Risk Factors For Prostate Cancer

OfficialreprintfromUpToDate
www.uptodate.com.scihub.ac2016UpToDate
Riskfactorsforprostatecancer
Author: AOliverSartor,MD
SectionEditors: NicholasVogelzang,MD,WRobertLee,MD,MS,MEd,JeromePRichie,MD,FACS
DeputyEditor: MichaelERoss,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Oct20,2016.
INTRODUCTIONProstatecanceristhesecondmostcommoncancerinmenworldwide,withanestimated
1,100,000casesand307,000deathsin2012[1].Thecurrentlifetimeriskofprostatecancerformenlivingin
theUnitedStatesisestimatedtobeapproximatelyoneinsix[2].
Ratesofprostatecancerdifferover50foldamongvariousinternationalpopulations(figure1)[3].However,
interpretationofthesedataiscomplicatedbydramaticchangesintheincidenceofprostatecancerintheUS
andotherWesterncountriesthathavetakenplaceoverthepastseveraldecades.Thesechangeshavebeen
primarilydrivenbytheincreasedfrequencyofprostatebiopsiesperformedinasymptomaticmenbecauseof
anelevatedprostatespecificantigen(PSA)level.IntheUnitedStates,theincidenceofprostatecancer
dramaticallyroseintheearly1990sconcomitantwiththeincreasingutilizationofPSAtesting.Afteraninitial
peak,incidenceratesfell,buttheyhavepersistedataratenearlytwicethatrecordedintheprePSAera.A
centralargumentagainstroutinePSAscreeningisthatmanyofthesecancers,ifleftundetected,wouldnever
havebecomeclinicallymeaningfulduringaman'slifetime.(See"Screeningforprostatecancer".)
Ascertainmentbiasesconstituteanimportant,butincomplete,explanationfortheobservedinternational
variationsinprostatecancerincidence.CountriesthatdonotutilizePSAtestingtypicallyhaveamuchlower
rateofprostatecancercomparedwiththosethatdo.Unlessstudiescontrolforthenumberofprostate
biopsiesperformed,itisdifficultifnotimpossibletobedefinitiveintheconclusions.
Oftheseveralknownprostatecancerriskfactors,themostimportantareage,ethnicity,geneticfactors,and
possiblydietaryfactors.Theknownriskfactorsforprostatecancerarereviewedhere.Screeningforprostate
cancerandtheclinicalmanifestationsanddiagnosisofthisdisorderarediscussedseparately.(See
"Screeningforprostatecancer"and"Clinicalpresentationanddiagnosisofprostatecancer".)
Thisreviewwillfocusonthemostcommonhistologictypeofprostatemalignancy(adenocarcinoma)which
comprisesover99percentofthemalignancieswhichaffectthisorgan.Otherhistologiesincludesmallcell
neuroendocrinetumors,sarcomas,andlymphomas,whicharerarelyencountered.(See"Interpretationof
prostatebiopsy".)
AGEProstatecancerhasoneofthestrongestrelationshipsbetweenageandanyhumanmalignancy
(figure2).
Clinicallydiagnosedprostatecancerrarelyoccursbeforetheageof40,buttheincidencerisesrapidly
thereafter[4,5].IndatafromtheNationalCancerInstitute'sSurveillance,Epidemiology,andEndResults
(SEER)program,theannualincidenceofnewcasesofprostatecancerinwhitemenin1995was
approximately0.1,0.6,and1percentinmenintheir50s,60s,and70s,respectively[5].Althoughthe
incidenceofnewcasesdeclinesformenintheir80s,thisalmostcertainlyisattributabletothefactthatfewer
ofthesemenhaveprostatespecificantigen(PSA)drivenbiopsies.
Theprevalenceofmalignancybaseduponhistologicexaminationoftheprostatefrommenwithoutclinical
SciHub https://www.uptodate.com/contents/riskfactorsforprostatecancer?source=search_result&search=D
evidenceofprostatecancerismuchhigherthantherateofclinicallydiagnoseddisease[6].Althoughthe
URL,DOI,
reportedprevalenceratesforoccultprostatecancerhavevariedsubstantiallyindifferentstudies,the
prevalenceincreaseddramaticallywithageinallstudies.
Thewidespreadprevalenceofoccultprostatecancerinoldermenandthedramaticincreasewithageare
illustratedbyareviewofautopsystudiesconductedinmultiplecountries[6]:
20to30years,2to8percentofmenwithoccultcancer
31to40years,9to31percent

Thevariabilitybetweenreportsmayreflectdifferencesinpathologictechniques,orgeographicdifferences
duetoenvironmentalorethnicfactors.
ETHNICITYProstatecancerismorecommoninblackthanwhiteorHispanicmen,perhapsrelatedtoa
combinationofdietaryand/orgeneticfactors(figure3)[5,79].Theannualizedaverageincidenceratesfor
menintheirearly70sper100,000populationisapproximately1600,1000,and700forAfricanAmericans,
whites,andAsianAmericans,respectively.AlthoughincidenceratesinNativeAmericansareevenlowerthan
inAsianAmericans,ascertainmentbiasespreventcrediblecomparisons.
Inadditiontohigherincidencerates,theageofonsetinAfricanAmericanmenisearlierthanforcomparative
groups.Inamultiinstitutionalseriesofover12,000cases,8.3percentofblacksand3.3percentofwhites
werelessthan50yearsofage[10].
ManystudieshavefoundthatAfricanAmericanmenalsohavehigherserumprostatespecificantigen(PSA)
levels,worseGleasonscores,andmoreadvancedstageofdiseaseatthetimeofdiagnosis[1113].Inthe
populationbasedProstateCancerOutcomesStudy,theincreasedriskofadvancedstagediseasepersisted
inAfricanAmericanmen,evenafteradjustmentforsocioeconomic,clinical,andpathologicvariables[11].One
reportfoundthatAfricanAmericanmendiagnosedatanearlystagestillhadahigherthanexpectedrateof
biochemicalrecurrence[14].
Poorhealthliteracyhasbeenimplicatedasafactorforadvancedstageatpresentation,irrespectiveofrace
[15].Alsoofinterest,AfricanAmericanmenaged60andolder(butnototheragegroups)withclinically
localizedprostatecancerreceivedaggressivetreatmentsignificantlylessoftenthaneitherCaucasianor
Hispanicmen[16].Similarresultshavebeennotedbyothers[17].Thereasonsforthedifferencesincare
receivedarenotcompletelyknownbutwhenstratifiedbypretreatmentstage,grade,andPSA,theresultsof
moststudiesdonotsupportdifferencesinoutcomeforAfricanAmericanmenascomparedwithCaucasians
[13,1719].
GENETICFACTORSAlthoughthereisevidencethatprostatecancerhasastronggeneticcomponent,
identifyingspecificgenesthatunderliethediseasehasprovenchallenging.Researchhassuggestedthe
involvementofvariousgenes,butresultshavebeeninconsistentacrossstudies.
Evidencesupportingtheroleofgeneticfactorscomesfromstudiesofrelativesofpatientswithprostate
cancer,fromgenomewideassociationstudies,andfromstudiesinpatientswithabnormalitiesinknown
cancerassociatedgenessuchasBRCA2andBRCA1.
URL,DOI,
FamilystudiesTheriskofprostatecancerisincreasedinmenwithoneormoreaffectedfirstdegree
relatives(brother,father)[2024].Thereisatrendtowardafurtherincreasedriskwithagreaternumberof
affectedfamilymembersmenwithtwoorthreeaffectedfirstdegreerelativeshada5and11foldincreased
riskofprostatecancer,respectively,inonecasecontrolstudy[20].Earlyageofonsetinafamilymemberalso
increasestherisk[2023,25].
ThemagnitudeofincreasedriskwasillustratedbyastudyfromtheProstateCancerdataBaseSweden
(PCBaSe)thatcomparedtheriskofprostatecancerin51,897menwhowerebrothersof32,807indexcases
[24].Theoverallriskofdevelopingprostatecancerformenwithonebrotherwiththediseasewas14.9and

