Breast cancer - Wikipedia

Breast cancer is cancer that develops from breast tissue. ... Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the ... Breastcancer FromWikipedia,thefreeencyclopedia Thisisthelatestacceptedrevision,reviewedon5June2022. Jumptonavigation Jumptosearch Cancerthatoriginatesinmammaryglands MedicalconditionBreastcancerAnillustrationofbreastcancerSpecialtyOncologySymptomsAlumpinabreast,achangeinbreastshape,dimplingoftheskin,fluidfromthenipple,anewlyinvertednipple,aredscalypatchofskinonthebreast[1]RiskfactorsBeingfemale,obesity,lackofexercise,alcohol,hormonereplacementtherapyduringmenopause,ionizingradiation,earlyageatfirstmenstruation,havingchildrenlateinlifeornotatall,olderage,priorbreastcancer,familyhistoryofbreastcancer,Klinefeltersyndrome[1][2][3]DiagnosticmethodTissuebiopsy[1]MammographyTreatmentSurgery,radiationtherapy,chemotherapy,hormonaltherapy,targetedtherapy[1]PrognosisFive-yearsurvivalrate≈85%(US,UK)[4][5]Frequency2.2millionaffectedasof2020[6]Deaths685,000(2020)[6] Breastcanceriscancerthatdevelopsfrombreasttissue.[7]Signsofbreastcancermayincludealumpinthebreast,achangeinbreastshape,dimplingoftheskin,fluidcomingfromthenipple,anewlyinvertednipple,oraredorscalypatchofskin.[1]Inthosewithdistantspreadofthedisease,theremaybebonepain,swollenlymphnodes,shortnessofbreath,oryellowskin.[8] Riskfactorsfordevelopingbreastcancerincludeobesity,alackofphysicalexercise,alcoholism,hormonereplacementtherapyduringmenopause,ionizingradiation,anearlyageatfirstmenstruation,havingchildrenlateinlifeornotatall,olderage,havingapriorhistoryofbreastcancer,andafamilyhistoryofbreastcancer.[1][2]About5–10%ofcasesaretheresultofageneticpredispositioninheritedfromaperson'sparents,[1]includingBRCA1andBRCA2amongothers.[1]Breastcancermostcommonlydevelopsincellsfromtheliningofmilkductsandthelobulesthatsupplytheseductswithmilk.[1]Cancersdevelopingfromtheductsareknownasductalcarcinomas,whilethosedevelopingfromlobulesareknownaslobularcarcinomas.[1]Therearemorethan18othersub-typesofbreastcancer.[2]Some,suchasductalcarcinomainsitu,developfrompre-invasivelesions.[2]Thediagnosisofbreastcancerisconfirmedbytakingabiopsyoftheconcerningtissue.[1]Oncethediagnosisismade,furthertestsaredonetodetermineifthecancerhasspreadbeyondthebreastandwhichtreatmentsaremostlikelytobeeffective.[1] Thebalanceofbenefitsversusharmsofbreastcancerscreeningiscontroversial.A2013Cochranereviewfoundthatitwasunclearifmammographicscreeningdoesmoreharmthangood,inthatalargeproportionofwomenwhotestpositiveturnoutnottohavethedisease.[9]A2009reviewfortheUSPreventiveServicesTaskForcefoundevidenceofbenefitinthose40to70yearsofage,[10]andtheorganizationrecommendsscreeningeverytwoyearsinwomen50to74yearsofage.[11]Themedicationstamoxifenorraloxifenemaybeusedinanefforttopreventbreastcancerinthosewhoareathighriskofdevelopingit.[2]Surgicalremovalofbothbreastsisanotherpreventivemeasureinsomehighriskwomen.[2]Inthosewhohavebeendiagnosedwithcancer,anumberoftreatmentsmaybeused,includingsurgery,radiationtherapy,chemotherapy,hormonaltherapy,andtargetedtherapy.[1]Typesofsurgeryvaryfrombreast-conservingsurgerytomastectomy.[12][13]Breastreconstructionmaytakeplaceatthetimeofsurgeryoratalaterdate.[13]Inthoseinwhomthecancerhasspreadtootherpartsofthebody,treatmentsaremostlyaimedatimprovingqualityoflifeandcomfort.[13] Outcomesforbreastcancervarydependingonthecancertype,theextentofdisease,andtheperson'sage.[13]Thefive-yearsurvivalratesinEnglandandtheUnitedStatesarebetween80and90%.[14][4][5]Indevelopingcountries,five-yearsurvivalratesarelower.[2]Worldwide,breastcanceristheleadingtypeofcancerinwomen,accountingfor25%ofallcases.[15]In2018,itresultedin2millionnewcasesand627,000deaths.[16]Itismorecommonindevelopedcountries[2]andismorethan100timesmorecommoninwomenthaninmen.[14][17] Contents 1Signsandsymptoms 2Riskfactors 2.1Lifestyle 2.2Genetics 2.3Medicalconditions 3Pathophysiology 4Diagnosis 4.1Classification 5Screening 6Prevention 6.1Lifestyle 6.2Pre-emptivesurgery 6.3Medications 7Management 7.1Surgery 7.2Medication 7.2.1Hormonaltherapy 7.2.2Chemotherapy 7.2.3Monoclonalantibodies 7.3Radiation 7.4Follow-upcare 8Prognosis 8.1Prognosticfactors 8.2Psychologicalaspects 9Epidemiology 10History 11Societyandculture 11.1Pinkribbon 11.2Breastcancerculture 11.3Emphasis 12Ethnicdifferences 13Pregnancy 14Hormones 14.1Birthcontrol 14.2Menopausalhormonereplacement 15Research 15.1Cryoablation 15.2Breastcancercelllines 15.3Molecularmarkers 15.3.1Metabolicmarkers 16Otheranimals 17References 18Externallinks Signsandsymptoms[edit] Breastcancershowinganinvertednipple,lump,andskindimpling Earlysignsofpossiblebreastcancer Breastcancermostcommonlypresentsasalumpthatfeelsdifferentfromtherestofthebreasttissue.Morethan80%ofcasesarediscoveredwhenapersondetectssuchalumpwiththefingertips.[18]Theearliestbreastcancers,however,aredetectedbyamammogram.[19][20]Lumpsfoundinlymphnodeslocatedinthearmpits[18]mayalsoindicatebreastcancer. Indicationsofbreastcancerotherthanalumpmayincludethickeningdifferentfromtheotherbreasttissue,onebreastbecominglargerorlower,anipplechangingpositionorshapeorbecominginverted,skinpuckeringordimpling,arashonoraroundanipple,dischargefromnipple/s,constantpaininpartofthebreastorarmpitandswellingbeneaththearmpitoraroundthecollarbone.[21]Pain("mastodynia")isanunreliabletoolindeterminingthepresenceorabsenceofbreastcancer,butmaybeindicativeofotherbreasthealthissues.[18][19][22] AnothersymptomcomplexofbreastcancerisPaget'sdiseaseofthebreast.Thissyndromepresentsasskinchangesresemblingeczema;suchasredness,discolorationormildflakingofthenippleskin.AsPaget'sdiseaseofthebreastadvances,symptomsmayincludetingling,itching,increasedsensitivity,burning,andpain.Theremayalsobedischargefromthenipple.ApproximatelyhalfthewomendiagnosedwithPaget'sdiseaseofthebreastalsohavealumpinthebreast.[23][24] Inflammatorybreastcancerisarare(onlyseeninlessthan5%ofbreastcancerdiagnosis)yetaggressiveformofbreastcancercharacterizedbytheswollen,redareasformedonthetopofthebreast.Thevisualeffectsofinflammatorybreastcancerisaresultofablockageoflymphvesselsbycancercells.Thistypeofbreastcancerisseeninmorecommonlydiagnosedinyoungerages,obesewomenandAfricanAmericanwomen.Asinflammatorybreastcancerdoesnotpresentasalumptherecansometimesbeadelayindiagnosis.[25] Mammarysecretorycarcinoma(MSC)isarareformofthesecretorycarcinomasthatoccursexclusivelyinthebreast.[26]Itusuallydevelopsinadultsbutinasignificantpercentageofcasesalsoafflictschildren:[27]MSCaccountsfor80%ofallchildhoodbreastcancers.[28]MSClesionsaretypicallyslowgrowing,painless,smallductalbreasttumorsthathaveinvadedthetissuearoundtheirductsoforigin,oftenspreadtosentinellymphnodesand/oraxillarylymphnodes,butrarelymetastasizedtodistanttissues.[29]ThesetumorstypicallyhavedistinctivemicroscopicfeaturesandtumorcellsthatcarryabalancedgenetictranslocationinwhichpartoftheNTRK3geneisfusedtopartoftheETV6gene[30]toformafusiongene,ETV6-NTRK3.ThisfusiongeneencodesachimericproteintermedETV6-NTRK3.TheNTRK3partofETV6-NTRK3proteinhasup-regulatedtyrosinekinaseactivitythatstimulatestwosignalingpathways,thePI3K/AKT/mTORandMAPK/ERKpathways,whichpromotecellproliferationandsurvivalandtherebymaycontributetothedevelopmentofMSC.[27]Conservativesurgery,modifiedradicalmastectomy,andradicalmastectomyhavebeenthemostfrequentproceduresusedtotreatadults,whilesimplemastectomy,localexcisionwithsentinellymphnodebiopsy,andcompleteaxillarydissectionhavebeenrecommendedtotreatchildrenwithMSC.[31]Inallcases,long-term,e.g.>20years,follow-upexaminationsarerecommended.[26][30]TherelativelyrarecasesofMSCthathavemetastasizedtodistanttissueshaveshownlittleornoresponsestochemotherapyandradiotherapy.ThreepatientswithmetastaticdiseasehadgooodpartialresponsestoEntrectinib,adrugthatinhibitsthetyrosinekinaseactivityoftheETV6-NTRK3fusionprotein.[32]Becauseofitsslowgrowthandlowrateofmetastasistodistanttissues,individualswithMSChavehad20yearsurvivalratesof93.16%.