Meme Kanserinde Adjuvant Endokrin Tedavide Gncel file. Kanserinde Adjuvant Endokrin Tedavide Gncel Durum E. Prof. Dr. Dilek D°NOL ‍ubatâ€2014

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  • MemeKanserindeAdjuvantEndokrinTedavideGncelDurum

    E.Prof.Dr.DilekDNOL

    ubat2014

  • Luminal AveB

    %6575

    HER2+

    %1520

    Basallike

    %15

    Luminal AlikeERvePR+HER2()Ki67dk

    Luminal Blike (HER2)ER+,HER2()veenazbiri:Ki67yksekPR()veyadk+

    Luminal Blike (HER2+)ER+HER2+PRveKi67

    HER2+/ER/PR

    Tripl negatif(duktal)

  • MemeKanserindeEndokrinTedavi(ER+Hastalar)

    Over ablasyonu supresyonu Tamoksifen Aromataz inhibitrleri

    Anastrazol Letrozol Exemestan

  • Relevanceofbreastcancerhormonereceptorsandotherfactorstotheefficacyofadjuvanttamoxifen:patientlevelmetaanalysisof

    randomised trials

    EarlyBreastCancerTrialists'CollaborativeGroup(EBCTCG)

    TheLancetVolume378,Issue9793,Pages771784 (August2011)

    DOI:10.1016/S01406736(11)609938

  • 04y 59y 1014yNks RR 0.53 0.68 0.97P

  • EBCTCG,LANCET2011

  • EBCTCG,LANCET2011

  • Figure1

    Source:TheLancet2011;378:771784 (DOI:10.1016/S01406736(11)609938)

    TermsandConditions

    ER+PR+

    ER+PR

    ERPR+

    ERPR

  • ATAC:AvsTinPostmenopausalWomenWithLocalizedBreastCancer

    PreviousATACresultsshowedlessdiseaserecurrenceinpostmenopausalwomenwithlocalizeddiseaseonanastrozolevstamoxifen[1]

    Anastrozolewelltoleratedbuthigherriskoffractures Currentstudyassessedlongtermefficacyandtoxicityofanastrozole[2]

    1.HowellA,etal.Lancet.2005;365:6062.2.ForbesJFM,etal.SABCS2007.Abstract41.

    Postmenopausalwomenwith

    earlystageinvasivebreastcancer

    (N=6241)

    Anastrozole(n=3125)

    Tamoxifen(n=3116)

    Longtermfollowup

    Year5

  • DFSincludesalldeathsasafirsteventT 2598 2516 2398 2304 2189 1932 774

    Patie

    nts(%)

    Atrisk:A 2618 2540 2448 2355 2268 2014 830

    FollowupTime(Years)

    HR

    0.830.87

    HR+ITT

    95%CI

    (0.730.94)(0.780.97)

    P Value

    .005.01

    A

    424575

    T

    497651

    0

    5

    10

    15

    20

    25

    0 1 2 3 4 5 6

    Absolutedifference: 1.6% 2.6% 2.5% 3.3%

    Anastrozole(A)Tamoxifen(T)

    ATAC-DFS (HR+)

    HowellA.2004SABCS.Abstract1.

    Genksler yllk%23hzladevamederCuzick etal.Lancet Oncol 2010

  • ATAC:EfficacyResults

    Outcome (Hormone ReceptorPositive Patients) HR (95% CI) P ValueDFS 0.85 (0.76-0.94) .003TTR 0.76 (0.67-0.87) .0001TTDR 0.84 (0.72-0.97) .022CLBC 0.60 (0.42-0.85) .004OS 0.97 (0.86-1.11) .70Death after recurrence 0.90 (0.75-1.07) .20

    ForbesJF,etal.SABCS2007.Abstract41.

    LongtermresultsshowedthatanastrozolesuperiortotamoxifenforDFS,TTR,TTDR,andCLBC,butnotforOSanddeathsafterrecurrence Similarfindingsobservedwhenanalysesrestrictedtohormonereceptor

    positivepopulation

  • Letrozole Therapy Alone or inSequence with Tamoxifen inWomen Breast CancerThe BIG198Collaborative Group

    NEJM361;766,2009

  • .

