Réduction de l’expression de l’e-cadhérine en tant que facteur pronostique dans le cancer de la vessie non invasif sur le muscle : revue systématique et méta-analyse

25 février 2020

Auteurs : T. Yang, J. Fan, H. Liang, D. He, X. Zeng, J. Fan, K. Wu
Référence : Prog Urol, 2020, 2, 30, 66-74




 




Introduction


Although transurethral resection followed by intravesical therapy is the standard treatment for non-muscle-invasive bladder cancer (NMIBC), the recurrence and progression rates remain high, and the prognosis is still far from being optimistic [1]. In addition to continuously improving the treatment methods, urologists have also devoted themselves to improving the accuracy of prognosis predictions. In the clinic, conventional parameters listed in the European Organization for Research and Treatment of Cancer (EORTC) risk table, such as tumor stage, grade, diameter, and number and concurrent carcinoma in situ (CIS), have been extensively applied to predict the prognosis of bladder cancer [2]. However, the EORTC risk table may still not be accurate [3]. Therefore, it is urgent and imperative to identify novel parameters to accurately predict the outcomes of NMIBC.


Studies have demonstrated the role of decreased E-cadherin expression in the process of epithelial-mesenchymal transition (EMT), which initiates tumor invasion and metastasis [4, 5]. In our previous study, we also observed a switch from E-cadherin to N-cadherin in bladder cancer tissues [6]. Furthermore, some studies have confirmed that decreased E-cadherin expression is correlated with poor survival in human cancers, such as breast cancer and colorectal cancer [7, 8]. For bladder cancer, a meta-analysis of the prognostic value of E-cadherin gene promoter hypermethylation has been published, indicating that it may contribute to an increased risk of bladder cancer among Asian populations [9]. Very recently, Xie et al. also reported that reduced E-cadherin expression was associated with poor prognosis and advanced clinicopathological characteristics in bladder cancer [10]. However, the biological characteristics of the two types of bladder tumors (including NMIBC and muscle-invasive bladder cancer) are totally different, and the exact role of E-cadherin in NMIBC is still unknown. Therefore, we further conducted a meta-analysis to assess the association between decreased E-cadherin expression and the outcomes of NMIBC.


Materials and methods


Search strategy


This meta-analysis was consistent with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched for studies on the prognostic value of E-cadherin expression in bladder cancer in the PubMed, Embase and Web of Science databases using the following terms: "E-cadherin", "E-CAD", "CHD1", "cadherin-1", "bladder cancer", "bladder tumor", "bladder carcinoma", "bladder neoplasm", "urothelial cancer", "urinary tract cancer", and "transitional cell carcinoma". The last search date was April 11, 2019. Furthermore, the references of all retrieved articles were manually searched for additional eligible studies.


Inclusion and exclusion criteria


The inclusion criteria in this meta-analysis were as follows: (1) articles that evaluated E-cadherin expression by immunohistochemistry in bladder cancer samples; (2) articles that evaluated the relationship between reduced E-cadherin expression and the prognosis of bladder cancer; and (3) articles that provided sufficient information to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for recurrence-free survival (RFS) or progression-free survival (PFS) in NMIBC. The exclusion criteria were as follows: (1) letters, reviews, conference abstracts, and case reports; (2) articles that could not offer enough data to calculate the HRs for RFS or PFS in NMIBC; (3) articles not published in English; (4) duplicate articles.


Data extraction


Two investigators independently reviewed each eligible study and extracted the following information: first author's name; year of publication; country of origin; number, sex and age of the patients; tumor stage and grade; definition of reduced, abnormal or negative E-cadherin expression; follow-up time; and outcomes of interest (i.e., RFS and PFS). The investigators subsequently crosschecked the data to ensure accuracy. If the HR and 95% CI were not explicitly presented in the article, we estimated them by calculation according to K-M curves and so on [11, 12]. All controversial problems were resolved through discussion among all authors. RFS was defined as the period between TURBt and tumor recurrence, and PFS was defined as the period between TURBt and tumor progression.


Quality assessment


Quality of the included studies was assessed by the Newcastle-Ottawa Scale, which was recommended by the Cochrane Non-Randomized Studies Methods Working Group. The assessment involved scores ranging from 0 to 9 and included the following three points: selection, comparability, and outcomes; scores higher than 6 were considered to be of high quality. Only high-quality studies were included in this meta-analysis.