[26] Inrarecases,whatinitiallyappearsasafibroadenoma(hard,movablenon-cancerouslump)couldinfactbeaphyllodestumor.Phyllodestumorsareformedwithinthestroma(connectivetissue)ofthebreastandcontainglandularaswellasstromaltissue.Phyllodestumorsarenotstagedintheusualsense;theyareclassifiedonthebasisoftheirappearanceunderthemicroscopeasbenign,borderlineormalignant.[33] Malignanttumorscanresultinmetastatictumors–secondarytumors(originatingfromtheprimarytumor)thatspreadbeyondthesiteoforigination.Thesymptomscausedbymetastaticbreastcancerwilldependonthelocationofmetastasis.Commonsitesofmetastasisincludebone,liver,lung,andbrain.[34]Whencancerhasreachedsuchaninvasivestate,itiscategorizedasastage4cancer,cancersofthisstateareoftenfatal.[35]Commonsymptomsofstage4cancerincludeunexplainedweightloss,boneandjointpain,jaundiceandneurologicalsymptoms.Thesesymptomsarecallednon-specificsymptomsbecausetheycouldbemanifestationsofmanyotherillnesses.[36]Rarelybreastcancercanspreadtoexceedinglyuncommonsitessuchasperipancreaticlymphnodescausingbiliaryobstructionleadingtodiagnosticdifficulties.[37] TumorinthebreastvisualizedbyBreast-Computertomography(Breast-CT) Mostsymptomsofbreastdisorders,includingmostlumps,donotturnouttorepresentunderlyingbreastcancer.Lessthan20%oflumps,forexample,arecancerous,[38]andbenignbreastdiseasessuchasmastitisandfibroadenomaofthebreastaremorecommoncausesofbreastdisordersymptoms.[39] Riskfactors[edit] Mainarticle:Riskfactorsofbreastcancer Riskfactorscanbedividedintotwocategories: modifiableriskfactors(thingsthatpeoplecanchangethemselves,suchasconsumptionofalcoholicbeverages),and fixedriskfactors(thingsthatcannotbechanged,suchasageandphysiologicalsex).[40] Theprimaryriskfactorsforbreastcancerarebeingfemaleandolderage.[41]Otherpotentialriskfactorsincludegenetics,[42]lackofchildbearingorlackofbreastfeeding,[43]higherlevelsofcertainhormones,[44][45]certaindietarypatterns,andobesity.Onestudyindicatesthatexposuretolightpollutionisariskfactorforthedevelopmentofbreastcancer.[46] Ifalladultsmaintainedthehealthiestpossiblelifestyles,includingnotdrinkingalcoholicbeverages,maintainingahealthybodycomposition,neversmoking,eatinghealthfulfood,andotheractions,thenalmostaquarterofbreastcancercasesworldwidecouldbeprevented.[47]Theremainingthree-quartersofbreastcancercasescannotbepreventedthroughlifestylechanges.[47] Lifestyle[edit] Seealso:Listofbreastcarcinogenicsubstances Alltypesofalcoholicbeverages,includingbeer,wine,orliquor,causebreastcancer. Drinkingalcohol,evenatlowlevels,increasestheriskofbreastcancer  Additionalriskfromdrinking[48][49]   Originalbreastcancerrisk(=100%) Drinkingalcoholicbeveragesincreasestheriskofbreastcancer,evenamongverylightdrinkers(womendrinkinglessthanhalfofonealcoholicdrinkperday).[48]Theriskishighestamongheavydrinkers.[50]Globally,aboutonein10casesofbreastcanceriscausedbywomendrinkingalcoholicbeverages.[50]Drinkingalcoholicbeveragesisamongthemostcommonmodifiableriskfactors.[51] Thecorrelationbetweenobesityandbreastcancerisanythingbutlinear.Studiesshowthatthosewhorapidlygainweightinadulthoodareathigherriskthanthosewhohavebeenoverweightsincechildhood.Likewiseexcessfatinthemidsectionseemstoinduceahigherriskthanexcessweightcarriedinthelowerbody.Thisimpliesthatthefoodoneeatsisofgreaterimportancethanone'sBMI.[52]Dietaryfactorsthatmayincreaseriskincludeahigh-fatdiet[53]andobesity-relatedhighcholesterollevels.[54][55]Dietaryiodinedeficiencymayalsoplayarole.[56]Evidenceforfiberisunclear.A2015reviewfoundthatstudiestryingtolinkfiberintakewithbreastcancerproducedmixedresults.[57]In2016,atentativeassociationbetweenlowfiberintakeduringadolescenceandbreastcancerwasobserved.[58] Smokingtobaccoappearstoincreasetheriskofbreastcancer,withthegreatertheamountsmokedandtheearlierinlifethatsmokingbegan,thehighertherisk.[59]Inthosewhoarelong-termsmokers,therelativeriskisincreased35%to50%.[59] Alackofphysicalactivityhasbeenlinkedtoabout10%ofcases.[60]Sittingregularlyforprolongedperiodsisassociatedwithhighermortalityfrombreastcancer.Theriskisnotnegatedbyregularexercise,thoughitislowered.[61] Hormonetherapytotreatmenopauseisalsoassociatedwithanincreasedriskofbreastcancer.[62]Theuseofhormonalbirthcontroldoesnotcausebreastcancerformostwomen;[63]ifithasaneffect,itissmall(ontheorderof0.01%peruser–year;comparabletotherateofmaternalmortalityintheUnitedStates[64]),temporary,andoffsetbytheusers'significantlyreducedriskofovarianandendometrialcancers.[64]Amongthosewithafamilyhistoryofbreastcancer,useofmodernoralcontraceptivesdoesnotappeartoaffecttheriskofbreastcancer.[65]ItislesscertainwhetherhormonalcontraceptivescouldincreasethealreadyhighratesofbreastcancerinwomenwithmutationsinthebreastcancersusceptibilitygenesBRCA1orBRCA2.[66] Breastfeedingreducestheriskofseveraltypesofcancers,includingbreastcancer.[67][68][69][70]Inthe1980s,theabortion–breastcancerhypothesispositedthatinducedabortionincreasedtheriskofdevelopingbreastcancer.[71]Thishypothesiswasthesubjectofextensivescientificinquiry,whichconcludedthatneithermiscarriagesnorabortionsareassociatedwithaheightenedriskforbreastcancer.[72] Otherriskfactorsincluderadiation[73]andcircadiandisruptionsrelatedtoshift-work[74]androutinelate-nighteating.[75]Anumberofchemicalshavealsobeenlinked,includingpolychlorinatedbiphenyls,polycyclicaromatichydrocarbons,andorganicsolvents[76]Althoughtheradiationfrommammographyisalowdose,itisestimatedthatyearlyscreeningfrom40to80yearsofagewillcauseapproximately225casesoffatalbreastcancerpermillionwomenscreened.[77] Genetics[edit] Geneticsisbelievedtobetheprimarycauseof5–10%ofallcases.[78]Womenwhosemotherwasdiagnosedbefore50haveanincreasedriskof1.7andthosewhosemotherwasdiagnosedatage50orafterhasanincreasedriskof1.4.[79]Inthosewithzero,oneortwoaffectedrelatives,theriskofbreastcancerbeforetheageof80is7.8%,13.3%,and21.1%withasubsequentmortalityfromthediseaseof2.3%,4.2%,and7.6%respectively.[80]Inthosewithafirstdegreerelativewiththediseasetheriskofbreastcancerbetweentheageof40and50isdoublethatofthegeneralpopulation.[81] Inlessthan5%ofcases,geneticsplaysamoresignificantrolebycausingahereditarybreast–ovariancancersyndrome.[82]ThisincludesthosewhocarrytheBRCA1andBRCA2genemutation.[82]Thesemutationsaccountforupto90%ofthetotalgeneticinfluencewithariskofbreastcancerof60–80%inthoseaffected.[78]Othersignificantmutationsincludep53(Li–Fraumenisyndrome),PTEN(Cowdensyndrome),andSTK11(Peutz–Jegherssyndrome),CHEK2,ATM,BRIP1,andPALB2.[78]In2012,researcherssaidthattherearefourgeneticallydistincttypesofthebreastcancerandthatineachtype,hallmarkgeneticchangesleadtomanycancers.[83] Othergeneticpredispositionsincludethedensityofthebreasttissueandhormonallevels.Womenwithdensebreasttissuearemorelikelytogettumorsandarelesslikelytobediagnosedwithbreastcancer–becausethedensetissuemakestumorslessvisibleonmammograms.Furthermore,womenwithnaturallyhighestrogenandprogesteronelevelsarealsoathigherriskfortumordevelopment.[84][85] Medicalconditions[edit] Breastchangeslikeatypicalductalhyperplasia[86]andlobularcarcinomainsitu,[87][88]foundinbenignbreastconditionssuchasfibrocysticbreastchanges,arecorrelatedwithanincreasedbreastcancerrisk. Diabetesmellitusmightalsoincreasetheriskofbreastcancer.[89]Autoimmunediseasessuchaslupuserythematosusseemalsotoincreasetheriskfortheacquisitionofbreastcancer.[90] Themajorcausesofsporadicbreastcancerareassociatedwithhormonelevels.Breastcancerispromotedbyestrogen.Thishormoneactivatesthedevelopmentofbreastthroughoutpuberty,menstrualcyclesandpregnancy.Theimbalancebetweenestrogenandprogesteroneduringthemenstrualphagescausescellproliferation.Moreover,oxidativemetabolitesofestrogencanincreaseDNAdamageandmutations.Repeatedcyclingandtheimpairmentofrepairprocesscantransformanormalcellintopre-malignantandeventuallymalignantcellthroughmutation.Duringthepremalignantstage,highproliferationofstromalcellscanbeactivatedbyestrogentosupportthedevelopmentofbreastcancer.Duringtheligandbindingactivation,theERcanregulategeneexpressionbyinteractingwithestrogenresponseelementswithinthepromotorofspecificgenes.TheexpressionandactivationofERduetolackofestrogencanbestimulatedbyextracellularsignals.