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Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 28-35

Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis

1 Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
2 Department of Colorectal Surgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
3 Department of Pathology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
4 Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Lifang Fan
Department of Pathology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang, Wuhan 430071, Hubei
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.206864

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 > Abstract 

Background: Tyrosine kinase growth factor receptors (TKGFRs) play an important role in the progression of cancer. A variety of studies have investigated the clinicopathologic correlation of these receptors and their influences on patient survival in different types of cancer. As the members of TKGFRs, the biomarkers c-MET, epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2) have been extensively investigated in biliary tract cancer (BTC). However, their prognostic value is still controversial. Our study aimed to evaluate the prognostic significance of the three markers in BTC patients based on the published studies. The correlation between high expression of these markers and clinical parameters or overall survival (OS) has been assumed in this paper.
Materials and Methods: Including PubMed, EMBASE, China National Knowledge Infrastructure, and Springer, a comprehensive search for the related literature published in Chinese and English has been done. Finally, 31 studies were selected in our research.
Results: Surprisingly, the meta-analysis indicated that HER-2 high expression was not correlated with age, gender, primary tumor, tumor node metastasis (TNM) stage, lymph node status, and differentiation. We also found that EGFR high expression was not associated with the parameters, such as age, gender, TNM stage, differentiation, or lymph node status. c-MET high-expression was not associated with age, differentiation, gender, TNM stage, or lymph node status. In addition, our study showed that HER-2, EGFR, and c-MET high expression had an adverse influence on OS in BTC, the pooled hazard ratio for HER-2, EGFR, and c-MET was statistically significant.
Conclusion: The present meta-analysis indicated that EGFR and HER-2 high expression have little impact on OS in patients with BTC while c-MET high expression influenced OS in patients with BTC to a large extent. However, c-MET, EGFR, and HER-2 expression did not show any correlation with those clinical parameters. c-MET may be a potential therapeutic target for BTC.

Keywords: Biliary tract cancer, c-MET, epidermal growth factor receptor, human epidermal growth factor receptor 2, meta-analysis

How to cite this article:
Zhou W, Jiang C, Zhan N, Lv X, Fan L, Ninu M. Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis. J Can Res Ther 2018;14, Suppl S1:28-35

How to cite this URL:
Zhou W, Jiang C, Zhan N, Lv X, Fan L, Ninu M. Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2021 Nov 30];14:28-35. Available from: https://www.cancerjournal.net/text.asp?2018/14/8/28/206864

 > Introduction Top

Biliary tract cancer (BTC) is one of the most common cancers among people, including cholangiocarcinoma, carcinoma of gallbladder, and ampulla cancer. The common sites of bile duct cancer were hilar bile duct, ductuli, and hepatic cuscommunis. Recently, the morbidity of BTC is approximately 1–10/10,000,[1],[2],[3] presenting a rising trend. Patients with BTC have a poor prognosis. Many factors have been identified, such as tumor node metastasis (TNM) stage, the depth of tumor invasion, status of lymph nodes, and distant metastasis, perineural status, differentiation. However, distinguishing outcomes are commonly observed among patients with the same stage. Therefore, it is vital to understand the significance of expression of the three markers, human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor (EGFR), and c-MET.

HER-2, EGFR, and c-MET are tyrosine growth factor family members. HER-2 is a 185-kDa transmembrane glycoprotein, encoded by proto-oncogene c-ErbB-2.[4] Both HER-2 and EGFR belong to ErbB family and can be activated by hepatocyte growth factor (HGF) and EGF. The three markers share approximately 5% overall homology and are composed of an N-terminus extracellular, a transmembrane lipophilic segment, and a C-terminus intracellular region containing a tyrosine kinase domain.[5] In c-MET, the N-terminus extracellular contains an alpha helix and a beta sheet, a transmembrane domain, and an intracellular tyrosine kinase.[6]

The previous studies reported that biomarkers with tyrosine kinase domain, such as HER-2, EGFR, and c-MET, are associated with poor prognosis in diverse types of cancer, such as gastric cancer,[7],[8] breast cancer,[9] and lung cancer.[10] Although similar results have been found in patients with BTC, some studies show that the three biomarkers did not affect prognosis in BTC. New chemotherapeutic agents, such as trastuzumab, cetuximab, and gefitinib, targeting tyrosine kinase growth factor receptors (TKGFRs) have not been widely applied in BTC. There seems to be no consensus on the prognostic significance of HER-2, EGFR, and c-MET. Therefore, in this study, we performed a systematic review to analyze the prognostic significance of the three markers expression in patients with BTC.

 > Materials And Methods Top

Publication and literature search

The following terms and their combinations were used as keywords in literature search: c-MET, EGFR, HER-2, cholangiocarcinoma, gallbladder, ampulla, biliary, ErbB2, carcinoma, cancer. A comprehensive search was operated in PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Springer with the criteria as listed below. The deadline of search is August 1, 2016.

Inclusion criteria

The inclusion criteria for the selection of literature in this study were as follows:

  1. An original dependent study of the correlation between the three markers and the prognosis of patients with BTC
  2. HER-2, EGFR, and c-MET were examined using immunohistochemistry (IHC)
  3. Subjects in every study comprised patients with high-expression and low-expression controls
  4. When multiple studies used the same study subject and had similar study content, the study with the most comprehensive date was selected
  5. Relevant information was extracted from the full text
  6. Literature must provide the original data of HER-2, EGFR, and c-MET expression, clinicopathological parameters, or overall survival (OS) rate; or be able to obtain the above information by calculation
  7. The language of the publications was English or Chinese.

Exclusion criteria

  1. Reviews, abstracts and conference papers, letters to the editors
  2. Literature before the year of 2000
  3. Studies with insufficient information or were of poor quality.

Data extraction

Data were independently extracted by two investigators from the full-length articles. General information extracted from these articles includes author, publication year, number of patients, cutoff value, detection method, the number of total patients, the number of high expression, hazard ratio (HR), and 95% confidence interval (CI) of OS. The quality of the eligible studies was individually assessed based on the Newcastle–Ottawa scale. Studies obtaining 7–9 stars were considered to be of “high quality,” 5–6 stars as “moderate quality,” and five stars below as “low quality.” The studies of low quality were excluded.

Statistical analysis

For clinical parameters, the odds ratio and 95% CI were used to present the statistical values derived from the efficacy analysis for dichotomous variables. We calculated HRs with their 95% CI, which takes into consideration the number and timing of events. To evaluate the relationships between HER-2, EGFR, c-MET, and OS, the significance of the pooled HR was determined by Z-test, and P < 0.05 was considered statistically significant. I2 was calculated to assess the impact of heterogeneity on results. When I2 was >50%, heterogeneity was considered significant; the random-effects model was used. Publication bias was investigated through a funnel plot by the Begg's tests, and P < 1.0 was regarded as statistically significant of publication bias. The Kaplan–Meier curves were read by Engauge Digitizer (Version 2.11; http://sourceforge.net). All the statistical analyses were performed by Stata software (Version 12.0; StataCorp LP, College Station, Texas, USA).

 > Results Top

Characterization of eligible studies

The characteristics of 465 studies were reviewed from the four databases, PubMed, EMBASE, CNKI, and Springer. The process of retrieved eliminating was mentioned in the methods [Figure 1]. Finally, 32 literature were eligible in our study. Twenty-seven literature provided complete original date about clinicopathological parameters. Fourteen literature assessed the prognostic value of HER-2, EGFR, or c-MET expression for OS in BTC patients by the Kaplan–Meier method. We obtained relevant data by directly extracting original data or by indirectly calculating from these studies.
Figure 1: Flowchart of the meta-analysis

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The main characteristics of the 32 eligible studies for aggregation are shown in [Table 1]. A total of 2885 BTC patients were included in this meta-analysis. In all the 32 studies, the expression of HER-2, c-MET, and EGFR was confirmed by IHC.
Table 1: Characteristics of the included studies

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Correlation of human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET high expression and overall survival

