www.elsevier.com/locate/breast

THEBREASTREVIEWObesityandbreastcancer:areviewoftheliteratureA.
R.
Carmichaela,*,T.
BatesbaThePrincessRoyalHospital,HaywardsHeath,Sussex,UKbTheBreastUnit,WilliamHarveyHospital,Ashford,Kent,UKReceived24October2002;receivedinrevisedform10March2003;accepted20March2003SummaryAwoman'sbuild,theriskofbreastcanceranditssubsequentprognosisseemtoberelated.
Inmostbutnotallcase–controlandprospectivecohortstudies,aninverserelationshiphasbeenfoundbetweenweightandbreastcanceramongpremenopausalwomen.
However,mostlargeepidemiologicalstudieshavefoundthatoverweightorobesewomenareatincreasedriskofdevelopingpostmenopausalbreastcancer.
Itissuggestedthathigherbodymassindexisassociatedwithamoreadvancedstageofbreastcanceratdiagnosisintermsoftumoursizebutdataonlymphnodestatusisnotsoconsistent.
Alltreatmentmodalitiesforbreastcancersuchassurgery,radiotherapy,chemotherapyandhormonaltreatmentmaybeadverselyaffectedbythepresenceofobesity.
Theoverallanddisease-freesurvivalisworseinmostbutnotallstudiesofprognosisofobesepre-andpostmenopausalwomenwithbreastcancer.
&2003ElsevierLtd.
Allrightsreserved.
IntroductionObesitywhichmightbeconsideredasthemalnu-tritionofthedevelopedworld,hasreachedendemicproportionsanditsprevalencecontinuestoincrease,particularlyintheafuentcountriesofEuropeandtheUnitedStates.
1InEurope,itisestimatedthat10–20%ofallmenand15–25%ofallwomenareobese.
EpidemiologicalsurveysofEnglandindicatethattheprevalenceofobesityhasalmosttripledbetween1980and1998,from6%to17%inmenandfrom8%to21%inwomenbetween16and64yearsofage(Fig.
1).
2Thisincreaseinobesityisseeninallagegroupsandhasoccurredsorapidlythatenvironmentalfactorsarethoughttoberesponsibleratherthanageneticcause.
Paradoxically,therehasbeena20%decreaseintheconsumptionofcaloriessince1970,whichmaybepartlyexplainedbyadecreaseinexpendi-tureofcaloriesduetodeclineinphysicalactivity.
3DenitionObesitycanbemeasuredasbodyweight,bodyweightrelativetoheightormaybeassessedbythedistributionoffatinthebody.
Bodymassindex(BMI)(weightinkg/heightinm2)orthetypeofobesitybythecentralorperipheraldistributionoffataretwomostwidelyusedandclinicallyARTICLEINPRESSKEYWORDSBreastneoplasms;Incidence;Bodymassindex;Diagnosis;Female;Human;Incidence;Middleage;Mortality;Postmenopausal;Premenopausal*Correspondingauthor.
RussellsHallHospital,Dudley,WestMidlandsDYI2HQ,UK.
E-mailaddress:homepac@doctors.
org.
uk(A.
R.
Carmichael).
0960-9776/$-seefrontmatter&2003ElsevierLtd.
Allrightsreserved.
doi:10.
1016/j.
breast.
2003.
03.
001TheBreast(2004)13,85–92relevantclassicationstoassessthedegreeofobesity(Table1).
4TypesofobesityCentralobesityisdenedasawaisthipratio(WHR)equaltoorgreaterthan0.
95inmenand0.
80inwomen.
Thedistributionoffatisindependentlyrelatedtothehealthrisksassociatedwithobesityi.
e.
coronaryheartdiseaseismorecommoninpatientswithcentralobesity.
5Skin-foldthicknessonthetrunkandextremities,computedtomogra-phyandmagneticresonanceimaginghaveallbeenusedtomeasurethedegreeandtypeofobesity.