[91]Interestingly,theERdirectlybindingwiththeseveralproteins,includinggrowthfactorreceptors,canpromotetheexpressionofgenesrelatedtocellgrowthandsurvival.[92] Raisedprolactinlevelsinthebloodareassociatedwithincreasedriskofbreastcancer.[93] Pathophysiology[edit] Seealso:Carcinogenesis Ductsandlobules,themainlocationsofbreastcancers Overviewofsignaltransductionpathwaysinvolvedinprogrammedcelldeath.Mutationsleadingtolossofthisabilitycanleadtocancerformation. Breastcancer,likeothercancers,occursbecauseofaninteractionbetweenanenvironmental(external)factorandageneticallysusceptiblehost.Normalcellsdivideasmanytimesasneededandstop.Theyattachtoothercellsandstayinplaceintissues.Cellsbecomecancerouswhentheylosetheirabilitytostopdividing,toattachtoothercells,tostaywheretheybelong,andtodieatthepropertime. Normalcellswillself-destruct(programmedcelldeath)whentheyarenolongerneeded.Untilthen,cellsareprotectedfromprogrammeddeathbyseveralproteinclustersandpathways.OneoftheprotectivepathwaysisthePI3K/AKTpathway;anotheristheRAS/MEK/ERKpathway.Sometimesthegenesalongtheseprotectivepathwaysaremutatedinawaythatturnsthempermanently"on",renderingthecellincapableofself-destructingwhenitisnolongerneeded.Thisisoneofthestepsthatcausescancerincombinationwithothermutations.Normally,thePTENproteinturnsoffthePI3K/AKTpathwaywhenthecellisreadyforprogrammedcelldeath.Insomebreastcancers,thegeneforthePTENproteinismutated,sothePI3K/AKTpathwayisstuckinthe"on"position,andthecancercelldoesnotself-destruct.[94] Mutationsthatcanleadtobreastcancerhavebeenexperimentallylinkedtoestrogenexposure.[95]Additionally,G-proteincoupledestrogenreceptorshavebeenassociatedwithvariouscancersofthefemalereproductivesystemincludingbreastcancer.[96] Abnormalgrowthfactorsignalingintheinteractionbetweenstromalcellsandepithelialcellscanfacilitatemalignantcellgrowth.[97][98]Inbreastadiposetissue,overexpressionofleptinleadstoincreasedcellproliferationandcancer.[99] IntheUnitedStates,10to20percentofwomenwithbreastcancerorovariancancerhaveafirst-orsecond-degreerelativewithoneofthesediseases.Menwithbreastcancerhaveanevenhigherlikelihood.Thefamilialtendencytodevelopthesecancersiscalledhereditarybreast–ovariancancersyndrome.Thebestknownofthese,theBRCAmutations,conferalifetimeriskofbreastcancerofbetween60and85percentandalifetimeriskofovariancancerofbetween15and40percent.Somemutationsassociatedwithcancer,suchasp53,BRCA1andBRCA2,occurinmechanismstocorrecterrorsinDNA.Thesemutationsareeitherinheritedoracquiredafterbirth.Presumably,theyallowfurthermutations,whichallowuncontrolleddivision,lackofattachment,andmetastasistodistantorgans.[73][100]However,thereisstrongevidenceofresidualriskvariationthatgoeswellbeyondhereditaryBRCAgenemutationsbetweencarrierfamilies.Thisiscausedbyunobservedriskfactors.[101]Thisimplicatesenvironmentalandothercausesastriggersforbreastcancers.TheinheritedmutationinBRCA1orBRCA2genescaninterferewithrepairofDNAcrosslinksandDNAdoublestrandbreaks(knownfunctionsoftheencodedprotein).[102]ThesecarcinogenscauseDNAdamagesuchasDNAcrosslinksanddoublestrandbreaksthatoftenrequirerepairsbypathwayscontainingBRCA1andBRCA2.[103][104]However,mutationsinBRCAgenesaccountforonly2to3percentofallbreastcancers.[105]Levinetal.saythatcancermaynotbeinevitableforallcarriersofBRCA1andBRCA2mutations.[106]Abouthalfofhereditarybreast–ovariancancersyndromesinvolveunknowngenes.Furthermore,certainlatentviruses,maydecreasetheexpressionoftheBRCA1geneandincreasetheriskofbreasttumors.[107] GATA-3directlycontrolstheexpressionofestrogenreceptor(ER)andothergenesassociatedwithepithelialdifferentiation,andthelossofGATA-3leadstolossofdifferentiationandpoorprognosisduetocancercellinvasionandmetastasis.[108] Diagnosis[edit] Mosttypesofbreastcancerareeasytodiagnosebymicroscopicanalysisofasample–orbiopsy–oftheaffectedareaofthebreast.Also,therearetypesofbreastcancerthatrequirespecializedlabexams. Thetwomostcommonlyusedscreeningmethods,physicalexaminationofthebreastsbyahealthcareproviderandmammography,canofferanapproximatelikelihoodthatalumpiscancer,andmayalsodetectsomeotherlesions,suchasasimplecyst.[109]Whentheseexaminationsareinconclusive,ahealthcareprovidercanremoveasampleofthefluidinthelumpformicroscopicanalysis(aprocedureknownasfineneedleaspiration,orfineneedleaspirationandcytology,FNAC)tohelpestablishthediagnosis.Aneedleaspirationcanbeperformedinahealthcareprovider'sofficeorclinic.Alocalanestheticmaybeusedtonumbthebreasttissuetopreventpainduringtheprocedure,butmaynotbenecessaryifthelumpisn'tbeneaththeskin.Afindingofclearfluidmakesthelumphighlyunlikelytobecancerous,butbloodyfluidmaybesentoffforinspectionunderamicroscopeforcancerouscells.Together,physicalexaminationofthebreasts,mammography,andFNACcanbeusedtodiagnosebreastcancerwithagooddegreeofaccuracy. Otheroptionsforbiopsyincludeacorebiopsyorvacuum-assistedbreastbiopsy,[110]whichareproceduresinwhichasectionofthebreastlumpisremoved;oranexcisionalbiopsy,inwhichtheentirelumpisremoved.Veryoftentheresultsofphysicalexaminationbyahealthcareprovider,mammography,andadditionalteststhatmaybeperformedinspecialcircumstances(suchasimagingbyultrasoundorMRI)aresufficienttowarrantexcisionalbiopsyasthedefinitivediagnosticandprimarytreatmentmethod.[111][non-primarysourceneeded] MRIshowingbreastcancer Excisedhumanbreasttissue,showinganirregular,dense,whitestellateareaofcancer2cmindiameter,withinyellowfattytissue High-gradeinvasiveductalcarcinoma,withminimaltubuleformation,markedpleomorphism,andprominentmitoses,40xfield Micrographshowingalymphnodeinvadedbyductalbreastcarcinoma,withanextensionofthetumorbeyondthelymphnode Neuropilin-2expressioninnormalbreastandbreastcarcinomatissue F-18FDGPET/CT:Abreastcancermetastasistotherightscapula Needlebreastbiopsy Elastographyshowsstiffcancertissueonultrasoundimaging. Ultrasoundimageshowsirregularlyshapedmassofbreastcancer. Infiltrating(invasive)breastcarcinoma Mammogramsshowinganormalbreast(left)andabreastwithcancer(right) Classification[edit] Mainarticle:Breastcancerclassification Breastcancersareclassifiedbyseveralgradingsystems.Eachoftheseinfluencestheprognosisandcanaffecttreatmentresponse.Descriptionofabreastcanceroptimallyincludesallofthesefactors. Histopathologictypesofbreastcancer,withrelativeincidencesandprognoses Histopathology.Breastcancerisusuallyclassifiedprimarilybyitshistologicalappearance.Mostbreastcancersarederivedfromtheepitheliumliningtheductsorlobules,andthesecancersareclassifiedasductalorlobularcarcinoma.Carcinomainsituisgrowthoflow-gradecancerousorprecancerouscellswithinaparticulartissuecompartmentsuchasthemammaryductwithoutinvasionofthesurroundingtissue.Incontrast,invasivecarcinomadoesnotconfineitselftotheinitialtissuecompartment.[112] Grade.Gradingcomparestheappearanceofthebreastcancercellstotheappearanceofnormalbreasttissue.Normalcellsinanorganlikethebreastbecomedifferentiated,meaningthattheytakeonspecificshapesandformsthatreflecttheirfunctionaspartofthatorgan.Cancerouscellslosethatdifferentiation.Incancer,thecellsthatwouldnormallylineupinanorderlywaytomakeupthemilkductsbecomedisorganized.Celldivisionbecomesuncontrolled.Cellnucleibecomelessuniform.Pathologistsdescribecellsaswelldifferentiated(lowgrade),moderatelydifferentiated(intermediategrade),andpoorlydifferentiated(highgrade)asthecellsprogressivelylosethefeaturesseeninnormalbreastcells.Poorlydifferentiatedcancers(theoneswhosetissueisleastlikenormalbreasttissue)haveaworseprognosis. Stage.BreastcancerstagingusingtheTNMsystemisbasedonthesizeofthetumor(T),whetherornotthetumorhasspreadtothelymphnodes(N)inthearmpits,andwhetherthetumorhasmetastasized(M)(i.e.spreadtoamoredistantpartofthebody).Largersize,nodalspread,andmetastasishavealargerstagenumberandaworseprognosis.Themainstagesare: Stage0isapre-cancerousormarkercondition,eitherductalcarcinomainsitu(DCIS)orlobularcarcinomainsitu(LCIS). Stages1–3arewithinthebreastorregionallymphnodes. Stage4is'metastatic'cancerthathasalessfavorableprognosissinceithasspreadbeyondthebreastandregionallymphnodes. StageT1breastcancer StageT2breastcancer StageT3breastcancer Metastaticorstage4breastcancer Whereavailable,imagingstudiesmaybeemployedaspartofthestagingprocessinselectcasestolookforsignsofmetastaticcancer.However,incasesofbreastcancerwithlowriskformetastasis,therisksassociatedwithPETscans,CTscans,orbonescansoutweighthepossiblebenefits,astheseproceduresexposethepersontoasubstantialamountofpotentiallydangerousionizingradiation.