30.3percentatages65and75years,respectively,comparedwith4.8and12.9percent,respectively,inthe

generalSwedishpopulation.Therewasasimilarmagnitudeofincreasedriskwhentheanalysiswasrestricted
tothedevelopmentofnonlowriskprostatecancerandhighriskprostatecancer,andtherewasamore
markedincreaseinriskwhenmorethanonebrotherhadprostatecancer.
Additionalevidencecomesfromastudyof45,000Scandinaviantwinpairsconcordanceforcancerin
identicaltwinswashigherforprostatecancerthaneitherbreastorcolorectalcancer(CRC)[26].Thisstudy
estimatedthatasmuchas42percentoftheriskofprostatecancercouldbeexplainedbyheritablefactors.
Inadditiontoaffectingtheriskofdevelopingprostatecancer,geneticfactorsmayinfluencetheprognosisin
menwhododevelopprostatecancer.InaSwedishstudybasedupon610menwithprostatecancerwhose
fathersalsohadprostatecancer,thesurvivalofsonscorrelatedthatoftheirfathers[27].Whenfathers
survivedforfiveyearsormore,thehazardratiofordeathintheirsonswas0.62(95%CI0.410.94),
comparedwiththosewhosefathershadsurvivedfewerthan24months.
GenomewideassociationstudiesGenomewideassociationstudieshaveidentifiedallelesthatare
associatedwithanincreasedsusceptibilitytoprostatecancer[2837].Thestudiesrelyuponthepresenceof
geneticvariations,knownassinglenucleotidepolymorphisms(SNPs).Thisapproachhasidentifiedmultiple
fociinthe8q24region[2835]andthe17qregion[36,37],aswellasotherinchromosomes[34,35].
Thisapproachisillustratedbyastudythatutilized2893Swedishmenwithprostatecancerand1781controls.
TheriskofprostatecancerwasevaluatedusingapaneloffiveSNPsfromthreelociin8q24,aswellassingle
sitesin17q12and17q24.3[37].AlthoughtheincreasedriskwasrelativelylimitedifanyoneoftheseSNPs
waspresent(riskratios[RR]1.22to1.53),theriskincreaseddramaticallyiffourofthefiveSNPswere
present(RR4.47,95%CI2.936.80).TheriskwasfurtherincreasediffourorfiveoftheSNPswerepresent
andthesubjecthadafamilyhistoryofprostatecancerinafirstdegreerelative(RR9.46,95%CI3.6224.72).
Despitetheassociationofthesegeneticvariantswiththedevelopmentofprostatecancer,noneofthefive
wassignificantlyassociatedwithprognosticparametersinmenwithprostatecancer(Gleasonscore,serum
prostatespecificantigen[PSA]levelatdiagnosis,age).Althoughtheinformationfromapanelofthese
markersmaybeusefulinidentifyingmenwhoareathighriskforprostatecancer,additionalprospective
evaluationsarenecessarytoestablishtheutilityofthisapproachinadditionalpopulations.
AlthoughtheSNPsarenotnecessarilywithinaknowngene,theycanbeusedtoidentifycandidategenes
thatrequirefurtherconfirmation.AmongthegenesthathavebeensuggestedinthiswayareHOXB13,
MSMB(betamicroseminoprotein),LMTK2,KLK3,CPNE3,IL16,CDH13,andHNF1B[34,35,38].Genes
identifiedthroughsuchgenomewideassociationstudiesmayeventuallyhavearoleinprostatecancer
screeningorastherapeutictargets.Alternatively,giventheincreasinglyappreciatedcomplexityofthenon
codinggenome,itisalsoplausiblethattheseSNPsaffectnoncodingRNAexpressioninwaysthatareyetto
befullyappreciated.
Limitationsingeneticscreeningshouldalsobenoted.Limitedstudiesinvariousethnicgroupshavebeen
reportedoutsideofthe8q24region,andsignificantvariationinthecontributionofvariousSNPstoprostate
SciHub
cancerriskinvariousethnicgroupswouldnotbeunexpected.Lackofcurrent"riskSNPs"cannotbeequated
https://www.uptodate.com/contents/riskfactorsforprostatecancer?source=search_result&search=D
tolowerrisk,asanumberofunidentifiedgeneticfactorsmaycontributetoriskinameaningfulway.
URL,DOI,
Deletionofsequencesfromchromosome8pisacommoneventinthegenomeofprostatetumors[39].
Resultsfromgeneticlinkagestudieshavealsoprovidedsomeevidencethatgermline8palterationsmaybe
linkedtohereditaryprostatecancer[40,41].Whetherthereisalinkagebetweenthegermlineandsomatic
geneticchangeshasyettobeconclusivelydemonstrated.
Thesegenomeassociationstudiesprovideevidencesupportingthegeneticcomplexityofprostatecancer
[42].WhenmultipleSNPsareconsideredinaggregate,thesestudieshaveapredictivepowerforprostate
cancerthatappearstobesimilartothatofserumPSA.Additionalstudieswillberequiredtodetermine
whethertheycanbecombinedwithPSAlevelsandotherclinicalfactors(ie,age,race,familyhistory,prior

biopsies)inidentifyingmenwhoareatparticularlyhighriskofbeingdiagnosedwithprostatecancer.
DNArepairgenemutationsGermlinemutationsinDNArepairgenesaremorecommoninmenwith
prostatecancerthaninthegeneralpopulationandareassociatedwithmoreaggressivedisease.
Inastudyof692menwithmetastaticprostatecancer,germlineDNAwasanalyzedforthepresenceof
mutationsin20DNArepairgenesknowntobeassociatedwithcancerpredispositionsyndromes[43].This
cohortwasnotselectedonthebasisofafamilyhistoryofprostatecancer.Mutationswereidentifiedin82
men(11.8percent).Thiswassignificantlymorefrequentthaninacohortof499menwithlocalizedprostate
cancer(4.6percent)orinacohortof53,105menwithoutcancer(2.7percent).
Mutationswereidentifiedin16ofthe20genesstudied.ThemostcommonlyinvolvedgenewasBRCA2(37
men,5.3percent).OthergenesinvolvedincludedATM(11,1.6percent),CHEK2(10,1.9percentofthose
analyzed),BRCA1(6,0.9percent),RAD51D(3,0.4percent),andPALB2(3,0.4percent).Mutationswere
alsoidentifiedin11otherDNArepairgenes.
BRCA2ThemostfrequentlymutatedDNArepairgeneisBRCA2.ProstatecancerinmenwithBRCA2
mutationsappearstobeassociatedwithahigherGleasonscore[44,45]andasubstantiallyworseprognosis
[4650].
InastudyfromIcelandthatincluded30menwitha999del5mutationinBRCA2,prostatecancerwas
diagnosedatearlierage(69versus74years)andwasassociatedwithasignificantlyshortersurvival(2.1
versus12.4years)[46].Similarly,inamultinationalcohortstudyofmenwithprostatecancerthatincluded183
menfromknownBRCA2familiesand119fromBRCA1families,thosefromBRCA2familieshada
significantlyshortersurvival(4.0versus8.0years)[47].
TheIMPACTstudyislookingatthefeasibilityandroleofPSAscreeninginmenwhoarecarriersforBRCA1
orBRCA2mutations[51].Thestudyincludes1520menwhoarecarriersforeitherBRCA1orBRCA2
mutationsaswellas959controlswhoaretestednegativeforapathogenicBRCAmutationintheirfamily.The
meanageatstudyenrollmentwas54years.Menwerereferredforconsiderationofbiopsybasedupona
criterionofPSA3.0ng/ml.Atthebaselinescreening,199men(8percent)werereferredforbiopsy.Prostate
cancerwasdetectedin59cases(2.4percentoftheentirecohort),and75percentofthesehadintermediate
orhighriskdisease.Therewerenostatisticallysignificantdifferencesbetweenmutationcarriersorcontrolsat
thisbaselineevaluation.Resultsfromadditionalroundsofscreeningwillberequiredtoassessthevalueof
screeninginthispopulation.
Althoughtheoverallriskofprostatecancerbeforetheageof50islow,andthereisnoevidencethatearly
detectionthroughscreeningimprovessurvivalinanypopulation,guidelinesfromtheAmericanSocietyof
ClinicalOncologists(ASCO)suggestthatmenwithinheritedmutationsbeginscreeningforprostatecancer
priortoage50[52].GuidelinesfromtheNationalComprehensiveCancerNetwork(NCCN)recommendthat
therisksandbenefitsofprostatecancerscreeningbediscussedatage40inthishighriskgroup[53].(See
"Screeningforprostatecancer"and"Geneticcounselingandtestingforhereditarybreastandovariancancer"
and"Overviewofhereditarybreastandovariancancersyndromes".)
LynchsyndromeLynchsyndromeisthemostcommoncauseofinheritedCRC.Itischaracterizedbya
significantlyincreasedriskforCRCandendometrialcanceraswellasariskofseveralothermalignancies.
URL,DOI,
Lynchsyndromeisanautosomaldominantdisorderthatiscausedbyagermlinemutationinoneofseveral
DNAmismatchrepair(MMR)genes.
Astudyof4127menfromfamilialcancerregistriesfoundthatthecumulativeriskofprostatecancerwas
significantlyincreasedcomparedwiththegeneralpopulation(6.3versus2.6percentatage60years,and30
versus18percentatage80years)[54].(See"Lynchsyndrome(hereditarynonpolyposiscolorectalcancer):
Clinicalmanifestationsanddiagnosis".)
FanconianemiaFanconianemiaisaninheritedbonemarrowfailuresyndromecharacterizedby