ObesityandtheincidenceofbreastcancerTherelationshipbetweenbreastcancerandobesityisnotstraightforward.
PremenopausalwomenInmostbutnotallcase–controlandprospectivecohortstudies,aninverserelationshiphasbeenfoundbetweenweightandbreastcanceramongpremenopausalwomen6–11(Table2).
Ameta-analysisofsomeofthesestudiesreachedtheconclusionthatinpremenopausalwomenthereisasignicanttrendforadecreasedrelativerisk(RR)forbreastcancerinassociationwithincreasingBMI.
12Thisincreasedincidenceofbreastcancerinleanyoungwomenisfoundtobestrongestamongsttheyoungestagegroup(p35years)andisconsistentregardlessofbreastcancerratesinthecountryofresidence,weightatthetimeofdiagnosis,adolescenceorchildhood.
13Insomeepidemiologicalstudiestheexcessincidenceofbreastcanceramongleanwomeninthisagegroupislimitedtotumoursthatarelessthan2.
0cmindiameter,arenotassociatedwithmetastasestolymphnodes,andarewelldifferentiated.
14Thesendingssuggestthattheapparentexcessriskofbreastcanceramongleanpremenopausalwomenmayresultatleastinpartfromeasier,andthusearlier,diagnosisoflessaggressivetumours.
However,ahighBMIissignicantlyassociatedwithanincreasedriskofinammatorybreastcancer(IBC),whichisthemostlethalformofbreastcancerinbothpremenopausalandpost-menopausalwomen.
15Inastudyof68womenwithIBCtreatedattheM.
D.
Anderson,womeninthehighestBMItertile(BMI426.
65kg/m2)relativetothelowesttertile(BMIo22.
27)hadasignicantlyincreasedriskofIBC(IBCvs.
non-IBC,oddsratio[OR]:2.
45,95%condenceinterval[CI]:1.
05–5.
73;IBCvs.
non-breastcancer,OR:4.
52,95%CI:1.
85–11.
04).
Thisassociationwasnotsignicantlymodiedbymenopausalstatus.
15Apopulation-basedcase–controlstudyconductedinNewMexicoofHispanic(n694)andnon-Hispanic(n813)whitewomenfoundthatweightchangefromageARTICLEINPRESSFigure1Obesity(BMI30–39.
9)rateinEnglandamongmenandwomenbetween16to64yearsofage1980–1998(HealthSurveyforEngland1998).
2Table1Degreeofoverweightandobesity.
GradeBMIDescriptionUngradedBMIo20UnderweightGrade0BMI20–24.
9DesirableweightGrade1BMI25–29.
9OverweightGrade2BMI30–39.
9ObeseGrade3BMIX40MorbidlyobeseAdaptedfromWHOTechnicalReportSeriesno.
854.
486A.
R.
Carmichael,T.
Bates18tousualadultweightwasassociatedwithincreasedriskofbreastcanceramongHispanics(4thquartilevs.
baseline,OR:2.
41;95%CI:1.
45–4.
03)withnosubstantialvariationbymenopausalstatus.
Increasedriskfromweightgainwaslargelyrestrictedtowomenwhowereleanatage18andthosehormonereceptorpositivetumours.
16Somedatasuggestthatadultweightgainandcentralobesityincreasetheriskofpremenopausalbreastcancer.
13,14,17,18Astudyof216pre-andpostmenopausalwomenwithinvasivebreastcarci-nomashowedthattheRRofbreastcancerincreaseswithincreasingWHR(lessthan0.
731.
00;0.
73–761.
90;0.
77–0.
802.
83;greaterthan0.
806.
46).
18PostmenopausalwomenMostlargeepidemiologicalstudieshavefoundthatoverweightorobesewomenareatincreasedriskofdevelopingpostmenopausalbreastcancer(Table3).
6,19–25TheRRofdevelopingpostmeno-pausalbreastcancerwasfoundtobe1.
26(95%CI:1.
09,1.
