity with sarcoma arising after exposure to methylcholanthrene. In 1989 Salmon et al discovered the expression of erb-b2 in breast and ovarian cancer. Since then, the discovery of the various receptors and development of corresponding antagonists has improved the survival rate of many lethal cancers. The identification of parameters that reflect biological behavior of individual cancer tissues correlating with tumor aggressiveness is a key determinant of prognosis and a fundamental issue for the improvement of cancer therapy. Despite recent progress in defining the molecular mechanisms of cancer development and tumor progression, only a few individual biomarkers providing prognostic information and a therapeutic potential have been identified. Among them, the EGFR pathways attracted the most attention of cancer investigators. The epidermal growth factor receptor (EGFR) was the first identified growth factor receptor and is implicated in the widest number of human cancers. In this study we have attempted to identify the mutant EGFR in gastric cancer patients using Immunohistochemistry methods. PURPOSE OF STUDY: Worldwide, Gastric Cancer is the fourth most common cancer and the second leading cause of cancer death. In India, Gastric cancer is the most common cancer and the most common cause of cancer death. Worldwide esophageal cancer ranks fifth in the mortality rate among tumour sites. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000-more than lung, breast, or colorectal cancer. For gastric cancer, the 5-year overall survival rate remains poor, even in comparison with the dismal survival rates from the 1970s. The underlying reasons for this disappointingly low survival rate are multifold: (a) Ineffective screening tools and guidelines. (b) Cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation. (c) High risk for recurrent disease after gastrectomy or definitive chemotherapy. (d) Unreliable noninvasive tools to measure complete response to Chemotherapy; and (e) Limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. The EGFR monoclonal antibodies has already been shown to have promising results in metastatic breast cancer, head and neck cancer and in lung cancer.The results are encouraging from the colorectal and head and neck cancer trials for antibodies against EGFR. Active clinical research in esophageal cancer patients towards antibody inhibition of EGFR is in their phase I trials. This study focuses on the identification of EGFR status in gastric cancers in Indian population. STATISTICAL ANALYSIS: Categorical variables sex, histopathology type, site, mitosis and EGFR were given in frequencies with percentage. Continuous variable (age) given with mean, standard deviation, minimum and maximum age. 'Epi info 6' Software is used in this analysis. Categorical variables associations with positivity were analysed using chi square test. Continuous variable associated with positivity were analysed using students ‘t’ test. Correlation between age and positivity were analysed using Pearson correlation coefficient and graphical representation of the same is given in scattered diagram. The Incidence of positivity was given in proportion with 95% confidence interval. The risk factors associated with positivity were analysed using multivariate logistical regression. SUMMARY AND CONCLUSION: Within only a few years, anticancer therapeutic development against advanced cancers has moved from almost a standstill, with a paucity of new agents showing potential for major effect, to the rapid development of agents targeted against the inherent basis of cancer. This transition is based largely on the exponential rate of information acquisition regarding the cancer cell, particularly in terms of aberrant growth signal transduction and the microenvironment of the cell. In our study, the presence of EGFR in gastric malignancy was 32% ranging from 16%-52% with a confidence interval of 95%. This may form the basis for targeting EGFR in carcinoma of stomach. The mean age of the patients with EGFR positivity is 3 years less than those showing negative for EGFR receptor. Similarly the degree for positivity is also negatively correlated with age. The sex of the patient, the histopathology of the tumor, the degree of differentiation is not related to the EGFR status. However the sample studied is small and the significance of these factors are to be studied in a larger population. The correlation between EGFR positivity and the differentiation of tumors is that the poorly differentiated tumors express the EGFR more commonly than the moderate and well differentiated tumours. Poorly differentiated tumours staining positive for EGFR is almost 50%. Also the intensity of staining is high in poorly differentiated tumours. Although the GI malignancies are a heterogeneous group of malignancies, several common features make them excellent candidates for the investigation of EGFR inhibitors such as aggressive tumors with poor prognoses, common overexpression of EGFR, and limited treatment option availability. Initial studies in a variety of GI malignancies have already shown initial promise and one agent, cetuximab, is already approved for use in refractory colorectal cancer. While further analyses of single-agent EGFR inhibitors and combinations with cytotoxics need to continue, studies that have randomised cohorts will yield definitive results. The EGFR protein is just one target in a network of protein-cell signals. In order to best target this network, we will need to maximize our understanding of the interactions of all the proteins that affect this network. Hence, adequately designed clinical trials are necessary to ensure that the usefulness of Signal transduction inhibitors is correctly evaluated and that potentially useful agents are not rejected solely on the basis of poor performance in an inadequately designed trial with an inappropriate clinical or biologic end point. The full potential of these new agents may only be realized with the implementation of radically different therapeutic development, evaluation, and treatment paradigms. There are literature evidence stating that these receptors may be useful for as screening tool, as a sensitizer, for assessing the invasiveness, metastatic potential and the prognosis of the tumor. However we will be able to draw a firm conclusion from large volume studies on Indian population, with long term patients follow up. Thus identification of the presence of EGFR status in gastric cancers may help to target the tumor cells in addition to the present multimodality management.

Item Type: Thesis (Masters)
Uncontrolled Keywords: Gastric Malignancies ; Epidermal Growth factor Receptor Status.
Subjects: MEDICAL > General Surgery
Depositing User: Devi S
Date Deposited: 05 Jun 2018 17:39
Last Modified: 06 Jun 2018 02:36
URI: http://repository-tnmgrmu.ac.in/id/eprint/8214

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