[113][114] Receptorstatus.Breastcancercellshavereceptorsontheirsurfaceandintheircytoplasmandnucleus.Chemicalmessengerssuchashormonesbindtoreceptors,andthiscauseschangesinthecell.Breastcancercellsmayormaynothavethreeimportantreceptors:estrogenreceptor(ER),progesteronereceptor(PR),andHER2.ER+cancercells(thatis,cancercellsthathaveestrogenreceptors)dependonestrogenfortheirgrowth,sotheycanbetreatedwithdrugstoblockestrogeneffects(e.g.tamoxifen),andgenerallyhaveabetterprognosis.Untreated,HER2+breastcancersaregenerallymoreaggressivethanHER2-breastcancers,[115][116]butHER2+cancercellsrespondtodrugssuchasthemonoclonalantibodytrastuzumab(incombinationwithconventionalchemotherapy),andthishasimprovedtheprognosissignificantly.[117]Cellsthatdonothaveanyofthesethreereceptortypes(estrogenreceptors,progesteronereceptors,orHER2)arecalledtriple-negative,althoughtheyfrequentlydoexpressreceptorsforotherhormones,suchasandrogenreceptorandprolactinreceptor. DNAassays.DNAtestingofvarioustypesincludingDNAmicroarrayshavecomparednormalcellstobreastcancercells.Thespecificchangesinaparticularbreastcancercanbeusedtoclassifythecancerinseveralways,andmayassistinchoosingthemosteffectivetreatmentforthatDNAtype. Stage1Abreastcancer Stage1Bbreastcancer Stage2Abreastcancer Stage2Abreastcancer Stage2Bbreastcancer Stage2Bbreastcancer Stage2Bbreastcancer Stage3Abreastcancer Stage3Abreastcancer Stage3Abreastcancer Stage3Bbreastcancer Stage3Bbreastcancer Stage4breastcancer Screening[edit] Mainarticle:Breastcancerscreening AmobilebreastcancerscreeningunitinNewZealand Breastcancerscreeningreferstotestingotherwise-healthywomenforbreastcancerinanattempttoachieveanearlierdiagnosisundertheassumptionthatearlydetectionwillimproveoutcomes.Anumberofscreeningtestshavebeenemployedincludingclinicalandselfbreastexams,mammography,geneticscreening,ultrasound,andmagneticresonanceimaging. Aclinicalorselfbreastexaminvolvesfeelingthebreastforlumpsorotherabnormalities.Clinicalbreastexamsareperformedbyhealthcareproviders,whileself-breastexamsareperformedbythepersonthemselves.[118]Evidencedoesnotsupporttheeffectivenessofeithertypeofbreastexam,asbythetimealumpislargeenoughtobefounditislikelytohavebeengrowingforseveralyearsandthussoonbelargeenoughtobefoundwithoutanexam.[119][120]MammographicscreeningforbreastcancerusesX-raystoexaminethebreastforanyuncharacteristicmassesorlumps.Duringascreening,thebreastiscompressedandatechniciantakesphotosfrommultipleangles.Ageneralmammogramtakesphotosoftheentirebreast,whileadiagnosticmammogramfocusesonaspecificlumporareaofconcern.[121] Anumberofnationalbodiesrecommendbreastcancerscreening.Fortheaveragewoman,theU.S.PreventiveServicesTaskForceandAmericanCollegeofPhysiciansrecommendsmammographyeverytwoyearsinwomenbetweentheagesof50and74,[11][122]theCouncilofEuroperecommendsmammographybetween50and69withmostprogramsusinga2-yearfrequency,[123]whiletheEuropeanCommissionrecommendsmammographyfrom45to75every2to3years,[124]andinCanadascreeningisrecommendedbetweentheagesof50and74atafrequencyof2to3years.[125]Thesetaskforcereportspointoutthatinadditiontounnecessarysurgeryandanxiety,therisksofmorefrequentmammogramsincludeasmallbutsignificantincreaseinbreastcancerinducedbyradiation.[126] TheCochranecollaboration(2013)statesthatthebestqualityevidenceneitherdemonstratesareductionincancerspecific,norareductioninallcausemortalityfromscreeningmammography.[9]Whenlessrigoroustrialsareaddedtotheanalysisthereisareductioninmortalityduetobreastcancerof0.05%(adecreaseof1in2000deathsfrombreastcancerover10yearsorarelativedecreaseof15%frombreastcancer).[9]Screeningover10yearsresultsina30%increaseinratesofover-diagnosisandover-treatment(3to14per1000)andmorethanhalfwillhaveatleastonefalselypositivetest.[9][127]Thishasresultedintheviewthatitisnotclearwhethermammographyscreeningdoesmoregoodorharm.[9]Cochranestatesthat,duetorecentimprovementsinbreastcancertreatment,andtherisksoffalsepositivesfrombreastcancerscreeningleadingtounnecessarytreatment,"itthereforenolongerseemsbeneficialtoattendforbreastcancerscreening"atanyage.[128]WhetherMRIasascreeningmethodhasgreaterharmsorbenefitswhencomparedtostandardmammographyisnotknown.[129][130] Prevention[edit] Lifestyle[edit] Womencanreducetheirriskofbreastcancerbymaintainingahealthyweight,reducingalcoholuse,increasingphysicalactivity,andbreast-feeding.[131]Thesemodificationsmightprevent38%ofbreastcancersintheUS,42%intheUK,28%inBrazil,and20%inChina.[131]Thebenefitswithmoderateexercisesuchasbriskwalkingareseenatallagegroupsincludingpostmenopausalwomen.[131][132]Highlevelsofphysicalactivityreducetheriskofbreastcancerbyabout14%.[133]Strategiesthatencourageregularphysicalactivityandreduceobesitycouldalsohaveotherbenefits,suchasreducedrisksofcardiovasculardiseaseanddiabetes.[40] TheAmericanCancerSocietyandtheAmericanSocietyofClinicalOncologyadvisedin2016thatpeopleshouldeatadiethighinvegetables,fruits,wholegrains,andlegumes.[134]Highintakeofcitrusfruithasbeenassociatedwitha10%reductionintheriskofbreastcancer.[135]Marineomega-3polyunsaturatedfattyacidsappeartoreducetherisk.[136]Highconsumptionofsoy-basedfoodsmayreducerisk.[137] Pre-emptivesurgery[edit] Removalofbothbreastsbeforeanycancerhasbeendiagnosedoranysuspiciouslumporotherlesionhasappeared(aprocedureknownas"prophylacticbilateralmastectomy"or"riskreducingmastectomy")maybeconsideredinwomenwithBRCA1andBRCA2mutations,whichareassociatedwithasubstantiallyheightenedriskforaneventualdiagnosisofbreastcancer.[138][139]Evidenceisnotstrongenoughtosupportthisprocedureinanyonebutwomenatthehighestrisk.[140]BRCAtestingisrecommendedinthosewithahighfamilyriskaftergeneticcounseling.Itisnotrecommendedroutinely.[141]ThisisbecausetherearemanyformsofchangesinBRCAgenes,rangingfromharmlesspolymorphismstoobviouslydangerousframeshiftmutations.[141]Theeffectofmostoftheidentifiablechangesinthegenesisuncertain.Testinginanaverage-riskpersonisparticularlylikelytoreturnoneoftheseindeterminate,uselessresults.Removingthesecondbreastinapersonwhohasbreastcancer(contralateralrisk‐reducingmastectomyorCRRM)mayreducetheriskofcancerinthesecondbreast,however,itisunclearifremovingthesecondbreastinthosewhohavebreastcancerimprovessurvival.[140] Medications[edit] Theselectiveestrogenreceptormodulatorsreducetheriskofbreastcancerbutincreasetheriskofthromboembolismandendometrialcancer.[142]Thereisnooverallchangeintheriskofdeath.[142][143]Theyarethusnotrecommendedforthepreventionofbreastcancerinwomenataverageriskbutitisrecommendedtheybeofferedforthoseathighriskandovertheageof35.[144]Thebenefitofbreastcancerreductioncontinuesforatleastfiveyearsafterstoppingacourseoftreatmentwiththesemedications.[145]Aromataseinhibitors(suchasexemestaneandanasatrozole)maybemoreeffectivethanselectiveestrogenreceptormodulators(suchastamoxifen)atreducingbreastcancerriskandtheyarenotassociatedwithanincreasedriskofendometrialcancerandthromboembolism.[146] Management[edit] Mainarticle:Breastcancermanagement Themanagementofbreastcancerdependsonvariousfactors,includingthestageofthecancerandtheperson'sage.Treatmentsaremoreaggressivewhenthecancerismoreadvancedorthereisahigherriskofrecurrenceofthecancerfollowingtreatment. Breastcancerisusuallytreatedwithsurgery,whichmaybefollowedbychemotherapyorradiationtherapy,orboth.Amultidisciplinaryapproachispreferable.