46)inwomenwithBMIof28kg/m2oraboveonanalysisofpooleddatafromsevenprospectivecohortstudiesincluding337819womenand4385incidentinvasivebreastcancercases.
10Adultweightgainisanestablishedriskfactorforbreastcancerinpostmenopausalwomen.
6,26,27Inapopulation-basedcase–controlstudyinallofSwe-den,whichincluded3345(84%ofalleligible)womenaged50–74yearswithinvasivebreastcancer,and3454(82%ofallselected)controlsofsimilarage,womenwhohadgained30kgormoresinceage18hadanoddsratioof2.
04(95%CI:1.
20–3.
48)ofbreastcancercomparedwiththosewhohadmaintainedtheirweightunchanged.
Theeffectofweightgainwasunequivocalamongnon-usersbutnotamongusersofhormonereplacementtherapy.
Theexactmechanismforthisincreasedriskofbreastcancerinobesewomenisnotfullyunder-stoodbutitisthoughtthatthisisafunctionoflifetimeexposuretooestrogen,sincetheoestrogenmilieuisimportantintheinitiationandprogressionofbreastcancerlesions.
Oestrogenandperhaps,progesteroneaffecttherateofcelldivisionwhichcausesproliferationofbreastepithelialcells.
ProliferatingcellsaresusceptibletogeneticerrorsduringDNAreplicationwhich,ifuncorrected,canultimatelyleadtomalignantphenotype.
28Inpostmenopausalwomen,themainsourceofoestrogenisfromtheconversionofandrogenprecursorandrostenedioneintheperiph-eraladipocytestooestrogen;thegreatertheamountofadiposetissue,thegreatertheconver-sionandhencethegreatertheexposureofbreastcellstooestrogen.
29Thiscouldexplainthelowerincidenceofbreastcancerinpre-menopausalobesewomen,asfrequentanovulatorycyclesinthesewomenmayreducetheiroverallexposuretooestrogen.
Obesityisassociatedwithlowerlevelsofsexhormonebindingglobulins(SHBG),whichincreasethebioavailabilityofoestrogeninpostmenopausalobesewomen.
20,30Insulinresistanceiscommoninobesewomenandisassociatedwithhyper-insulinaemia.
Insulincanstimulatemammaryepitheliuminvitroviatheeffectsofinsulinlikegrowthfactor1(IGF1)whichhasasynergisticeffectwithoestrogeninpromotingmammarycarcinogenesis.
29,31–36Analternativehypothesissuggeststhatobesityisassociatedwithearlyageofmenarche,lateageofmenopauseandinfertility,whichmaximisethenumberofovulatorycycles,thisincreasesthelifetimecumulativeexposureofmammaryepitheliumtooestrogenwhichincreasestheriskofbreastcancer.
37–40However,inlargerstudiestheassociationbetweenobesityandbreastcancerpersistsevenafteradjustmentforthesefactorsarguingagainsttheprepositionthatthesereproductivepathwaysareinthecausalpathway.
39ARTICLEINPRESSTable2RelativeriskestimatesforpremenopausalbreastcancerbyBMI.
Author(year)AgeCases/controlsBMIRR(CI)London8(1989)30–55658/115534o211.
04290.
6(0.
4,0.
8)Vatten11(1992)20–49164/25336o221.
04270.
6(0.
5,0.
8)Huang6(1997)30–552517/95256o201.
04310.
62(0.
45,0.
86)Obesityandbreastcancer:areviewoftheliterature87ObesityandthediagnosisofbreastcancerItissuggestedthathigherBMIisassociatedwithamoreadvancedstageofbreastcanceratdiagno-sis.
41Astudyofnewlydiagnosedbreastcancercases(n966)inBaltimorefrom1991to1997foundthatwomenwhowereobese(BMIX27.
3)weremorelikelytobeatanadvancedstage(morethan2cmindiameter)atdiagnosiscomparedwithwomenwithaBMIofo27.
3(OR:1.
57,95%CI:1.