pancytopenia,predispositiontomalignancy,andpresenceofspecificphysicalabnormalities.Fanconianemia

hasbeenassociatedwithmutationsinanumberofgenesresponsibleforDNArepair.Populationbased
studiessuggestthattheremaybeanassociationwithanincreasedriskofprostatecancer[5557].
HOXB13ThehomeoboxB13(HOXB13)genecodesforatranscriptionfactorthatisimportantinprostate
development.TheG84EvariantofthehomeoboxB13(HOXB13)genewasidentifiedbysequencingofthe
17q2122regioninfourfamilieswithhereditaryprostatecancer[58].Confirmatorystudiesin5083unrelated
subjectswithprostatecancerand1401controlsfounda20foldincreaseinthefrequencyofthisvariantin
menwithprostatecancercomparedwiththosewithoutprostatecancer(1.4versus0.1percent).The
molecularpathwaysandimplicationsforthemolecularpathogenesisofprostatecancerduetoabnormalities
inHOXB13remaintobeidentified.(See"Molecularbiologyofprostatecancer",sectionon'HOXB13'.)
DIETComprehensivereviewsoftheassociationbetweenintakeofnutrientsandtheriskofprostatecancer
areavailable[59,60].Themostimportantcomponentsofthedietandtheintakeofsomevitaminandmineral
supplementswillbediscussedhere.Theuseofsomeofthesecompoundsaschemopreventiveagentsis
discussedindetailelsewhere.(See"Chemopreventionstrategiesinprostatecancer".)
AnimalfatAdiethighinanimalfatmaybeanimportantfactorinthedevelopmentofprostatecancer[61
65].Inparticular,intakeoflargeamountsofalphalinolenicacidandlowamountsoflinoleicacidappeartobe
associatedwithincreasedriskthiscombinationiscommoninredmeatandsomedairyproducts[6466].
VegetablesAdietlowinvegetablesmaybeanotherriskfactorforprostatecancer[62,67,68].Acase
controlstudyfoundahigherprostatecancerriskinmenwhoconsumelessthan14servingsofvegetables
weekly,comparedwith28ormoreservings(adjustedoddsratio1.54)[67].
Ontheotherhand,therewasnoassociationbetweenfruitand/orvegetableconsumptionandtheriskof
prostatecanceramong29,361meninthescreeningarmoftheProstate,Lung,ColorectalandOvarian
(PLCO)CancerScreeningTrial,1338ofwhomdevelopedprostatecancer[69].Highintakeofcruciferous
vegetables(particularlybroccoliandcauliflower)wasassociatedwithasignificantlylowerriskofextra
prostatictumors(stageIIIorIV(table1AB))atpresentation.BecausethePLCOtrialcontrolsforprostate
cancerscreening,thesedatamaybeviewedasaparticularlyimportantstudyofdietaryhabitsandprostate
cancerrisk.
LycopeneandtomatobasedproductsTomatobasedproductsarerichinlycopene,whichhaspotent
antioxidantproperties.Theseobservationshaveledtoanalysesoftheimpactoflycopeneandtomatobased
productsontheincidenceandnaturalhistoryofprostatecancer.
Initialstudiesoftheimpactoflycopenecontainingfoodsontheriskofprostatecancergaveconflictingresults
[7072]a2007UnitedStatesFoodandDrugAdministrationevidencebasedreviewconcludedthattherewas
nocredibleevidencetosupportanassociationbetweenlycopeneintakeandareducedriskofprostate
cancer,andonlylimitedevidencetosupportanassociationbetweentomatoconsumptionandreduced
prostatecancerrisk[73].
Morerecently,ananalysisofaprospectivecohortof51,529menfromtheHealthProfessionalsFollowup
SciHub
Studyhassuggestedthatdietaryintakeoflycopeneisassociatedwithalowerincidenceofprostatecancer
URL,DOI,
andadecreasedriskoflethalprostatecancer[74].Analysisoftumorbiomarkerswasconsistentwitha
possibleroleofinhibitionoftumorneoangiogenesisasthemechanismunderlyingtheseobservations.
Potentialexplanationsforthedifferencebetweentheseobservationsandtheconflictingresultsseenearlier
includemoredetailedassessmentofdietarylycopene,awiderrangeoflycopenelevelscomparedwithearlier
studies,andthefocusonthemoreaggressiveprostatecancers.However,thesedataareobservationaland
thepossibleroleofconfoundingfactorscannotbeexcluded.
SoyintakePhytoestrogens(flavones,isoflavones,lignans)arenaturallyoccurringplantcompoundsthat

haveestrogenlikeactivity.Genisteinanddaidzein,thepredominantisoflavonesinhumannutrition,are
derivedmainlyfromsoybeansandotherlegumes.
Itispostulatedthatphytoestrogenssuchasthosefoundinsoyfoodsmayreduceprostatecancerriskeither
viatheirinherentestrogenicproperties(whichfavorablyaltersthehormonalmilieu),orbyinhibitionofthe
enzyme5AR,whichdecreasesconcentrationsofthemoreprostateactiveandrogendihydrotestosterone.
ThehigherintakeofsoyproductsamongAsianmenhasbeenhypothesizedtobeonereasonforthelower
incidenceofprostatecanceramongthesemen.
Althoughfewhumanstudieshavebeenconducted,cohortstudieshaveshownamodestprotectivebenefitof
soyintakeonprostatecancerrisk[7577].Ametaanalysisoftwocohortandsixcasecontrolstudies
addressingtheprotectivebenefitofsoyfoodintakeontheriskofprostatecanceryieldedanoverallrisk
estimateof0.70(95%CI0.590.83)[78].Theutilityofsoyproteinasachemopreventiveagentisdiscussed
elsewhere.(See"Chemopreventionstrategiesinprostatecancer".)
Omega3fattyacidsandfishoilCasecontrolanalysesofserumsamplesfromtwolargetrials(Prostate
CancerPreventionTrial[PCPT],SeleniumandVitaminECancerPreventionTrial[SELECT])foundthathigh
levelsofomega3fattyacids,suchasthosefoundinfishoil,wereassociatedwithanincreasedriskof
clinicallysignificant,highgradeprostatecancer[79,80].Thesestudiescannotbeconsidereddefinitive,but
thesedataconcerningtheeffectofomega3fattyacidsonprostatecancerriskshouldbeconsideredin
balancingthepotentialrisksandbenefitsoftheseagents.(See"Fishoilandmarineomega3fattyacids".)
AlcoholA2001metaanalysisbasedupon235studiesthatincludedover117,000casesfailedtoidentifya
consistentrelationshipbetweenalcoholintakeandprostatecancer[81].Thisissuewassubsequently
addressedintheprospectiveProstateCancerPreventionTrial[82].Therewasnoassociationbetween
alcoholconsumptionandprostatecancerriskin10,660menwithnoormoderatealcoholintake(0to<50
g/day).However,amongthe260menconsuming50g/day(2.4percentoftheentirepopulation),therelative
riskofhighgradeprostatecancerwas2.0(95%CI1.33.1).
CoffeeIncreasingconsumptionofcoffeeappearstobeassociatedwithadecreasedriskoflethalprostate
cancer(definedasfatalormetastatic).Aprospectiveanalysisofalmost48,000menfromtheHealth
ProfessionalsFollowupStudyidentified5035menwithconfirmedprostatecancer,including642whodiedor
hadmetastaticdisease,identifiedovera20yearperiod[83].Thedecreaseinriskoflethalprostatecancer
wasinverselyproportionaltoincreasesincoffeeconsumption(relativerisk0.44,95%CI0.220.75,forthose
drinkingsixormorecupsofcoffeeperday),andthedecreasedriskwaspresentaftercontrollingforother
knownprostatecancerriskfactors.Theinverserelationshipappearedtoberelatedtocoffeecomponents
otherthancaffeineasimilarlevelofprotectionwasseenforthosedrinkingregularanddecaffeinatedcoffee.
Vitaminandmineralsupplements
MultivitaminsTheregularuseofmultivitaminsdoesnotappeartoaffecttheriskofearlyorlocalized
prostatecancer[84].However,tworeportshaveobservedanincreasedriskofadvancedorfatalprostate
cancerinmenusingrelativelylargeamountsofmultivitamins[84,85].
SciHub
Thepotentialrelationshipbetweentheselfreportedfrequencyofmultivitaminuseandprostatecancerwas
illustratedbyaprospectivestudyof295,000men[84].Multivariateanalysesshowednosignificantincreasein
URL,DOI,
theoverallincidenceofprostatecancer,regardlessofthefrequencyofmultivitaminuse.However,therewas
anincreaseinbothadvancedandfatalcasesofprostatecanceramongmenusingmultivitaminsmorethan
seventimesperweekcomparedwiththoseusingsuchvitaminslessfrequentlyornotatall(RR1.32,95%CI
1.041.67andRR1.98,95%CI1.073.66,respectively).
Thisincreasedriskofadvancedorfatalprostatecancermayhavebeenduetotheincreaseduseof
multivitaminsinmenwithsymptomsofundiagnoseddisease.Additionalstudyofapossiblerelationshipis
needed.
FolicacidDietarysupplementationwithfolicacidwasassociatedwithanincreasedincidenceof

