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Role of HER family members in predicting prognoses in epithelial ovarian cancer: a meta-analysis

Abstract

Aims and background

Human epidermal receptor (HER) family receptors are commonly overexpressed in various human tumors, and their overexpression is thought to play a critical role in tumor progression. The aim of this meta-analysis was to evaluate the prognostic significance of HER family members in epithelial ovarian cancer (EOC).

Methods

Relevant studies published between January 1, 1980, and April 24, 2013, that evaluated the associations of HER family members with overall survival (OS), progression-free survival (PFS), response to platinum-based chemotherapy, lymph node metastasis, or ascites in EOC were identified via searches of PubMed and EMBASE.

Results

We identified 37 eligible articles that met the inclusion criteria. The results of the meta-analysis revealed that significantly poorer OS of patients with EOC was predicted by high Her-2 expression levels (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.31-2.19). Furthermore, high Her-2 expression was significantly associated with poor PFS (HR 1.88, 95% CI 1.46-2.41) and an increased risk of ascites (risk ratio 1.21, 95% CI 1.02-1.42).

Conclusions

High levels of expression of Her-2 are significantly related to poor survival and an increased risk of ascites in patients with EOC. Future prospective cohorts with larger samples are needed to verify the prognostic value of Her-2 expression in EOC.

Tumori 2015; 101(6): 595 - 602

Article Type: REVIEW

DOI:10.5301/tj.5000343

Authors

Weixiang Ouyang, Linjuan Xu, Zaiju Huang, Jianfeng Guo, Jing Cai, Xuejiao Gao, Zehua Wang

Article History

Disclosures

Financial support: The National Natural Science Foundation of China (approval nos. 81472443 and 81272860).
Conflict of interest: None.

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Introduction

Cancer represents a major public health challenge worldwide. Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women and is expected to have caused 14,030 deaths in the United States in 2013 (1). Despite great advances that have been made in surgery and chemotherapy, the 5-year survival for patients with EOC remains below 50% due to recurrence and the development of resistance to chemotherapeutics (2). Clinical features, such as stage, grade, adequacy of debulking, and histologic type, are the most important prognostic factors for predicting clinical outcome. However, immunocytochemical studies have suggested that, independent of tumor stage and grade, there is considerable heterogeneity among serous papillary ovarian carcinomas and that the detection of particular markers might aid the prediction of outcomes. The early identification of some molecular markers that are indicative of prognoses is of great value in terms of appropriate adjustments to therapeutic regimens.

The human epidermal growth factor receptor (HER) tyrosine kinase family consists of 4 homologue members: HER1 (epidermal growth factor receptor, also known as EGFR or ErbB1), HER2 (p185 Neu or ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (3, 4). All 4 members share a common overall structure that includes an extracellular ligand-binding domain, a single hydrophobic transmembrane region, and a cytoplasmic tyrosine kinase domain. Members of the HER family are extensively expressed in epithelial, mesenchymal, and neuronal tissues and play important roles in the regulation of the normal growth and differentiation of cells (5, 6). In many human cancers, HER family members tend to be aberrantly expressed and are involved in proliferation, migration and invasion, differentiation, and angiogenesis (7-8-9). However, the results of studies that have investigated the association between the overexpression of the HER family members and EOC outcomes are not consistent (10-11-12). Therefore, it is necessary to more precisely and objectively ascertain the clinical implications of HER family members in EOC.

Immunohistochemistry (IHC) remains a major technique for the determination of protein status due to its practically and reliability (13). Most studies of the expression of the HER family receptors in ovarian cancer have employed IHC analyses. In this article, we searched the literature for articles that have employed IHC-based detection and conducted a meta-analysis for improved assessment of the value of the HER family receptors as prognostic predictors in EOC.

Materials and methods

Literature search and selection

A systematic search of the literature published between January 1, 1980, and April 24, 2013, was conducted by searching PubMed and EMBASE. We used the following search words to identify the potentially relevant studies: “ovarian cancer,” “Her1,” “ErbB1,” “EGFR,” “Her2,” “Neu,” “ErbB2,” “Her3,” “ErbB3,” “Her4,” and “ErbB4.” The reference lists from the relevant articles were examined to identify additional studies that were not identified in the original search. This meta-analysis was planned and performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (14).

