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  • Neue Daten zur endokrinen Therapie des Mammakarzinoms

    C. WolfMedizinisches Zentrum ULM - Kooperatives Brustzentrum ULM/ NEU ULM

    2010

  • Adjuvante Therapie

    Postmenopause: NCIC CTG MA.27 (Paul Goss)

    Prmenopause: Interaction Goserelin -Tamoxifen (A. Sverrisdottir)

  • S1-1. Final analysis of NCIC CTG MA.27: A randomized phase II trial of Exemestane versus

    Anastrozole in postmenopausal women with hormone receptor positive primary breast

    cancerPaul Goss

  • S1-5. Interaction between Goserelin and Tamoxifen in a controlled clinical trial of

    adjuvant endocrine therapy inpremenopausal breast cancer

    A. Sverrisdottir

  • Fazit

    Effizienz TAM gleichwertig mit Goserelin Kombinationstherapie nicht berlegen Abhngigkeit vom ER-status

    Contra: Hohes menolytisches Potential der CHT (CMF) induziert post-

    menopausales H- niveau-> auf der Basis moderner Therapie-schemata fraglich

  • Metastasierte Situation

    endokrine Resistenz

  • S1-6. TAMRAD: A GINECO randomized phase II trial of Everolimus in combination with Tamoxifen versus Tamoxifen alone in

    patients (pts) with hormone-receptor positive, HER2 negative metastatic breast cancer (MBC)

    with prior exposure to Aromatase inhibitors (AI)

    T. Bachelot

  • 13

    TAMRAD PROTOCOL

    Randomized Phase IIMetastatic patients with prior exposure to AI

    Stratification: Primary or secondary hormone resistance Primary: Relapse during adjuvant AI; progression within 6

    months of starting AI treatment in metastatic setting Secondary: Late relapse ( 6 months) or prior response and

    subsequent progression to metastatic AI treatment No crossover planned

    B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD)

    A : Tamoxifen, 20 mg/d (TAM)

  • 14

    Patient CharacteristicsTAM

    n = 57TAM + RAD

    n = 54Median age, years (range) 66 (42-86) 62.5 (41-81)

    Median duration of metastatic disease (months) 14.4 (0-102) 13.2 (1.2-94.8)

    Disease stage, n (%)BoneBone onlyVisceral3 or more

    45 (78.9)13 (22.8)30 (52.6)16 (28.1)

    41 (75.9)16 (29.6)31 (57.4)14 (25.9)

    Previous anti-aromatase treatment, n (%)Adjuvant onlyMetastatic onlyAdjuvant + metastatic

    19 (33.3)33 (57.9)5 (8.8)

    15 (27.8)34 (63.0)5 (9.2)

    Previous adjuvant TAM treatment, n (%) 23 (40.4) 17 (31.5)

    Previous chemotherapy, n (%)AdjuvantMetastatic

    32 (56.1)15 (26.3)

    25 (46.3)13 (24.1)

    Primary hormone resistance, n (%) 28 (49.1) 26 (49.1)

    Secondary hormone resistance, n (%) 29 (50.9) 27 (50.9)

  • 15

    Primary Endpoint: Clinical Benefit RateP = 0.045 (exploratory analysis)

    0

    10

    20

    30

    40

    50

    60

    70

    TAM TAM + RAD

    CB

    R, %

    of P

    atie

    nts

    42.1%(29.1-55.9)

    61.1%(46.9-74.1)

  • 16

    Time to ProgressionHazard Ratio (HR) = 0.53; 95% CI (0.35-0.81)Exploratory log-rank: P = 0.0026

    TAM: 4.5 mo.TAM + RAD: 8.6 mo.

    Month

    0.0

    0.10.2

    0.30.4

    0.5

    0.60.7

    0.80.9

    1.0

    0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

    Prob

    abili

    ty o

    f Sur

    viva

    l

    TAM TAM + RAD

    Patients at riskTAM + RAD: n =

    TAM : n = 5457

    4544

    3930

    3424

    2822

    2513

    1911

    126

    71

    10

    00

    2616

    167

    92

    10

  • 17Time to Progression As a Function of Intrinsic Hormone Resistance

    Primary hormone resistance (n = 54) TAM: 3.9 mo. TAM + RAD: 5.4 mo. HR = 0.74 (0.42-1.3)

    Secondary hormone resistance (n = 56) TAM: 5.0 mo. TAM + RAD: 17.4 mo. HR = 0.38 (0.21-0.71)

    TAM TAM + RAD

    0.00.10.20.30.40.50.60.70.80.91.0

    0 6 12 18 24 30

    Prob

    abili

    ty o

    f Sur

    viva

    lPr

    obab

    ility

    of S

    urvi

    val

    Months

    0.00.10.20.30.40.50.60.70.80.91.0

    Months0 6 12 18 24 30

  • 18

    Conclusions TAM + mTOR Inhibitor nach AI- Vorbehandlung:

