Despite a worldwide decline in its incidence, GC remains one of the most common malignancies in China, where GC incidence (29.9 new diagnoses per 100,000 people) remains high17. Currently, according to epidemiological research worldwide GC predominantly affects elderly males17,18. In the present study, 64.8% (114/176) of the patients were 60 years old or older. The Lauren classification, tumor location, HER2 protein expression status, tumor differentiation and size are essential clinicopathological features which have been reported in the research of GC. In our study, HER2 protein and P53 expression status were two important clinicopathological characteristics that were investigated to show the association between the expression of these genes with other GC-related factors.
In the current study, we found an overall HER2 protein positive rate of 23.9% for the GC patients. Such finding is similar to those of various other studies from American and European researchers who have reported gastric cancer HER2 protein positive rates ranging from 10 to 22.8%4,5. However, some Asian studies have reported rates ranging from 11.7 to 15.74%14,19,20. The importance of the HER2 protein status in GC remains controversial and more and more researchers are studying the significance of HER2 protein expression in GC. In general, Lauren classification can be divided into the intestinal subtype, diffuse subtype and mixed subtype. In this study, there was a significant relationship between HER2 protein expression and the intestinal subtype of GC. Specifically, the intestinal subtype patients were more likely to be HER2 protein positive than the other two subtypes. Our results are also similar to those of most of the reported studies, which revealed that the intestinal histological subtype was predominant in HER2 protein positive patients12,13,15,21. In addition, HER2 protein expression was found to be associated with differentiated histology. High rates of HER2 protein positive GCs were detected among well-differentiated and moderately-differentiated GCs when compared with the poorly differentiated GCs. This result is similar to that reported by Oh et al. indicating that HER2 protein overexpression was associated with intestinal subtype and well-differentiated and moderately-differentiated GC tumors22. In addition, the positive rate of HER2 protein is 31.3% higher in gastric cancer patients with negative vascular invasion (25/80) and the result has obvious statistical significance (p=0.036). Some studies have reported findings similar to those of this study regarding the anatomical location of the tumor, indicating that there is no difference between distal and proximal GC tumors2,11,23. The efficacy of trastuzumab in breast cancer therapy has led to emerging interest in its therapeutic effect in patients with HER2 protein positive GC. The ToGA trial, a randomized, controlled, multicenter, phase III study, was designed to evaluate the efficacy of trastuzumab (an anti-HER2 protein drug) in association with chemotherapy for the therapy of advanced gastric carcinoma9. The expression rate of HER2 protein in the ToGA study was 22.1%, which is similar to our findings. Additionally, also similar to our study, the ERBB2 expression was an advantage in the intestinal GC type compared with the other two types. However, the ToGA study revealed that HER2 protein expression was correlated with the location of the tumor, indicating that the tumor was prevalent in the proximal of stomach. The finding of no significant correlation between HER2 protein expression and the location of the tumors in our study could be explained by the small number of enrolled patients in our research.
In China, a study conducted by Qiu et al. in 2014, analyzed the immunohistochemical expression in 838 GC cases and found prevalent HER2 protein expression in 11.2%15. They found predominant HER2 protein expression in intestinal GC type, and they detected a significant association between the expression of HER2 protein and the proximal GC. The frequency of HER2 protein expression was much lower than that in our study. The apparent discrepancies between the various other studies and our study can be reconciled if we consider the immunohistochemical method used and the differences among the enrolled patients. A second study conducted at Sun Yat-sen University by Liu et al. in 2016 found HER2 protein expression in 40.3% of 678 patients analyzed24. Such a high rate of HER2 protein expression may be due to the enrolled patients, which only included stage I-III GC patients, while our study included patients with I-IV grade of GC according to the eighth edition of the American Joint Committee on Cancer TNM staging system. In addition, both studies concluded that HER2 protein expression was significantly correlated with tumor histological classification and HER2 protein was preferentially expressed in the intestinal subtype of GC tumor. Moreover, the GC intestinal subtype was seen more in well differentiated carcinoma and lower stage of tumors. Accordingly, it is not difficult to explain why the study by Liu et al. found higher HER2 protein expression compared to our current study. A review of the previous research reveals that the Lauren classification was considered as one of the most important predictive factors of prognosis in GC25. Also, the intestinal subtype and well differentiated tumor cells had a consequential relationship with a better prognosis25,26.
HER2 protein expression was regarded as the most crucial advancement in gastric carcinoma over the coming years at the American Society of Clinical Oncology (ASCO) annual meeting in 2014. In the current study, we compared our results to GC clinicopathological characteristics. The expression rate of P53 by IHC analysis was 72.2% (127/176). Additionally, the HER2 protein expression status was significantly correlated with the P53 expression (p<0.001). Also, according to previous studies, there is a correlation between HER2 protein expression status and P53 nuclear staining, but further research on the relationship is warranted27. Moreover, P53 expression also significantly correlated with some clinicopathological features: HER2 protein expression (p=0.04), younger patients below 60 years old (p=0.03), tumors lager than 5 cm in size (p=0.01), and Ki67 (p=0.0001)16. Furthermore, in the current study, the overexpression of P53 was considered to be an independent prognostic factor28. Younger patients with larger tumor and high proliferation index, as measured by the level of Ki67 expression, indicate a more aggressive biological behavior of tumor cells and have worse prognosis29,30. However, Moundhri et al. reported that there was no relationship between P53 with sex, tumor location, Lauren classification, T-stage and lymph node metastasis16. Similarly, we found that there was an obvious significant difference between the HER2 protein expression and P53 expression (p<0.001). However, in our current study we did not find significant correlation between P53 and age, sex, tumor size, Ki67 and some additional clinicopathological factors.
Our study has several inherent limitations. (1). It is a retrospective study rather than a prospectively designed study and the data is limited. (2). Our research was a single-center investigation and the selection bias was inevitable, while the benefit of single-center is that we could ensure the accuracy and consistency of the research methods and data. (3). Since the follow-up time of the enrolled patients was too short and the high rate of missed interview, we could not perform a correlation analysis of the prognosis and obtain an accurate correlation between prognosis and clinicopathological factors. (4). The potential mechanism of HER2 protein overexpression as well as that of P53 overexpression in intestinal type GC require further experimental study.