Statistical analysis


HRs with their 95% CIs were applied to evaluate the impact of reduced E-cadherin expression on the risk of NMIBC. In some studies, the HRs and their 95% CIs were described directly. Otherwise, we calculated the values from the available data in those studies. Heterogeneity across studies was evaluated by the Q test and I2 statistic. I2>50% and P <0.05 were considered to indicate significant heterogeneity, and the random-effects model was used; moreover, meta-regression analysis was used to explore the source of heterogeneity. In addition, we performed subgroup analyses to investigate the association between reduced E-cadherin expression and RFS and PFS. Begg's and Egger's tests were used to evaluate publication bias, and sensitivity analysis was used to evaluate the stability of the pooled results. All P -values were two-sided and considered statistically significant when P < 0.05, and all statistical analyses were performed with Stata Version 13.0 software (Stata Corporation, College Station, TX, USA).


Result


Search results and characteristics of the included studies


A total of 1973 articles were identified from the three databases, and by reviewing the titles and abstracts, 1925 articles were excluded because they were irrelevant to the objective of this meta-analysis or duplicates. Subsequently, we read the full text of the remaining 48 articles, and 33 articles were further excluded for the following reasons: reviews (N =5), muscle-invasive bladder cancer samples were presented in all samples and detailed information on NMIBC was not given (N =5), no outcomes of interest (N =12), data could not be extracted (n=9), and not bladder cancer (N =2). Finally, a total of 15 studies [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27] with 1538 NMIBC patients were included in this meta-analysis, of which 4 studies [15, 16, 18, 22] included both NMIBC and MIBC, and we extracted the detailed information of NMIBC. The study selection process is shown in Figure 1. The main characteristics of the included studies are listed in Table 1. The number of patients ranged from 45 to 233, and the mean age ranged from 64 to 69 years.


Figure 1
Figure 1. 

Flow diagram of the study selection process.




Impact of reduced E-cadherin expression on RFS and PFS in NMIBC


The pooled results revealed that patients with reduced E-cadherin expression had poor RFS (pooled HR 2.16, 95% CI 1.22-3.85) with significant heterogeneity (I2=86.5%, P =0.000) (Figure 2A). Subgroup analyses were performed according to study location, the cutoff value of the E-cadherin expression level and the method of HR estimation (Table 2). The results demonstrated that reduced E-cadherin expression was significantly associated with RFS in both Asian and non-Asian patients. The pooled HR was 2.13 (95% CI 1.31-3.47) extracted from articles in which the definition of negative/reduced E-cadherin expression was less than 90% of tumor cells with membranous staining, while the other group showed that E-cadherin expression had no impact on RFS. When the HR estimation method was taken into consideration, the pooled HR directly extracted from the studies was 2.24 (95% CI 0.61-8.19), and the pooled HR obtained from the calculation was 1.89 (95% CI 1.37-2.62).


Figure 2
Figure 2. 

Meta-analysis of the effects of E-cadherin expression on recurrence-free survival (A) and progression-free survival (B) in patients with NMIBC.




The pooled results revealed that patients with reduced E-cadherin expression had a poor PFS (pooled HR 1.91, 95% CI 1.52-2.40) with no significant heterogeneity (I2=0%, P =0.543) (Figure 2B). Similar to that for RFS, subgroup analyses were performed, and the results showed no significant association between E-cadherin expression and PFS in Asian patients (pooled HR 1.48, 95% CI 0.85-2.59) (Table 2).


For both RFS and PFS, meta-regression analysis showed that nation, cutoff of the E-cadherin expression level, and HR estimation were not significant contributors to interstudy heterogeneity.


Sensitivity analysis


We performed sensitivity analysis to assess the stability of our results by omitting individual studies. The results suggested that none of the individual studies significantly affected the pooled estimate (Figure 3A and B).


Figure 3
Figure 3. 

Sensitivity analysis of the effects of E-cadherin expression on recurrence-free survival (A) and progression-free survival (B) in patients with NMIBC. Funnel plot for the effects of E-cadherin expression on recurrence-free survival (C) and progression-free survival (D) in patients with NMIBC.