    BG198,ilkanalizThurlimann B,etal.NEngl JMed 2005;353:274757

  • BIG198TrialNEJM361;766,2009

  • Letrozol LetrTam TamLetr

    DFS %78.6 %77.8 %77.3

    OS %87.5 %87.7 %85.9

    Regan MM,etal.Lancet Oncol 12;1101,2011(8.1yltakipsonular)

  • TAM% LETR% p

    SVO 1 1 0.91

    TromEmb 3.5 1.5

  • BIG198deKardiyovaskler YanEtkilerMouridsen Hetal.JCO25:5715,2007

    TAM% LETR% pKardiyakOlay 4.7 4.8G35KVO(ouhiperkolesteremi)

    1.4 2.4 .001

    TrombEmb 3.9 1.7

  • MetaanalysisofRandomizedTrials:AIsvsTamoxifen

    DesignsofCohort1andCohort2Tamoxifen AI

    TrialsATAC

    BIG198/IBCSG1898

    TrialsGABG/ARNOIES/BIG297

    ITAABCSGVIII

    Cohort1:directcomparisonasmonotherapy(N=9,856)

    Cohort2:comparisonafter23yrsoftamoxifen(N=9,015)

    R

    R

    5yrs

    23yrs 23yrs

    5yrsIngleJN,etal.SABCS2008.Abstract12.

  • Tamoxifen19.2%15.3%

    AI

    Recurrence Rates (% yr) and Log Rank AnalysesYrs 0-1 Yrs 2-4 Yrs 5+

    Al 1.69 (163/9647) 2.31 (261/11297) 2.33 (160/6879)Tamoxifen 2.46 (234/9510) 2.81 (307/10938) 2.78 (180/6478)Rate ratio, from (O-E)/V

    0.67 SE 0.08-38.4/96.6

    0.81 SE 0.0829.5/137.9

    0.83 SE 0.10-15.7/83.0

    Yrs

    Recurren

    ce,%

    0

    10

    20

    30

    40

    0 5

    50

    8

    5yrgain2.9%(SE0.7)8yrgain3.9%(SE1.0)Logrank2P

  • Recurrence Rates (% yr) and Log Rank AnalysesYrs 0-1 Yrs 2-4 Yrs 5+

    Al 1.68 (187/11134) 2.81 (149/5298) 3.21 (23/716)Tamoxifen 2.76 (303/10962) 3.00 (150/5007) 3.87 (27/697)Rate ratio, from (O-E)/V

    0.60 SE 0.07 -51.0/118.4

    0.83 SE 0.11 -5.6/72.6

    0.85 SE 0.27 -2.0/12.1

    IngleJN,etal.SABCS2008.Abstract12.

    *Timesinceallocatedtreatmentsdiffer(andapproximatetimesincediagnosis).

    ComparisonofTamoxifen vs AI:Cohort2RecurrenceRates

    Cohort223yrsoftamoxifen,then23yrs(AIvstam)

    ERpositive (N=9,015)

    Tamoxifen16.1%12.6%

    AI

    Yrs

    Recurren

    ce,%

    0

    10

    20

    30

    40

    0 3

    50

    6

    3yrgain3.1%(SE0.6)6yrgain3.5%(SE1.1)Logrank2P

  • ErkenEvreMemeKanserindeEndokrinTedavi(lk5yl)

    PremenopozalTamoksifen

    +/ Over abl/sup(?)

    Postmenopozal

    TamoksifenAromataz inh.Tamoksifen Aromataz inh.Aromataz inh Tamoksifen

    Yksekrisklipostmen memeCada ilktercihAolmal.Ardktedaviyanetkilerasndanyararlolabilir Kardiyovaskler hast Endometriyal patoloji Osteoporoz/krk

  • EBCOWG,Lancet2007

    Over Supresyonu ile lgili almalarn Meta-Analizi

    Early Breast Cancer Overview Group

    16 randomize alma (1987-2001) N = 9022, ER veya PR + hasta % 92 ER+

    Medyan FU 7.3 yl Aks (-) % 51 LHRH agonistleri genellikle 2-3 yl, birka

    almada 5 yl kullanlm

  • n Nkste p Nksten sonraki mortalitede

    p

    LHRH vs takip 338 -% 28.46 .08 -% 17.8 .49

    Tam+/-LHRH 1013 -% 14.5 .20 -% 15.9 .33

    KT(+/-Tam) vs +/-LHRH 3307 -12.2 .04 -% 15 .04

    KT vs LHRH 3184 +% 3.9 .52 -% 6.7 .40

    KT vs LHRH+Tam 1577 -% 10.1 .25 -% 11.1 .37

    EBCOWG, Lancet 2007

  • ya n Nks HR (%) p Nksten sonra mortalite HR (%)

    p

    Sist Tx yok +/- (LHRH+Tam)=40 336 -64.7

  • BeYldanUzunEndokrinTedavi

    MA.17(Letr vsPlasebo)NSABPB33(Exem.vsPlasebo)ATLAS(Tam5ylvs10yl)aTTom (Tam5ylvs10yl)

  • MA17

    JNatl Cancer nst 97:1262,2995(30aytakip)Ann Oncol 19:877,2008(64aytakip)Breast Cancer Res Treat 112:45,2008