15–2.
14).
TheassociationbetweenBMIandstageatdiagnosiswasstrongeramongwomenyoungerthan50years(OR:2.
34,95%CI:1.
34–4.
08)comparedwithwomen50yearsorolder(OR:1.
30,95%CI:0.
89–1.
91).
42Astudyof1361newlydiagnosedbreastcancerrevealedthatoddsoflate-stagedisease(denedasmorethan2cmindiameterandnodepositive)wereincreasedwithhigherBMI(ORforhighesttolowesttertile1.
46,95%CI:1.
10–1.
93)andlargerbracupsize(ORforcupDvs.
cupA1.
61,95%CI:1.
04–2.
48).
Theserelationshipswerenotmodiedbythemethodofdiagnosiswhetherbyclinicalexaminationorscreendetection.
43However,presenceofconfoundingfactorsmightcontributetothedelayinpresenta-tionofbreastcancerinobesepatients,suchaswomenfromlowersocio-economicstatusaremorelikelytobeobeseandalsomorelikelytopresentlate.
1,44–47Moststudieshavefoundapositiveassociationbetweentumoursizeandobesitybutdataonlymphnodestatusisnotsoconsistent.
Astudyof176node-positivebreastcancerpatientsdemonstratedanindependentassociationbetweenmetastasisandprimaryratio(M/P)andobesity(P0.
0002)suggestingthatobesityisassociatedwithearlyaxillary37metastasesfromprimarytumourandARTICLEINPRESSTable3RelativeriskestimatesforpostmenopausalbreastcancerbyBMI.
Author(year)AgeCases/controlsBMIRR(CI)London8(1989)30–55420/115534o211.
04291.
0(0.
8,1.
5)Tretli24(1989)7000/5700001g/cm1.
1(0.
7,0.
9)Folsom20(1990)55–69229/1839o24.
41.
0428.
351.
1(0.
8,1.
5)Sellers25(1992)55–69493/37105Nofamilyhistoryo22.
91.
027.
5–30.
71.
3(1.
0,1.
8)430.
71.
5(1.
1,2.
1)Positivefamilyhistoryo22.
91.
027.
5–30.
71.
7(0.
9,2.
9)430.
72.
2(1.
4,3.
6)Tornberg22(1994)4551466/47003o221X281.
13(1.
01,1.
10)Huang6(1997)30–552517/95256o201.
028.
1–311.
24(0.
97,1.
59)4311.
13(0.
87,1.
46)Li21(1999)50–64479/435p21.
51X27.
61.
5(1.
1,2.
3)VandenBrandt10(2000)X504385/337819o211X281.
26(1.
09,1.
46)Morimoto23(2002)50–791030/85917p22.
61431.
12.
52(1.
6–3.
9)88A.
R.
Carmichael,T.
Batesmorerapidgrowthofmetastases.
Thishypothesisissupportedbyastudyof248womenwithbreastcancerswhichdemonstratedthatobesepostmeno-pausalwomentendtohavemoreaxillarynodeinvolvementthantheirleanercounterparts(P0.
001).
17Obesityisreportedtobeassociatedwithanincreasedincidenceofhormonereceptorpositivetumoursinsomestudieswhileotherssuggestanincreaseofhormonereceptornegativetumours.
48–50Thisdiscrepancymaybeexplainedbydifferencesinlaboratorytechniquesorcriteriaforhormoneresponsiveness.
Itisalsoreportedthatobesityisastatisticallysignicantdeterminantofpatient-relateddelayinthediagnosisofbreastcancer.
Obesewomenaretwiceaslikelytopresenttoahealth-careprofes-sionalmorethan3monthsafterrstnoticingthesymptoms.
51Itispostulatedthatobesewomenaremorelikelytohavebigbreastsandabreastlumpmaybelessobviouswhichwouldleadtoadelayinseekingmedicalattention.
Alternatively,presenceofconfoundingfactorssuchasincreasedprepon-deranceofobesityinthelowersocio-economicclasses,bothofwhichisassociatedwithdelayindiagnosisofbreastcancer.