The studies included in this meta-analysis met the following criteria: (1) all patients had primary EOC; (2) all surgical specimens were obtained from the first surgery prior to any therapeutic intervention; (3) the articles reported hazard ratios (HRs) and 95% confidence intervals (CIs) from multivariate survival analysis of overall survival (OS) or progression-free survival (PFS), provided odds ratios (ORs) and 95% CIs for tumor responses to platinum-based chemotherapy, or presented risk ratios (RRs) and 95% CIs for lymph node metastasis or ascites, or the articles contained sufficient data to assess the ORs (or RRs) and the 95% CIs; and (4) the studies were published in English or Chinese. Non-original research, reviews, abstracts, letters, and studies of nonepithelial or recurrent ovarian cancer were excluded from this meta-analysis. Duplicate publications were also excluded.

Data extraction

For each study, 2 researchers independently assessed the data and resolved any disagreements by discussion. We extracted the following information from each study: the first author; the year of publication; the age of the patients at the time of diagnosis (mean or median); the country in which the research was performed; the number of patients analyzed in the study; the study design (e.g., prospective, randomized, retrospective); the stages and tumor types of the ovarian cancers studied; the anti-HER family antibodies used and the response criteria; the line of treatment; the chemotherapy regimens; the results of multivariate survival analyses (HR and 95% CI for OS or PFS); the numbers of marker-positive and marker-negative tumors that were responders and ­nonresponders; and the number of patients with lymph node metastases or ascites.

Statistical analyses

All the statistical analyses in this meta-analysis were performed with STATA, version 11 (Stata Corporation, College Station, TX, USA; http://www.stata.com).

Risk estimates were extracted as HRs, ORs, or RRs with 95% CIs. The HRs were used as measures of the prognostic value. A log HR and its 95% CI based on multivariate survival analysis were extracted from each study. Hazard ratios >1 indicated poorer survival among cases that were biomarker-positive. Regarding the ORs and RRs, if the risk estimate or its 95% CI was not reported, we calculated it using the methods described by Parmar et al (15). To assess the heterogeneity between studies, we used the Q statistic and the I2 statistic (16). A p<0.05 or an I2>50% was considered to represent significant heterogeneity between studies, and in such cases, the DerSimonian-Laird random-effects model (17) was applied in the meta-analysis; otherwise, the Mantel-Haenszel fixed-effects model (18) was used. If the resulting Q statistic and I2 statistic conflicted, we adopted the conclusion of the I2 statistic.

The potential publication and selection biases were assessed via funnel plots and tested with Egger test (19). A p<0.05 was considered to indicate a statistically significant publication bias.

Results

Study characteristics

We identified 37 eligible articles that involved 6271 patients with EOC (supplementary Tab. I, available online at www.tumorijournal.com). A flow diagram of the literature search is shown in Fig. 1. The mean/median ages were similar in all studies with the exception of 7 articles (10, 20-21-22-23-24-25) that did not report the ages of the patients. Six articles focused only on patients with serous carcinomas (11, 21, 26-27-28-29), and 1 article each focused on transitional cell carcinomas (22) and endometrioid carcinomas (30). The studies included in this meta-analysis were all retrospective trials.

The literature search and selection process. IHC = immunohistochemistry.

Nineteen trials evaluated the relationships between the expression of HER family members and OS with multivariate analyses (10-11-12, 20, 21, 23, 31-32-33-34-35-36-37-38-39-40-41-42-43), 9 studies reported adjusted PFS (11, 23, 31, 32, 38, 42-43-44, 48), 14 studies assessed chemotherapy responses (20, 24-25-26, 29, 32, 33, 38, 45-46-47, 49-50-51), 4 studies provided lymph node metastasis data (22, 25, 30, 52), and 9 studies reported ascites (24, 25, 27, 28, 45, 46, 51-52-53).

Meta-analysis

Association between HER family member expression statuses and OS

Meta-analysis of 7 studies (11, 12, 21, 23, 35, 36, 38) revealed that high EGFR expression predicted significantly poorer OS in patients with EOC (pooled adjusted HR = 1.60, 95% CI 1.02-2.53; Tab. I and Fig. 2). However, there was ­considerable heterogeneity between these studies (I2 = 76.8%, p = 0.000), and the sources of heterogeneity could not be determined in the meta-regression analysis. When the meta-analysis was restricted to results of studies of ­International Federation of Gynecology and Obstetrics (FIGO) II-IV tumors, serous tumors, or the EGFR-113 antibody, EGFR status was no longer of prognostic value (supplementary Fig. 1, available online at www.tumorijournal.com). Regarding Her-2, the results of the meta-analysis revealed high levels of expression of the receptor were significantly associated with poor OS in patients with EOC (pooled adjusted HR = 1.69, 95% CI 1.31-2.19). However, significant heterogeneity was also present in these studies (I2 = 60.5%, p = 0.002). This heterogeneity was reduced when the meta-analysis was restricted to results reported by studies of FIGO II-IV tumors (I2 = 8.1%, p = 0.297) or the p185 antibody (I2 = 0.0%, p = 0.775), and Her-2 status was also a predictor of poor survival. Meta-analyses of Her-3 and Her-4 were infeasible due to limited numbers of reports.

