primary preven+on of breast cancer: missed opportuni+eswith breast ca 2nd degree relave with breast...
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PrimaryPreven+onofBreastCancer:MissedOpportuni+es
MelissaMcNeil,MD,MACP
Withthanksto:
DebbieDinardo,MaggieBenson,AmyFarkasBriannaRossiter,SarahMerriam
andRachelVanderberg
Objec+ves
• Es+mateawoman’sbreastcancerrisk• Iden+fyriskfactorsthatshouldprompt
– Referraltoahighriskbreastclinic– Enhancedscreening– Ini+a+onofchemoprophylaxis
• Understandtheriskandbenefitsofchemopreven+on
• Counselawomanonselec+nganappropriatechemopreven+onagent
Outline
• Riskassessment• BreastCancerScreening• BreastCancerPrimaryPreven+on
– Selec+veestrogenreceptormodulators(SERMs):tamoxifenandraloxifene
– Aromataseinhibitors(AIs):exemestaneandanastrozole
• Choosingtheappropriateagent
BreastCancer
• MostcommoninvasivecanceramongU.S.women
• Secondleadingcauseofcancerdeathinwomen
• Effortsinprimarycarefocusonscreeningdespitethefactthat:
• Mul$plerandomizedplacebocontrolledtrialshavedemonstratedriskreduc$onwithchemopreven$oninwomenatincreasedriskofbreastcancer
www.cancer.org.
BreastCancerRiskAssessmentforthePrimaryCarePhysician
• Currentguidelinesrecommendincorpora+ngbreastcancerriskassessmentintorou+neprimarycaretoallowforanincreasedfocusonpreven+onofbreastcancer
4BreastCancerPreven+onStrategies
LifestyleModifica0on
Maintainhealthyweight
Exercise
Limi+ngETOH:<1drink/day
EnhancedScreening
Mammogramini+a+onandfrequency
Adjunctscreeningmodali+es
Chemo-preven0on
SERMs
AIs
SurgicalPreven0on
Mastectomy
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
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.
GoalsforBreastCancerRiskAssessment
• Iden+fywomenwhowouldbenefitfromreferraltoahighriskbreastclinicorgene+ccounselor
• Iden+fywomenwhowouldbenefitfromchemoprophylaxisprescribedbytheprimarycareprovider
Case1:ColleenColleenisa60yowomanwhopresentsforherannualvisitandisworriedaboutbreastcancer.Shehasapaternalauntandapaternalunclediagnosedwithbreastcancerat53and67respec+vely.Hermotherand3sistersarewithoutbreastcancer.Hermammogramshavebeennormal.
Whatshouldyoutellheraboutherfamilyhistoryofbreastcancer?
A. Becauseherfirstdegreerela+veshavenotbeenaffected,sheisnotatincreasedriskofbreastcancer.
B. Herfamilyhistorysuggestsshemaybeatincreasedrisk,andthisriskcanbees+matedbyusingtheGailModel.
C. Herfamilyhistorysuggestssheisatriskforhereditarybreastcancer.Sheshouldbereferredtoahighriskbreastclinicorgene+ccounselor.
Whatshouldyoutellheraboutherfamilyhistoryofbreastcancer?
A. Becauseherfirstdegreerela+veshavenotbeenaffected,sheisnotatincreasedriskofbreastcancer.
B. Herfamilyhistorysuggestsshemaybeatincreasedrisk,andthisriskcanbees+matedbyusingtheGailModel.
C. Herfamilyhistorysuggestssheisatriskforhereditarybreastcancer.Sheshouldbereferredtoahighriskbreastclinicorgene+ccounselor.
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.
HereditaryBreastCancer
• Womenwithafamilyhistorysugges+veofhereditarybreastcancershouldNOThaveriskstra+fica+onwithageneralbreastcancerriskassessmenttool
• RF’sforhereditarysyndromeswarrantreferraltohighriskbreastclinicorgene+ccounselor
SmithM.ClevClinJofMed.2014.
Indica+onsforReferral:NCCNGuidelines
• Knownmuta+onofbreastcancersuscep+bilitygeneinthefamily
• ≥2breastcancerprimariesinasingleindividual• ≥2breastcancersamong1st,2ndand3rddegreerela+vesonthesamesideofthefamily
• ≥1ovariancancerprimary• 1stor2nddegreerela+vewithdiagnosis≤age45• Malebreastcancer
DalyMBetal.NCCN.2015.
Case1:ColleenColleenisa60yowomanwhopresentsforherannualvisitandisworriedaboutbreastcancer.Shehasapaternalauntandapaternalunclediagnosedwithbreastcancerat53and67respec+vely.Hermotherand3sistersarewithoutbreastcancer.Hermammogramshavebeennormal.Sheshouldbereferredtoahighriskbreastcancerprogram
Case2:CharlokeCharlokeisa63yearoldpostmenopausalwomanwhopresentstoestablishcare.Hermotherwasdiagnosedwithbreastcanceraroundherage.Shehasnopersonalhistoryofbreastproblemsandtherearenootherrela+veswithbreastcancer.Menarcheatage12andherfirstbabywasatage32.Mammo:BIRADS2andheterogeneouslydensebreastsYouwanttouseariskstra+fica+ontooltoassessherriskforbreastcancer.
WhichofthefollowingisTRUE?
A. Youshouldnotuseageneralbreastcancerriskassessmenttoolbecauseshehasafirstdegreerela+vewithbreastcancer.Sheshouldbereferredtothehighriskbreastclinic.
B. Youdonotneedtouseabreastcancerriskassessmenttoolbecauseshehasincreasedbreastdensityandyouknowsheisalreadyathighrisk.
C. TheGailModelshouldbeusedtocalculateabreastcancerrisk
D. TheBCSCModelshouldbeusedtocalculateabreastcancerrisk
WhichofthefollowingisTRUE?
A. Youshouldnotuseageneralbreastcancerriskassessmenttoolbecauseshehasafirstdegreerela+vewithbreastcancer.Sheshouldbereferredtothehighriskbreastclinic.
B. TheGailModelhasbekerdiscrimina+onthantheBCSCModel,soisthepreferredriskassessmenttool.
C. TheTyrerCusickModelincludesamorecomprehensivelistofRF’s,includingbreastdensity,andisavailableasanonlinecalculator.
D. TheBCSCModelistheonlyriskassessmentmodelthatincorporatesbreastdensityintoitsriskstra+fica+on.
RiskAssessmentModels
• Es+materiskforbreastcancer• Useavarietyofriskfactors• Compareto“average”womanofsameage• Es+mate5-year,10-yearand/orlife+merisk• ShouldNOTbeusedforwomenwhoareatriskforhereditarybreastcancer
VisvanathanKetal.JofClinOnc.2013.
Whatis“HighRisk?”
• Anyonehigherriskthanaverage
• Chemopreven+on– Chemopreven+ontrials:5-yearrisk≥1.66%
– USPSTF/Freedman:5-yearrisk>3%
MoyerVA.AnnIntMed.2013.
RiskAssessmentModelsforthePCP
• GailModel– Na+onalCancerIns+tuteBreastCancerRiskAssessmentTool(BRCAT)
• BCSCModel– BreastCancerSurveillanceConsor+umriskpredic+onmodel
– JATice• Tyrer-CusickModel
GailModelhkp://www.cancer.gov/bcrisktool/
• Developed1989;modified1999• Calculates5-yearandlife+me(toage90)risk• Gail5-yearrisk>1.66%wascriteriaforenrollmentinSERMandMAP.3AIchemopreven+ontrials
CummingsSR.JNCI.2009.
GailModelRF’s
Pa0entCharacteris0cs
Age
Race/ethnicity
FamilyHistory
Knowngene+c
syndrome
1stdegreerela+ve
withbreastCA
Reproduc0veHistory
Ageofmenarche
Ageoffirstlivebirth
BreastCharacteris0cs
HxofDCISorLCIS
Hxofbreastbiopsy
MedicalHistory
Priorchestradia+on
*Doesnotincludebreastdensityordetailsaboutbenignbreastdisease
GailModel:Charloke’sRisk
BCSCModelhkps://tools.bcsc-scc.org/bc5yearrisk/calculator.htm
• Developed2008;modified2015• Calculates5-yearand10-yearrisk• Incorporatesbreastdensity• Morecomprehensivebenignbreastdisease• Notusedforenrollmentinchemopreven+ontrials
CummingsSR.JNCI.2009.TiceJA.JofClinOnc.2015.
BCSCModelRF’s
Pa0entCharacteris0cs
Age
Race/ethnicity
FamilyHistory
1stdegreerela+vewithbreastcancer
Reproduc0ve/HormonalHistory
(None)
BreastCharacteris0cs
BreastDensity
Hxofmastectomy
oraugmenta+on
Priorbreastbiopsyandresults
MedicalHistory
(None)
BCSC:Charloke’sRisk
WhichmodelshouldIusefordeterminingwhoshouldreceive
chemopreven+on?
• BCSC– Easytoaccessonlineorwithapp– IncludesbreastdensityandBBD– Bekerdiscrimina+onthanGail
• Gail– Cancalculatewithoutbreastdensity(youngerwomen)
– Bekervalidatedinthechemopreven+ontrials
RiskAssessmentSummary
• Step1:Lookforhighriskfamilyhistoryandrefer– NCCNguidelinesorabriefgene+cscreen– DoNOTapplyanoverallriskmodel
• Step2:AssessRF’s• Step3:Calculaterisk
– BCSCifhavebreastdensityordecidetolookforit– Gailifnobreastdensityavailable;wanttoadheretotrialcriteriaforchemopreven+on
YourPa+entisHighRisk,NowWhat?
• Lifestylemodifica+on– Weightmanagement– Alcoholintaketo<1drinkperday
• Enhancedscreening– Tomosynthesis– Frequencyofmammograms
• Chemoprophylaxis
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
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
CurrentRecommenda+ons• USPSTF2013
– Tamoxifenandraloxifene
• ASCO2013– Tamoxifen,raloxifeneandexemestane
• NCCN2016– Tamoxifen,raloxifene,exemestaneandanastrozole
Selec+veEstrogenReceptorModulators:SERMs
• Varyingestrogeneffectondifferent+ssues• BothareFDAapprovedforchemopreven+on
– Tamoxifenapprovedforbreastcancertreatment– RaloxifeneapprovedforosteoporosistreatmentEstrogenic Activity by Tissue
Tamoxifen Raloxifene
Breast - - Uterus + - Bone +/- +
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.
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
Case3:Judy
Judyisa53yopostmenopausalwhitefemaleseeninfollowupofabreastbiopsywhichrevealedmildductalhyperplasia.YoucalculateherGailscoreanditis3.8%.Shewantstodiscussherbreastcancerrisk.ThereisnohistoryofDVT/PE,TIA/CVA,endometrialcancer,orcataracts.
Whatdoyouadvise?
A. RecommendtamoxifenB. RecommendraloxifeneC. Tamoxifenorraloxifenebothseem
acceptable-letthepa+entdecidebasedonherpersonalpreference
D. Thisdecisionisabovemypaygrade—refertohighriskbreastclinic
Whatdoyouadvise?
A. Recommendtamoxifen,theSTARtrialdemonstratedthattamoxifenismoreeffec+veforbreastcancerchemopreven+on.
B.Recommendraloxifene,althoughsheisotherwisehealthyIams+llworriedaboutthesideeffectsoftamoxifen.
C.Tamoxifenorraloxifeneseemacceptable-letthepa+entdecidebasedonherpersonalpreference.
HowDoYouDecide?TamoxifenvRaloxifene
Raloxifene seems to have less risk, but also less efficacy…. So how do you choose?
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
FreedmanTables
• Decisionaidefortheuseoftamoxifenvsraloxifeneinwomenovertheageof50
• Comparesbenefit/riskprofilesstra+fiedbypresenceorabsenceofuterusandrace(white,black,Hispanic)
• Basedonageand5yearpredictedbreastcancerriskusingtheGailModel
Freedmanetal.JClinOncol.2011.
FreedmanTable:Raloxifeneisalmostalwayswins
Case3:Judy
Judyisa53yopostmenopausalwhitefemaleseeninfollowupofabreastbiopsywhichrevealedmildductalhyperplasia.YoucalculateherGailscoreanditis3.8%.Shewantstodiscussherbreastcancerrisk.ThereisnohistoryofDVT/PE,TIA/CVA,endometrialcancer,orcataracts.EligibleforeitherSERM,butriskbenefitofraloxifenewins.
NowBacktoCharloke...
