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