  • FU=64ay 4yl%

    Univariyet analiz Multivariyet analiz

    4yl%

    HR p HR p

    DFS .0001 .0001Letr 94.3 0.68 0.68Plasebo 91.4

    DDFS .082 .089Letr 96.3 0.80 0.81Plasebo 94.9

    OS .853 .828Letr 95.1 0.98 0.98Plasebo 95.1

    Ingle JN,etal.Ann Oncol 19;882,2008

  • Ingle JNetal,19;877,2008

    MA.17:Nodal Duruma GreEtkinlikAnalizi64aytakip

    HR p

    DFS

    N+ 0.51 0.0005

    N 0.74 0.01

    DDFS

    N+ 0.74 0.04

    N 0.90 >0.05

    OS

    N+ 0.84 >0.05

    N 1.24 >0.05

    Kontrlat.Ca 0.61 0.033

    KLCa yllkins.hz:0.28vs0.46

  • MA.17deTamoksifen AlrkenkiMenopozalDuruma GreEtkinlik

    PremenopozalPostmen.N=877

    PostmenopozalPostmenN=4289

    HR p HR p

    DFS 0.26 .0003nteraction p0.03

    0.67 .006

    DDFS 0.15 .02 0.45 .03

    Goss etal.Ann Oncol 24;355,2013

  • MA.17Trial,Crossover EtkiDikkateAlnarakYaplanDeerlendirme

    FU64ayLetrozol vsPlaseboHR p

    DFS 0.52

  • Group n EventsPlacebo 779 13Exemestane 783 16

    98%

    95%

    RR:1.2P=.63

    OSPatie

    nts*(%

    )

    YearsAfterRandomization0 1 2 3 4 5

    0

    20

    40

    60

    80

    100

    Tamoksifen x 5y Exemestan vs PlaseboNSABP B-33

    MamounasE,etal.SABCS2006.Abstract49.

    *Eligibleptswithfollowup

    Greyd 3toxicity:9%vs6%(P =.03)

  • MA.17:YanEtkilerLetrozol Plasebo p

    Scakbasmas 58 54 0.003

    Vajinal kana. 6 8 0.005

    Artrit 6 5 0.07

    Artralji 25 21

  • UzamTamoksifen Tedavisi

    ECOGTrial,N=194 Tam.devamvsTam.i5yldakes Devametmekdahaiyigibi

    Tormey,JNCI2001 Scottish Adj.Trial,N=342

    Sreklivs5yl SrekliTam.dahakt

    Stewart,JNCI2001 NSABPB14,N=1152

    5yldansonrarerand. 5yldanuzunTam.dahakt.

    Fisher,JNCI2001

  • Longtermeffectsofcontinuingadjuvanttamoxifen to10yearsversusstoppingat5yearsafterdiagnosisofoestrogen

    receptorpositivebreastcancer:ATLAS,arandomised trial

    ChristinaDavies,MBChB,Hongchao Pan,PhD,JonGodwin,DPhil,RichardGray,MSc,RodrigoArriagada,MD,Vinod Raina,MD,MirtaAbraham,MD,VictorHugoMedeirosAlencar,MD,Atef Badran,PhD,XavierBonfill,MD,JoanBradbury,MichaelClarke,DPhil,RoryCollins,FMedSci,SusanRDavis,MBBS,Antonella Delmestri,PhD,JohnFForbes,MD,Peiman Haddad,MD,MingFeng Hou,MD,MosheInbar,MD,HusseinKhaled,MD,JoannaKielanowska,MD,WingHongKwan,MD,Beela SMathew,MD,Indraneel Mittra,PhD,BettinaMller,MD,AntonioNicolucci,MD,Octavio Peralta,MD,Fany Pernas,Lubos Petruzelka,MD,Tadeusz Pienkowski,MD,Ramachandran Radhika,MD,

    Balakrishnan Rajan,MD,Maryna TRubach,MD,SeraTort,MD,GerardUrrtia,MD,MiriamValentini,MD,Yaochen Wang,MD,RichardPeto,FRSandfortheAdjuvantTamoxifen:LongerAgainstShorter(ATLAS)CollaborativeGroup

    TheLancetVolume381,Issue9869,Pages805816 (March2013)

    DOI:10.1016/S01406736(12)619631

    Copyright2013ElsevierLtdTermsandConditions

  • Figure1

    Source:TheLancet2013;381:805816 (DOI:10.1016/S01406736(12)619631)

    TermsandConditions

  • ATLAS:5vs 10YrsofTamoxifen inERPositiveDisease:RecurrenceandSurvival

    DaviesC,etal.SABCS2012.AbstractS12.DaviesC,etal.Lancet.2012;[Epubaheadofprint];2012,reprintedfromtheLancetwithpermissionfromElsevier.

    0

    10

    20

    30

    40

    50

    Cumulativeincide

    nce(%

    )

    A

    0Diagnosis

    5ATLASEntry