prostatecancerinasecondaryanalysisfromtheAspirin/FolatePolypPreventionStudy[86,87].
Aspartofatrialtoassessthechemopreventionofcolorectalpolyps,34histologicallyconfirmedcasesof
prostatecancerwerediagnosedamong643evaluablemenwhohadbeenrandomlyassignedtoeitherfolic
acid(1mg/day)orplacebo[86].Atamedianfollowupofsevenyears,thetenyearincidenceofprostate
cancerwassignificantlyincreasedinthosegivenfolicacid(9.7versus3.3percentwithplacebo,hazardratio
2.63,95%CI1.235.65).However,therewasnoincreaseintheriskofprostatecanceramongthosewith
higherbaselinedietaryfolateintake.
Thetotalnumberofcasesofprostatecancerwaslimitedinthistrial,andadditionalstudiesarerequiredto
understandtherelationshipbetweenfolicacidandthedevelopmentofprostatecancer.
SeleniumandvitaminETherelationshipbetweenprostatecancer,andseleniumintakeandlevelis
complex.
Themostcomprehensivedatacomefromanindividualpatientdatametaanalysisconductedbythe
EndogenousHormones,NutritionalBiomarkers,andProstateCancerCollaborativeGroup[88].Thisanalysis
includeddatafrom15studiesincluding6947menwithprostatecancerand8170controls.
Inthesubsetofcaseswhereseleniumlevelsweremeasuredintheblood,theseleniumlevelwasnot
associatedwithadifferenceintheriskofprostatecancer(oddsratio1.01,95%CI0.831.23).However,
highbloodlevelswereassociatedwithlowerriskofaggressivedisease(advancedstagediseaseand/or
prostatecancerdeath).
Inthosecaseswhereseleniumwasmeasuredinnailsratherthanblood,thelevelofnailseleniumwas
associatedwithadecreasedincidenceofprostatecancer(oddsratio0.29,95%CI0.220.40)inboth
nonaggressiveandaggressivedisease.
Resultsfromlargerandomizedtrialsspecificallyassessingthesecompoundsaschemopreventiveagents
haveprovidednoevidenceofanydecreaseinprostatecancerrisk,andinfact,theremaybeastatistically
significantincreasedriskwithvitaminE.(See"Chemopreventionstrategiesinprostatecancer",sectionon
'Selenium'and"Chemopreventionstrategiesinprostatecancer",sectionon'VitaminE'.)
ZincAtleasttwostudieshavesuggestedanassociationbetweenzincsupplementuseandan
increasedriskofprostatecancer[89,90].IntheHealthProfessionalsFollowUpStudy,whichincluded46,974
Americanmen,2901casesofprostatecancerwerediagnosedovera14yearperiod[89].Comparedwith
nonusers,menwhoconsumedover100mgofsupplementalzincdailyhada2.29foldincreasedriskof
prostatecancertheRRwas2.37inthosewhotookzincfor10ormoreyears.
CalciumandvitaminDAlinkbetweenintakeofdairyproductsandcalciumandahigherriskof
prostatecancerriskhasbeensuggestedinmany[9195]butnotallstudies[96,97].Inametaanalysis
examiningtheassociationofdairyproductandcalciumintakeandprostatecancerrisk,menwiththehighest
intakeofdairyproducts(relativerisk[RR]1.11,95%CI1.0to1.22)andcalcium(RR1.39,95%CI1.09to
SciHub
1.77)weremorelikelytodevelopprostatecancerthanthosewiththelowestintake[94].
URL,DOI,
EpidemiologicstudiessuggestthattherelationshipbetweenvitaminDlevelsandtheincidenceofprostate
canceriscomplex.VitaminDdeficiencyhasbeensuggestedasa"commonpathway"underlyingthe
associationofprostatecancerriskwithotherepidemiologicriskfactorsaswell(eg,age,AfricanAmerican
race,andgeographicareaofresidence)[98].Othershaveshownalinkbetweencertainhaplotypesofthe
vitaminDreceptor,vitaminDlevels,andtheriskofprostatecancer[8,93].
However,studiesdirectlyanalyzingvitaminDlevelsandtheriskofprostatecancerhavenotfullysupported
therelationship.StudiesfromScandinavia,wherethereisarelativelyhighincidenceofvitaminDdeficiency,
havesuggestedthatthereisanincreasedriskofprostatecancerinmenwithboththelowestandhighest

levelsofvitamin[99,100].
IntheUnitedStates,wherevitaminDdeficiencyislesscommon,studieshavenotclarifiedtherelationship
betweenvitaminDlevelsandtheriskofprostatecancer[101].Inanested,casecontrolstudyfromthe
Prostate,Lung,Colorectal,andOvarianCancerScreeningtrial,baselinelevelsofserumvitaminDwere
correlatedwiththesubsequentdevelopmentofprostatecancer[102].Therewasnostatisticallysignificant
trendinoverallprostatecancerriskassociatedwiththeserumvitaminDlevels,althoughhigherlevelsof
vitaminDwereassociatedwithincreasedaggressivenessinthosemendiagnosedwithprostatecancer,as
manifestedbyGleasonscore7orstageIIIorIVdiseaseatdiagnosis.
TheroleofvitaminDinchemopreventionofprostatecancerisdiscussedelsewhere.(See"Chemoprevention
strategiesinprostatecancer",sectionon'VitaminDanalogs'.)
CIGARETTESMOKINGCigarettesmokingmayhaveaneffectonboththeriskofdevelopingprostate
canceranditsprognosisonceadiagnosisisestablished.
Thelargestpublishedsystematicreviewandmetaanalysisoftheimpactofsmokingincludeddatafromover
50,000menwithprostatecancerandover11,000deaths[103].Inananalysisoftheprimaryendpointthere
wasasignificantlyincreasedriskofdeathfromprostatecancer(relativerisk1.24,95%CI1.181.31),andthe
increasedriskwascorrelatedwithincreasingnumberofcigarettessmoked.Therelationshipbetween
incidenceofprostatecancerandsmokingwasunclearwithdifferenttrendsinthepreandpostprostate
specificantigen(PSA)era.
Mostsmokingstudieshavefocusedonwhitepopulations.Smokingappearstohaveamuchlargerimpactin
AfricanAmericans.Inastudythatanalyzed1085menwithprostatecancer,therewasasubstantial
statisticallysignificantincreaseintheoverallincidenceofprostatecancerandofhighgradediseaseinheavy
smokersascomparedwithlightorneversmokers.AfricanAmericanheavysmokershadastatistically
significantincreasedriskofprostatecancerdiagnosis(oddsratio2.6)andhighgradeprostatecancer(odds
ratio1.9)comparedwithneversmokersandlightsmokers.
Smokingatthetimeofdiagnosisalsoappearstoincreasetheriskofrecurrenceandcancerprostate
mortality,althoughtheresultsdiffersomewhatinvariousstudies[104107].Asanexample,inastudyof5366
mendiagnosedwithprostatecancer,multivariateanalysisfoundastatisticallysignificantinprostatecancer
mortality(hazardratio1.61)andbiochemicalrecurrence(hazardratio1.61)whencurrentsmokerswere
comparedwithneversmokers[104].
Menwithprostatecancershouldbestronglyencouragedtostopsmoking.(See"Overviewofsmoking
cessationmanagementinadults".)
HORMONELEVELSANDOBESITYSerumconcentrationsofandrogensandinsulinlikegrowthfactorI
(IGFI)havebeenstudiedaspossibleriskfactorsforprostatecancer.
SexhormonesMultiplestudieshavelookedattherelationshipbetweenserumlevelsofvarioussex
hormonesandtheriskofdevelopingprostatecancer.Themostdefinitivedataregardingtherelationship
SciHub
betweenserumsexhormonelevelsandprostatecancercomefromapooledanalysisof18prospectivetrials,
whichincluded3886menwithprostatecancerand6438controls[108].Serumconcentrationsof
URL,DOI,
testosterone,dihydrotestosterone(DHT),andotheractiveandrogenderivativesobtainedpriortodiagnosis
wereNOTassociatedwithanincreasedriskofsubsequentprostatecancer.Inaddition,noassociationwas
seenwithprediagnosisserumlevelsofestrogens(estradiol,freeestradiol).
Inaddition,testosteronesupplementationasatreatmentforhypogonadismdoesnotappeartobeassociated
withanincreasedriskofprostatecancer,althoughmonitoringforprostateabnormalitiesisrecommended.
(See"Overviewoftestosteronedeficiencyinoldermen",sectionon'Prostatecancer'and"Testosterone
treatmentofmalehypogonadism",sectionon'Potentialadverseeffects'.)

