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AbstractBackground:Whetherdepressioncausesincreasedriskofthedevelopmentofbreastcancerhaslongbeendebated.Weconductedanupdatedmeta-analysisofcohortstudiestoassesstheassociationbetweendepressionandriskofbreastcancer.MaterialsandMethods:RelevantliteraturewassearchedfromMedline,Embase,WebofScience(uptoApril2014)aswellasmanualsearchesofreferencelistsofselectedpublications.Cohortstudiesontheassociationbetweendepressionandbreastcancerwereincluded.Dataabstractionandqualityassessmentwereconductedindependentlybytwoauthors.Random-effectmodelwasusedtocomputethepooledriskestimate.Visualinspectionofafunnelplot,BeggrankcorrelationtestandEggerlinearregressiontestwereusedtoevaluatethepublicationbias.Results:Weidentifiedelevencohortstudies(182,241participants,2,353cases)withafollow-updurationrangingfrom5to38years.ThepooledadjustedRRwas1.13(95%CI:0.94to1.36;I2=67.2%,p=0.001).Theassociationbetweentheriskofbreastcanceranddepressionwasconsistentacrosssubgroups.VisualinspectionoffunnelplotandBegg’sandEgger’stestsindicatednoevidenceofpublicationbias.Regardinglimitations,aone-timeassessmentofdepressionwithnomeasureofdurationweakensthetestofhypothesis.Inaddition,8differentscaleswereusedforthemeasurementofdepression,potentiallyaddingtothemultipleconceptualproblemsconcernedwiththedefinitionofdepression.Conclusions:Availableepidemiologicalevidenceisinsufficienttosupportapositiveassociationbetweendepressionandbreastcancer.IntroductionDepressionishighlyprevalentinthegeneralpopulation,anditisestimatedthat5.8%ofmenand9.5%ofwomenwillexperienceadepressiveepisodeina12-monthperiod.Thelifetimeincidenceofdepressionhasbeenestimatedatmorethan16%inthegeneralpopulation(WorldHealthOrganization,2001;Kessleretal.,2003;WorldHealthOrganization,2008).Breastcancerisbyfarthemostcommomcancerinwomen(InternationalAgencyforResearchonCancer,2008),theglobalburdenofbreastcancermeasuredbyincidenceandmortalityissubstantialandontheincrease(Bensonetal.,2012).Thereareanestimated1.5millioncasesdiagnosedannuallyandalmost0.5milliondiedfromthisdisease,representing14%offemalecancerdeathsintheworldwide(Jemaletal.,2011;Bensonetal.,2012).Manyfactorshavebeenshowntobeassociatedwiththeoccurrenceofbreastcancer,suchashavingafirstdegreerelativewithbreastcancer,bearingthefirstchildatalateage,alcoholconsumptionandlongtermuseofmenopausalestrogenreplacementtherapy(Kampertetal.,1988;Gailetal.,1989;Slatteryetal.,1993).However,ithaslongbeendebatedthatwhetherdepressionisanincreasedriskofthedevelopmentofbreastcancer.Depressionmayaffecttheendocrineandimmunefunction(Kowaletal.,1955;Milleretal.,1993),whichmayhaveinfluenceoncancerinitiationandprogression,includingbreastcancer.Importantly,womenthemselveswidelybelievedthatdepressionwasariskfactorinthedevelopmentoftheirbreastcancer(Mitchelletal.,1995).Howeverepidemiologyevidencesontheassociationbetweendepressionandbreastcancerincidencearemixedandinconclusive.Agreatmanyofstudieshaveassessedtheassociationbetweendepressionandsubsequentrisksofbreastcancer.Apreviousmeta-analysis(Oerlemansetal.,2007)focusingonbreastcancerpooledresultsfrom7prospectivestudiespublishedbefore2003asasecondaryanalysisandreportedapooledrelativeriskestimatedof1.59(95%confidenceintervals,0.74-3.44).Sincethensomecohortstudieshavebeenpublished,whichprovidestrongerevidenceoftheassociationbetweendepressionandbreastcancer.Therefore,weconductedameta-analysisofcohortstudiestodescribetheassociationbetweendepressionandriskofbreastcancer.MaterialsandMethodsSearchstrategyWeconductedasystematicliteraturesearch(uptoApril2014)ofMedline,Embase,WebofScienceforstudiesdescribingtheassociationbetweendepressionandbreastcancer.Weusedthefollowingterms“depression”or“depressivedisorder”or“majordepressivedisorder”or“depressivesymptoms”and“breastcancer”or“breastcarcinoma”combinedwith“cohortstudy”or“prospectivestudy”or“follow-upstudy”or“longitudinalstudy”.Inaddition,studiesfromreferencelistsofallrelevantpublicationsandreviewsweresearchedtoidentifypotentialpertinentstudies.StudyselectionStudiesmeetingthefollowingcriteriawouldbeincludedinthismeta-analysis:i)thestudywasacohortdesign(prospectivecohortorhistoricalcohort);ii)theexposurewasdepressionsymptomsordepressivedisorderwhichweremeasuredbyself-reportedscalesorstructuredclinicalintervieworcliniciandiagnosis;iii)theendpointwasdiagnosisorreportofbreastcancer,allparticipantswerefreeofanysubtypesofcanceratthebeginningofthestudy;iv)thestudyreportedtheRRorhazardrisk(HR)withcorresponding95%CIsfortheassociationbetweendepressionandbreastcancer;andv)studywaspublishedinEnglish.Ifmultipleindependentpublishedreportswerefromasamecohort,onlythelatestonewasincluded.Studyselectionwasindependentlyperformedbytwoauthors(S.H.LandD.X.X)andconflictswereresolvedthroughdiscussionwiththethirdreviewer(L.Z.X).DataextractionWeextractedthefollowinginformationfromeachretrievedarticle:nameofthefirstauthor,yearofpublication,studylocation,characteristicsofstudypopulationatbaseline,durationoffollow-ups,samplesize,numbersofcases,depressionandbreastcancermeasurements,adjustedeffectestimateandco