Meta-analysis of multivariate estimates for overall survival and progression-free survival

Factors Overall survival Progression-free survival
No. of studies Pooled HR (95% CI) Heterogeneity p value I 2 value, % Bias p value No. of studies Pooled HR (95% CI) Heterogeneity p value I 2 value, % Bias p value
CI = confidence interval; EGFR = epidermal growth factor receptor; HR = hazard ratio; IHC = immunohistochemistry.
EGFR
 All studies 7 1.60 (1.02-2.53) 0.000 76.8 0.301 4 1.40 (0.77-2.56) 0.011 73.3 0.710
 Studies restricted to stage II-IV tumors 2 3.08 (0.43-22.26) 0.000 91.8 2 1.89 (0.54-6.63) 0.009 85.3
 Studies restricted to serous tumors 2 0.83 (0.42-1.64) 0.144 53.1
 Studies using IHC staining with the EGFR-113 antibody 2 1.64 (0.75-3.59) 0.059 71.9
Her-2
 All studies 13 1.69 (1.31-2.19) 0.002 60.5 0.176 5 1.88 (1.46-2.41) 0.545 0.0 0.244
 Studies restricted to stage I-IV tumors 7 1.39 (1.17-1.63) 0.360 9.1 2 1.63 (1.08-2.47) 0.933 0.0
 Studies restricted to stage II-IV tumors 2 1.64 (1.07-2.51) 0.297 8.1
 Studies restricted to stage III-IV tumors 4 2.86 (1.40-5.83) 0.013 72.0 2 2.54 (1.58-4.07) 0.348 0.0
 Studies using IHC staining with the p185 antibody 3 1.54 (1.25-1.90) 0.775 0.0
 Studies using IHC staining with the c-erbB2 antibody 7 1.85 (1.04-3.27) 0.000 78.8
 Studies using IHC staining with the CB-11 antibody 4 2.94 (1.43-6.03) 0.021 69.0 4 1.97 (1.48-2.62) 0.449 0.0
Her-3 1 1.71 (1.10-2.67) - - - - - - - -
Her-4 - - - - - - - - - -

Forest plot shows the results from studies of the prognostic values of epidermal growth factor receptor (EGFR) and Her-2 expression. The adjusted hazard ratio (HR) estimates for overall survival in patients with these biomarker-positive tumors are shown. For each study, the HR, 95% confidence interval (CI), and relative weight are shown.

The relationship between HER family member statuses and PFS outcomes

Nine trials analyzed PFS outcomes in patients with ovarian cancer with different expressions of EGFR (11, 23, 38, 44) or Her-2 (31, 32, 42, 43, 48). Meta-analysis revealed that high-level Her-2 expression was significantly related to poor PFS (pooled adjusted HR = 1.88, 95% CI 1.46-2.41; Tab. I and Fig. 3), and the heterogeneity between studies was minimal (I2 = 0.0%, p = 0.545). When the meta-analysis was restricted to results of studies of FIGO I-IV tumors, III-IV tumors, or the CB11 antibody, Her-2 status was still a predictor of poor survival (supplementary Fig. 2, available online at www.tumorijournal.com). Regarding EGFR, we found no association between EGFR status and PFS risk (HR = 1.40, 95% CI 0.77-2.56), and significant heterogeneity existed in the relevant studies (I2 = 73.3%, p = 0.011).

Forest plot shows the results of the studies of the prognostic values of epidermal growth factor receptor (EGFR) and Her-2 expression. The adjusted hazard ratio (HR) estimates for progression-free survival in patients with these biomarker-positive tumors are shown. For each study, the HR, 95% confidence interval (CI), and relative weight are shown.