Publication bias evaluation


Both Egger's test and Begg's funnel plots were used to assess the potential publication bias in this meta-analysis. The results suggested that significant publication bias was not detected for either RFS (P Egger=0.147, P Begg=0.917) or PFS (P Egger=0.147, P Begg=0.533) (Figure 3C and D).


Discussion


Clinically, the EORTC risk table and CUETO scoring model have already been accepted as tools for predicting the risk of recurrence and progression of NMIBC [2, 28]; however, they still do not accurately accomplish this goal [3, 29]. Recently, additional prognostic factors, such as substage of T1 and LVI [30, 31, 32], have been estimated in selected patient populations. Many studies have demonstrated the value of decreased E-cadherin expression in the prognosis of some human cancer types [7, 8]. However, the exact role of E-cadherin in NMIBC is still unknown. According to our meta-analysis, E-cadherin was significantly associated with RFS and PFS in NMIBC, so we might predict the prognosis of patients according to the expression status of E-cadherin in NMIBC samples following TURBt.


We combined the outcomes of 15 studies with 1538 NMIBC patients and concluded that reduced or negative E-cadherin expression was significantly associated with poor RFS and PFS, although significant heterogeneity existed when pooling the survival data associated with RFS. We further conducted subgroup analysis according to the nation of the patients, the definition of negative/low E-cadherin expression and the method of HR estimation. The results showed that E-cadherin expression was significantly associated with RFS with slight heterogeneity when less than 90% of NMIBC cells were stained by immunohistochemistry, while the other subgroups showed that E-cadherin expression had no impact on RFS with significant heterogeneity. The potential reason could be different definitions of reduced E-cadherin expression in different studies. In subgroup analysis according to the nation of patients, the results showed that the expression of E-cadherin was only significantly associated with RFS for both Asian and non-Asian patients but not PFS in Asian patients. In subgroup analysis according to the methods of HR estimation, the results showed that the expression of E-cadherin was not significantly associated with RFS when the HR and 95% CI were directly extracted from the studies. The potential reason may be the limited number of NMIBC samples in this subgroup.


Unfortunately, we did not determine the source of heterogeneity for RFS by subgroup analysis and meta-regression analysis. However, in the subgroup analysis of the definition of negative/low E-cadherin expression, the heterogeneity was 56.9%, and the P -value was 0.055 when the definition of negative/low E-cadherin expression was less than 90% of tumor cells with membranous staining. In addition, in the subgroup analysis of the HR estimation method, the heterogeneity was 28.9%, and the P -value was 0.208 when the HR was calculated, while the direct extraction of HR had high heterogeneity. We speculated that the definition of negative E-cadherin expression as well as the HR estimation method may be sources of heterogeneity in these studies.


Inevitably, some limitations existed in our meta-analysis. First, the primary antibody sources and antibody dilution ratios in these studies varied, which led to different IHC sensitivities. Second, the definition of reduced E-cadherin expression among these studies, which resulted in that we could not draw a definitive conclusion about which was the most appropriate definition of reduced E-cadherin expression. Finally, the HRs of RFS or PFS were not reported in some studies, and we calculated them based on the detailed data reported in these articles, which may result in bias.


In conclusion, our meta-analysis indicates that reduced E-cadherin expression is significantly associated with poorer RFS and PFS in patients with NMIBC. Therefore, E-cadherin might be a useful prognostic factor for NMIBC patients. The E-cadherin expression, however, was not included in the prognostic factors in EAU guideline of NMIBC, and thus more work need to be done for the prognostic role of E-cadherin expression in NMIBC in future.


Funding


This study was supported by the National Natural Science Foundation of China (NSFC 81572516 to KW), International Science and Technology Cooperation and Exchange Program in Shaanxi Province (2016KW-021 to KW), and the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University, China (No. XJTU1AF-CRF-2015-002 to DH).


