|Year : 2016 | Volume
| Issue : 1 | Page : 323-333
High HER-2 protein levels correlate with clinicopathological features in colorectal cancer
Sheng-Jie Sun1, Qian Lin2, Qiong Sun1, Juan Li1, Xing-Yang Zhang1, Zhi-Gang Tan3, Yan Song3, Yi-tong Guo4, Ying Li1
1 Department of Oncology, South Building Clinic Division, General Hospital of People's Liberation Army, Beijing, People’s Republic of China
2 Department of Ultrasound, South Building Clinic Division, General Hospital of People's Liberation Army, Beijing, People’s Republic of China
3 Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
4 Department of Internal Medicine, Shenyang Ninth People's Hospital, Shenyang, Liaoning, People’s Republic of China
|Date of Web Publication||13-Apr-2016|
Department of Oncology, General Hospital of People's Liberation Army, No. 28 Fuxing Road, Haidian District, Beijing - 100853
People’s Republic of China
Source of Support: None, Conflict of Interest: None
Aim: To obtain a correlation between HER-2 expression and the clinicopathological features incolorectal cancers. (CRCs) using a meta.analysis based approach.
Materials and Methods: Electronic databases and reference lists were searched for relevant published studies. After inclusion and exclusion criteria were applied, case and control studies related to research topic were included in present meta-analysis. Data analysis was performed using Comprehensive Meta Analysis. (CMA) 2.0 software.
Result: A total of 30 studies comprising 4,942 CRC patients and 521 healthy controls met the inclusion criteria. Our major results implied that the expression level of HER-2 was significantly higher in CRC patients than healthy controls (odds ratio (OR) = 10.436, 95% confidence interval (CI) = 5.498–19.810, P < 0.001). Sample stratification based on Dukes stages suggested that increased expression level of HER-2 protein was found in CRC patients with Dukes C/D compared with CRC patients with Dukes A/B (OR = 0.335, 95% CI = 0.198–0.568, P < 0.001). The current meta-analysis also found that, in CRC patients with lymph node metastasis (LNM), the HER-2 expression was significantly higher than that in CRC patients without LNM (OR = 1.987, 95%CI = 1.209–3.265, P = 0.007).
Conclusion: Our meta-analysis study strongly suggests that HER-2 expression levels are clearly correlated with the clinicopathological features in CRC; therefore, HER-2 may be a potential biomarker for diagnosis and prognosis of CRC.
Keywords: Clinicopathological features, colorectal cancer, disease-free survival, dukes stage, HER-2, lymph node metastasis, meta-analysis, prognosis
|How to cite this article:|
Sun SJ, Lin Q, Sun Q, Li J, Zhang XY, Tan ZG, Song Y, Guo Yt, Li Y. High HER-2 protein levels correlate with clinicopathological features in colorectal cancer. J Can Res Ther 2016;12:323-33
|How to cite this URL:|
Sun SJ, Lin Q, Sun Q, Li J, Zhang XY, Tan ZG, Song Y, Guo Yt, Li Y. High HER-2 protein levels correlate with clinicopathological features in colorectal cancer. J Can Res Ther [serial online] 2016 [cited 2019 Nov 11];12:323-33. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/323/155977
| > Introduction|| |
Colorectal cancer (CRC) arises due to uncontrolled cell growth in the rectum or colon, both part of the large intestine. CRC is one of the most common cancers and is ranked second in cancer mortality in the western world. Although the exact pathogenesis of CRC is unknown, the development of CRC is characterized by a complex interaction between environmental carcinogens, genetic alterations, and the host immune system., The early-stage CRC is mostly asymptomatic, hence, approximately two-thirds of patients with CRCs present with more advanced cancer stage at diagnosis., Dukes' staging of CRC is based on the local extent of tumor, lymphatic spread, venous spread, and histological features. Thus, Dukes stage A: The cancer is only in the inner lining of the bowel; Dukes stage B: The cancer has invaded the muscle; Dukes stage C: The cancer has invaded the nearby lymph nodes; and Dukes stage D: The cancer has metastasized., CRC migrates through the lymphatic route; depositing tumor cells into local lymph nodes, known as lymph node metastasis (LNM); and clinicopathological features such as poor differentiation, depth of wall penetration, and lymphovascular invasion are associated with LNM in CRC. Relapse and metastasis are the main causes of death in CRC patients, with 20-50% deaths occurring within 5 years after diagnosis linked to extensive metastatic spread., Significant efforts are directed at investigating the underlying mechanisms involved in progression to metastatic CRC, but lack of adequate biomarkers has impeded the progress in CRC research.
