Reduced E-cadherin expression as a

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LITERATURE REVIEW

Reduced E-cadherin expression as a

prognostic factor in non-muscle-invasive bladder cancer: A systematic review and meta-analysis

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

T. Yang

^a

, J. Fan

^a

, H. Liang

^b

, D. He

^a

, X. Zeng

^c

, J. Fan

^a

, K. Wu

^a^,∗

aDepartmentofUrology,FirstAfﬁliatedHospitalofXi’anJiaotongUniversity,710061Xi’an, PRChina

bDepartmentofPathology,FirstAfﬁliatedHospitalofXi’anJiaotongUniversity,710061 Xi’an,PRChina

cCenterforEvidence-BasedandTranslationalMedicine,ZhongnanHospital,Wuhan University,430071Wuhan,PRChina

Received27September2019;accepted14December2019 Availableonline12February2020

KEYWORDS Bladdercancer;

E-cadherin;

Prognosticfactor;

Meta-analysis

Abstract

Introductionand objectives.—The exact role ofE-cadherinin non-muscle-invasivebladder cancer(NMIBC)isstillunknown,andtheaimsofthisstudy weretoprovewhether reduced E-cadherinexpressioncanbeaprognosticfactorinpatientswithNMIBC.

Materialsandmethods.—A meta-analysiswas conducted to assess theprognostic value of reducedE-cadherinexpressioninNMIBC.ThePubMed,EmbaseandWebofSciencedatabases wereincludedinthestudysearch.

∗Correspondingauthorat:DepartmentofUrology,FirstAfﬁliatedHospitalofXi’anJiaotongUniversity,710061Xi’an,PRChina.

E-mailaddress:kaijiewu@163.com(K.Wu).

https://doi.org/10.1016/j.purol.2019.12.004

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Results.—Fifteenstudieswithatotalof1538NMIBCpatientswereincluded.Theresultsshowed thatreducedE-cadherinexpressionwassigniﬁcantlyassociatedwithpoorrecurrence-freesurvival(RFS)(pooledHR2.16,95%CI1.22—3.85)andprogression-freesurvival(PFS)(pooledHR 1.91,95%CI1.52—2.40)inNMIBCpatients.

Conclusion.—E-cadherincanbeaprognosticfactorforpatientswithNMIBC.

MOTSCLÉS Cancerdelavessie; E-cadhérine; Facteurpronostique; Méta-analyse

Résumé

Introductionetobjectifs.—Le rôleexact dela E-cadhérinedanslecancerdela vessienon invasifsurlemuscle(NMIBC)estencoreinconnu,etlesobjectifsdecetteétudeétaientde prouversilaréductiondel’expressiondelaE-cadhérinepeutêtreunfacteurpronostiquechez lespatientsatteintsdeNMIBC.

Matériauxetmethods.—Uneméta-analyseaétémenéepourévaluerlavaleurpronostiquede l’expressionréduitedelaE-cadhérinedanslaNMIBC.LesbasesdedonnéesPubMed,Embase etWebofScienceontétéinclusesdanslarecherchedel’étude.

Résultats.—Quinzeétudesportantsuruntotalde1538patientsNMIBContétéincluses.Les résultatsontmontréquel’expressionréduitedel’E-cadhérineétaitassociéedemanièresigni- ﬁcativeàunesurviesansrécidivemediocre(HRcombinée2,16,IC95%,1,22—3,85)etàune surviesansprogression(HRcombinée1,91,IC95%1,52—2,40)chezlespatientsNMIBC.

Conclusion.—LaE-cadhérinepeutêtreunfacteur pronostiquepourlespatients atteintsde NMIBC.

Introduction

Although transurethral resection followed by intravesical therapyis thestandardtreatmentfor non-muscle-invasive bladder cancer (NMIBC), the recurrence and progression ratesremainhigh,andtheprognosisisstillfarfrombeing optimistic [1]. In addition to continuously improving the treatment methods, urologists have also devoted them- selvestoimproving theaccuracy ofprognosispredictions.