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Main characteristics of all studies included in the meta-analysis.
Author  Year  Country  Patient (M/F)  Mean age (year)  Stage  Grade  Definition of negative E-cadherin  Quality score  Median follow-up (mouth) 
Shariat [13 2001  USA  53 (42/11)  66.8  Ta-T1, Tis  I-III  The proportion of tumor cells with membranous staining less than 90%  131 
Mahnken [14 2005  Germany  69 (57/12)  68  T1  II-III  <20% of tumor cells displayed membrane-bound staining  ≥24 
Clairotte [15]a  2006  France  71  NA  T1-T3  I-III  negative (ie, complete absence of immunoreactivity) or heterogeneous (ie, when the tumor is composed of positive and negative areas) staining  NA 
Mhawech-Fauceglia [16]a  2007  Switzerland  45 (40/5)  NA  T1  Low-High  no staining, weak intensity, strong intensity but in <10% of cells or weak intensity in >10% of cells  NA 
Erdemir [17 2007  Turkey  52 (36/16)  64  T1  High  The proportion of tumor cells with membranous staining less than 90%  56.4 
Yu [18]a  2010  China  76  NR  Ta-T1  Low-High  Less than 10% of the tumour cells were stained  NA 
Gudjonsson [19 2011  Sweden  52 (40/12)  70  Ta  I-III  90% of tumour cell membrane  37.2 
Khorrami [20 2012  Iran  180 (151/29)  65  Superficial  Low  After being stained with hematoxylin, a pathologist counted the cells and compared them with a normal sample. Decreased cell counts were considered as negative immunoexpression  26 
Muramaki [21 2012  Japan  115 (95/20)  69  Ta-T1  I-III  The proportion of tumor cells with membranous staining≤90%  34 
Zhao [22]a  2014  China  64  NA  T1  Low-High  All integral optical density (IOD) values<50%  NA 
Liu [23 2015  Japan  161  NR  Ta-T1  I-III  Total scores were≤3b  47 
Breyer [24 2016  Germany  233 (195/38)  NR  Ta  I-III  Staining intensity waslost (0), weak (+) or moderate (++).  NR 
Raspollini [25 2016  Italy  92 (80/12)  72.2  T1  High  The proportion of tumor cells with membranous staining less than 90%  NR 
Otto [26 2017  Germany  226 (173/53)  72  T1  II-III  <90% positive staining of urothelial carcinomaareas  44 
SÅ‚awomir [27 2018  Poland  49 (59/17)  70.6  T1  High  Total scores were≤5c  34.8 



[a] 
The bladder samples of these papers, included both NMINC and MIBC, we extracted the detailed information of NMIBC, herein the message of mean age, Male/Female ratio and median follow-up which offered in the paper were not applicable.
[b] 
Total scores were calculated by combining immunohistochemical staining intensity and staining extent. Staining intensity was scored as 0 (no staining at all), 1 (weak), 2 (medium), or 3 (strong), and staining extent was scored as 0 (0%-5%), 1 (5%-25%), 2 (26%-75%), or 3 (75%-100%).
[c] 
Total score is a product of the percent positive cells (0, no cells with positive reaction; 1, ≤10% cells with positive reaction; 2, 11% to 50% cells with positive reaction; 3, 51% to 80% cells with positive reaction; 4, >80% cells with positive reaction) and staining intensity (0, no colour reaction; 1, poor colour reaction; 2, moderate colour reaction; 3, intensive colour reaction).


Table 2 - Stratifed analysis of pooled HR of NMIBC patients with reduced E-cadherin expression on RFS and PFS.
Stratified analysis  Recurrence-free Survival 
Progression-free Survival 
Pooled HR
(95% CI)* 
Heterogeneity
(I2/P -value) 
Meta-regression
P -value 
Pooled HR
(95% CI)* 
Heterogeneity
(I2/P -value) 
Meta-regression
P -value 
Nation       0.108      0.352 
Asia  3.78 (1.32-10.85)  89.0%/0.000    2.02 (1.56-2.62)  3.3%/0.407   
Non-Asia  1.68 (1.10-2.57)  57.0%/0.030    1.48 (0.85-2.59)  0.0%/0.728   
Cutoff of E-cad       0.945      0.619 
90%  2.13 (1.31-3.47)  56.9%/0.055    2.19 (1.38-3.46)  46.3%/0.150   
Non-90%  2.00 (0.77-5.20)  86.5%/0.000    1.79 (1.28-2.54)  0.00%/0.747   
HR estimate       0.654      0.211 
Directly  2.24 (0.61-8.19)  92.7%/0.000    2.85 (1.39-5.86)  23.6%/0.270   
Calculated  1.89 (1.37-2.62)  28.9%/0.208    1.79 (1.39-2.28)  0.00%/0.763   




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