HER family member statuses and chemotherapy responses

Overall, 14 studies evaluated the relationship between the HER family member statuses and chemotherapy responses. There was no evidence indicating that EGFR or Her-2 status might be predictive of chemotherapy response (pooled OR = 0.87, 95% CI 0.57-1.34 and pooled OR = 0.70, 95% CI 0.39-1.28, respectively; Tab. II and Fig. 4). Again, no study reported data related to Her-3 or Her-4.

A meta-analysis of univariate odds ratio estimates for response to platinum-based chemotherapy

Factors No. of studies Pooled OR (95% CI) Heterogeneity p value I 2 value, % Bias p value
CI = confidence interval; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; OR = odds ratio.
EGFR
 All studies 7 0.87 (0.57-1.34) 0.108 42.5 0.828
 Studies using IHC staining with the 31G7 antibody 2 1.19 (0.51-2.81) 0.286 12.0
 Studies restricted to stage III-IV tumors 3 1.36 (0.67-2.78) 0.330 9.9
Her-2
 All studies 9 0.70 (0.39-1.28) 0.044 48.1 0.309
 Studies restricted to stage III-IV tumors 4 0.76 (0.20-2.85) 0.003 78.4
 Studies using IHC staining with the c-erbB2 antibody 5 0.56 (0.22-1.39) 0.015 64.6
 Studies using IHC staining with the CB-11 antibody 3 0.44 (0.13-1.51) 0.028 66.9
Her-3 - - - - -
Her-4 - - - - -

Forest plot shows the unadjusted odds ratio (OR) estimates for response rates of patients receiving platinum-based chemotherapy. For each study, the OR, 95% confidence interval (CI), and relative weight are shown. EGFR = epidermal growth factor receptor.

High versus low expression of HER family members and the risk of lymph node metastasis

There were 4 studies that reported on the relationship between HER status and lymph node metastasis. The results of the meta-analysis indicated no evidence of increased risks of lymph node metastasis among patients with EOC with ­high-level expressions of EGFR, Her-2, Her-3, or Her-4 (pooled RREGFR = 0.73, 95% CI 0.45-1.20; pooled RRHer-2 = 1.68, 95% CI 0.15-19.35; pooled RRHer-3 = 1.22, 95% CI 0.77-1.94; and RRHer-4 = 4.87, 95% CI 0.68-34.91; respectively; Tab. III).

A meta-analysis of univariate risk ratio estimates for lymph node metastasis and ascites

Factors Lymph node metastasis Ascites
No. of studies Pooled RR (95% CI) Heterogeneity p value I 2 value, % Bias p value No. of studies Pooled RR (95% CI) Heterogeneity p value I 2 value, % Bias p value
CI = confidence interval; EGFR = epidermal growth factor receptor; RR = risk ratio.
EGFR 2 0.73 (0.45-1.20) 0.565 0.0 - 4 1.07 (0.95-1.21) 0.187 37.4 0.161
Her-2 2 1.68 (0.15-19.35) 0.089 65.4 - 5 1.21 (1.02-1.42) 0.324 14.1 0.149
Her-3 3 1.22 (0.77-1.94) 0.214 35.1 0.941 1 2.30 (0.94-5.65) - - -
Her-4 1 4.87 (0.68-34.91) - - - 2 2.30 (0.36-14.92) 0.000 93.9 -

High versus low expression of HER family members and the incidence of ascites

The meta-analysis results indicated that high-level Her-2 expression was significantly related to an increased risk of ascites (pooled RR = 1.21, 95% CI 1.02-1.42; Tab. III), and the heterogeneity between studies was low (I2 = 14.1%, p = 0.324). Regarding EGFR (25, 27, 45, 46), Her-3 (52), and Her-4 (28, 52), we found no associations between the statuses of these receptors and the risk of ascites (pooled RREGFR = 1.07, 95% CI 0.95-1.21; RRHer-3 = 2.30, 95% CI 0.94-5.65; and pooled RRHer-4 = 2.30, 95% CI 0.36-14.92, respectively).

Risks of publication and selection biases

We evaluated the risk of publication bias with a funnel plot (funnel plots display the relationships between the sample sizes and the effect sizes of a group of studies). There was no asymmetry in the funnel plot for any of the biomarkers; thus, there was no evidence of publication bias (Fig. 5), and this finding was confirmed by the results of an Egger test (Tabs. I-II-III).