1,44–47ObesityandthetreatmentofbreastcancerThetreatmentofbreastcancercomprisessurgery,radiotherapy,chemotherapyandhormonaltreat-ment.
Allthesetreatmentmodalitiesmaybeadverselyaffectedbythepresenceofobesity.
Obesityandloco-regionalsurgeryABMIof30ormoreisanindependentprognosticfactorfortheriskofsurgicalinfectioninpatientswithbreastcancer.
52,53Axillarysurgeryistechni-callymorechallenginginobesewomenandisshowntobeassociatedwithanincreasedincidenceofaxillarydrainageandlymphoedema,especiallyifaxillarysurgeryisfollowedbyinfection.
54,55Ax-illarysurgeryinobesepatientsisassociatedwithanincreasedincidenceofradiotherapy-relatedlong-termcomplications,whichincludelymphoedema,reductioninshouldermobilityandbrachialplexo-pathy.
56EarlyresultsfromtheAxillaryLymphaticMappingAndNodalAxillaryClearance(ALMANAC)studyandothersentinelnodebiopsystudiessuggestthatobesityisanindependentpredictoroffailureoflessinvasiveaxillaryproceduressuchassentinelnodebiopsy.
57ObesityandradiotherapyThereisclearevidencethatthelargebreastwhichiscommoninobesewomenisassociatedwithtechnicaldifcultiesinprovidinganadequatedosetowholeofthebreast.
Someauthorshavesuggestedtheuseofmoreaggressivesurgicaltechniquessuchasreductionmammoplastyinobesewomentoachieveadequateoncologicaltreatment.
58Theincidenceofradiotherapy-relatedcomplicationsishigherinobesepatients.
ObesityandchemotherapyChemotherapyisassociatedwithadecreasedincidenceofamenorrhoeainobesewomencom-paredtotheirleancounterparts(71%vs.
80%).
59Itissuggestedthatoestrogenproductioncontinuesinobesepostmenopausalwomenduetoaromatisationintheperipheraladiposetissuewhichwouldcompromiseanyindirectadvantageofchemother-apyduetochemicallyinducedmenopauseparticu-larlyinpatientswithoestrogenreceptorpositivetumours.
Whenthebloodleukocytenadirisusedasasurrogatemarkerforthedrugeffect,obesepatientswhoreceiveintravenouscyclophospha-midemethotrexateand5-uorouracilhavelesssevereleukocytenadirsthantheleanpatientswhichsuggeststhatwhentheobesearetreatedaccordingtostandardschedulestheymaybesignicantlyunder-dosed.
60Furthermore,obesepatientsmaybegivenalowerdoseofchemother-apyinordertoavoidtoxicity,whichwouldcontributetowardsapoorerprognosis.
61ObesityandtheprognosisofbreastcancerTheoverallanddisease-freesurvivalisworseinmostbutnotallstudiesofprognosisofobesepre-andpostmenopausalwomenwithbreastcancer.
Thiseffectisapparentafteradjustmentforstageatdiagnosisandtheadequacytreatmentandmaybepartlyduetodelayeddetectionandmorerapidgrowthofmetastatictissueduetoimpairedcellularimmunityandhigheroestrogenlevels.
62–66TheAmericanCancerSociety'sCancerPreven-tionStudyII(CPS-II),aprospectivemortalitystudywhichincluded424168postmenopausalwomenand2852breastcancerdeathsfoundatfollow-upof14yearsthatbreastcancermortalityratesincreasedcontinuallyandsubstantiallywithin-creasingBMI(RR:3.
08,95%CI:2.
09–4.
51forBMI440.
0comparedtoBMI18.
5–20.
49).
Ifcausal,ARTICLEINPRESSObesityandbreastcancer:areviewoftheliterature89themultivariate-adjustedRRestimatesinthisstudycorrespondtoapproximately30–50%ofbreastcancerdeathsamongpostmenopausalwo-menintheUSpopulationbeingattributabletooverweight.