    CBR TAM+ RAD001 (Everolimus) : 61%TAM : 42%

    TTP/ OS TTP: HR = 0.53; 95% CI, 0.35-0.81 Survival: HR = 0.32; 95% CI, 0.15-0.68

    TOX-profil akzeptabel

    CBR v.a. fr Patientinnen mit sekundrer end. Resistenz

  • S1-3. A comparison of Fulvestrant 500 mg with Anastrozole as first-line treatment for advanced

    breast cancer: Follow-up analysis from the FIRST study

    JFR Robertson

  • S1-4. A randomized, placebo-controlled, phase 2 study of AMG 479 with Exemestane (E) or

    Fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) locally

    advanced (LA) or metastatic (M) breast cancer (BC)

    PA Kaufmann

  • Das Ziel bestimmt den Weg

  • Endokrine Responsivenes:Und was ist mitdem

    - Target (ER- status)

    - Metabolismus des Therapeutikums?

    - Str-Variablen (Ki67)

  • Ki67ACOSOG Z1031: Biomarker Outcomes and the Predictive Value of the baseline PAM50 Based Intrisic Subtype (M.Ellis e.a.)

    In allen 3 Armen identisch: Ki67 level (pr-/posttherapeutisch) PEPI score 0 (ER+/T1/2N0/Ki6710%

    ANA vs LET vs EXE: Therapeutische Wirksamkeit (cPR/ cPR) und Vernderungen der Ki67expression identisch

    PEPI 0 1-2 3-5 5-11

    LumA 20 (30,3%) 12 (18,2%) 23 (34,8%) 11 (16,7%)

    LumB 12 (12%) 39 (39%) 51 (51%) 2 (2%)

    Her2neu 0 1 (25%) 2 (59%)

  • CYP2D6HR pos MammaCa- UDP-Glucuronytransferase (UGT2B7) polymorphismus

    Leyland Jones -BIG 1-98:

    CYP2D6 Profil nicht geeignet als Prdiktor von- Wirksamkeit (breast cancer free survival)- Hitzewallungen (kein Prdiktor der therapeutischen Wirksamkeit)

    Rae et al: ATAC:

    CYP2D6 spielt keine relevante Role in der Selektion endokriner TherapieCYP2D6*SNP: keine Prdiktion des outcome (weder ANA noch TAM)

    CYP2D6 scoring system (low vs intermediate vs high metabolizers)Kein Einfluss von selektiven Serotonin reuptake hemmern auf Wirksamkeit (UGT2B7 activity)___________________________________________________________________

    CYP2D6 Genotyping spielt keine relevante Role in der Selektion endokriner Therapie und wird nicht empfohlen

    Ungeklrte Fragen- Cyp2D6 und CYP3A4: Bessere Prdiktion?- Welche Tam- Metabolit-konzentrationen sind relevant?- Interaktion Tam metabolite ER/Her2neu

  • Weitere endokrine Risiken:

    Slide Number 1Adjuvante TherapieS1-1. Final analysis of NCIC CTG MA.27: A randomized phase II trial of Exemestane versus Anastrozole in postmenopausal women with hormone receptor positive primary breast cancer Paul GossSlide Number 4S1-5. Interaction between Goserelin and Tamoxifen in a controlled clinical trial of adjuvant endocrine therapy in premenopausal breast cancer A. SverrisdottirSlide Number 6Slide Number 7Slide Number 8Slide Number 9FazitMetastasierte Situationendokrine ResistenzS1-6. TAMRAD: A GINECO randomized phase II trial of Everolimus in combination with Tamoxifen versus Tamoxifen alone inpatients (pts) with hormone-receptor positive, HER2 negative metastatic breast cancer (MBC) with prior exposure to Aromatase inhibitors (AI) T. BachelotTAMRAD PROTOCOLPatient CharacteristicsPrimary Endpoint: Clinical Benefit RateTime to ProgressionTime to Progression As a Function of Intrinsic Hormone ResistanceConclusionsS1-3. A comparison of Fulvestrant 500 mg with Anastrozole as first-line treatment for advanced breast cancer: Follow-up analysis from the FIRST studyJFR RobertsonSlide Number 20Slide Number 21Slide Number 22Slide Number 23S1-4. A randomized, placebo-controlled, phase 2 study of AMG 479 with Exemestane (E) or Fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) locally advanced (LA) or metastatic (M) breast cancer (BC)PA KaufmannSlide Number 25Slide Number 26Slide Number 27Das Ziel bestimmt den WegSlide Number 29Slide Number 30Slide Number 31Endokrine Responsivenes:Und was ist mitdemKi67ACOSOG Z1031: Biomarker Outcomes and the Predictive Value of the baseline PAM50 Based Intrisic Subtype (M.Ellis e.a.)CYP2D6HR pos MammaCa- UDP-Glucuronytransferase (UGT2B7) polymorphismusWeitere endokrine Risiken: