中村清吾(英文)：The current strategy for hereditaly breast cancer in Japan

ThecurrentstrategyforhereditalybreastcancerinJapanDirector,Breast

CenterProfessorofBreastSurgicalOncologyShowaUniversity,Tokyo,JapanBoardchairmanofJBCS（JapaneseBreastCancerSociety)SeigoNakamura,MD.PhDSCIENCEVOL.2667OCTOBER1994ＢＲＣＡ１ＢＲＣＡ２PrecisionMedicinePresentedByJorgeReis-Filhoat2014ASCOAnnualMeetingRightdrugforrightpatientOlaparibforBRCA1/2mutatedBC(PARP)EnzaltamideforAR(+)BCSlide39PresentedByJorgeReis-Filhoat2014ASCOAnnualMeetingASCOHowMuchBreastand

OvarianCancerIs

HereditaryinJapan?SporadicFamilyclustersHereditaryOvarianCancerBreastCancer5%–10%5%–10%15%-20%AsianBRCAConsortiumChina:ZhenHuIndia:RajivSarin,SunitaSaxenaHongKong:AvaKwongIndonesia:TeguhAryandonoJapan:SeigoNakamuraKorea:KimSung-Won,KOHBRAMalaysia:SooTeoPhilippines:RodneyDofitasSingapore:PhilipIauThailand:PimpichaPatmasiriwatTaiwan:CSHuangVietnam:OlphiraGinsburg,LeMongQuangRe:AngelinaJolie’sdoublemastectomyandthequestionofwhoownsourgenes2June2013Itisestimatedthatatleast60%oftheworld’s7billionpeopleareAsians,butyetlessthan5%oftheknownBRCAcarriersthathavebeenidentifiedareAsians[1].InordertoshareknowledgeofandimprovethequalityofhereditarybreastandovariancancerpatientsinAsia,wehaveestablishedtheAsianBRCAconsortiuminOctober2011.Theconsortiumhasmembersin12AsiancountriesandwelcomesnewmemberswithasharedvisionofcollaboratingforresearchinAsia.Weurgentlyneedtoadvocateforchangeinthelegalprotectionagainstgeneticdiscrimination,andtoadvocatethatgovernmentsshouldatleastpayfortestingfees,surveillanceandriskreducingstrategiessothatweareabletoofferthebeststrategiesforBRCAcarriersregardlessofwheretheylive.Authors:ABRCAConsortium

1.TeoSooHwang(Malaysia)2.KimSung-Won(Korea)3.AvaKwong(HongKong)4.PhilipIau(Singapore)5.RajivSarin(India)6.SeigoNakamura(Japan)7.ShaoZhimin(China)8.TeguhAryandono(Indonesia)9.PimpichaPatmasiriwat(Thailand)10.LeHuang(Vietnam)11.OphiraGinsburg(Bangladesh)12.RodneyDofitas(Philippines)DataCollectionStudyinJapan(2012.10)Total260

casesNegative164

cases63.1%BRCA2

Uncertain

9

cases

3.5%BRCA1

Uncertain

7

cases

2.7%BRCA2

Positive

34cases

13.1%BRCA1?2

Positive

1cases

0.4%BRCA1

Positive

45cases

17.3%Positive80cases

30.7%Uncertain

16cases＊6.2%＊：＋4casesBRCA1:deleterious＋BRCA2:uncertain?3casesBRCA2:deleterious＋BRCA1:uncertain?1caseBRCA1

（+）BRCA2

（+）BRCA1/2（-）BRCA1/2mutationandbreastcancerincidencebyageＣｏｎｆｉｇｕｒａｔｉｏｎｏｆHBOCｄａｔａｂａｓｅConsortiumPublicationsMembersDatarepositoryDatautility

Research

Clinicalassistance

etc..ComparisonAsianHBOCMyriaddatabaseEtc.MedicalsocietiesParticipationAnalysisJapaneseBreastCancerSocietyetc.QualityIndicatorsOutcomemeasureQualityImprovementClinicalpracticeguidelinePts&familiesMedicalnformaMemberregistryHomepagemaintenanceDatamanagementOverseasdatabaseDatacenterPCRegistryMedicalInstitutionsSurveyClinicalsurveyDatabase（annualreport）TypeofBreastCancer

withBRCA1/2mutationinprobandsandfamilymembersTNB62.2%TNB14.3%Her2Type8.1%Her2Type2.9%LuminalType82.9%LuminalType29.7%n=37n=35ClassificationofprobandsandfamilymemberswithbreastcancerBRCA1BRCA2L63X105804del44Q934X2R2318X43561delG2I2675V2S1882X2Total46Total35Mutations

detected

in

more

thantwofamiliesTheJapaneseHBOCConsortiumEstablishedin2012http://hboc.jp/index.htmlConstructJapaneseHBOCDatabaseDevelopHBOCGuidelinesandResearchPromoteHBOCEducationalActivitiesOuraimistoraisetheawarenessofHBOCinJapan,andtoprovideaneffectivehealthcaresystemforHBOCpatientsandtheirfamilies.TrialregistrationTrialregistrationwasprovidedbytheregistrationcommitteemembers(4institutions).NationwideregistrationstartedinMarch2016.HoshiGeneralHospitalShowaUniversitySt.Luke`sHospitalCancerInstituteHospitalTotally3935including846familywereenrolledNegative608

cases73.5%BRCA2

Uncertain

32cases

3.5%BRCA2

Positive

76cases

9.2%BRCA1?2

Positive

1cases

0.1%BRCA1

Positive88cases

10.6%Positive165cases

20.0%Uncertain

54cases

6.6%BRCA1

Uncertain

21cases

2.5%BRCA1?2

Uncertain

1cases

0.1%Registrystatus～September2015Totally827probandsTrendoftreatmentHBOC1damagedgene1normalgeneTumordevelops2normalgenes2damagedgenesInhereditarycancer,onedamagedgeneisinherited.1damagedgene1normalgeneTumordevelops2damagedgenes?2006MyriadGeneticLaboratories,Inc.MyriadGenetics,Inc.RisksofBreastCancerwithBRCA1orBRCA2MutationBreastcancerriskbyage(women)BRCA1BRCA2Ashkenaziwomenw/BRCA1/2GeneralpopulationUS4019%12%5050%28%33%2%6064%48%7085%84%56%7%EastonDF,FordD,BishopT,andtheBreastCancerLinkageConsortium,1995.AmJHumGen56:265-271.EastonDF,etal.,andtheBreastCancerLinkageConsortium,1999.JNCI91:1310-1319.FordD,EastonDF,StrattonM,NarodS,etal.,1998,AmJHumGenetics62:676-689.StruewingJP,HargeP,WacholderW,etal.NEJM,1997.336(20):1401-1408.FordD,EastonDG,BishopT,NarodS,1994.Lancet343:692-695.IssueofDensebreastdependingonageResource:EasternRadiologistsBreastImagingCenter1997-2010ReferenceDataDensebreastismorecommon

amongAsianwomen１(fatty)２３４(dense)Asian0.915.950.127.1Caucasian6.527.353.712.5African-American8.331.051.78.9AJR:188,2007Chemo前1Warner(2004)JAMAMRI

SenoBright

Contrast-EnhancedSpectralMammography搭載可能裝置(GE)SenographeEssential

SenographeDSLaVerite

SenographeDSDepister既設のEssential/DSシリーズ

＊既設裝置には、最新バージョンへのアップグレードが必要造影剤とエネルギーサブトラクションを用いたマンモグラフィCase1.40y.o.femaleMammographyLMLO2minLCC4minContralateralBreastCancerRiskBRCA1/2MutationCarriersBRCA1BRCA2BRCA1orBRCA2Womenw/priorhxbreastcancerRiskofnewbreastcadxbyage7060%52%3%/year<1%peryearToughChoices:Losingabreastisprobablybetterthanfacingcancer

FearChemotherapy

Radiation

??????①②③④⑤⑥⑦GenotypeBRCA1BRCA2BRCA2BRCA1BRCA2BRCA1BRCA1Ageatonset39484733366233癌subtypeTNTNLuminalTNLuminalTNTNStageⅡⅡⅢⅡⅢⅡⅡOp.methodBt+SNB+IMPNSM+SNB+IMPBt+Ax+IMPNSM+SNBt+AxBt+AxBt+SNB+IMPChemoTxYYYYYYYAgeatCRRM