[147]Hormonereceptor-positivecancersareoftentreatedwithhormone-blockingtherapyovercoursesofseveralyears.Monoclonalantibodies,orotherimmune-modulatingtreatments,maybeadministeredincertaincasesofmetastaticandotheradvancedstagesofbreastcancer.Althoughthisrangeoftreatmentisstillbeingstudied.[148] Surgery[edit] Chestafterrightbreastmastectomy Surgeryinvolvesthephysicalremovalofthetumor,typicallyalongwithsomeofthesurroundingtissue.Oneormorelymphnodesmaybebiopsiedduringthesurgery;increasinglythelymphnodesamplingisperformedbyasentinellymphnodebiopsy. Standardsurgeriesinclude: Mastectomy:Removalofthewholebreast. Quadrantectomy:Removalofone-quarterofthebreast. Lumpectomy:Removalofasmallpartofthebreast. Oncethetumorhasbeenremoved,ifthepersondesires,breastreconstructionsurgery,atypeofplasticsurgery,maythenbeperformedtoimprovetheaestheticappearanceofthetreatedsite. Alternatively,womenusebreastprosthesestosimulateabreastunderclothing,orchooseaflatchest.Nippleprosthesiscanbeusedatanytimefollowingthemastectomy. Medication[edit] Medicationsusedafterandinadditiontosurgeryarecalledadjuvanttherapy.Chemotherapyorothertypesoftherapypriortosurgeryarecalledneoadjuvanttherapy.Aspirinmayreducemortalityfrombreastcancerwhenusedwithothertreatments.[149][150] Therearecurrentlythreemaingroupsofmedicationsusedforadjuvantbreastcancertreatment:hormone-blockingagents,chemotherapy,andmonoclonalantibodies. Hormonaltherapy[edit] Somebreastcancersrequireestrogentocontinuegrowing.Theycanbeidentifiedbythepresenceofestrogenreceptors(ER+)andprogesteronereceptors(PR+)ontheirsurface(sometimesreferredtotogetherashormonereceptors).TheseER+cancerscanbetreatedwithdrugsthateitherblockthereceptors,e.g.tamoxifen,oralternativelyblocktheproductionofestrogenwithanaromataseinhibitor,e.g.anastrozole[151]orletrozole.Theuseoftamoxifenisrecommendedfor10years.[152]Tamoxifenincreasestheriskofpostmenopausalbleeding,endometrialpolyps,hyperplasia,andendometrialcancer;usingtamoxifenwithanIntraUterineSystemreleasinglevonorgestrelmightincreasevaginalbleedingafter1to2years,butreducessomewhatendometrialpolypsandhyperplasia,butnotnecessarilyendometrialcancer.[153]Letrozoleisrecommendedforfiveyears. Aromataseinhibitorsareonlysuitableforwomenaftermenopause;however,inthisgroup,theyappearbetterthantamoxifen.[154]Thisisbecausetheactivearomataseinpostmenopausalwomenisdifferentfromtheprevalentforminpremenopausalwomen,andthereforetheseagentsareineffectiveininhibitingthepredominantaromataseofpremenopausalwomen.[155]Aromataseinhibitorsshouldnotbegiventopremenopausalwomenwithintactovarianfunction(unlesstheyarealsoontreatmenttostoptheirovariesfromworking).[156]CDKinhibitorscanbeusedincombinationwithendocrineoraromatasetherapy.[157] Chemotherapy[edit] Chemotherapyispredominantlyusedforcasesofbreastcancerinstages2–4,andisparticularlybeneficialinestrogenreceptor-negative(ER-)disease.Thechemotherapymedicationsareadministeredincombinations,usuallyforperiodsof3–6months.Oneofthemostcommonregimens,knownas"AC",combinescyclophosphamidewithdoxorubicin.Sometimesataxanedrug,suchasdocetaxel,isadded,andtheregimeisthenknownas"CAT".Anothercommontreatmentiscyclophosphamide,methotrexate,andfluorouracil(or"CMF").Mostchemotherapymedicationsworkbydestroyingfast-growingand/orfast-replicatingcancercells,eitherbycausingDNAdamageuponreplicationorbyothermechanisms.However,themedicationsalsodamagefast-growingnormalcells,whichmaycauseserioussideeffects.Damagetotheheartmuscleisthemostdangerouscomplicationofdoxorubicin,forexample.[citationneeded] Monoclonalantibodies[edit] Trastuzumab,amonoclonalantibodytoHER2,hasimprovedthefive-yeardiseasefreesurvivalofstage1–3HER2-positivebreastcancerstoabout87%(overallsurvival95%).[158]Between25%and30%ofbreastcancersoverexpresstheHER2geneoritsproteinproduct,[159]andoverexpressionofHER2inbreastcancerisassociatedwithincreaseddiseaserecurrenceandworseprognosis.Trastuzumab,however,isveryexpensive,anditsusemaycauseserioussideeffects(approximately2%ofpeoplewhoreceiveitdevelopsignificantheartdamage).[160]AnotherantibodypertuzumabpreventsHER2dimerizationandisrecommendedtogetherwithtrastuzumabandchemotherapyinseveredisease.[161][162] Radiation[edit] Internalradiotherapyforbreastcancer Radiotherapyisgivenaftersurgerytotheregionofthetumorbedandregionallymphnodes,todestroymicroscopictumorcellsthatmayhaveescapedsurgery.Whengivenintraoperativelyastargetedintraoperativeradiotherapy,itmayalsohaveabeneficialeffectontumormicroenvironment.[163][164]Radiationtherapycanbedeliveredasexternalbeamradiotherapyorasbrachytherapy(internalradiotherapy).Conventionallyradiotherapyisgivenaftertheoperationforbreastcancer.Radiationcanalsobegivenatthetimeofoperationonthebreastcancer.Radiationcanreducetheriskofrecurrenceby50–66%(1/2–2/3reductionofrisk)whendeliveredinthecorrectdose[165]andisconsideredessentialwhenbreastcanceristreatedbyremovingonlythelump(LumpectomyorWidelocalexcision).Inearlybreastcancer,partialbreastirradiationdoesnotgivethesamecancercontrolinthebreastastreatingthewholebreastandmaycauseworsesideeffects.[166] Follow-upcare[edit] Careafterprimarybreastcancertreatment,otherwisecalled'follow-upcare',canbeintensiveinvolvingregularlaboratorytestsinasymptomaticpeopletotrytoachieveearlierdetectionofpossiblemetastases.Areviewhasfoundthatfollow-upprogramsinvolvingregularphysicalexaminationsandyearlymammographyaloneareaseffectiveasmoreintensiveprogramsconsistingoflaboratorytestsintermsofearlydetectionofrecurrence,overallsurvivalandqualityoflife.[167] Multidisciplinaryrehabilitationprogrammes,oftenincludingexercise,educationandpsychologicalhelp,mayproduceshort-termimprovementsinfunctionalability,psychosocialadjustmentandsocialparticipationinpeoplewithbreastcancer.[168] Prognosis[edit] Breastsafterdoublemastectomyfollowedbynipple-sparingreconstructionwithimplants Anextremeexampleofanadvancedrecurrentbreastcancerwithanulceratingaxillarymass Prognosticfactors[edit] Thestageofthebreastcanceristhemostimportantcomponentoftraditionalclassificationmethodsofbreastcancer,becauseithasagreatereffectontheprognosisthantheotherconsiderations.Stagingtakesintoconsiderationsize,localinvolvement,lymphnodestatusandwhethermetastaticdiseaseispresent.Thehigherthestageatdiagnosis,thepoorertheprognosis.Thestageisraisedbytheinvasivenessofdiseasetolymphnodes,chestwall,skinorbeyond,andtheaggressivenessofthecancercells.Thestageisloweredbythepresenceofcancer-freezonesandclose-to-normalcellbehaviour(grading).Sizeisnotafactorinstagingunlessthecancerisinvasive.Forexample,DuctalCarcinomainSitu(DCIS)involvingtheentirebreastwillstillbestagezeroandconsequentlyanexcellentprognosiswitha10-yeardiseasefreesurvivalofabout98%.[169] Stage1cancers(andDCIS,LCIS)haveanexcellentprognosisandaregenerallytreatedwithlumpectomyandsometimesradiation.[170] Stage2and3cancerswithaprogressivelypoorerprognosisandgreaterriskofrecurrencearegenerallytreatedwithsurgery(lumpectomyormastectomywithorwithoutlymphnoderemoval),chemotherapy(plustrastuzumabforHER2+cancers)andsometimesradiation(particularlyfollowinglargecancers,multiplepositivenodesorlumpectomy).[medicalcitationneeded] Stage4,metastaticcancer,(i.e.spreadtodistantsites)hasapoorprognosisandismanagedbyvariouscombinationofalltreatmentsfromsurgery,radiation,chemotherapyandtargetedtherapies.Ten-yearsurvivalrateis5%withouttreatmentand10%withoptimaltreatment.[171] Thebreastcancergradeisassessedbycomparisonofthebreastcancercellstonormalbreastcells.Theclosertonormalthecancercellsare,theslowertheirgrowthandthebettertheprognosis.Ifcellsarenotwelldifferentiated,theywillappearimmature,willdividemorerapidly,andwilltendtospread.Welldifferentiatedisgivenagradeof1,moderateisgrade2,whilepoororundifferentiatedisgivenahighergradeof3or4(dependinguponthescaleused).ThemostwidelyusedgradingsystemistheNottinghamscheme.