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PrimaryPreven+onofBreastCancer:MissedOpportuni+es
MelissaMcNeil,MD,MACP
Withthanksto:
DebbieDinardo,MaggieBenson,AmyFarkasBriannaRossiter,SarahMerriam
andRachelVanderberg
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Objec+ves
• Es+mateawoman’sbreastcancerrisk• Iden+fyriskfactorsthatshouldprompt
– Referraltoahighriskbreastclinic– Enhancedscreening– Ini+a+onofchemoprophylaxis
• Understandtheriskandbenefitsofchemopreven+on
• Counselawomanonselec+nganappropriatechemopreven+onagent
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Outline
• Riskassessment• BreastCancerScreening• BreastCancerPrimaryPreven+on
– Selec+veestrogenreceptormodulators(SERMs):tamoxifenandraloxifene
– Aromataseinhibitors(AIs):exemestaneandanastrozole
• Choosingtheappropriateagent
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BreastCancer
• MostcommoninvasivecanceramongU.S.women
• Secondleadingcauseofcancerdeathinwomen
• Effortsinprimarycarefocusonscreeningdespitethefactthat:
• Mul$plerandomizedplacebocontrolledtrialshavedemonstratedriskreduc$onwithchemopreven$oninwomenatincreasedriskofbreastcancer
www.cancer.org.
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BreastCancerRiskAssessmentforthePrimaryCarePhysician
• Currentguidelinesrecommendincorpora+ngbreastcancerriskassessmentintorou+neprimarycaretoallowforanincreasedfocusonpreven+onofbreastcancer
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4BreastCancerPreven+onStrategies
LifestyleModifica0on
Maintainhealthyweight
Exercise
Limi+ngETOH:<1drink/day
EnhancedScreening
Mammogramini+a+onandfrequency
Adjunctscreeningmodali+es
Chemo-preven0on
SERMs
AIs
SurgicalPreven0on
Mastectomy
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RiskFactorsforBreastCancer
Pa0entCharacteris0cs
Age
Race/ethnicity
Height/weight
FamilyHistory
Degreeofrela+on
Ageofdiagnosis
Otherrelatedcancers
Reproduc0ve/HormonalHistory
Menarche
Firstbirth
Menopause
UseofHRT
BreastCharacteris0cs
BreastDensity
Priorbreastbiopsy
Benignbreastdisease
MedicalHistory
Hxofchestradia+on
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UnderstandingMagnitudeofRiskRR≥2.0 RR1.5-2.0 RR1.0-1.5
1stdegreerela+vewithbreastCA
2nddegreerela+vewithbreastCA
Nulliparityorage≥30atfirstlivebirth
Extremelydensebreastsonmammo
Priorbreastbiopsy
Heterogeneouslydensebreastsonmammo
LCISorbxprolifera+vewithatypia
NelsonHD.AnnalsIntMed.2012.WangAT.MayoClinProc.2014.KerlikowskiK.AnnInternMed.2015.
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GoalsforBreastCancerRiskAssessment
• Iden+fywomenwhowouldbenefitfromreferraltoahighriskbreastclinicorgene+ccounselor
• Iden+fywomenwhowouldbenefitfromchemoprophylaxisprescribedbytheprimarycareprovider
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Case1:ColleenColleenisa60yowomanwhopresentsforherannualvisitandisworriedaboutbreastcancer.Shehasapaternalauntandapaternalunclediagnosedwithbreastcancerat53and67respec+vely.Hermotherand3sistersarewithoutbreastcancer.Hermammogramshavebeennormal.
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Whatshouldyoutellheraboutherfamilyhistoryofbreastcancer?
A. Becauseherfirstdegreerela+veshavenotbeenaffected,sheisnotatincreasedriskofbreastcancer.
B. Herfamilyhistorysuggestsshemaybeatincreasedrisk,andthisriskcanbees+matedbyusingtheGailModel.
C. Herfamilyhistorysuggestssheisatriskforhereditarybreastcancer.Sheshouldbereferredtoahighriskbreastclinicorgene+ccounselor.
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Whatshouldyoutellheraboutherfamilyhistoryofbreastcancer?
A. Becauseherfirstdegreerela+veshavenotbeenaffected,sheisnotatincreasedriskofbreastcancer.
B. Herfamilyhistorysuggestsshemaybeatincreasedrisk,andthisriskcanbees+matedbyusingtheGailModel.
C. Herfamilyhistorysuggestssheisatriskforhereditarybreastcancer.Sheshouldbereferredtoahighriskbreastclinicorgene+ccounselor.