ApossiblelinkbetweenandrogenicstimulationandprostatecancerprovidedtherationalefortheProstate
CancerPreventionTrialandtheREDUCETrial,whichusedfinasterideanddutasteride,respectively,toblock
theconversionoftestosteronetoitsmoreactivederivativeDHT.Theresultsandinterpretationofthistrialare
discussedseparately.(See"Chemopreventionstrategiesinprostatecancer",sectionon'5Alphareductase
inhibitors'.)
InsulinandinsulinlikegrowthfactorMultiplestudieshaveanalyzedtherelationshipbetweeninsulin
andinsulinlikegrowthfactor(IGF)andthesubsequentdevelopmentofprostatecancer.
Ametaanalysisbaseduponindividualpatientdatafrom3700menwithprostatecancerand5200controls
foundamodestincreasedriskofprostatecancerinthosemenwiththehighestcirculatinglevelsofIGFI
(oddsratio1.38,95%CI1.191.60,forthehighestversuslowestquintile)[109].Theassociationappeared
strongestforlowgrade,ratherthanhighgrade,prostatecancers.
Similarly,most[110113]butnotall[114]seriessupportarelationshipbetweenhigherseruminsulinlevels,
waisthipratio(WHRamarkerofbodyfatdistribution)andprostatecancerrisk.Inarepresentativecase
controlstudyofChinesemen,thoseinthehighesttertilesofWHRandseruminsulinlevelshadan8.55fold
higherriskofprostatecancerthanmeninthelowesttertilesofbothfactors[111].
ObesityMultiplestudiesanalyzingtherelationshipbetweentheincidenceofprostatecancerandweight.
Althoughthesestudieshavevariedsubstantiallyintheirresults,metaanalyseshaveconsistently
demonstratedasmallbutstatisticallysignificantassociationbetweenobesityandprostatecancerincidence
[115118].
Interpretationoftheeffectofweightonprostatecancerincidencemaybemademoredifficultbythe
observationthatincreasingbodymassindexisassociatedwithadecreaseinserumprostatespecificantigen
(PSA),whichmayminimizethediagnosisofprostatecancerbaseduponPSAscreening[119].(See
"Measurementofprostatespecificantigen",sectionon'Othereffectsonnormalrange'.)
Amongpatientswithprostatecancer,thereisaclearrelationshipbetweenobesityanddisease
aggressiveness,withanincreaseinbothbiochemicalrecurrenceratefollowingtreatmentandprostate
cancerspecificmortality[120,121].Theincreasesinrecurrencerateandmortalityareproportionaltothe
degreeofobesity.
PhysicalactivityAlthoughthedatalinkingbodymassindexandprostatecanceraggressivenesswould
suggestthatregularphysicalactivitymaybebeneficial,whetherexerciseprotectsagainstthedevelopmentor
progressionofprostatecancerisuncertain.ThisissuewasaddressedinastudyusingdatafromtheHealth
ProfessionalsFollowupStudy,acohortof47,620UnitedStateshealthprofessionalsfollowedfrom1986to
2000[122].Therewasnoassociationoverallbetweenprostatecancerincidenceandtotal,vigorousornon
vigorousphysicalactivityintheentirepopulation.However,menovertheageof65whowereinthehighest
categoryofvigorousactivity(morethanthreehoursperweekofvigorousactivity)hadasignificantlylowerrisk
ofadvanced(RR0.33,95%CI0.170.62)orfatal(RR0.26,95%CI0.110.66)prostatecancer.Youngermen
derivednobenefit.However,inallagegroups,menwithhighlevelsofphysicalactivity(morethan29
metabolicequivalenthoursversusnone)werelesslikelytobediagnosedwithhighgrade(Gleasonscore7)
SciHub
prostatecancers. https://www.uptodate.com/contents/riskfactorsforprostatecancer?source=search_result&search=D
URL,DOI,
Some(butnotall)ofthebeneficialeffectsofexerciseinoldermenmayberelatedtosunexposurewhile
exercisingoutdoors(seebelow).Inasampleofmeninthiscohort,menwhoreportedhigherlevelsofphysical
activityhadhighercirculatinglevelsof25hydroxyvitaminD[123].However,whilebothvigorousandnon
vigorousactivitywereassociatedwithhighervitaminDconcentrations,onlyvigorousactivitywasassociated
withalowerriskofadvancedprostatecancer.
Incontrasttothesedata,anotherreportfromthesameinvestigatorssuggeststhatyoungleanmenwhoare
morephysicallyactivehaveanincreasedriskofdevelopingmetastaticdiseaseandfatalprostatecancerif
theyhadahighenergyintake[124].