[172] Youngerwomenwithanageoflessthan40yearsorwomenover80yearstendtohaveapoorerprognosisthanpost-menopausalwomenduetoseveralfactors.Theirbreastsmaychangewiththeirmenstrualcycles,theymaybenursinginfants,andtheymaybeunawareofchangesintheirbreasts.Therefore,youngerwomenareusuallyatamoreadvancedstagewhendiagnosed.Theremayalsobebiologicfactorscontributingtoahigherriskofdiseaserecurrenceforyoungerwomenwithbreastcancer.[173] Psychologicalaspects[edit] Notallpeoplewithbreastcancerexperiencetheirillnessinthesamemanner.Factorssuchasagecanhaveasignificantimpactonthewayapersoncopeswithabreastcancerdiagnosis.Premenopausalwomenwithestrogen-receptorpositivebreastcancermustconfronttheissuesofearlymenopauseinducedbymanyofthechemotherapyregimensusedtotreattheirbreastcancer,especiallythosethatusehormonestocounteractovarianfunction.[174] Inwomenwithnon-metastaticbreastcancer,psychologicalinterventionssuchascognitivebehavioraltherapycanhavepositiveeffectsonoutcomessuchasanxiety,depressionandmooddisturbance.[175]Physicalactivityinterventionsmayalsohavebeneficialeffectsonhealthrelatedqualityoflife,anxiety,fitnessandphysicalactivityinwomenwithbreastcancerfollowingadjuvanttherapy.[176] Epidemiology[edit] Mainarticle:Epidemiologyofbreastcancer Age-standardizeddeathfrombreastcancerper100,000inhabitantsin2004[177]  nodata  <2  2–4  4–6  6–8  8–10  10–12  12–14  14–16  16–18  18–20  20–22  >22 Worldwide,breastcanceristhemost-commoninvasivecancerinwomen.[178]Alongwithlungcancer,breastcanceristhemostcommonlydiagnosedcancer,with2.09millioncaseseachin2018.[179]Breastcanceraffects1in7(14%)ofwomenworldwide.[180](Themostcommonformofcancerisnon-invasivenon-melanomaskincancer;non-invasivecancersaregenerallyeasilycured,causeveryfewdeaths,andareroutinelyexcludedfromcancerstatistics.)Breastcancercomprises22.9%ofinvasivecancersinwomen[181]and16%ofallfemalecancers.[182]In2012,itcomprised25.2%ofcancersdiagnosedinwomen,makingitthemost-commonfemalecancer.[183] In2008,breastcancercaused458,503deathsworldwide(13.7%ofcancerdeathsinwomenand6.0%ofallcancerdeathsformenandwomentogether).[181]Lungcancer,thesecondmost-commoncauseofcancer-relateddeathsinwomen,caused12.8%ofcancerdeathsinwomen(18.2%ofallcancerdeathsformenandwomentogether).[181] Theincidenceofbreastcancervariesgreatlyaroundtheworld:itislowestinless-developedcountriesandgreatestinthemore-developedcountries.Inthetwelveworldregions,theannualage-standardizedincidenceratesper100,000womenareasfollows:18inEasternAsia,22inSouthCentralAsiaandsub-SaharanAfrica,26inSouth-EasternAsia,26,28inNorthAfricaandWesternAsia,42inSouthandCentralAmerica,42,49inEasternEurope,56inSouthernEurope,73inNorthernEurope,74inOceania,78inWesternEurope,and90inNorthAmerica.[184]Metastaticbreastcanceraffectsbetween19%(UnitedStates)and50%(partsofAfrica)ofwomenwithbreastcancer.[185] Thenumberofcasesworldwidehassignificantlyincreasedsincethe1970s,aphenomenonpartlyattributedtothemodernlifestyles.[186][187]Breastcancerisstronglyrelatedtoagewithonly5%ofallbreastcancersoccurringinwomenunder40yearsold.[188]Thereweremorethan41,000newlydiagnosedcasesofbreastcancerregisteredinEnglandin2011,around80%ofthesecaseswereinwomenage50orolder.[189]BasedonU.S.statisticsin2015therewere2.8millionwomenaffectedbybreastcancer.[178]IntheUnitedStates,theage-adjustedincidenceofbreastcancerper100,000womenrosefromaround102casesperyearinthe1970stoaround141inthelate-1990s,andhassincefallen,holdingsteadyaround125since2003.However,age-adjusteddeathsfrombreastcancerper100,000womenonlyroseslightlyfrom31.4in1975to33.2in1989andhavesincedeclinedsteadilyto20.5in2014.[190] History[edit] Breastcancersurgeryin18thcentury Becauseofitsvisibility,breastcancerwastheformofcancermostoftendescribedinancientdocuments.[191]Becauseautopsieswererare,cancersoftheinternalorganswereessentiallyinvisibletoancientmedicine.Breastcancer,however,couldbefeltthroughtheskin,andinitsadvancedstateoftendevelopedintofungatinglesions:thetumorwouldbecomenecrotic(diefromtheinside,causingthetumortoappeartobreakup)andulceratethroughtheskin,weepingfetid,darkfluid.[191] TheoldestdiscoveredevidenceofbreastcancerisfromEgyptanddatesback4200years,totheSixthDynasty.[192]Thestudyofawoman'sremainsfromthenecropolisofQubbetel-Hawashowedthetypicaldestructivedamageduetometastaticspread.[192]TheEdwinSmithPapyrusdescribeseightcasesoftumorsorulcersofthebreastthatweretreatedbycauterization.Thewritingsaysaboutthedisease,"Thereisnotreatment."[193]Forcenturies,physiciansdescribedsimilarcasesintheirpractices,withthesameconclusion.Ancientmedicine,fromthetimeoftheGreeksthroughthe17thcentury,wasbasedonhumoralism,andthusbelievedthatbreastcancerwasgenerallycausedbyimbalancesinthefundamentalfluidsthatcontrolledthebody,especiallyanexcessofblackbile.[194]Alternativelyitwasseenasdivinepunishment.[195] MastectomyforbreastcancerwasperformedatleastasearlyasAD548,whenitwasproposedbythecourtphysicianAetiosofAmidatoTheodora.[191]Itwasnotuntildoctorsachievedgreaterunderstandingofthecirculatorysysteminthe17thcenturythattheycouldlinkbreastcancer'sspreadtothelymphnodesinthearmpit.Intheearly18thcenturytheFrenchsurgeonJeanLouisPetitperformedtotalmastectomiesthatincludedremovingtheaxillarylymphnodes,asherecognizedthatthisreducedrecurrence.[196]Petit'sworkbuiltonthemethodsofthesurgeonBernardPeyrilhe,whointhe17thcenturyadditionallyremovedthepectoralmuscleunderlyingthebreast,ashejudgedthatthisgreatlyimprovedtheprognosis.[197]ButpoorresultsandtheconsiderablerisktothepatientmeantthatphysiciansdidnotsharetheopinionofsurgeonssuchasNicolaesTulp,whointhe17thcenturyproclaimed"thesoleremedyisatimelyoperation".TheeminentsurgeonRichardWisemandocumentedinthemid17thcenturythatfollowing12mastectomies,twopatientsdiedduringtheoperation,eightpatientsdiedshortlyaftertheoperationfromprogressivecancerandonlytwoofthe12patientswerecured.[198]Physicianswereconservativeinthetreatmenttheyprescribedintheearlystagesofbreastcancer.Patientsweretreatedwithamixtureofdetoxpurges,bloodlettingandtraditionalremediesthatweresupposedtoloweracidity,suchasthealkalinearsenic.[199] Whenin1664AnneofAustriawasdiagnosedwithbreastcancer,theinitialtreatmentinvolvedcompressessaturatedwithhemlockjuice.WhenthelumpsincreasedtheKing'sphysiciancommencedatreatmentwitharsenicointments.[200]Theroyalpatientdied1666inatrociouspain.[201]Eachfailingtreatmentforbreastcancerledtothesearchfornewtreatments,spurningamarketinremediesthatwereadvertisedandsoledbyquacks,herbalists,chemistsandapothecaries.[202]Thelackofanesthesiaandantisepticsmademastectomyapainfulanddangerousordeal.[198]Inthe18thcentury,awidevarietyofanatomicaldiscoverieswereaccompaniedbynewtheoriesaboutthecauseandgrowthofbreastcancer.TheinvestigativesurgeonJohnHunterclaimedthatneuralfluidgeneratedbreastcancer.Othersurgeonsproposedthatmilkwithinthemammaryductsledtocancerousgrowths.Theoriesabouttraumatothebreastascauseformalignantchangesinbreasttissuewereadvanced.Thediscoveryofbreastlumpsandswellingsfueledcontroversiesabouthardtumorsandwhetherlumpswerebenignstagesofcancer.Medicalopinionaboutnecessaryimmediatetreatmentvaried.[203]ThesurgeonBenjaminBelladvocatedremovaloftheentirebreast,evenwhenonlyaportionwasaffected.[204] Radicalmastectomy,Halsted'ssurgicalpapers Breastcancerwasuncommonuntilthe19thcentury,whenimprovementsinsanitationandcontrolofdeadlyinfectiousdiseasesresultedindramaticincreasesinlifespan.Previously,mostwomenhaddiedtooyoungtohavedevelopedbreastcancer.[205]In1878,anarticleinScientificAmericandescribedhistoricaltreatmentbypressureintendedtoinducelocalischemiaincaseswhensurgicalremovalwerenotpossible.[206]WilliamStewartHalstedstartedperformingradicalmastectomiesin1882,helpedgreatlybyadvancesingeneralsurgicaltechnology,suchasaseptictechniqueandanesthesia.TheHalstedradicalmastectomyofteninvolvedremovingbothbreasts,associatedlymphnodes,andtheunderlyingchestmuscles.Thisoftenledtolong-termpainanddisability,butwasseenasnecessarytopreventthecancerfromrecurring.[207]BeforetheadventoftheHalstedradicalmastectomy,20-yearsurvivalrateswereonly10%;Halsted'ssurgeryraisedthatrateto50%.