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HereditaryBreastCancer
• 5%ofallbreastcancers• Highriskmuta+ons
– BRCA1:55-70%– BRCA2:45-70%– LiFraumeni:50%byage60– Cowden/PTENhamartomatumorsyndrome:85%– Peutz-Jeghers:45%
• Iden+fica+onofthesegene+csyndromesmaychangescreening(MRI)and/orpreven+onstrategy(mastectomy)
SmithM.ClevClinJofMed.2014.
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HereditaryBreastCancer
• Womenwithafamilyhistorysugges+veofhereditarybreastcancershouldNOThaveriskstra+fica+onwithageneralbreastcancerriskassessmenttool
• RF’sforhereditarysyndromeswarrantreferraltohighriskbreastclinicorgene+ccounselor
SmithM.ClevClinJofMed.2014.
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Indica+onsforReferral:NCCNGuidelines
• Knownmuta+onofbreastcancersuscep+bilitygeneinthefamily
• ≥2breastcancerprimariesinasingleindividual• ≥2breastcancersamong1st,2ndand3rddegreerela+vesonthesamesideofthefamily
• ≥1ovariancancerprimary• 1stor2nddegreerela+vewithdiagnosis≤age45• Malebreastcancer
DalyMBetal.NCCN.2015.
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Case1:ColleenColleenisa60yowomanwhopresentsforherannualvisitandisworriedaboutbreastcancer.Shehasapaternalauntandapaternalunclediagnosedwithbreastcancerat53and67respec+vely.Hermotherand3sistersarewithoutbreastcancer.Hermammogramshavebeennormal.Sheshouldbereferredtoahighriskbreastcancerprogram
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Case2:CharlokeCharlokeisa63yearoldpostmenopausalwomanwhopresentstoestablishcare.Hermotherwasdiagnosedwithbreastcanceraroundherage.Shehasnopersonalhistoryofbreastproblemsandtherearenootherrela+veswithbreastcancer.Menarcheatage12andherfirstbabywasatage32.Mammo:BIRADS2andheterogeneouslydensebreastsYouwanttouseariskstra+fica+ontooltoassessherriskforbreastcancer.
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WhichofthefollowingisTRUE?
A. Youshouldnotuseageneralbreastcancerriskassessmenttoolbecauseshehasafirstdegreerela+vewithbreastcancer.Sheshouldbereferredtothehighriskbreastclinic.
B. Youdonotneedtouseabreastcancerriskassessmenttoolbecauseshehasincreasedbreastdensityandyouknowsheisalreadyathighrisk.
C. TheGailModelshouldbeusedtocalculateabreastcancerrisk
D. TheBCSCModelshouldbeusedtocalculateabreastcancerrisk
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WhichofthefollowingisTRUE?
A. Youshouldnotuseageneralbreastcancerriskassessmenttoolbecauseshehasafirstdegreerela+vewithbreastcancer.Sheshouldbereferredtothehighriskbreastclinic.
B. TheGailModelhasbekerdiscrimina+onthantheBCSCModel,soisthepreferredriskassessmenttool.
C. TheTyrerCusickModelincludesamorecomprehensivelistofRF’s,includingbreastdensity,andisavailableasanonlinecalculator.
D. TheBCSCModelistheonlyriskassessmentmodelthatincorporatesbreastdensityintoitsriskstra+fica+on.
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RiskAssessmentModels
• Es+materiskforbreastcancer• Useavarietyofriskfactors• Compareto“average”womanofsameage• Es+mate5-year,10-yearand/orlife+merisk• ShouldNOTbeusedforwomenwhoareatriskforhereditarybreastcancer
VisvanathanKetal.JofClinOnc.2013.
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Whatis“HighRisk?”
• Anyonehigherriskthanaverage
• Chemopreven+on– Chemopreven+ontrials:5-yearrisk≥1.66%
– USPSTF/Freedman:5-yearrisk>3%
MoyerVA.AnnIntMed.2013.
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RiskAssessmentModelsforthePCP
• GailModel– Na+onalCancerIns+tuteBreastCancerRiskAssessmentTool(BRCAT)
• BCSCModel– BreastCancerSurveillanceConsor+umriskpredic+onmodel
– JATice• Tyrer-CusickModel
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GailModelhkp://www.cancer.gov/bcrisktool/
• Developed1989;modified1999• Calculates5-yearandlife+me(toage90)risk• Gail5-yearrisk>1.66%wascriteriaforenrollmentinSERMandMAP.3AIchemopreven+ontrials
CummingsSR.JNCI.2009.
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GailModelRF’s
Pa0entCharacteris0cs
Age
Race/ethnicity
FamilyHistory
Knowngene+c
syndrome
1stdegreerela+ve
withbreastCA
Reproduc0veHistory
Ageofmenarche
Ageoffirstlivebirth
BreastCharacteris0cs
HxofDCISorLCIS
Hxofbreastbiopsy
MedicalHistory
Priorchestradia+on
*Doesnotincludebreastdensityordetailsaboutbenignbreastdisease
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GailModel:Charloke’sRisk
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BCSCModelhkps://tools.bcsc-scc.org/bc5yearrisk/calculator.htm
• Developed2008;modified2015• Calculates5-yearand10-yearrisk• Incorporatesbreastdensity• Morecomprehensivebenignbreastdisease• Notusedforenrollmentinchemopreven+ontrials
CummingsSR.JNCI.2009.TiceJA.JofClinOnc.2015.
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BCSCModelRF’s
Pa0entCharacteris0cs
Age
Race/ethnicity
FamilyHistory
1stdegreerela+vewithbreastcancer
Reproduc0ve/HormonalHistory
(None)
BreastCharacteris0cs
BreastDensity
Hxofmastectomy
oraugmenta+on
Priorbreastbiopsyandresults
MedicalHistory
(None)
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BCSC:Charloke’sRisk
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WhichmodelshouldIusefordeterminingwhoshouldreceive
chemopreven+on?
• BCSC– Easytoaccessonlineorwithapp– IncludesbreastdensityandBBD– Bekerdiscrimina+onthanGail
• Gail– Cancalculatewithoutbreastdensity(youngerwomen)
– Bekervalidatedinthechemopreven+ontrials
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RiskAssessmentSummary
• Step1:Lookforhighriskfamilyhistoryandrefer– NCCNguidelinesorabriefgene+cscreen– DoNOTapplyanoverallriskmodel
• Step2:AssessRF’s• Step3:Calculaterisk
– BCSCifhavebreastdensityordecidetolookforit– Gailifnobreastdensityavailable;wanttoadheretotrialcriteriaforchemopreven+on
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YourPa+entisHighRisk,NowWhat?
• Lifestylemodifica+on– Weightmanagement– Alcoholintaketo<1drinkperday
• Enhancedscreening– Tomosynthesis– Frequencyofmammograms
• Chemoprophylaxis
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Screening:SpecialSitua+ons• >20%Life+meriskforBreastCancer(BRCA,radia+ontothechestages10-30,atypicalhyperplasia/LCIS,veryhighriskfamilyhistorywithoutiden+fiedmuta+on)
– AnnualMammogram+MRI• ModeratelyincreasedriskforBreastCancer(e.g.increasedbreastdensity,1-2rela+veswithbreastcancer)
– Considerannualscreening,startatyoungerage(40),and/ortomosynthesis
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UnderuseofChemopreven+on
Freedman,JNatlCancerInst.2003.Waters,BreastCancerResTreat.2010.
0 1,000,000 2,000,000 3,000,000 4,000,000 5,000,000 6,000,000 7,000,000 8,000,000 9,000,000
10,000,000
Women eligible for chemoprevention
Women with net positive benefit
Women using chemoprevention
Num
ber o
f Wom
en
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CurrentRecommenda+ons• USPSTF2013
– Tamoxifenandraloxifene
• ASCO2013– Tamoxifen,raloxifeneandexemestane
• NCCN2016– Tamoxifen,raloxifene,exemestaneandanastrozole
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Selec+veEstrogenReceptorModulators:SERMs
• Varyingestrogeneffectondifferent+ssues• BothareFDAapprovedforchemopreven+on
– Tamoxifenapprovedforbreastcancertreatment– RaloxifeneapprovedforosteoporosistreatmentEstrogenic Activity by Tissue
Tamoxifen Raloxifene
Breast - - Uterus + - Bone +/- +
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DosingandSideEffects:Tamoxifenv.RaloxifeneDose/ Duration
Population Serious Adverse Effects
Tamoxifen 20 mg daily for 5 years
Pre/post menopausal women 35 +
• VTE • Endometrial
CA • Cataracts
Raloxifene 60 mg daily for 5 years
Post-menopausal women 35 +
• VTE
Nelson et al. Intern Med. 2013.
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Benefits:Tamoxifenv.RaloxifeneTamoxifen v. Placebo
4 RCTs Raloxifene v. Placebo
2 RCTs Tamoxifen v. Raloxifene
STAR
Risk of invasive
breast cancer
↓ 7 cases with tamoxifen
↓ 9 cases with raloxifene
↓ 5 cases with tamoxifen
Risk of VTE ↑ 4 cases with tamoxifen
↑ 7 cases with raloxifene
↑ 4 cases with tamoxifen
Risk of endometrial
cancer
↑ 4 cases with tamoxifen -- ↑ 5 cases with
tamoxifen
Risk of cataracts -- -- ↑ 15 cases with
tamoxifen
Nelson et al. Intern Med. 2013.
Change in # of cases/1,000 women over 5 years
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Case3:Judy
Judyisa53yopostmenopausalwhitefemaleseeninfollowupofabreastbiopsywhichrevealedmildductalhyperplasia.YoucalculateherGailscoreanditis3.8%.Shewantstodiscussherbreastcancerrisk.ThereisnohistoryofDVT/PE,TIA/CVA,endometrialcancer,orcataracts.
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Whatdoyouadvise?
A. RecommendtamoxifenB. RecommendraloxifeneC. Tamoxifenorraloxifenebothseem
acceptable-letthepa+entdecidebasedonherpersonalpreference
D. Thisdecisionisabovemypaygrade—refertohighriskbreastclinic
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Whatdoyouadvise?
A. Recommendtamoxifen,theSTARtrialdemonstratedthattamoxifenismoreeffec+veforbreastcancerchemopreven+on.
B.Recommendraloxifene,althoughsheisotherwisehealthyIams+llworriedaboutthesideeffectsoftamoxifen.
C.Tamoxifenorraloxifeneseemacceptable-letthepa+entdecidebasedonherpersonalpreference.
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HowDoYouDecide?TamoxifenvRaloxifene
Raloxifene seems to have less risk, but also less efficacy…. So how do you choose?
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SummaryofSERMsTamoxifen Raloxifene
Reduces invasive breast cancer
Reduces invasive breast cancer, but not as effective as tamoxifen
Pre/postmenopausal women Postmenopausal women only
Higher rates of thromboembolic disease, endometrial cancer, and cataracts
Higher rates of thromboembolic disease, but less than tamoxifen
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FreedmanTables
• Decisionaidefortheuseoftamoxifenvsraloxifeneinwomenovertheageof50
• Comparesbenefit/riskprofilesstra+fiedbypresenceorabsenceofuterusandrace(white,black,Hispanic)
• Basedonageand5yearpredictedbreastcancerriskusingtheGailModel
Freedmanetal.JClinOncol.2011.
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FreedmanTable:Raloxifeneisalmostalwayswins
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Case3:Judy
Judyisa53yopostmenopausalwhitefemaleseeninfollowupofabreastbiopsywhichrevealedmildductalhyperplasia.YoucalculateherGailscoreanditis3.8%.Shewantstodiscussherbreastcancerrisk.ThereisnohistoryofDVT/PE,TIA/CVA,endometrialcancer,orcataracts.EligibleforeitherSERM,butriskbenefitofraloxifenewins.
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NowBacktoCharloke...
• 63yearoldpostmenopausal,whitewoman
• HerpastmedicalhistoryissignificantforOAandaprovokedleulowerextremityDVT
• ShehasneverhadaDXA• HerGail(3.2%)andBCSC(2.8%)riskswerebothaboveaverage
• YouarehesitanttoprescribeaSERMgivenherhistoryofDVT
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IsCharlokeacandidateforchemopreven+onwithanAI?
A. Yes,IwouldoffereitherexemestaneoranastrozoleandaDXAatage65.
B. Yes,Iwouldoffereitherexemestaneoranastrozole+vitaminDandcalciumsupplementa+on.
C. Yes,IwouldobtainaDXAfirstandthendiscusschemopreven+onwitheitherexemestaneoranastrozole.
D. No,givenherhistoryofDVTsheisnotacandidateforchemopreven+onwithAIs.
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IsCharlokeacandidateforchemopreven+onwithanAI?
A. Yes,IwouldoffereitherexemestaneoranastrozoleandaDXAatage65.
B. Yes,Iwouldoffereitherexemestaneoranastrozole+vitaminDandcalciumsupplementa+on.
C. Yes,IwouldobtainaDXAfirstandthendiscusschemopreven+onwitheitherexemestaneoranastrozole.
D. No,givenherhistoryofDVTsheisnotacandidateforchemopreven+onwithAIs.
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AromataseInhibitors
• Inhibittheendogenousconversionofandrogenstoestrogens
• NCCNrecommendstheuseofexemestaneandanastrozole
• ASCOrecommendsexemestanex5years• NotcurrentlyFDAapprovedforbreastcancerchemopreven+on
Olin.AnnPharmacother.2014.