Based on the previous report, a combined HR >1 indicated a worse OS but HR >2 is considered strongly predictive.[43] In our study, HER-2, EGFR, and c-MET high expression were statistically significant with the OS in BTC patients, the pooled HRs value were 1.65 (95% CI, 1.11–2.45) [Figure 2], 1.59 (95% CI, 1.14–2.21) [Figure 3], and 2.24 (95% CI, 1.45–3.45) [Figure 4], they were negatively related to BTC patients survival. Subgroup analyses were performed after stratifying the data by region. In the Asian subgroup, HER-2 high expression had a mild negative effect on OS with the pooled HR of 1.62 (95% CI, 0.92–2.85); EGFR high expression also slightly but adversely affected OS in BTC patients, with the pooled HR of 1.31 (95% CI, 0.94-1.82); however, the Z-test revealed no statistical significance either in HER-2 or in EGFR. In the non-Asian subgroup, the pooled HR for HER-2 and EGFR was 1.88 (95% CI, 1.21–2.92) and 2.99 (95% CI: 1.73–5.16), respectively, suggesting that HER-2 and EGFR high expression were negatively related to BTC patient survival. Considering that all the c-MET studies enrolled were from Japan and China, two Asia countries, we did not divide data according to the region, but the overall HR indicated that c-MET was a reliable predictor for poor OS in patients with BTC.
Figure 2: Meta-analysis for the association between human epidermal growth factor receptor 2 overexpression and biliary tract cancer survival and subgroup analysis of the Asian and non-Asian

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Figure 3: Meta-analysis for the association between epidermal growth factor receptor overexpression and biliary tract cancer survival and subgroup analysis of the Japan and China

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Figure 4: Meta-analysis for the association between c-MET overexpression and biliary tract cancer survival and subgroup analysis of the Asian and non-Asian

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Correlation of human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET expression and clinicopathological parameters in biliary tract cancer patients

Our result showed that HER-2 high expression did not correlate with age (P = 0.791), gender (P = 0.741), primary tumor (P = 0.940), TNM stage (P = 0.381), lymph node status (P = 0.487), and differentiation (P = 0.277). EGFR high expression was not associated with these elements, including age (P = 0.586), gender (P = 0.52), TNM stage (P = 0.224), differentiation (P = 0.167), and lymph node status (P = 0.723). c-MET high expression showed no association with age (P = 0.261), gender (P = 0.727), differentiation (P = 0.371), TNM stage (P = 0.286), lymph node status (P = 0.739), and perineural invasive status (P = 0.929) as well, no statistical significance was found. Detailed information was exhibited in [Table 2], [Table 3], [Table 4].
Table 2: Relationships between human epidermal growth factor receptor 2 and clinicopathological parameters

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Table 3: Relationships between epidermal growth factor receptor and clinicopathological parameters

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Table 4: Relationships between c-MET and clinicopathological parameters

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Evaluation of publication bias in overall survival

The estimation of publication bias was based on the OS by Begg's funnel plot and the P value. The result of publication bias for HER-2, EGFR, and c-MET was P = 0.230 [Figure 5]a, P = 0.592 [Figure 5]b, and P = 0.308 [Figure 5]c, respectively, showing no significant publication bias in OS.
Figure 5: Begg's funnel plot (a) ErbB-2, (b) epidermal growth factor receptor, (c) c-MET

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Sensitivity analysis

To test whether the inclusion criteria of the meta-analysis affected the final results, we deleted one single study from the overall pooled analysis each time to check the influence of the removed data set to the overall HRs. The results of sensitivity analysis are shown in [Figure 6]. We found that no study had an obvious impact on our overall results and verified the stability and reliability of our results.
Figure 6: Sensitivity analysis (a) ErbB-2, (b) epidermal growth factor receptor, (c) c-MET

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 > Discussion Top

The result obtained from a meta-analysis considerably depends on the quality of the selected studies, and it is also substantially influenced by the results of previous studies. Therefore, we applied a strict screening of the related literature, trying to avoid bias and to obtain a reliable conclusion. The process of screening is presented in [Figure 1]. A total of 32 studies were included in this study according to the inclusion and exclusion criteria.

To date, among the various biomarkers associated with tumorigenesis, many studies have demonstrated the correlation of biomarkers and prognosis, indicating that these makers may have complementary roles in improving the diagnosis and prognosis of cancers.[44] Considering the prevalence of cancer, improving early detection, screening, and treatment is extremely important.[45] Identifying the risk of mortality and disease recurrence in cancer patients is critical in guiding surveillance and selecting adjunctive therapies. It has been reported that HER-2, EGFR, and c-MET were related to clinicopathological parameters and OS in breast cancer or colon cancer.