[208] Breastcancerstagingsystemsweredevelopedinthe1920sand1930stodeterminingtheextenttowhichacancerhasdevelopedbygrowingandspreading.[207]Thefirstcase-controlledstudyonbreastcancerepidemiologywasdonebyJanetLane-Claypon,whopublishedacomparativestudyin1926of500breastcancercasesand500controlsofthesamebackgroundandlifestylefortheBritishMinistryofHealth.[209]RadicalmastectomiesremainedthestandardofcareintheUSAuntilthe1970s,butinEurope,breast-sparingprocedures,oftenfollowedbyradiationtherapy,weregenerallyadoptedinthe1950s.[207]In1955GeorgeCrileJr.publishedCancerandCommonSensearguingthatcancerpatientsneededtounderstandavailabletreatmentoptions.CrilebecameaclosefriendoftheenvironmentalistRachelCarson,whohadundergoneaHalstedradicalmastectomyin1960totreathermalignbreastcancer.[210]TheUSoncologistJeromeUrbanpromotedsuperradicalmastectomies,takingevenmoretissue,until1963,whentheten-yearsurvivalratesprovedequaltotheless-damagingradicalmastectomy.[207]Carsondiedin1964andCrilewentontopublishedawidevarietyofarticles,bothinthepopularpressandinmedicaljournals,challengingthewidespreadusedoftheHalstedradicalmastectomy.In1973CrilepublishedWhatWomenShouldKnowAbouttheBreastCancerControversy.Whenin1974BettyFordwasdiagnosedwithbreastcancer,theoptionsfortreatingbreastcancerwereopenlydiscussedinthepress.[211]Duringthe1970s,anewunderstandingofmetastasisledtoperceivingcancerasasystemicillnessaswellasalocalizedone,andmoresparingproceduresweredevelopedthatprovedequallyeffective.[212] Inthe1980sand1990s,thousandsofwomenwhohadsuccessfullycompletedstandardtreatmentthendemandedandreceivedhigh-dosebonemarrowtransplants,thinkingthiswouldleadtobetterlong-termsurvival.However,itprovedcompletelyineffective,and15–20%ofwomendiedbecauseofthebrutaltreatment.[213]The1995reportsfromtheNurses'HealthStudyandthe2002conclusionsoftheWomen'sHealthInitiativetrialconclusivelyprovedthathormonereplacementtherapysignificantlyincreasedtheincidenceofbreastcancer.[213] Societyandculture[edit] Seealso:BreastcancerawarenessandListofpeoplewithbreastcancer Beforethe20thcentury,breastcancerwasfearedanddiscussedinhushedtones,asifitwereshameful.Aslittlecouldbesafelydonewithprimitivesurgicaltechniques,womentendedtosuffersilentlyratherthanseekingcare.Whensurgeryadvanced,andlong-termsurvivalratesimproved,womenbeganraisingawarenessofthediseaseandthepossibilityofsuccessfultreatment.The"Women'sFieldArmy",runbytheAmericanSocietyfortheControlofCancer(latertheAmericanCancerSociety)duringthe1930sand1940swasoneofthefirstorganizedcampaigns.In1952,thefirstpeer-to-peersupportgroup,called"ReachtoRecovery",beganprovidingpost-mastectomy,in-hospitalvisitsfromwomenwhohadsurvivedbreastcancer.[214] Thebreastcancermovementofthe1980sand1990sdevelopedoutofthelargerfeministmovementsandwomen'shealthmovementofthe20thcentury.[215]Thisseriesofpoliticalandeducationalcampaigns,partlyinspiredbythepoliticallyandsociallyeffectiveAIDSawarenesscampaigns,resultedinthewidespreadacceptanceofsecondopinionsbeforesurgery,lessinvasivesurgicalprocedures,supportgroups,andotheradvancesincare.[216] Pinkribbon[edit] Thepinkribbonisasymboltoshowsupportforbreastcancerawareness. Mainarticle:Pinkribbon Apinkribbonisthemostprominentsymbolofbreastcancerawareness.Pinkribbons,whichcanbemadeinexpensively,aresometimessoldasfundraisers,muchlikepoppiesonRemembranceDay.Theymaybeworntohonorthosewhohavebeendiagnosedwithbreastcancer,ortoidentifyproductsthatthemanufacturerwouldliketoselltoconsumersthatareinterestedinbreastcancer.[217]Inthe1990sbreastcancerawarenesscampaignswerelaunchedbyUSbasedcorporations.Aspartofthesecauserelatedmarketingcampaignscorporationsdonatedtoavarietyofbreastcancerinitiativesforeverypinkribbonproductthatwaspurchased.[218]TheWallStreetJournalnoted"thatthestrongemotionsprovokedbybreastcancertranslatetoacompany'sbottomline".WhilemanyUScorporationsdonatedtoexistingbreastcancerinitiativesotherssuchasAvonestablishedtheirownbreastcancerfoundationsonthebackofpinkribbonproducts.[219] Wearingordisplayingapinkribbonhasbeencriticizedbytheopponentsofthispracticeasakindofslacktivism,becauseithasnopracticalpositiveeffect.Ithasalsobeencriticizedashypocrisy,becausesomepeoplewearthepinkribbontoshowgoodwilltowardswomenwithbreastcancer,butthenopposethesewomen'spracticalgoals,likepatientrightsandanti-pollutionlegislation.[220][221]Criticssaythatthefeel-goodnatureofpinkribbonsandpinkconsumptiondistractssocietyfromthelackofprogressonpreventingandcuringbreastcancer.[222]Itisalsocriticizedforreinforcinggenderstereotypesandobjectifyingwomenandtheirbreasts.[223]In2002BreastCancerActionlaunchedthe"ThinkBeforeYouPink"campaignagainstpinkwashingtotargetbusinessesthathaveco-optedthepinkcampaigntopromoteproductsthatcausebreastcancer,suchasalcoholicbeverages.[224] Breastcancerculture[edit] Inher2006bookPinkRibbons,Inc.:BreastCancerandthePoliticsofPhilanthropySamanthaKingclaimedthatbreastcancerhasbeentransformedfromaseriousdiseaseandindividualtragedytoamarket-drivenindustryofsurvivorshipandcorporatesalespitch.[225]In2010GayleSulikarguedthattheprimarypurposesorgoalsofbreastcancerculturearetomaintainbreastcancer'sdominanceasthepre-eminentwomen'shealthissue,topromotetheappearancethatsocietyisdoingsomethingeffectiveaboutbreastcancer,andtosustainandexpandthesocial,political,andfinancialpowerofbreastcanceractivists[226]InthesameyearBarbaraEhrenreichpublishedanopinionpieceinHarper'sMagazine,lamentingthatinbreastcancerculture,breastcancertherapyisviewedasariteofpassageratherthanadisease.Tofitintothismold,thewomanwithbreastcancerneedstonormalizeandfeminizeherappearance,andminimizethedisruptionthatherhealthissuescauseanyoneelse.Anger,sadness,andnegativitymustbesilenced.Aswithmostculturalmodels,peoplewhoconformtothemodelaregivensocialstatus,inthiscaseascancersurvivors.Womenwhorejectthemodelareshunned,punishedandshamed.Thecultureiscriticizedfortreatingadultwomenlikelittlegirls,asevidencedby"baby"toyssuchaspinkteddybearsgiventoadultwomen.[227] Emphasis[edit] In2009theUSsciencejournalistChristieAschwandencriticizedthattheemphasisonbreastcancerscreeningmaybeharmingwomenbysubjectingthemtounnecessaryradiation,biopsies,andsurgery.One-thirdofdiagnosedbreastcancersmightrecedeontheirown.[228]Screeningmammographyefficientlyfindsnon-life-threatening,asymptomaticbreastcancersandprecancers,evenwhileoverlookingseriouscancers.AccordingtothecancerresearcherH.GilbertWelchscreeningmammographyhastakenthe"brain-deadapproachthatsaysthebesttestistheonethatfindsthemostcancers"ratherthantheonethatfindsdangerouscancers.[228] In2002itwasnotedthatasaresultofbreastcancer'shighvisibility,thestatisticalresultscanbemisinterpreted,suchastheclaimthatoneineightwomenwillbediagnosedwithbreastcancerduringtheirlives–aclaimthatdependsontheunrealisticassumptionthatnowomanwilldieofanyotherdiseasebeforetheageof95.[229]By2010thebreastcancersurvivalrateinEuropewas91%atoneyearsand65%atfiveyears.IntheUSAthefive-yearsurvivalrateforlocalizedbreastcancerwas96.8%,whileincasesofmetastasesitwasonly20.6%.Becausetheprognosisforbreastcancerwasatthisstagerelativelyfavorable,comparedtotheprognosisforothercancers,breastcancerascauseofdeathamongwomenwas13.9%ofallcancerdeaths.Thesecondmostcommoncauseofdeathfromcancerinwomenwaslungcancer,themostcommoncancerworldwideformenandwomen.Theimprovedsurvivalratemadebreastcancerthemostprevalentcancerintheworld.In2010anestimated3.6millionwomenworldwidehavehadabreastcancerdiagnosisinthepastfiveyears,whileonly1.4millionmaleorfemalesurvivorsfromlungcancerwerealive.[230] Ethnicdifferences[edit] Thereareethnicdisparitiesinthemortalityratesforbreastcanceraswellasinbreastcancertreatment.BreastcanceristhemostprevalentcanceraffectingwomenofeveryethnicgroupintheUnitedStates.Breastcancerincidenceamongblackwomenaged45andolderishigherthanthatofwhitewomeninthesameagegroup.Whitewomenaged60–84havehigherincidenceratesofbreastcancerthanBlackwomen.Despitethis,Blackwomenateveryagearemorelikelytosuccumbtobreastcancer.