Chinese People Met In Gastric Cancer Samples, Its Ehrs - 2, The Expression Of Egfr And Igf1r Protein And Activate The Adjustment Research

Background:Although the incidence of gastric cancer has been declining in recent ten years, it remains one of the most frequent causes of cancer death. Early diagnosis significantly prolong the survival time by providing more chance of radically resection. However, the recurrence rate of gastric cancer is high and the prognosis of advanced disease is very poor. Past years has witnessed the development of targeted agents, and the application of targeted therapy in gastric cancer is attracting more and more attention.MET, HER-2, EGFR and IGF1R encoded by oncogenes are all cell membrane receptors. Via binding to specific molecular ligands, these receptors activate the down-stream signal pathways mediated by the receptor tyrosine kinases (RTKs). These receptors have become important targets for cancer therapy baseed the fact that the overexpression or activation of these proteins could change the biological behavior of cancer cells. Previous studies have indicated that they can interact with other receptors and there are some cross-talks within their different downstream pathways. Moreover, poor prognosis of patients with gastric cancer makes it an urgent need to find some prognostic or predictive factors in order to maximize the therapeutic effect and minimize the adverse effects in the treatment of these patients. Some studies have evaluated the prognostic value of these receptors, but the conclusions are still uncertain.This thesis presents a retrospective study which assesses the prognostic relevance of these receptors and determines the expression frequency of MET, HER-2, EGFR and IGF1R by immunohistochemistry assays. Moreover, the relations of the expression of these receptors to clinicopathologic characteristics and the mutual expression relations within these receptors were also examined.Part I. The expression and activation of MET, HER-2, EGFR and IGF1R of Chinese gastric cancer patientsObjectiveTo determine the expression and activation frequency of MET, HER-2, EGFR and IGF1R of Chinese gastric cancer patients; and identify the relationships between each molecular’s expression and their linkage with the clinicopathologic characteristics.Methods:The study group comprised155patients who underwent gastrectomy at Fudan University Shanghai Cancer Center from September2007to Feburary2010. By applying immunohistochemistry techniques, we analyzed the expressions of MET, HER-2, EGFR, IGF1R and p-MET, p-HER-2, p-EGFR,p-IGF1R via tissue micro array(TMA) of surgically removed primary tumors. Samples were prepared into formalin-fixed paraffin-embedded specimens.Results:Among a total of135evaluable cases, MET expression (IHC score2&3) was found in25tumors (18.5%), p-MET expression in13tumors (9.6%), HER2expression in13(9.6%), p-HER2in10tumors (7.4%), EGFR expression in36tumors (26.7%), p-EGFR in6tumors (4.4%), IGF1R in56tumors (40.3%) and p-IGF1R in26tumors (19.3%). MET expression correlated with histological grade (P=0.047), Lauren type (P=0.049) and lymph node metastases (P=0.037); HER-2expression with tumor site (P=0.032) and histological grade (P=0.001); p-HER2expression with lymph node metastases (P=0.029); EGFR expression with age (P=0.022) and pathological stage (P=0.015); IGF1R expression with sex (P=0.030), Lauren type (P=0.005), nerve invasion (P=0.008) and lymph node metastases (P=0.035); p-IGF1R expression with nerve invasion (P=0.041).There is a strong correlation between MET and HER-2with a co-expression rate of5.9%(8/135), EGFR and IGF1R with a coexpression rate of17.8%(24/135), MET and IGF1R with a coexpression rate of11.9%(16/135), MET and EGFR with a coexpression rate of9.6%(13/135), HER-2and IGF1R expression with a co-expression rate of6.7%(9/135). There is no correlation between the expression of EGFR and HER-2, with the lowest co-expression rate of4.4%(6/135).Conclusions:MET、HER2、EGFR and IGF1R have their own expression types. There are strong correlations, except for HER-2and EGFR, within the expression of each other, among which the strongest correlations are between MET and HER-2, as well as EGFR and IGF1R. This clinical evidence is a foundation for the application of multi-target regimen in biological cancer therapy.Part II. The impact of MET, HER-2, EGFR and IFG1R expressions and activation on clinical outcomes of Chinese patients who underwent radical resection of gastric cancerObjectiveBecause it has been seen that the prognosis varied among the patients with the same stage, there was a need to find new prognostic factors. The aim of this study was to evaluate the clinical implication of MET、HER、EGFR and IGF1R expressions and activation on the prognostics of gastric cancer patients.Methods:A total of141patients who received curative gastrectomy for gastric cancer at Fudan University Shanghai Cancer Center were retrospectively analyzed during the follow-ups with a median time of35.1months. The3-year disease free survival (DFS) rate and overall survival rate were summarized. The expression and activation frequencies of MET, HER-2, EGFR, IGF1R and p-MET, p-HER2, p-EGFR, p-IGF1R among this population was derived from the first part of this project. Univariate and multi-variate analysis was applied in evaluation of impact on patients’survival.Results:In the whole population analysis, the3-year DFS rate was61.0%(86/141) and the3-year OS rate was68.1%(96/141). After the IHC staining on the tissue micro array (TMA),126cases were evaluable. Multivariate survival analysis showed that the positive expression of p-MET [hazard ratio (HR)2.47,95%confidence interval (95%CI)1.04-5.87; P=0.04] and lymph node metastases [HR2.71,95%CI1.34-5.48; P=0.005] are significant predictors of poor DFS. Lymph node metastases [HR2.35,95%CI1.075-5.133; P=0.032] was independent prognostic factors of overall survival. The co-expression rate of MET and HER2was5.6%(7/126) and its positivity significantly correlated with patients survival. In sub-group analysis according to the pathological stage, there were significant differences of3-year DFS rate (P=0.011and P<0.001, seperately) and3-year OS rate (P=0.002and P<0.001, seperately) according to whether p-MET and HER-2expression or not in Stage I-II. The positive MET expression in Stage Ⅲ patients was significantly correlated with DFS (P=0.025).Conclusions:The p-MET expression and lymph node metastases were significant predictors of poor DFS. Moreover, lymph node metastases is the independent prognostic factor of OS. It indicated that the activating status of MET is a valuable sign for short-term survival prediction. The anti-MET strategy may be proven correct for such patients. Furthermore, the poor prognosis of patients with co-expression of MET and HER-2suggested that there is a potential for the combined application of more than one targeted agents, which may greatly improve the clinical outcomes of these patients.