Thus,althoughtherearemanybenefitsfromregularphysicalexercise,itisnotclearthatareducedincidence
ofprostatecancerisamongthem.
OTHERFACTORS
5alphareductaseinhibitorsTheUnitedStatesFoodandDrugAdministrationhasconcludedthat
although5alphareductaseinhibitorslowertheprostatespecificantigen(PSA),theypotentiallyincreasethe
riskofhighgradeprostatecancer.Theroleoftheseagentsforprostatecancerchemopreventionisdiscussed
separately.(See"Chemopreventionstrategiesinprostatecancer",sectionon'5Alphareductaseinhibitors'.)
InfectionandchronicinflammationSeveraldifferentinfectiousetiologieshavebeenpostulatedas
contributoryfactorsinthedevelopmentofprostatecancer.
ProstatitisSeveralcasecontrolandcohortstudies,aswellastwometaanalyses,suggestasignificant
butmodestincreaseintheriskofprostatecancerinmenwithprostatitis(RR=1.6)andinthosewithahistory
ofsyphilisorgonorrhea(RR=1.4)[125,126].Despiteasignificantbodyofworkrelatinginflammationto
cancer,acauseandeffectrelationshiphasnotbeenestablishedbetweenprostatecancerandprostatitis.
Furthermore,PSAvaluescanbeelevatedwithprostatitis,leadingtomoreprostatebiopsiesandagreater
likelihoodofmakingthediagnosisofcancer.
Asdiscussedintheintroduction,ascertainmentbiasesaresignificantinprostatecancer.Anyfactor
associatedwithanelevationintheserumPSAwouldbeexpectedtoleadtomorebiopsiesbeingperformed,
andconsequently,morecancersbeingdetected.(See'Introduction'above.)
TrichomonasvaginalisinfectionCasecontrolseriesfromtheHealthProfessionalsFollowupStudy
andthePhysiciansHealthStudybothhaveshownanincreasedincidenceofseropositivityforantibodies
againsttrichomonasvaginalisinmenwhosubsequentlyarediagnosedwithprostatecancer[127,128].This
associationwasmorepronouncedinthosewithmoreadvancedorhigherGleasongradetumors.
Environmentalcarcinogens
AgentOrangeExposuretoAgentOrange,anherbicidedefoliantsprayedextensivelyinVietnam
between1965and1971thatcontaineddioxins,appearstobeassociatedwithanincreasedincidenceof
prostatecancer.ThecasesofprostatecancerarisinginthoseexposedtoAgentOrangeappeartobemore
aggressive[129131].
TheinitialstudiesthatanalyzedapossiblerelationshipbetweenexposuretoAgentOrangeandthe
subsequentdevelopmentofprostatecanceryieldedconflictingresults[129,132134].Thesestudieswere
limitedbyrelativelylimitednumbersofpatients,theyoungageofthecohortsinvolved,andpotentialbiasesof
recallaboutAgentOrangeexposure.
ThemostextensivestudyanalyzedthehistoryofAgentOrangeexposureinacohortof13,124Vietnam
veteransfromtheVeteransAdministrationelectronicmedicalrecorddatabase[135].Prostatecancer
developedsignificantlymorefrequentlyinthoseexposedtoAgentOrange(239of6214menexposed[3.8
percent]versus124of6930unexposed[2.0percent]).Amongthosewithprostatecancer,aGleasonscoreof
8to10wassignificantlymorefrequentinthoseexposedtoAgentOrange,aswasthelikelihoodofhaving
URL,DOI,
metastaticdiseaseatpresentation(21.8versus10.5and13.4versus4percent,respectively).Therewasno
differenceinthehistoryofPSAscreeninginthosewithandwithoutAgentOrangeexposure,andahistoryof
AgentOrangeexposurewasestablishedpriortothediagnosisofprostatecancerinallcases.
ChlordeconeChlordeconeisanorganochlorineinsecticidewithestrogenicproperties,whichwaswidely
usedintheWestIndiesfrom1973to1993.Chlordeconehasbeenshowntobecarcinogenicinlaboratory
animalmodels.Acasecontrolseriescomparedplasmalevelsofchlordeconeandexposurehistoryin623
menwithprostatecancerwith671controls[136].Therewasastatisticallysignificantincreaseintheincidence
ofprostatecancer,whichwasrelatedtothemeasuredlevelofthisagentaswellasexposurehistory.The
mechanismsunderlyingtheseobservationsrequirefurtherstudy.
BisphenolAExposuretoabnormalconcentrationsofestrogenearlyinlifemayinitiatechangesin
prostatestemcells.Thesechangeshavebeenpostulatedtopersistintolaterlifeandpotentiallycontributeto
thedevelopmentofprostatecancer[137].
BisphenolAiswidelyusedinthemanufactureofavarietyofproductssuchasplasticsandresinsthatare
widelypresentintheenvironment.InvitrostudiesandanimalmodelshavedemonstratedthatbisphenolA
hassignificantestrogeniceffectsonhumanprostatestemcells,atconcentrationsconsistentwithitspresence
intheenvironment[138].Thepotentialcontributionofexposuretobisphenolearlyinlifetothesubsequent
developmentofprostatecancerremainsuncertain.
UseofNSAIDsIntakeofaspirinandothernonsteroidalantiinflammatorydrugs(NSAIDs)hasbeen
associatedwithadecreasedriskofsomecancers,particularlycolorectalcancer.(See"NSAIDs(including
aspirin):Roleinpreventionofcolorectalcancer".)
AninverseassociationbetweenlongtermNSAIDuseandprostatecancerriskhasalsobeensuggested,
althoughthemagnitudeoftheriskreductionisunclear[139142].Thelargestcohortstudyexaminedthe
associationbetweenNSAIDuseandprostatecancerincidenceamong70,144menintheAmericanCancer
SocietyCancerPreventionStudyIINutritionCohort[139].InformationonuseofNSAIDwasobtainedfrom
questionnairescompletedatstudyentryandfivetosixyearslater.Overanineyearfollowupperiod,4853
casesofincidentprostatecancerwerediagnosed.Longdurationregularuse(30ormorepillspermonthfor
fiveormoreyears)ofeitherNSAIDs(relativerisk[RR]0.82,95%CI0.710.94)oradultstrengthaspirin(RR
0.85,95%CI0.730.99)wasassociatedwithasignificantlyreducedincidenceofprostatecancer.
Ontheotherhand,ametaanalysisthatincluded12publishedcasecontrolorcohortstudiesconcludedthat
theremaybeamodestprotectiveeffectofaspirin(oddsratio0.9,95%CI0.820.99)butthatthedatafor
nonaspirinNSAIDsweretooheterogeneousformetaanalysis[143].Thelackofprospectivetrialsmakesit
difficulttodrawconclusionsinthisarea.
StatinsMultipleobservationalstudieshaveraisedthepossibilitythatuseofstatinsmayaffecttheoverall
riskofcancerandofspecificcancers.However,metaanalysesofrandomizedtrialshaveconsistentlyshown
noeffectofstatinsoncancerincidenceorcancermortality.(See"Statins:Possiblenoncardiovascular
benefits",sectionon'Cancer'.)
Severallargestudieshavelookedspecificallyontheimpactofstatinuseontheriskofdevelopingprostate
cancer,andontheriskofprostatecancermortality.Resultsoftheseanalysessuggestthatstatinusereduces
theriskofadvanced,clinicallysignificantdisease,althoughthereareconflictingdataregardingtheeffecton
overallincidenceofprostatecancer.Ametaanalysisthatincludeddatafromsixrandomizedtrialsand13
observationalstudiesfoundnorelationshipbetweenstatinuseandtheincidenceofprostatecancereitherin
sixrandomizedtrialsor13observationalstudies(relativerisks[RRs]1.06,95%CI0.931.20and0.89,95%
CI0.651.24,respectively)[144].However,statinusewasassociatedwithadecreasedriskofadvanced
prostatecancer(RR0.77,95%CI0.640.93).
Thevariableresultsareillustratedbytwolargestudies:
URL,DOI,
TheHealthProfessionalsFollowupStudyidentified2579casesofprostatecancer,whichincluded316
withregionallyinvasive,metastatic,orfataldisease[145].Therewasnoassociationbetweenstatinuse
andtheoverallriskofprostatecancer(RR0.96,95%CI0.851.09).However,multivariateanalysisfound
asignificantdecreaseintheriskofadvanceddiseaseaftercontrollingforknownriskfactors(RR0.51,
95%CI0.300.86).Furthermore,thedecreaseinriskwasmorepronouncedwhenthedurationofstatin
usewasconsidered.
Inaretrospectivestudyofover55,000mentakingeitherastatinoranantihypertensivemedication,there
wasastatisticallysignificant31percentreductionintheincidenceofprostatecancercomparedwithmen

onanantihypertensivemedication(hazardratio[HR]0.69,95%CI0.520.90)[146].Theriskreduction