[231] Breastcancertreatmenthasimprovedgreatlyinrecentyears,butblackwomenarestilllesslikelytoobtaintreatmentcomparedtowhitewomen.[231]Riskfactorssuchassocioeconomicstatus,late-stage,orbreastcanceratdiagnosis,geneticdifferencesintumorsubtypes,differencesinhealthcareaccessallcontributetothesedisparities.Socioeconomicdeterminantsaffectingthedisparityinbreastcancerillnessincludepoverty,culture,aswellassocialinjustice.InHispanicwomen,theincidenceofbreastcancerislowerthaninnon-Hispanicwomenbutisoftendiagnosedatalaterstagethanwhitewomenwithlargertumors. Blackwomenareusuallydiagnosedwithbreastcanceratayoungeragethanwhitewomen.ThemedianageofdiagnosisforBlackwomenis59,incomparisonto62inWhitewomen.TheincidenceofbreastcancerinBlackwomenhasincreasedby0.4%peryearsince1975and1.5%peryearamongAsian/PacificIslanderwomensince1992.Incidencerateswerestablefornon-HispanicWhite,Hispanics,andNativewomen.Thefive-yearsurvivalrateisnotedtobe81%inBlackwomenand92%inWhitewomen.ChineseandJapanesewomenhavethehighestsurvivalrates.[231] Povertyisamajordriverfordisparitiesrelatedtobreastcancer.Low-incomewomenarelesslikelytoundergobreastcancerscreeningandthusaremorelikelytohavealate-stagediagnosis.[231]Ensuringwomenofallethnicgroupsreceiveequitablehealthcare[clarificationneeded]canpositivelyaffectthesedisparities.[citationneeded] Pregnancy[edit] Pregnancyatanearlyagedecreasestheriskofdevelopingbreastcancerlaterinlife.[232]Theriskofbreastcanceralsodeclineswiththenumberofchildrenawomanhas.[232]Breastcancerthenbecomesmorecommoninthe5or10yearsfollowingpregnancybutthenbecomeslesscommonthanamongthegeneralpopulation.[233]Thesecancersareknownaspostpartumbreastcancerandhaveworseoutcomesincludinganincreasedriskofdistantspreadofdiseaseandmortality.[234]Othercancersfoundduringorshortlyafterpregnancyappearatapproximatelythesamerateasothercancersinwomenofasimilarage.[235] Diagnosingnewcancerinapregnantwomanisdifficult,inpartbecauseanysymptomsarecommonlyassumedtobeanormaldiscomfortassociatedwithpregnancy.[235]Asaresult,canceristypicallydiscoveredatasomewhatlaterstagethanaverageinmanypregnantorrecentlypregnantwomen.Someimagingprocedures,suchasMRIs(magneticresonanceimaging),CTscans,ultrasounds,andmammogramswithfetalshieldingareconsideredsafeduringpregnancy;someothers,suchasPETscansarenot.[235] Treatmentisgenerallythesameasfornon-pregnantwomen.[235]However,radiationisnormallyavoidedduringpregnancy,especiallyifthefetaldosemightexceed100cGy.Insomecases,someoralltreatmentsarepostponeduntilafterbirthifthecancerisdiagnosedlateinthepregnancy.Earlydeliveriestospeedthestartoftreatmentarenotuncommon.Surgeryisgenerallyconsideredsafeduringpregnancy,butsomeothertreatments,especiallycertainchemotherapydrugsgivenduringthefirsttrimester,increasetheriskofbirthdefectsandpregnancyloss(spontaneousabortionsandstillbirths).[235]Electiveabortionsarenotrequiredanddonotimprovethelikelihoodofthemothersurvivingorbeingcured.[235] Radiationtreatmentsmayinterferewiththemother'sabilitytobreastfeedherbabybecauseitreducestheabilityofthatbreasttoproducemilkandincreasestheriskofmastitis.Also,whenchemotherapyisbeinggivenafterbirth,manyofthedrugspassthroughbreastmilktothebaby,whichcouldharmthebaby.[235] Regardingfuturepregnancyamongbreastcancersurvivors,thereisoftenfearofcancerrecurrence.[236]Ontheotherhand,manystillregardpregnancyandparenthoodtorepresentnormalcy,happinessandlifefulfillment.[236] Hormones[edit] Birthcontrol[edit] Inbreastcancersurvivors,non-hormonalbirthcontrolmethodssuchasthecopperintrauterinedevice(IUD)shouldbeusedasfirst-lineoptions.[237]Progestogen-basedmethodssuchasdepotmedroxyprogesteroneacetate,IUDwithprogestogenorprogestogenonlypillshaveapoorlyinvestigatedbutpossibleincreasedriskofcancerrecurrence,butmaybeusedifpositiveeffectsoutweighthispossiblerisk.[238] Menopausalhormonereplacement[edit] Inbreastcancersurvivors,itisrecommendedtofirstconsidernon-hormonaloptionsformenopausaleffects,suchasbisphosphonatesorselectiveestrogenreceptormodulators(SERMs)forosteoporosis,andvaginalestrogenforlocalsymptoms.Observationalstudiesofsystemichormonereplacementtherapyafterbreastcanceraregenerallyreassuring.Ifhormonereplacementisnecessaryafterbreastcancer,estrogen-onlytherapyorestrogentherapywithanintrauterinedevicewithprogestogenmaybesaferoptionsthancombinedsystemictherapy.[239] Research[edit] Treatmentsarebeingevaluatedinclinicaltrials.Thisincludesindividualdrugs,combinationsofdrugs,andsurgicalandradiationtechniquesInvestigationsincludenewtypesoftargetedtherapy,[240]cancervaccines,oncolyticvirotherapy,[241]genetherapy[242][243]andimmunotherapy.[244] ThelatestresearchisreportedannuallyatscientificmeetingssuchasthatoftheAmericanSocietyofClinicalOncology,SanAntonioBreastCancerSymposium,[245]andtheSt.GallenOncologyConferenceinSt.Gallen,Switzerland.[246]Thesestudiesarereviewedbyprofessionalsocietiesandotherorganizations,andformulatedintoguidelinesforspecifictreatmentgroupsandriskcategory. Fenretinide,aretinoid,isalsobeingstudiedasawaytoreducetheriskofbreastcancer.[247][248]Inparticular,combinationsofribociclibplusendocrinetherapyhavebeenthesubjectofclinicaltrials.[249] A2019reviewfoundmoderatecertaintyevidencethatgivingpeopleantibioticsbeforebreastcancersurgeryhelpedtopreventsurgicalsiteinfection(SSI).Furtherstudyisrequiredtodeterminethemosteffectiveantibioticprotocolanduseinwomenundergoingimmediatebreastreconstruction.[250] Cryoablation[edit] Asof2014cryoablationisbeingstudiedtoseeifitcouldbeasubstituteforalumpectomyinsmallcancers.[251]Thereistentativeevidenceinthosewithtumorslessthan2centimeters.[252]Itmayalsobeusedinthoseinwhosurgeryisnotpossible.[252]Anotherreviewstatesthatcryoablationlookspromisingforearlybreastcancerofsmallsize.[253] Breastcancercelllines[edit] Seealso:Listofbreastcancercelllines Partofthecurrentknowledgeonbreastcarcinomasisbasedoninvivoandinvitrostudiesperformedwithcelllinesderivedfrombreastcancers.Theseprovideanunlimitedsourceofhomogenousself-replicatingmaterial,freeofcontaminatingstromalcells,andofteneasilyculturedinsimplestandardmedia.Thefirstbreastcancercelllinedescribed,BT-20,wasestablishedin1958.Sincethen,anddespitesustainedworkinthisarea,thenumberofpermanentlinesobtainedhasbeenstrikinglylow(about100).Indeed,attemptstoculturebreastcancercelllinesfromprimarytumorshavebeenlargelyunsuccessful.Thispoorefficiencywasoftenduetotechnicaldifficultiesassociatedwiththeextractionofviabletumorcellsfromtheirsurroundingstroma.Mostoftheavailablebreastcancercelllinesissuedfrommetastatictumors,mainlyfrompleuraleffusions.Effusionsprovidedgenerallylargenumbersofdissociated,viabletumorcellswithlittleornocontaminationbyfibroblastsandothertumorstromacells. ManyofthecurrentlyusedBCClineswereestablishedinthelate1970s.Averyfewofthem,namelyMCF-7,T-47D,MDA-MB-231andSK-BR-3,accountformorethantwo-thirdsofallabstractsreportingstudiesonmentionedbreastcancercelllines,asconcludedfromaMedline-basedsurvey. Molecularmarkers[edit] Metabolicmarkers[edit] Clinically,themostusefulmetabolicmarkersinbreastcanceraretheestrogenandprogesteronereceptorsthatareusedtopredictresponsetohormonetherapy.NeworpotentiallynewmarkersforbreastcancerincludeBRCA1andBRCA2[254]toidentifypeopleathighriskofdevelopingbreastcancer,HER-2,[medicalcitationneeded]andSCD1,forpredictingresponsetotherapeuticregimens,andurokinaseplasminogenactivator,PA1-1andSCD1forassessingprognosis.[medicalcitationneeded] Otheranimals[edit] Mammarytumorforbreastcancerinotheranimals Mousemodelsofbreastcancermetastasis References[edit] ^abcdefghijklm"BreastCancerTreatment(PDQ®)".NCI.23May2014.Archivedfromtheoriginalon5July2014.Retrieved29June2014. ^abcdefghWorldCancerReport2014.WorldHealthOrganization.2014.pp. Chapter5.2.ISBN 978-92-832-0429-9. ^"KlinefelterSyndrome".EuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment.24May2007.Archivedfromtheoriginalon27November2012. 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