In the clinic, conventional parameters listed in the Euro- pean Organization for Research and Treatment of Cancer (EORTC) risktable, suchastumorstage, grade,diameter, and numberand concurrentcarcinoma in situ (CIS),have beenextensivelyappliedtopredicttheprognosisofbladder cancer[2].However,theEORTC risktablemaystillnotbe accurate[3].Therefore,itisurgentandimperativetoiden- tifynovelparameterstoaccuratelypredicttheoutcomesof 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 bladdercancertissues[6].Furthermore,somestudieshave conﬁrmed that decreased E-cadherin expression is corre- lated withpoor survivalin human cancers,suchasbreast cancer and colorectalcancer [7,8]. Forbladder cancer, a meta-analysis of the prognostic value of E-cadherin gene promoter hypermethylation has been published, indicat- ingthat itmay contributetoan increasedrisk of bladder

cancer among Asian populations [9]. Very recently, Xie etal.alsoreportedthatreducedE-cadherinexpressionwas associatedwithpoorprognosisandadvancedclinicopatho- logical characteristics in bladder cancer [10]. However, the biological characteristics of the two types of bladder tumors (includingNMIBC and muscle-invasive bladder cancer) are totally different, and the exact role of E- cadherinin NMIBCis stillunknown. Therefore,wefurther conductedameta-analysistoassesstheassociationbetween 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 Sci- encedatabases usingthe following terms: ‘‘E-cadherin’’,

‘‘E-CAD’’, ‘‘CHD1’’, ‘‘cadherin-1’’, ‘‘bladder cancer’’,

‘‘bladder tumor’’, ‘‘bladder carcinoma’’, ‘‘bladder neo- plasm’’,‘‘urothelialcancer’’,‘‘urinarytractcancer’’,and

‘‘transitional cell carcinoma’’. The last search date was April11,2019.Furthermore,thereferencesofallretrieved articlesweremanuallysearchedforadditionaleligiblestud- ies.

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Figure1. Flowdiagramofthestudyselectionprocess.

Inclusion and exclusion criteria

The inclusion criteria in this meta-analysis were as fol- lows: (1) articles that evaluated E-cadherin expression by immunohistochemistry in bladder cancer samples; (2) articles that evaluatedthe relationship between reduced E-cadherinexpressionandtheprognosisofbladdercancer;

and(3)articlesthatprovidedsufﬁcientinformationtoesti- matehazardratios(HRs)andtheir95%conﬁdenceintervals (CIs)forrecurrence-free survival(RFS)or progression-free survival(PFS)inNMIBC.Theexclusioncriteriawereasfol- lows:(1)letters, reviews,conference abstracts,and case reports; (2) articles that could not offer enough data to calculatetheHRsforRFSor PFSin NMIBC;(3)articlesnot publishedinEnglish;(4)duplicatearticles.

Data extraction

Two investigators independently reviewed each eligible studyandextractedthefollowinginformation:ﬁrstauthor’s name;year of publication;countryof origin;number, sex andageofthepatients;tumorstageandgrade;deﬁnition of reduced, abnormal or negative E-cadherin expression;

follow-up time; and outcomes of interest (i.e., RFS and

PFS).Theinvestigatorssubsequentlycrosscheckedthedata toensureaccuracy.IftheHRand95%CIwerenotexplicitly presentedinthearticle,weestimatedthembycalculation according toK-M curvesand soon [11,12].All controver- sial problems wereresolved throughdiscussion among all authors. RFS was deﬁned as the period between TURBt andtumor recurrence,andPFS wasdeﬁnedastheperiod betweenTURBtandtumorprogression.

Quality assessment

Quality of the included studies was assessed by the Newcastle—OttawaScale, whichwasrecommendedbythe CochraneNon-RandomizedStudiesMethodsWorkingGroup.

The assessment involved scores ranging from 0 to 9 and includedthefollowingthreepoints:selection,comparabil- ity,andoutcomes;scoreshigherthan6wereconsideredto beofhighquality.Onlyhigh-qualitystudies wereincluded inthismeta-analysis.

Statistical analysis

HRswiththeir95%CIswereappliedtoevaluatetheimpactof reducedE-cadherinexpressionontheriskofNMIBC.Insome

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Table1 Maincharacteristicsofallstudiesincludedinthemeta-analysis.