wasgreaterforthosewithhighgradeprostatecancer(HR0.40,95%CI0.240.65)comparedwiththose
withlowgradelesions(HR0.86,95%CI0.621.20).
Acohortstudyof11,772mendiagnosedwithnonmetastaticprostatecancerbetween1998and2009
foundthatprostatecancermortalitywassignificantlydecreasedinthosewhowereusingstatinsafterthe
diagnosisofprostatecancer(HR0.76,95%CI0.660.88)[147].Thedifferenceinprostatecancer
mortalitywasmorepronouncedinthosewhohadalsobeenonstatinspriortothediagnosisofprostate
cancer(HR0.55,95%CI0.410.74).Theeffectofstatinswasleastpronouncedinthosewhoonlyused
statinsafterthediagnosisofprostatecancerwasestablished(HR0.82,95%CI0.710.96).
VasectomyWhetherapriorvasectomyalsoincreasesaman'sriskofgettingprostatecanceris
controversial,withsomebutnotallstudiesshowingaweakassociation.
IntheCancerPreventionStudyII,7451of363,726mendiedfromprostatecancerbetween1982and
2012[148].Therewasnoassociationbetweenvasectomyandprostatecancermortality(HR1.01,95%
CI0.931.10).Theincidenceofprostatecancerwasinvestigatedinasubsetof66,542mentherewasno
associationwitheitheroverallprostatecancerincidence(HR1.02,95%CI0.961.08)orhighgrade
prostatecancer(HR0.91,95%CI0.781.07).
Inacohortstudyofalmost50,000menintheHealthProfessionalsFollowupStudy,6023men
developedprostatecancer[149].Onmultivariableanalysisincorporatingarangeofpotentially
confoundingfactors,vasectomywasassociatedwithastatisticallysignificantincreaseintheriskofhigh
grade(Gleason8to10),lethal(deathorthedevelopmentofmetastaticdisease),oradvanced(T3bor
higher,orlethal)prostatecancer(relativerisks[RRs]1.22,1.19,and1.20,respectively).(See"Overview
ofvasectomy",sectionon'Prostatecancer'.)
EjaculatoryfrequencyAnassociationbetweenejaculatoryfrequencyandalowerriskofprostatecancer
hasbeensuggestedintwocasecontrolstudies:
Inastudywhichcomparedmenundertheageof70whohadprostatecancerwithagematchedcontrols,
menwhohadfiveormoreejaculationsperweekwhileintheir20s(butnottheir30sor40s)hada
significantlylowerriskofprostatecancer(oddsratio0.66)thanthosewhohadfewerejaculations[150].
AreportfromtheHealthProfessionalsFollowupStudycomparedmenwhodevelopedprostatecancer
(n=3839)withcontrolsofasimilaragegroupwhohadsimilarejaculatoryfrequencybutnoprostate
cancer[151].Onmultivariableanalysis,theincidenceofprostatecancerwassignificantlyreducedfor
menhavingmorethan21ejaculationspermonthcomparedwiththosewith4to7ejaculationspermonth
betweenages20and29years(HR0.81,95%CI0.720.92).TheHRforthosereportingthe21
ejaculationsversus4to7ejaculationspermonthbetweenages40and49yearswas0.78(95%CI0.69
0.89).
Thevalidityofthisrelationshiphasbeencalledintoquestionbecauseofthelackofassociationofprostate
cancerwithejaculationfrequencyinoldermenandthefactthatotherstudieshavefailedtoshowaprotective
effectfrombeingmarriedorhavingmoresexualpartners[125].Moreover,theproblemofrecallbiasalso
castsdoubtontheinterpretationofstudiesthatusethismethodology.
URL,DOI,
UltravioletlightexposureInonecasecontrolstudyexposuretoultraviolet(UV)lighthadaprotective
effectonthedevelopmentofprostatecancer[152].Furthermore,caseswithlowUVexposuredevelopedata
youngermedianage(68versus72yearsold).Asimilarassociatedhasbeenreportedbyothers[153155].It
isnotclearthatanyexposurepatterncansuccessfullyreducetheriskofprostatecancerwithoutincreasing
theriskforbasalcellskincancer[155].(See"Epidemiology,pathogenesis,andclinicalfeaturesofbasalcell
carcinoma",sectionon'UVradiation'.)
Althoughthemechanismunderlyingthisassociationisunclear,involvementofvitaminDand/oritsreceptor
hasbeenhypothesized[155].(See'CalciumandvitaminD'above.)

DiagnosticradiologicproceduresApossibleincreaseinriskofprostatecancerduetodiagnostic
radiologicprocedureswassuggestedinacasecontrolseriesof431mendiagnosedatage60yearsorless
and409matchedcontrols[156].Proceduresassociatedwithanincreasedriskincludedbariumenemaand
hiporpelvisxraysatleastfiveyearspriortothediagnosisofprostatecancer.
EBRTforrectalcancerAlthoughexternalbeamradiationtherapy(EBRT)forprostatecanceris
associatedwithanincreasedriskofrectalcancer,RTforrectalcancerhasnotbeenassociatedwithan
increasedriskofsubsequentprostatecancer.(See"Colorectalcancer:Epidemiology,riskfactors,and
protectivefactors",sectionon'Otherriskfactors'.)
InastudybasedupontheSurveillance,Epidemiology,andEndResults(SEER)database,theriskofprostate
cancerwasdecreasedby72percentin1572menwhohadpreviouslyreceivedEBRTasacomponentof
theirtreatmentforrectalcancer[157].Incontrast,theincidenceorprostatecanceramong3114menwith
rectalcancerand24,578withcoloncancerwhoweretreatedwithoutRTwassimilartothatexpectedinthe
generalpopulation.
IncontrasttothefindingsfromtheSEERstudy,adecreaseintheincidenceofprostatecancerwasnot
observedintwoSwedishstudiesofmenreceivingEBRTforrectalcancer[158].Apossibleexplanationfor
thediscrepantfindingsisthatsubstantiallylowerdosesofEBRTwereusedintheSwedishstudies(25Gyin
fivefractionsversustypicalregimensof45to54Gyin1.8to2GyfractionsintheUnitedStates).
Atleasttwomechanismscouldcontributetoareductionintheapparentriskofprostatecancerfollowing
EBRTforpelviccancer.IncidentalRTtotheprostatemayhaveabiologiceffect,reducingorsterilizing
subclinicalareasofdisease.AlternativelyinadvertentirradiationoftheprostatecandecreasetheserumPSA,
whichwoulddiminishthediagnosisofprostatecancerwithoutaffectingitsincidence[159,160].
DepressionTheantecedentdiagnosisofadepressivedisorderadverselyaffectsthechoiceoftherapy.In
acohortstudyof41,275menwithclinicallylocalizedprostatecancerfromtheSurveillance,Epidemiology,and
EndResults(SEER)Medicaredatabase,1894(4.6percent)hadbeendiagnosedwithadepressioninthe
twoyearspriortodiagnosisofprostatecancer[161].Thesemenweresignificantlylesslikelytoreceive
definitivetreatment(radicalprostatectomyorRT)andmorelikelytobemanagedwithandrogendeprivation
therapyalone,activesurveillance,orwatchfulwaitingcomparedwiththosewithoutsuchahistory.
USINGRISKFACTORSTOESTIMATEPROSTATECANCERRISKAnonlineprostatecancerrisk
calculatorhasbeendeveloped(andindependentlyvalidated[162])inanattempttopermitmenbeing
screenedforprostatecancertoestimatetheirriskofbeingdiagnosedwiththediseaseonprostatebiopsy
baseduponcertainriskfactorssuchasage,serumprostatespecificantigen(PSA)level,theresultsofdigital
rectalexamination(DRE),familyhistory,race,andpriorhistoryofanegativebiopsy[163].Theriskestimates
arebasedondatafromover5000menwhowereenrolledinthecontrolgroupofthefinasterideprostate
cancerpreventiontrial,andtheyapplyonlytomenage50andolder,withoutapriordiagnosisofprostate
cancer,whohaveundergonescreeningwithserumPSAandDREwithinthelastyear.
Theutilityofriskcalculatorssuchastheseislimitedastheydonotprovideguidanceastowhatlevelofrisk
shouldpromptprostatebiopsy.Regardless,theyareusefulintermsofcommunicatingrisktopatientsand
helpingtounderstandthatriskisacontinuumofPSAlevel.
URL,DOI,
Prostatecancerscreeningandprostatecancerchemopreventionarediscussedelsewhere.(See
"Chemopreventionstrategiesinprostatecancer"and"Screeningforprostatecancer".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easyto
readmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmore
detailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowant

indepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremail
thesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsby
searchingon"patientinfo"andthekeyword(s)ofinterest.)
BeyondtheBasicstopic(see"Patienteducation:Prostatecancerscreening(BeyondtheBasics)")
SUMMARY
Themostimportantriskfactorforthedevelopmentofprostatecancerisincreasingage.Although
prostatecancerisrareinmenlessthan40years,itsincidenceincreasesprogressivelythereafter.(See
'Age'above.)
EpidemiologicstudieshaveshownthattheriskofprostatecancerishigherinAfricanAmericans
comparedwithotherethnicgroups.Prostatecanceroccursatanearlierageintheseindividualsandis
associatedwithamoreaggressiveclinicalcoursethaninotherethnicgroups.(See'Ethnicity'above.)
Geneticfactors,especiallygermlinemutationsinDNArepairgenes,suchasBRCA2,appeartoplayan
importantroleinthedevelopmentcertainprostatecancersandmaybeassociatedwithmoreaggressive
disease.Genomewideassociationstudiesarebeingusedtoidentifyothergeneticfactorsthatinfluence
theriskofprostatecancerinthebroaderpopulation.(See'Geneticfactors'above.)
Otherfactors,suchasdiet,hormonelevels,andobesity,havebeenstudiedwiththegoalofdeveloping
strategiestoreducetheriskofprostatecancer.Althoughsuchfactorsmayhavesomeeffecton
incidence,theirroleappearslimited.(See'Diet'aboveand'Hormonelevelsandobesity'aboveand
"Chemopreventionstrategiesinprostatecancer".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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NationalCancerInstitute'sSurveillance,Epidemiology,andEndResults(SEER)
database.Screeninginthe1980sledtoaprogressiveriskintheincidenceof
disease,withtheratebeinghigherinblacks.Theremovaloftheseincidentcases
ledtoadeclineinnewcasesofprostatecancerafter1992.
DatafromFarkasA,SchneiderD,PerrottiM,etal.Nationaltrendsintheepidemiology
ofprostatecancer,1973to1994:evidencefortheeffectivenessofprostatespecific
antigenscreening.Urology199852:444.
URL,DOI,
Tumornodemetastasis(TNM)stagedefinitionsforprostatecancer
Primarytumor(T)
Clinical(cT)
TX Primarytumorcannotbeassessed
T0 Noevidenceofprimarytumor
T1 Clinicallyinapparenttumorneitherpalpablenorvisiblebyimaging
T1a Tumorincidentalhistologicfindingin5%orlessoftissueresected