The HER2 protein (also known as HER2 or neu, ErbB-2) is a 185-kDa transmembrane receptor tyrosine kinase that belongs to the four-member family of epidermal growth factor receptors which also include HER1 (also known as the EGFR), HER-3, and HER-4. The tyrosine kinase activity of HER-2 intracellular domain which triggers signal transduction has important roles in cell proliferation, differentiation, and survival. Aberrant expression of HER2 triggers the abnormal activation of multiple downstream signal transduction pathways; resulting in increased cell proliferation and differentiation, decreased apoptosis, and enhanced tumor cell motility and angiogenesis., High HER2 expression correlates with poor survival, notably observed in breast and gastric cancers., HER-2 over expression is mainly achieved through gene amplification, resulting in increased transcription of the gene, increasing HER-2 receptors on the cell membrane, and consequently, increasing cell proliferation.,,, However, significant amount of HER-2 is also found in the intracellular compartment. The clinical impact of this enhanced intracellular HER2 levels in CRC is not known, because its nature and influence on cell behavior is not understood. A role for HER2 in CRC has been suspected, nevertheless, whether HER-2 is an independent prognostic factor in CRC is highly controversial. Several studies observed a questionable role for HER-2 protein in CRC, noting no apparent association between HER-2 expression and patients' age, gender, tumor location, tumor grade, stage, and survival., On the other hand, other studies showed that HER2 is a potential therapeutic target and a biomarker in CRC.,, To address the role of HER-2 in CRC, we conducted a meta-analysis to obtain a correlation between HER2 expression and clinicopathological features in CRC such as tumor, node, metastasis (TNM) stage, Dukes stage, LNM, differentiation state, tumor size, overall survival (OS) rate, and disease-free survival (DFS) rate.
| > Materials and Methods|| |
Data sources and searches
PubMed, EBSCO, Cochrane Library database, Ovid, SpringerLink, Embase, Web of Science, Wanfang database, China National Knowledge Infrastructure (CNKI), and VIP database (since inception to October 2014) were systematically searched to identify all relevant studies using combination of key words and free words. Search terms for literature search were: (”genes, erbB-2” or “c-erbB-2 gene” or “c-erbB-2 gene” or “genes, neu” or “genes, HER-2” or “HER2 gene” or “c-erbB-2 proto-oncogenes” or “erbB 2 genes” or “orphans receptor” or “human epidermal growth factor receptor-2” or “HER2” or “HER-2”) and (”colorectal neoplasms” or “colorectal neoplasms” or “colon cancer” or “tumors, colorectal” or “neoplasm, colorectal”). No restrictions on language were set in this comprehensive search. Bibliographies cited in articles were also searched manually to retrieve other potential publications.
All retrieved articles and included studies were evaluated for eligibility based on following inclusion and exclusion criteria. Inclusion criteria for eligibility of a study in this meta-analysis were: (i) Case–control design; (ii) subjects in case and control groups were pathological CRC patients and healthy controls, respectively; (iii) studies should provide the required information on case and control groups such as country, age, ethnicity, gender, detection method, pathological types, and HER2 expression; and (iv) if the same patient population was involved in several publications, the most complete study was included. Exclusion criteria were: (i) studies were irrelevant to topic; (ii) duplicated publication; (iii) lack of document data integrity; and (iv) studies published in language other than English and Chinese.
Data collection and quality assessment
Two investigators reviewed each eligible study and extracted data, independently. Following information was collected from all eligible studies:First author, published year, country, ethnicity, number of CRC patients and controls, gender, age, HER-2 protein expression levels, differentiation levels, tumor position, Dukes stage, LNM, tumor size, TNM stage, 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS. Discrepancies between the two investigators were consulted by discussion with a third investigator. The quality assessment for each eligible study was conducted using Critical Appraisal Skill Program (CASP) (http://www.casp-uk.net/). The CASP criteria for case and control studies include Section A (CASP01–CASP07); Section B (CASP08–CASP09), and Section C (CASP10–CASP11). In detail, the 11 questions were described as following: Whether the study addresses a clearly focused issue or not (CASP01); whether an appropriate method was used to answer their question or not (CASP02); whether the cases were recruited in an acceptable way or not (CASP03); whether the controls were selected in an acceptable way or not (CASP04); whether the exposure was accurately measured to minimize bias (CASP05); what confounding factors have the authors accounted for or have the authors taken account of the potential confounding factors in the design and/or in their analysis (CASP06); what are the results of this study (CASP07); how precise are the results (CASP08); do you believe the results (CASP09); can the results be applied to the local population (CASP10); do the results of this study fit with other available evidence (CASP11).
Analyses were conducted using Comprehensive Meta Analysis (CMA) 2.0 software (Biostat Inc, Englewood, New Jersey, USA). We calculated odds ratio (OR) with 95% confidence interval (95%CI) to evaluate the correlation between HER-2 expression and clinicopathological features of CRC in case and control studies. Z-test was employed to detect the significance of overall effect size. Forest plots were draw to reflect the comparisons of ORs and 95%CI among the study groups. The variations and heterogeneities between each study were estimated utilizing Cochran's Q-statistic (P < 0.05 was considered significant). We also quantified the effect of heterogeneity using I2. We considered the value of P < 0.05 or I2 exceeding 50% as an indicator of heterogeneity. If heterogeneity was detected, the random-effects model was employed, otherwise, fixed-effects model was used. Sensitivity analysis was performed to evaluate whether removal of one single study could influence the overall outcomes. Funnel plots, classic fail-safe N, and Egger's test were applied to evaluate the publication bias., All tests were two-sided with P < 0.05 indicating a significant difference.
| > Results|| |
Study selection and description
The initial database and manual search retrieved a total of 684 relevant articles. After excluding duplicates (n = 19), nonhuman studies (n = 31), letters, reviews, meta-analyses (n = 22), and unrelated topics (n = 466); 146 full-text articles remained. Full texts and data integrity were then reviewed, and another 41 articles were excluded. Another 75 studies were excluded due to lack of data integrity. In the end, a total of 30 studies were included in present meta-analysis [Figure 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,, These studies contained a combined total of 4,942 CRC patients and 512 healthy controls from 30 studies published between 1994 and 2014. Of these, 20 studies were performed in Asians, nine studies in Caucasians, and one study among Africans. In our meta-analysis data, immunohistochemistry (IHC) was used to detected HER-2 protein expression to find a link between the expression patterns of HER-2 and various aspects of CRC progression. The baseline characteristics of these 30 included studies investigated the correlation between HER-2 protein expression and clinicopathological features of CRC in case and control designs are summarized in [Table 1]. The methodological quality of CASP criteria for each included studies are presented in [Figure 2].
|Figure 1: Flow chart for selection of studies for inclusion and exclusion in this meta-analysis. Thirty studies included in present meta-analysis|
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|Table 1: The basic characteristics for all eligible studies in present meta-analysis investigated the correlation between HER-2 expression and the clinicopathological features of colorectal cancer|
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|Figure 2: Methodological quality of Critical Appraisal Skill Program for each 30 included studies investigated the correlation between HER-2 expression and the clinicopathological features of colorectal cancer|
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HER-2 protein expression in CRC patients and healthy controls
Since significant heterogeneity existed (I2= 62.6%, P = 0.001), random-effects model was applied. The major result in our meta-analysis revealed that the expression level of HER-2 was higher in CRC patients compared with healthy controls (OR = 10.436, 95%CI = 5.498–19.810, P < 0.001) [Figure 3]a.