Author Year Country Patient (M/F)

Mean age (year)

Stage Grade Deﬁnitionof negativeE-cadherin

Quality score

Median follow-up (mouth) Shariat[13] 2001 USA 53

(42/11)

66.8 Ta-T1,Tis I—III Theproportionof tumorcellswith membranous staininglessthan 90%

8 131

Mahnken [14]

2005 Germany 69 (57/12)

68 T1 II—III <20%oftumorcells displayed

membrane-bound staining

6 ≥24

Clairotte [15]^a

2006 France 71 NA T1—T3 I—III negative(ie,

completeabsenceof immunoreactivity) orheterogeneous (ie,whenthetumor iscomposedof positiveand negativeareas) staining

7 NA

Mhawech

—Fauceglia [16]^a

2007 Switzerland 45 (40/5)

NA T1 Low—High nostaining,weak intensity,strong intensitybutin

<10%ofcellsor weakintensityin

>10%ofcells

6 NA

Erdemir [17]

2007 Turkey 52 (36/16)

64 T1 High Theproportionof

tumorcellswith membranous staininglessthan 90%

7 56.4

Yu[18]^a 2010 China 76 NR Ta—T1 Low—High Lessthan10%ofthe tumourcellswere stained

7 NA

Gudjonsson [19]

2011 Sweden 52 (40/12)

70 Ta I—III 90%oftumourcell

membrane

6 37.2

Khorrami [20]

2012 Iran 180

(151/29)

65 Superﬁcial Low Afterbeingstained withhematoxylin,a pathologistcounted thecellsand comparedthemwith anormalsample.

Decreasedcell countswere consideredas negative

immunoexpression

8 26

Muramaki [21]

2012 Japan 115 (95/20)

69 Ta—T1 I—III Theproportionof tumorcellswith membranous staining≤90%

8 34

Zhao[22]^a 2014 China 64 NA T1 Low—High Allintegraloptical density(IOD) values<50%

7 NA

Liu[23] 2015 Japan 161 NR Ta—T1 I—III Totalscores

were≤3^b

6 47

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Table1(Continued)

Author Year Country Patient (M/F)

Mean age (year)

Stage Grade Deﬁnitionof negativeE-cadherin

Quality score

Median follow-up (mouth) Breyer[24] 2016 Germany 233

(195/38)

NR Ta I—III Stainingintensity waslost(0),weak(+) ormoderate(++).

7 NR

Raspollini [25]

2016 Italy 92 (80/12)

72.2 T1 High Theproportionof

tumorcellswith membranous staininglessthan 90%

6 NR

Otto[26] 2017 Germany 226 (173/53)

72 T1 II—III <90%positive stainingofurothelial carcinomaareas

8 44

Sławomir [27]

2018 Poland 49 (59/17)

70.6 T1 High Totalscores

were≤5^c

7 34.8

aThebladdersamplesofthesepapers,includedbothNMINCandMIBC,weextractedthedetailedinformationofNMIBC,hereinthe messageofmeanage,Male/Femaleratioandmedianfollow-upwhichofferedinthepaperwerenotapplicable.

b Totalscoreswerecalculatedbycombiningimmunohistochemicalstainingintensityandstainingextent.Stainingintensitywasscored as0(nostainingatall),1(weak),2(medium),or3(strong),andstainingextentwasscoredas0(0%—5%),1(5%—25%),2(26%—75%),or 3(75%—100%).

c Totalscoreisaproductofthepercentpositivecells(0,nocellswithpositivereaction;1,≤10%cellswithpositivereaction;2,11%to 50%cellswithpositivereaction;3,51%to80%cellswithpositivereaction;4,>80%cellswithpositivereaction)andstainingintensity (0,nocolourreaction;1,poorcolourreaction;2,moderatecolourreaction;3,intensivecolourreaction).

studies,theHRsandtheir95%CIsweredescribeddirectly.

Otherwise,wecalculatedthevaluesfromtheavailabledata in those studies. Heterogeneity across studies was evalu- atedbytheQtestandI²statistic.I²>50%andP<0.05were considered to indicate signiﬁcant heterogeneity, and the random-effectsmodelwasused;moreover,meta-regression analysiswasusedtoexplorethesourceofheterogeneity.In addition,weperformedsubgroupanalysestoinvestigatethe associationbetweenreducedE-cadherinexpressionandRFS andPFS.Begg’sandEgger’stestswereusedtoevaluatepub- licationbias,andsensitivityanalysiswasusedtoevaluate thestabilityof thepooledresults. AllP-valueswere two- sidedandconsideredstatisticallysigniﬁcantwhenP<0.05, andallstatisticalanalyseswereperformedwithStataVer- sion13.0software(StataCorporation,CollegeStation,TX, USA).