T1b Tumorincidentalhistologicfindinginmorethan5%oftissueresected
T1c Tumoridentifiedbyneedlebiopsy(eg,becauseofelevatedPSA)
T2 Tumorconfinedwithinprostate*
T2a Tumorinvolvesonehalfofonelobeorless
T2b Tumorinvolvesmorethanonehalfofonelobebutnotbothlobes
T2c Tumorinvolvesbothlobes
T3 Tumorextendsthroughtheprostatecapsule
T3a Extracapsularextension(unilateralorbilateral)
T3b Tumorinvadesseminalvesicle(s)
T4 Tumorisfixedorinvadesadjacentstructuresotherthanseminalvesiclessuchasexternalsphincter,
rectum,bladder,levatormuscles,and/orpelvicwall
Pathologic(pT)
pT2 Organconfined
pT2a Unilateral,onehalfofonesideorless
pT2b Unilateral,involvingmorethanonehalfofsidebutnotbothsides
pT2c Bilateraldisease
pT3 Extraprostaticextension
pT3a Extraprostaticextensionormicroscopicinvasionofbladderneck
pT3b Seminalvesicleinvasion
pT4 Invasionofrectum,levatormuscles,and/orpelvicwall
Regionallymphnodes(N)
Clinical
NX Regionallymphnodeswerenotassessed
N0 Noregionallymphnodemetastasis
N1 Metastasisinregionallymphnode(s)
Pathologic
pNX Regionalnodesnotsampled
pN0 Nopositiveregionalnodes
pN1 Metastasesinregionalnode(s)
Distantmetastasis(M)
M0 Nodistantmetastasis
M1 Distantmetastasis
M1a Nonregionallymphnode(s)
M1b Bone(s)
M1c Othersite(s)withorwithoutbonedisease
*Tumorfoundinoneorbothlobesbyneedlebiopsy,butnotpalpableorreliablyvisiblebyimaging,isclassifiedasT1c.
Invasionintotheprostaticapexorinto(butnotbeyond)theprostaticcapsuleisclassifiednotasT3butasT2.
ThereisnopathologicT1classification.
SciHub
PositivesurgicalmarginshouldbeindicatedbyanR1descriptor(residualmicroscopicdisease).
Whenmorethanonesiteofmetastasisispresent,themostadvancedcategoryisused.pM1cismostadvanced.
URL,DOI,
UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.Theoriginalsourcefor
thismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerNewYork,Inc.
URL,DOI,
TNManatomicstageprognosticgroupsforprostatecancer*
Primarytumor Regionallymph Distantmetastasis

Stage PSA Gleason
(T) nodes(N) (M)
I T1ac N0 M0 PSA<10 Gleason

6
T2a N0 M0 PSA<10 Gleason

6

T12a N0 M0 PSAX
GleasonX
IIA T1ac N0 M0 PSA<20 Gleason7
T1ac N0 M0 PSA Gleason

10<20 6
T2a N0 M0 PSA Gleason

10<20 6
T2a N0 M0 PSA<20 Gleason7
T2b N0 M0 PSA<20 Gleason

7
T2b N0 M0 PSAX GleasonX
IIB T2c N0 M0 AnyPSA Any

Gleason
T12 N0 M0 PSA20 Any

Gleason
T12 N0 M0 AnyPSA Gleason

8
III T3ab N0 M0 AnyPSA Any

Gleason
IV T4 N0 M0 AnyPSA Any
Gleason
AnyT N1 M0 AnyPSA Any

Gleason
AnyT AnyN M1 AnyPSA Any

Gleason
Note:cTNMistheclinicalclassification,pTNMisthepathologicclassification.
PSA:prostatespecificantigen.
*WheneitherPSAorGleasonisnotavailable,groupingshouldbedeterminedbyTstageand/oreitherPSAorGleason
asavailable.
UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.Theoriginalsourcefor
thismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerNewYork,Inc.
URL,DOI,
ContributorDisclosures
AOliverSartor,MD Grant/Research/ClinicalTrialSupport:Bayer[Prostatecancer(Radium223)]
Dendreon[Prostatecancer(SipuleucelT)]Endocyte[Prostatecancer(EC1169)]Innocrin[Prostatecancer
(VT464)]Johnson&Johnson[Prostatecancer(Abiraterone)]SanofiAventis[Prostatecancer
(Cabazitaxel)].Consultant/AdvisoryBoards:Bayer[Prostatecancer(Radium223)]Bellicum[Prostatecancer
(vaccinedevelopment)]BristolMyersSquibb[Prostatecancer(Nivolumab)]Celgene[Prostatecancer
(Lenalidomide)]Dendreon[Prostatecancer(SipuleucelT)]Johnson&Johnson[Prostatecancer(ARN509,

Abiraterone)]Medivation[Prostatecancer(Enzalutamide)]OncogeneX[Prostatecancer(Custirsen)]
SanofiAventis[Prostatecancer(Cabazitaxel)]Tokai[Prostatecancer(Galeterone)]NRGOncology
[Genitourinarycancer(CochairmanofGenitourinarycancercommittee)]. NicholasVogelzang,
MD Speaker'sBureau:Pfizer[Kidneycancer(Sunitinib,axitinib)]Bayer[Prostatecancer(Radium223)]
Novartis[Kidneycancer,PNET(Pazopanib,everolimus)Sanofi[Prostatecancer(Cabazitaxel)],BMS
[Kidneycancer(BMSnivolumab)]Genentech/Roche[Bladdercancer(Atezolizumab)Dendreon[Prostate
cancer(SpiulucelT)]Medivation/Astellas[Prostatecancer(Enzalutamide)].Consultant/AdvisoryBoards:
Amgen[Prostatecancer(Denosumab)]Bayer[Prostatecancer(Radium223)]Pfizer[Kidneycancer
(Sunitinib,axitinib)]Novartis[Kidneycancer,PNET(Pazopanib,everolimus)]Sanofi[Prostatecancer
(cabazitaxel)]BMS[Kidneycancer(BMSnivolumab)]Genentech/Roche(Bladdercancer(Atezolizumab)]
Exelexis[Kidneycancer(Cabozantinib)]CeruleanClinicalCareOptions[Kidneycancer(Liposomal
irinotecan)]DavaOncology/PERDendreonMedivation/Astellas[Prostate(Enzalutamide)],Janssen
[Prostatecancer(Abiraterone)]Heron[Nauseacontrol(Liposomalgranisetron)]Eisai[Kidneycancer
(Levantinib)]Agensys[Kidneycancer(Newtargetedagent)]BoehringerIngelheim[Mesothelioma
(Nerantinib)].Employment:USOncology[GUresearch(none)].EquityOwnership/StockOptions:Caris
[Genetictestingforcancer(none)]. WRobertLee,MD,MS,MEd Consultant/AdvisoryBoards:Medivation
[Prostatecancer(enzalutamide)]FerringPharmaceuticals[Prostatecancer(Degarelix)]. JeromePRichie,
MD,FACS Employment:MetamarkGenetics[Prostatecancerhealthcaredelivery]Norelevantconflicton
topic. MichaelERoss,MD Nothingtodisclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconform
toUpToDatestandardsofevidence.
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Risk Factors For Prostate Cancer

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Primarytumor Regionallymph Distantmetastasis

I T1ac N0 M0 PSA<10 Gleason

T2a N0 M0 PSA<10 Gleason

IIA T1ac N0 M0 PSA<20 Gleason7

T1ac N0 M0 PSA Gleason

T2a N0 M0 PSA Gleason

T2a N0 M0 PSA<20 Gleason7

T2b N0 M0 PSA<20 Gleason

T2b N0 M0 PSAX GleasonX

IIB T2c N0 M0 AnyPSA Any

T12 N0 M0 PSA20 Any

T12 N0 M0 AnyPSA Gleason

III T3ab N0 M0 AnyPSA Any

AnyT N1 M0 AnyPSA Any

AnyT AnyN M1 AnyPSA Any

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