• 63yearoldpostmenopausal,whitewoman
• HerpastmedicalhistoryissignificantforOAandaprovokedleulowerextremityDVT
• ShehasneverhadaDXA• HerGail(3.2%)andBCSC(2.8%)riskswerebothaboveaverage
• YouarehesitanttoprescribeaSERMgivenherhistoryofDVT
IsCharlokeacandidateforchemopreven+onwithanAI?
A. Yes,IwouldoffereitherexemestaneoranastrozoleandaDXAatage65.
B. Yes,Iwouldoffereitherexemestaneoranastrozole+vitaminDandcalciumsupplementa+on.
C. Yes,IwouldobtainaDXAfirstandthendiscusschemopreven+onwitheitherexemestaneoranastrozole.
D. No,givenherhistoryofDVTsheisnotacandidateforchemopreven+onwithAIs.
IsCharlokeacandidateforchemopreven+onwithanAI?
A. Yes,IwouldoffereitherexemestaneoranastrozoleandaDXAatage65.
B. Yes,Iwouldoffereitherexemestaneoranastrozole+vitaminDandcalciumsupplementa+on.
C. Yes,IwouldobtainaDXAfirstandthendiscusschemopreven+onwitheitherexemestaneoranastrozole.
D. No,givenherhistoryofDVTsheisnotacandidateforchemopreven+onwithAIs.
AromataseInhibitors
• Inhibittheendogenousconversionofandrogenstoestrogens
• NCCNrecommendstheuseofexemestaneandanastrozole
• ASCOrecommendsexemestanex5years• NotcurrentlyFDAapprovedforbreastcancerchemopreven+on
Olin.AnnPharmacother.2014.
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.
WhataboutBoneMineralDensity?
• AIshavedeleteriouseffectsonBMD• MAP.3substudydemonstratedworsenedBMDinExemestanegroupat2years
• IBIS-IIsubstudystra+fiedwomenbasedonBMDandwomenwithosteoporosisreceivedanastrozole+bisphosphonatewhichcanakenuatethisconcern
Cheungetal.LancetOncol.2012.
Sestaketal.LancetOncol.2014.
Anastrozole+Bisphosphonate
Sestaketal.LancetOncol.2014.
BacktoCharloke…
• NoconcernforosteoporosisorosteopeniaonDXA
• Youprescribeanastrozole1mgdaily
• Ata3monthfollowupvisitCharloketellsyouherhotflasheshavereturnedwithavengeance
ManagementonChemopreven+on• Only60%ofwomenwhostartchemopreven+onwillcomplete5years
Roetzheim.Breast.2015.
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.
ManagementConsidera+onsinPa+entsonSERMs
• Tamoxifen‒ VisualSymptoms‒ VaginalSpo{ng
• SERMs
‒ An+cipatedelec+vesurgery‒ VTE,CVA,immobility
Discon+nue
Promptevalua+on
NCCNClinicalPrac+ceGuidelinesinOncology.BreastCancerRiskReduc+on.2016.
Pu{ngitAllTogether
• 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
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
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
SharedDecisionMaking
SERMs AIs
• Menopausal symptoms • Thromboembolic events • Uterine cancer (tamoxifen) • Cataracts (tamoxifen)
• Menopausal symptoms • Arthralgias • Decline in bone mineral
density
PrimaryPreven+on:MakingitEasy
• Step1:Assessrisk– Familyhistoryineveryone– RiskcalculatorinwomenpostmenopausalusingeitherGailorBCSCriskcalculator
• Step2:Managementofhighrisk– Ifpremenopausalandconcerningfamilyhistory,considerreferraltoahighriskbreastprogram
– Ifpostmenopausal,and5yearriskgreaterthan3%,discusschemoprophylaxis
PrimaryPreven+on:MakingitEasy
• Step3:Pickingachemopreven+veagent– Assessriskfortreatmentincludingbonemineraldensitymeasurement
– IfBMDis>-1.5,startraloxifene– IfBMDis<-1.5,startaromataseinhibitor
• Step4:Monitorandmanagesideeffects
Challenge:DOSOMETHING
• Takeanenhancedfamilyhistoryincludingfirst,secondandthirddegreerela+ves
• Calculateabreastcancerriskscoreinwomenwhoarepostmenopausal
• Considerstar+ngtreatmentevenifonlyinthosepa+entwithgoodbonesandlowrisksonraloxifene
Ques+onsandDiscussion