Result

Search results and characteristics of the included studies

A total of 1973 articles were identiﬁed from the three databases,andbyreviewingthetitlesandabstracts,1925 articleswereexcludedbecausetheywereirrelevanttothe objectiveofthismeta-analysisorduplicates.Subsequently, wereadthe fulltextofthe remaining48articles,and33 articles were further excluded for the following reasons:

reviews (N=5), muscle-invasive bladder cancer samples werepresentedinallsamplesanddetailedinformationon NMIBCwasnotgiven(N=5),nooutcomesofinterest(N=12),

data couldnot beextracted (n=9), andnot bladder cancer(N=2).Finally,atotalof15studies[13—27]with1538 NMIBCpatientswereincludedinthismeta-analysis,ofwhich 4studies[15,16,18,22]includedbothNMIBCandMIBC,and weextractedthedetailedinformationofNMIBC.Thestudy selectionprocessisshowninFig.1.Themaincharacteristics oftheincludedstudiesarelistedinTable1.Thenumberof patientsrangedfrom45to233,andthemeanage ranged from64to69years.

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

The pooledresultsrevealedthat patientswithreducedE- cadherin expression had poor RFS (pooled HR 2.16, 95%

CI 1.22—3.85) with signiﬁcant heterogeneity (I²=86.5%, P=0.000) (Fig. 2A). Subgroup analyses were performed according to study location, the cutoff value of the E- cadherinexpressionlevelandthemethodofHRestimation (Table2).TheresultsdemonstratedthatreducedE-cadherin expression was signiﬁcantly associated with RFS in both Asianandnon-Asianpatients.ThepooledHRwas2.13(95%

CI 1.31—3.47) extracted from articles in which the deﬁ- nitionof negative/reducedE-cadherin expression wasless than 90% of tumor cells withmembranous staining,while theothergroupshowedthatE-cadherinexpression hadno impactonRFS.WhentheHRestimationmethodwastaken intoconsideration, thepooledHRdirectly extracted from thestudieswas2.24(95%CI0.61—8.19),andthepooledHR obtainedfromthecalculationwas1.89(95%CI1.37—2.62).

Thepooledresultsrevealedthatpatientswithreduced E-cadherin expression had a poor PFS (pooled HR 1.91,

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Figure2. Meta-analysisoftheeffectsofE-cadherinexpressiononrecurrence-freesurvival(A)andprogression-freesurvival(B)inpatients withNMIBC.

95%CI1.52—2.40)withnosigniﬁcantheterogeneity(I²=0%, P=0.543) (Fig. 2B). Similar to that for RFS, subgroup analyses were performed, and the results showed no sig- niﬁcant association between E-cadherin expression and PFS in Asianpatients (pooledHR 1.48,95% CI 0.85—2.59) (Table2).

ForbothRFS andPFS,meta-regressionanalysisshowed thatnation,cutoffoftheE-cadherinexpressionlevel,and

HRestimationwerenotsigniﬁcantcontributorstointerstudy heterogeneity.

Sensitivity analysis

We performed sensitivity analysis to assess the stability of our results by omitting individual studies. The results

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Table2 StratifedanalysisofpooledHRofNMIBCpatientswithreducedE-cadherinexpressiononRFSandPFS.

Stratiﬁed analysis

Recurrence-freeSurvival Progression-freeSurvival PooledHR

(95%CI)*

Heterogeneity (I²/P-value)

Meta- regression P-value

PooledHR (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 Cutoffof

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

suggested thatnone of the individualstudies signiﬁcantly affectedthepooledestimate(Fig.3AandB).

Publication bias evaluation

BothEgger’stestandBegg’sfunnelplotswereusedtoassess the potential publication bias in this meta-analysis. The resultssuggested that signiﬁcant publicationbiaswasnot detectedforeitherRFS (PEgger=0.147,PBegg=0.917)orPFS (PEgger=0.147,PBegg=0.533)(Fig.3CandD).

