The discrepancies

among results can be due to factors such as, patient definition, diagnostic methods, and classification of HER2+. It has been suggested that poorer survival in HER2-positive patients with squamous cell carcinoma could be due to increased resistance to radiation therapy (55) and cisplatinum-based chemotherapy (56). Moreover, the addition of Inhibitors,research,lifescience,medical trastuzumab in head and neck squamous cell carcinoma cell lines seemed to enhance the effect of irradiation (57). The statistically significant heterogeneity and publication bias amongst the included studies may be due to several factors. There is a slight variation in the patient eligibility for each study. These differences in patient definition can lead to potential bias and could drive the analysis in one direction. Excluding studies that appear to be outliers may have potentially Inhibitors,research,lifescience,medical reduced heterogeneity. Due to the limited number of studies available in this area, excluding these studies will reduce sample size and consequently increase heterogeneity

once again. Similarly, the classification system used between each study for HER2+ varies. Studies such as Hu et al. (30), Reichelt et al. (31), Wei et al. (43) and Sato-Kuwabara et al. (40) have classified HER2+ as IHC ≥2 while Mimura et al. (37) have drawn the line at IHC ≥1, and Langer et al. (35) have classified HER2+ as IHC 3+. Similarly Inhibitors,research,lifescience,medical with FISH, Langer et al. (35), Inhibitors,research,lifescience,medical Mimura et al. (37), Thompson et al. (29) and Hu et al. (30) have classified HER2+ as FISH 2+, while Sato-Kuwabara et al. (40) have classified HER2+ as FISH 3+. A standardized classification system is required in order to determine the full potential of HER2+ in EC. Misclassification of IHC results will consequently affect results of FISH. There was a variation in event rate between the diagnostic methods. The ER Inhibitors,research,lifescience,medical of HER2+ was high through IHC, in comparison to the ER of HER2+ through FISH (for both BE & EC). Ahmed et al. (58) has stated that in the

case of breast cancer results of IHC and FISH BAY 872243 require a minimum of 95% concordance, which we have not seen in the current study. Barrett et al. (59) has Megestrol Acetate highlighted that IHC 2+ weak positive are often not accompanied by a FISH positive or represent gene amplification in breast cancer tissues. The HercepTest™ is considered valid for the identification of HER2+ in the case of gastric cancer (60), no classification system has been implemented for EC. The accuracy of the IHC HER2+ results is vital in determining the FISH status. The validity of the results can also be questioned by the diagnostic method each study has used. Studies such as Reichelt et al. (31) provided strong clinical and experimental data and by collaborating these data they have provided survival outcomes of patients, which was vital in the survival analysis. This study also had strong FISH and IHC concordance.