39484733386541CRRMNSM+IMPNSM+IMPNSM+IMPNSM+IMPBtBtNSM+IMPRRSO--Y-YY-OccultBC-DCIS--DCIS--CRRM

atShowauniversityBMJ2014;348:g226doi:10.1136/bmj.g226SurvivalBenefitofRRMGenetictestingfora

choiceofbreastcancersurgeryoptionConservativeoperationMastectomypositive162（12.5%）14（87.5%）negative3928（71.8%）11（28.2%）BreastcancersurgeryNumberofTotalSubjectsTestResultsMostcancersinBRCA1mutationcarriersarebasal-likeButmostbasal-likebreastcancersarenotinBRCA1carriersIsBRCA1functiondifferentinthem?=BRCA1+SorlieTetal.PNAS03Basal-like=BRCA2+IntrinsicgenelistappliedtoVan’tVeerdataset(Nature2002)GuiltbyAssociation:

Basal-likeBreastCancerandBRCA1PARPInhibitorMechanismofActionBRCA1BRCA21.PLATINUMCHEMOTHERAPY

InflictsDNAdamageviaadductsandDNAcrosslinking2.PARP1 UPREGULATION Base-excisionrepairofDNAdamage3.INHIBITIONOFPARP1

DisablesDNAbase-excisionrepair4.REPLICATIONFORKCOLLAPSE

DoublestrandDNAbreakCELLSURVIVALCELLDEATHPARP1PARP1BSI-201PtPtPtPtPtPARP139OverviewofTamoxifenBreastCancer

PreventionTrials:AllBreastCancersIBIS-1=InternationalBreastCancerInterventionStudy-1.CuzickJetal.Lancet.2003;361:296-300.RoyalMarsdenNSABP-P1ItalianIBIS-1AlltamoxifenpreventiveAlltamoxifenadjuvant0.30.50.621.01.5HazardRatioTamoxifeninveryhighriskwomen1310.19.96.85.71.45.13.4051015LCISAtypicalhyperplasia≥2relativesAllwomenRateper1,000FisherJNCI1998;90:1371PlaceboTamoxifen

Definitionofgeneticcounseling

NationalSocietyofGeneticCounseling(2006)

GeneticcounselingistheprocessofhelpingPeopleunderstandandadapttothemedical,Psychological

andfamilialimplicationsofgeneticcontributionstodisease.Thisprocessintegrates

thefollowing:Interpretationoffamilyandmedicalhistoriestoassessthechanceofdiseaseoccurrence

orrecurrence.Educationaboutinheritance,testing,management,prevention,resourcesandresearch.Counselingtopromoteinformedchoicesandadaptationtotheriskorcondition.Ｑｕｅｓｔｉｏｎａｒｅ：■Breastcancerbeforeage40?

(or35?)■Twoormorebreastcancersinafamily,oneunderage40?■Malebreastcanceratanyage?□Ovariancanceratanyage?□Twoprimarybreastcancersinanindividual?□Bothbreastandovariancancerinanindividual?□Triplenegativebreastcancer?□ApreviouslyidentifiedBRCAmutationinthefamily?Ａｎｓｗｅｒ：Youmayhaveagreater-than-averageriskforbreastandovariancancer.Testingmayclarifyyourrisk.Understandingyourcancerriskisthefirststepinmanagingit.ThenumberofpathogenicvariantsTotal827casesBRCA2positive:76cases,9.2%BRCA1-2positive:1case,0.1%BRCA1positive:88cases,10.6%165positivecases

20.0%BRCA2uncertain:32cases,3.5%BRCA1uncertain:21cases,2.5%54uncertain

cases＊6.6%BRCA1-2uncertain:1cases,0.1%＊：＋8casesBRCA1:Positive＋BRCA2:Uncertain?5casesBRCA1:Positive＋BRCA1:Uncertain?1caseBRCA2:Positive＋BRCA1:Uncerta