Funnel plots. A) Funnel plots show the relationships between the effect sizes of the individual studies (hazard ratio for adjusted overall survival, horizontal) and the precision of the study estimates (standard error, vertical axis) for the epidermal growth factor receptor (EGFR) and Her-2 studies. B) Funnel plots show the relationships between the effect sizes of the individual studies (odds ratios for the unadjusted response to platinum-based chemotherapy, horizontal) and the precision of the study estimates (standard errors, vertical axis) for the studies of EGFR and Her-2.

Discussion

Several lines of evidence have shown that the HER family (i.e., HER1, HER2, HER3, and HER4) plays an important role in mediating growth factor signaling (7-8-9, 54). Abnormal signaling in these pathways results in dysregulated cell proliferation, evasion from apoptosis, angiogenesis, migration, and metastasis, all of which are characteristics of cancer cells. To our knowledge, the role of the HER family in EOC remains unclear. Thus, we performed this meta-analysis to evaluate the prognostic significance of HER family members as detected with IHC of surgery specimens. The individual biomarker assay data were organized according to OS, PFS, chemotherapy response, lymph node metastasis, and ascites.

Although an earlier meta-analysis showed that overexpression of EGFR and Her-2 are associated with poor patient outcome, the authors of this study did not compare other indicators, including PFS, chemotherapy response, lymph node metastasis, and ascites (55). Additionally, these authors did not collect data from multivariate survival analyses. Multivariate data are known to be more reliable. Among the 4 proteins, high levels of EGFR, Her-2, and Her-3 expression were significantly associated with poor OS in patients with EOC. Regarding PFS, only EGFR and Her-2 were examined. The results related to Her-2 seemed to reveal the most consistent association with OS. However, we did not find evidence that the HER family members might be used as predictors of chemotherapy response or lymph node metastasis. Regarding ascites, the results of the meta-analysis revealed that only patients with high-level Her-2 expression were at an increased risk of ascites.

Many biomarkers have been studied in ovarian cancer using IHC, but the results are conflicting. Immunohistochemistry with anti-HER antibodies remains the predominant ­method that is used to assess HER family receptor statuses (56). All of the studies included in this meta-analysis used IHC staining to detect the expressions of EGFR, Her-2, Her-3, and Her-4. However, differences in commercially available antibodies, the duration and type of fixation, the method of tissue embedding, the prolonged storage of specimens as unstained slides, and the lack of a uniform scoring system for the interpretation of HER family receptor IHC staining can all influence the determinations of EGFR, Her-2, Her-3, and Her-4, which can, in turn, result in heterogeneity between studies. For example, when the meta-analysis was restricted to the results reported in studies that used the p185 antibody, the heterogeneity was reduced.

There are several limitations to our meta-analysis. Studies of HER family members in ovarian cancer have been sporadic. Even the percentages of biomarker-positive patients vary considerably between individual studies. For example, EGFR has been reported to be overexpressed in 14.8%-73.7% of ovarian cancers, and HER2 has been reported to be overexpressed in 6.0%-75.5%. The lack of knowledge regarding the prognostic value of HER family member expression in ovarian cancer might partly be explained by the low prevalence of such cancers in the general population, which would result in slower patient recruitment and underpowered studies. For example, the Her-3 and Her-4 data came from only 5 studies. Therefore, false-positive and false-negative results cannot be excluded. Additionally, there was significant heterogeneity between the studies. Indeed, intratumor heterogeneity could explain some discrepancy between IHC and patient outcome. When analyzing the association between EGFR expression status and OS, the heterogeneity was reduced when the meta-analysis was restricted to results reported by studies of serous tumors (I2 = 53.1%, p = 0.144) (supplementary Fig. 1). Furthermore, tumor stage can also affect the heterogeneity (supplementary Figs. 1 and 2).

Conclusion

The results of our study revealed that the overexpression of Her-2 is significantly associated with poor survival and an increased risk of ascites in patients with EOC. However, at this point, Her-2 is unlikely to be useful as a clinical prognostic predictor. We suggest that future well-designed and prospective studies of larger cohorts are needed to confirm this conclusion. Additionally, the standardization of IHC practices should receive attention.

Acknowledgment

The authors thank the Department of Obstetrics and Gynecology, Union Hospital, Wuhan, China.

Disclosures

Financial support: The National Natural Science Foundation of China (approval nos. 81472443 and 81272860).
Conflict of interest: None.
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Authors

Affiliations

  • Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan - China
  • Weixiang Ouyang and Linjuan Xu contributed equally to this work

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