In our systematic review, most of the selected articles came from Asia, indicating an obvious region differences. We found that EGFR, HER-2, and c-MET high expression were not related to age, differentiation, TNM stage, gender, or lymph node status. High expression of the three markers was associated with poor OS in BTC patients in different degree. Our findings indicated that the expression levels of TKGFRs, like the three markers that we studied, were not associated with clinicopathological parameters but correlated with the OS. Understanding the precise mechanisms of HER-2, EGFR, and c-MET in BTC pathogenesis could help to develop a new treatment for BTC patients although the molecular mechanism of the three markers associated with prognosis of BTC remains to be determined.

In regard to EGFR, it was enhanced in human cholangiocarcinoma,[46] the activation of EGFR by bile acids can induce cox-2 expression via mitogen-activated protein Kinase (MAPK) cascade that may play a role in the progression of cholangiocarcinoma.[47] The activation of EGFR also activates other transduction pathways, such as Ras/Ras/MAPK and Akt/mammalian target of rapamycin, that can influence cell proliferation, motility, and apoptosis.[48],[49] Inhibition of EGFR pathway leads to suppression of tumor growth, inhibition of angiogenesis, and induction of antimetastatic apoptosis properties in cholangiocarcinoma.[50],[51] In addition, EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition.[52] Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of EGFR.[53] c-MET, combined with HGF, regulates VEGF and heparanase expression via PI3K/Akt/MAPK/STAT3 and PI3K/Akt/NF-Kβ signaling pathways for cancer metastasis and growth.[54],[55] This c-MET/HGF pathway plays an important role in cancer invasion.[56] HER-2 regulates cancer cell proliferation,[57] increases metastatic potential,[58] and affects adhesion or invasion of the cancer cell.[59]

Several limitations of this study should be mentioned. First, limited numbers of available articles and the data quality. Although we have searched most pertinent articles in four different databases, the number of eligible studies in this meta-analysis is still limited due to the rarity of BTC. In some literature, the selected study period, the retrieved publications, and blinding design were not described precisely. In addition, some articles were a retrospective study. Therefore, the present results concerning the prognostic role of the three markers in BTC need to be further confirmed by high-quality studies. Second, heterogeneity among some of these studies was relatively large, which might be caused by baseline characteristics of the patients, such as age, different counties, histological type of cancer, adjuvant treatment, the duration of follow-up, and adjustments for other factors. Third, the location of the BTC was not taken into account, which may influence the accuracy of results. Fourth, if these statistics were not reported by the authors, we extrapolated them from the survival curves, necessarily making assumptions about the censoring process which introduced an element of decreased reliability. Moreover, the detection method of biomarkers should be further optimized. All the studies in our meta-analysis relied on IHC to assess HER-2, EGFR, and c-MET expression due to its convenience. However, IHC is a semiquantitative method, which can be easily influenced by the subjective perceptions of the pathologist. The various primary antibodies used and the experimental designs may also lead to inconsistency. In addition, the cutoff for determining the three makers high expression differed widely among studies, from 0% to 50%, and there is no widely accepted scoring system to evaluate EGFR, HER-2, and c-MET expression of BTC. Given all these limitations, an objective gold standard in determining the three markers high expression is expected. Even though, the relationship between EGFR overexpression and its mutations is still obscure and often leads to false-overexpression results.

Given that TKGFRs play major roles in biliary tract carcinogenesis in animal models,[60],[61] HER-2, EGFR, and c-MET, as the representatives of TKGFRs, may play important roles in biliary tract carcinogenesis as well. To better understand and use HER-2, EGFR, and c-MET as biomarkers in the clinical, further research with standardized, unbiased methods, and large worldwide sample sizes are required. Targeting c-MET in BTC may be a new therapeutic strategy in future.

 > Conclusion Top

The evidence from the meta-analysis indicated that HER-2, EGFR, and c-MET high expression were relatively associated with worse OS of BTC although it needs to be considered with caution due to the limitations as we described.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2], [Table 3], [Table 4]


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