|Figure 3: Forest plot, sensitivity analysis, and publication bias in patients with colorectal cancer and healthy controls showed the correlation betweenHER-2 expression and the clinicopathological features of colorectal cancer ((a) Forest plot implied that the expression level of HER-2 was significantly higher in colorectal cancer patients than healthy controls;(b) sensitivity analysis suggested the stabilization of the study; and (c) publication bias test confirmed the existence of publication bias). CI = Confidence interval|
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HER-2 protein expression and CRC pathological features
Heterogeneities in CRC differentiation stage, Dukes stages, LNM, tumor sizes, and CRC TNM stages were discovered; thus, random-effects model was employed (differential levels: P =0.00, I2= 64.9%; Dukes stages: P =0.005, I2= 58.9%; LNM: P =0.00, I2= 79.3%; tumor sizes: P =0.012, I2= 53.3%; and TNM stages: P =0.00, I2= 88.8%). Fixed-effects model was utilized in case where no heterogeneities were observed between HER-2 protein expression and CRC location (P = 0.599, I2= 0.00%). The result in this meta-analysis showed that an increased expression level of HER-2 was found in CRC patients with Dukes C/D compared with CRC patients with Dukes A/B (OR = 0.335, 95%CI = 0.198–0.568, P < 0.001). This meta-analysis also identified that expression level of HER-2 in CRC patients with LNM was at higher level than that in CRC patients without LNM (OR = 1.987, 95%CI = 1.209–3.265, P = 0.007). However, no significant associations were found between HER-2 expression and CRC locations, CRC differentiation levels, tumor sizes, and CRC TNM stages (Rectal vs colon: OR = 1.123, 95%CI = 0.858–1.468, P = 0.399; high differentiation vs low differentiation: OR = 0.917, 95%CI = 0.612–1.375, P = 0.676; big tumors vs small tumors: OR = 0.922, 95%CI = 0.641–1.326, P = 0.662; and TNM I/II stage vs TNM III/IV stage: OR = 0.822, 95%CI = 0.328–2.056, P = 0.675) [Figure 4].
|Figure 4: Forest plot showed the correlation between HER-2 positive expression and clinicopathological features of colorectal cancer. (c and d) Colorectal cancer patients with Dukes C/D or with lymph node metastasis were associated with an increased expression level of HER-2 compared with colorectal cancer patients with Dukes C/D or without lymph node metastasis. (a, b, e, and f) No significant associations were found between HER-2 expression and colorectal cancer locations, colorectal cancer differentiation levels, tumor sizes, and colorectal cancer TNM stages. TNM = Tumor, node, metastasis|
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HER-2 protein expression and CRC prognosis
The random-effects model was used since significant heterogeneity existed between studies investigating HER-2 protein expression in CRC patients and OS (3-year OS: P =0.001, I2= 71.9% and 5-year OS: P =0.00, I2= 81.7%). No significant heterogeneities of HER-2 protein expression in CRC patients and DFS were observed, therefore, fixed-effect model was applied (3-year DFS: P =0.133, I2= 46.4% and 5-year DFS: P =0.362, I2= 7.9%). The result in our meta-analysis suggested that CRC patients with HER-2 positive expression had a decreased3-year DFS rate compared with CRC patients with HER-2 negative expression. Nevertheless, no significant association was found between HER-2 protein expression and 3-year OS, 5-year OS and 5-year DFS (3-year OS: OR = 0.618, 95% CI = 0.291–1.314, P = 0.211; 5-year OS: OR = 0.557, 95% CI = 0.249–1.247, P = 0.155; and 5-year DFS: OR = 0.719, 95% CI = 0.444–1.163, P = 0.178) [Figure 5].
|Figure 5: Forest plot showed the correlation between HER-2 positive expression and overall survival rate and disease-free survival rate of colorectal cancer. (a) Colorectal cancer patients with HER-2 positive expression had a decreased 3-year disease-free survival rate compared with colorectal cancer patients with HER-2 negative expression. (b-d) No significant association was found between HER-2 protein expression and 3-year overall survival rate, 5-year overall survival rate, and 5-year disease-free survival rate|
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Sensitivity analysis and publication bias of HER-2 protein expression in CRC patients
Sensitivity analysis indicated that the overall pooled ORs could not be affected by one single study [Figure 3]b. Moreover, classic fail-safe N and Egger's regression test confirmed the existence of publication bias (P < 0.05) [Figure 3]c.
Sensitivity analysis and publication bias of HER-2 protein expression and CRC pathological features
Sensitivity analysis showed that no single studies had the weight to impact the result on the correlation between HER-2 expression level and CRC pathological features in the present meta-analysis [Figure 6]. Symmetrical funnel plots indicated there is no publication bias in tumorlocations, tumor differential levels, Dukes stages, and LNM and TNM stages. Egger's regression test and classic fail-safe N confirmed the absence of publication bias, eliminating publication bias in our present study (all P > 0.05). Nevertheless, Egger's regression test and classic fail-safe N suggested the existence of publication bias for tumor sizes [Figure 7].
|Figure 6: Sensitivity analysis of the meta-analysis investigated the correlation between HER-2 positive expression and the clinical characteristics of colorectal cancer. The sensitivity analysis suggested that the results of HER-2 positive expression and the clinical characteristics of colorectal cancer were stable|
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|Figure 7: Publication bias of the meta-analysis investigated the correlation between HER-2 positive expression and the clinical characteristics of colorectal cancer. Symmetrical funnel plots indicated there is no publication bias in tumor locations, tumor differential levels, Dukes stages, lymph node metastasis, and TNM stages. Egger's regression test and classic fail-safe N suggested the existence of publication bias for tumor sizes|
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Sensitivity analysis and publication bias of HER-2 protein expression and CRC prognosis
Sensitivity analysis suggested that no single study had the weight to impact on overall pooled ORs. We did not discover any obvious asymmetry from the shape of the funnel plots. Furthermore, Egger's regression test and classic fail-safe N indicated that no significant publication bias was detected in this meta-analysis [Figure 8].
|Figure 8: Sensitivity analysis and publication bias of the meta-analysis showed the correlation between HER-2 positive expression and overall survival rate and disease-free survival rate of colorectal cancer. Sensitivity analysis suggested the stability of results for HER-2 protein expression level and colorectal cancer3-year overall survival rate (a), 5-year overall survival rate (b), 3-year disease-free survival rate (c), and 5-year disease-free survival rate (d). Funnel plots, Egger's regression test, and classic fail-safe N confirmed the absence of publication bias in 3-year overall survival rate (e), 5-year overall survival rate (f), 3-year disease-free survival rate (g), and 5-year disease-free survival rate (h)|
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| > Discussion|| |
The proto-oncogene HER-2 is a member of the growth factor receptor family with intrinsic protein tyrosine kinase activity and its increased activity promotes cell transformation. HER-2 is involved in the tumor genesis and progression of various solid tumor types, such as breast cancer, pulmonary adenocarcinoma, gastric cancer, and CRC.,,, Specifically, CRC patients have increased HER-2 levels compared to healthy controls. Moreover, the results in our meta-analysis showed that CRC with elevated HER-2 positive levels were more invasive and was at more advanced cancer stage. Consistent with the results from our meta-analysis, overexpression of HER-2 is found in several tumors such as breast, stomach, lung, and urinary bladder; and HER-2 positive tumors invariably belong to advanced clinical stages of these diseases and areassociated with a worse prognosis., Lu et al., reported that overexpression of EGFR and Her2 seems to be associated with malignant transformation. EGFR and Her2 is often overexpressed in primary CRC and associated with poor survival, which is consistent with current study. Our results also identified that 3-year DFS of patients showing HER-2 positivity was significantly shorter than HER-2 negative patients, consistent with one previous study which suggested that HER2-positive tumors displayed aggressive behavior, for example, in breast cancer. HER-2 belongs to the ErbB/HER family of type I transmembrane growth factor receptors that play a vital role in normal cell proliferation and tissue growth, as well as in the development of carcinoma through influencing cell migration, proliferation and differentiation, and apoptosis. The activation of HER-2 which initiates signal cascade pathways is essential for cell proliferation and differentiation. Clarification of HER-2 related mechanisms in CRC progression will allow identification of molecular markers within the HER-2 pathway which will be useful in predicting prognosis in CRC to benefit selection of patients for adjuvant therapy.
We also acknowledge that the inherent limitations of this study might lead to biased results. First, the current study was retrospective and the number of patients was limited. Second, the present study focused only in the IHC overexpression of HER-2. Given the vulnerability of IHC to various technical issues, florescence in situ hybridization has been proposed as an alternative or adjunct method for the evaluation of HER-2. Third, the majority of 30 eligible studies were performed in Asians and only one study was performed in Africans, which may lead our meta-analysis to bias. Moreover, studies published in language other than English and Chinese were not included in our meta-analysis.
In summary, our results demonstrate that HER-2 expression is correlated with more invasive and advanced stages of CRC. Furthermore, HER-2 expression can be considered as a potential factor to predict poor outcomes in CRC. Future studies need to investigate the molecular mechanism of HER-2-mediated carcinogenesis to further define its correlation to cancer prognosis and its potential role as a target for therapies.
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