Discussion

Clinically,the EORTC risk table and CUETO scoring model havealreadybeenacceptedastoolsforpredictingtherisk 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—32], have been estimated in selected patientpopulations. Manystudies have demonstratedthe valueof decreased E-cadherinexpression in theprognosis ofsomehumancancertypes[7,8].However,theexactrole of E-cadherin in NMIBCis stillunknown. According toour meta-analysis,E-cadherinwassigniﬁcantlyassociatedwith RFSandPFSinNMIBC,sowemightpredicttheprognosisof patientsaccordingtotheexpressionstatusofE-cadherinin NMIBCsamplesfollowingTURBt.

We combined the outcomes of 15 studies with 1538 NMIBCpatientsandconcludedthatreducedor negativeE- cadherinexpression wassignificantlyassociatedwithpoor RFS and PFS, although significant heterogeneity existed whenpoolingthesurvivaldataassociatedwithRFS.Wefur- ther conductedsubgroup analysis according tothe nation ofthe patients,the definitionof negative/lowE-cadherin

expression and the method of HR estimation.The results showedthatE-cadherinexpressionwassigniﬁcantlyassoci- atedwithRFSwithslightheterogeneitywhenlessthan90%

ofNMIBCcellswerestainedbyimmunohistochemistry,while the other subgroups showed that E-cadherin expression had noimpact onRFS with significant heterogeneity.The potential reasoncouldbedifferent definitionsof reduced E-cadherinexpressionindifferentstudies.Insubgroupanal- ysisaccordingtothenationofpatients,theresultsshowed thattheexpressionofE-cadherinwasonlysignificantlyasso- ciatedwithRFSfor both Asianand non-Asianpatients but not PFS in Asian patients. In subgroup analysis according tothemethods ofHRestimation,theresults showedthat theexpressionofE-cadherinwasnotsignificantlyassociated withRFSwhenthe HRand95% CIweredirectlyextracted fromthestudies.The potentialreasonmaybethelimited numberofNMIBCsamplesinthissubgroup.

Unfortunately,we didnotdeterminethesourceofhet- erogeneityforRFSbysubgroupanalysisandmeta-regression analysis.However,inthesubgroupanalysisofthedefinition of negative/low E-cadherin expression, theheterogeneity was56.9%,andtheP-valuewas0.055whenthedefinition ofnegative/lowE-cadherinexpressionwaslessthan90%of tumor cells withmembranous staining.Inaddition,in the subgroupanalysisoftheHRestimationmethod,thehetero- geneitywas28.9%,andtheP-valuewas0.208whentheHR wascalculated,whilethedirectextractionofHRhadhigh heterogeneity.Wespeculatedthatthedefinitionofnegative E-cadherinexpressionaswellastheHRestimationmethod maybesourcesofheterogeneityinthesestudies.

Inevitably,somelimitationsexistedinourmeta-analysis.

First, the primary antibody sources and antibody dilution ratios in these studies varied, which led todifferent IHC sensitivities.Second, the deﬁnitionofreducedE-cadherin expressionamongthesestudies,whichresultedinthatwe

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Figure3. SensitivityanalysisoftheeffectsofE-cadherinexpressiononrecurrence-freesurvival(A)andprogression-freesurvival(B)in patientswithNMIBC.FunnelplotfortheeffectsofE-cadherinexpressiononrecurrence-freesurvival(C)andprogression-freesurvival(D) inpatientswithNMIBC.

couldnotdrawadeﬁnitiveconclusionaboutwhichwasthe mostappropriatedeﬁnitionofreducedE-cadherin expression. Finally, theHRs of RFS or PFS werenot reportedin somestudies,andwecalculatedthembasedonthedetailed datareportedinthesearticles,whichmayresultinbias.

In conclusion,ourmeta-analysisindicates thatreduced E-cadherinexpressionissigniﬁcantlyassociatedwithpoorer RFSandPFSinpatientswithNMIBC.Therefore,E-cadherin mightbeausefulprognosticfactorforNMIBCpatients.The E-cadherin expression, however, was not included in the prognosticfactorsinEAUguidelineofNMIBC,andthusmore workneedtobedonefortheprognosticroleofE-cadherin expressioninNMIBCinfuture.

Funding

This study wassupported bythe National NaturalScience FoundationofChina(NSFC81572516toKW),International ScienceandTechnologyCooperationandExchangeProgram in ShaanxiProvince (2016KW-021 toKW), andthe Clinical ResearchAwardoftheFirstAfﬁliatedHospitalofXi’anJiao- tongUniversity,China(No.XJTU1AF-CRF-2015-002toDH).

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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