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AromataseInhibitorsforPrimaryPreven+on
Exemestane v. Placebo (MAP.3)
Anastrozole v. Placebo (IBIS-II)
Risk of invasive
breast cancer
NNT 36 over 7 years
HR 0.35 (95% CI 0.18-0.70)
NNT 26 at 5 years
HR 0.47 (95% CI 0.32-0.68)
• NoheadtoheadcomparisonsofAIsvSERMsorexemestanev.anastrozoleBUTtheriskreduc+onisimpressive
Gossetal.NEnglJMed.2011.Cuziketal.Lancet.2014.
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WhataboutBoneMineralDensity?
• AIshavedeleteriouseffectsonBMD• MAP.3substudydemonstratedworsenedBMDinExemestanegroupat2years
• IBIS-IIsubstudystra+fiedwomenbasedonBMDandwomenwithosteoporosisreceivedanastrozole+bisphosphonatewhichcanakenuatethisconcern
Cheungetal.LancetOncol.2012.
Sestaketal.LancetOncol.2014.
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Anastrozole+Bisphosphonate
Sestaketal.LancetOncol.2014.
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BacktoCharloke…
• NoconcernforosteoporosisorosteopeniaonDXA
• Youprescribeanastrozole1mgdaily
• Ata3monthfollowupvisitCharloketellsyouherhotflasheshavereturnedwithavengeance
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ManagementonChemopreven+on• Only60%ofwomenwhostartchemopreven+onwillcomplete5years
Roetzheim.Breast.2015.
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ManagementonChemopreven+on• BothSERMsandAIscancausehotflashes
‒ AvoidHT,Paroxe+ne,Citalopram,Fluoxe+neinwomenontamoxifen
‒ Gabapen+n,Venlafaxine,mul+pleotheragentswithanecdotalevidence
• Arthralgias(AIs)‒ Analgesics,some+mesineffec+ve‒ Duloxe+ne,glucosamine/chondroi+n,omega3fakyacids,vitaminD,exercisecurrentlyunderinves+ga+on
Euhus.Breast.2015.NCCNClinicalPrac+ceGuidelinesinOncology.BreastCancerRiskReduc+on.2016.
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ManagementConsidera+onsinPa+entsonSERMs
• Tamoxifen‒ VisualSymptoms‒ VaginalSpo{ng
• SERMs
‒ An+cipatedelec+vesurgery‒ VTE,CVA,immobility
Discon+nue
Promptevalua+on
NCCNClinicalPrac+ceGuidelinesinOncology.BreastCancerRiskReduc+on.2016.
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Pu{ngitAllTogether
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• High risk family history? • History of radiation? • History of breast disease?
Risk Assessment
• Consider referral • Consider enhanced screening
• Gail • BCSC – breast density
Woman at increased risk of breast cancer (Greater than 3% 5 year risk)
No and Post Menopausal Yes
Not at increased risk
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Premenopausal Contraindications to
SERMs?
Increased Risk for Breast Cancer
Tamoxifen (assess risk
benefit profile)
Modifiable risk factor reduction strategies
Post Menopausal Contraindications to
SERMs?
Yes No
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Premenopausal Contraindications to
SERMs?
Increased Risk for Breast Cancer
Post Menopausal Contraindications to
SERMs?
Raloxifene or AIs
No
+/- Uterus Osteoporosis
Uterus No Osteoporosis
No Uterus No Osteoporosis
Raloxifene or AIs
Raloxifene
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SharedDecisionMaking
SERMs AIs
• Menopausal symptoms • Thromboembolic events • Uterine cancer (tamoxifen) • Cataracts (tamoxifen)
• Menopausal symptoms • Arthralgias • Decline in bone mineral
density
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PrimaryPreven+on:MakingitEasy
• Step1:Assessrisk– Familyhistoryineveryone– RiskcalculatorinwomenpostmenopausalusingeitherGailorBCSCriskcalculator
• Step2:Managementofhighrisk– Ifpremenopausalandconcerningfamilyhistory,considerreferraltoahighriskbreastprogram
– Ifpostmenopausal,and5yearriskgreaterthan3%,discusschemoprophylaxis
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PrimaryPreven+on:MakingitEasy
• Step3:Pickingachemopreven+veagent– Assessriskfortreatmentincludingbonemineraldensitymeasurement
– IfBMDis>-1.5,startraloxifene– IfBMDis<-1.5,startaromataseinhibitor
• Step4:Monitorandmanagesideeffects
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Challenge:DOSOMETHING
• Takeanenhancedfamilyhistoryincludingfirst,secondandthirddegreerela+ves
• Calculateabreastcancerriskscoreinwomenwhoarepostmenopausal
• Considerstar+ngtreatmentevenifonlyinthosepa+entwithgoodbonesandlowrisksonraloxifene
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Ques+onsandDiscussion