67Astudyof735node-positivepatientsfoundatamedianfollow-upof10.
7years,the10-year,disease-freeratefornon-obesepatientswas54%(95%CI:50–58%)comparedwith40%(CI:33–47%)forpatientsclassiedasobese.
Althoughobesepatientstendedtohavesomewhatlessfavourableoutcomebasedonstandardprognosticcriteria,aproportional-hazardsregressionmodeladjustingforotherfactorsindicatedthatriskfordiseaserecurrenceamongobesepatientswas1.
33timesthatofthenon-obesepopulation(CI:1.
05–1.
68).
68Thenegativeeffectofobesityonbreastcancersurvivalhasalsobeendemonstratedinseveralsmall-scalestudies.
Astudyof213womenwithbreastcancerfoundthattheestimatedsurvivalprobabilityforwomenwithBMIof20wasabout12%higherthanthosewithBMIof24,overa10-yearfollow-up.
69Theprognosisofbreastcancerwaspoorinbothpremenopausalandpostmeno-pausalobesewomen.
70Premenopausalobesewo-menhadupto70%decreasedsurvivalandrecurrence-freeintervalofbreastcancerafteradjustmentforstageatdiagnosisandtreat-ment.
65,71Ameta-analysisof8029womenfoundthatBMIhadaprognosticsignicanceinbreastcancer,hazardratio1.
56(95%CI:1.
22–2.
00).
However,thiseffectwasfoundtobeheteroge-neousandsomestudieshavereportednoadversesurvivaleffectofhighBMI.
7,72–77ThesedifferencesinreportedsurvivalinbreastcancerpatientswithhighBMIcanpartlybeexplainedbytheuseofdifferingdenitionsofobesitybyvariousstudiesandthefactthatsomestudieshaveanalysedthedataforoverweightandobesepatientstogether.
However,thepossibilityofpublicationbiasagainstnegativestudiesshouldnotbedismissed.
Thereisindirectevidencethatpoorsurvivalinwomenwithbreastcancerinlowersocio-economicclassesmaybepartlyexplainedbythegreaterincidenceofobesityinlowersocialclasses.
30,45,47,78,79Thehostfactorssuchascellularimmunityandnutritionthatmaydeterminemetas-tasesandrecurrenceofbreastcancermaybeunfavourableindeprivedobesepatientsoflowersocio-economicstatus.
45,80Itisalsosuggestedthatwomenfromlowersocio-economicclassestendtohavepooraccessandutilisationofthediagnosticandtherapeuticsupportforbreastcancer.
81Insummary,consistent,independentandpositiveassociationhasbeenfoundbetweenobesityandbreastcancerinpostmenopausalwomen,andinthemajorityoftheliteraturebetweenobesityandpoorprognosisofbreastcancerinbothpre-andpostmenopausalwomen.
Theattributable-riskes-timatesduetoobesityarecomparabletothoseduetoapositivefamilyhistory(6–19%).
70,82Itissuggestedthatreductionofobesitycandecreasethecasesofbreastcancerbyone-tenthinEuropewithaconsequentreductioninmortality.
83Despiteadecreaseinmortalityfrombreastcancerinrecentyears,breastcancerkills12000womenayearintheUnitedKingdomalone,andtensofthousandsinEurope.
Itisfearedthatincreasingobesityinwomenwillmanifestitseffectofincreasedincidenceofbreastcancerinpostmeno-pausalwomeninthecomingyears.
Sinceobesityisoneofthefewriskfactorsforbreastcancerwhichcanbemodiedthroughoutlife,84apublichealthpolicy,planningandhealtheducationcampaignareurgentlyrequiredtoaddresstherisingproblemsofobesityandbreastcancer.
AcknowledgementsIamgratefulforthehelpofthestaffoftheRosewellLibrary,ConquestHospital,St.
Leonard-on-Sea.
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