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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)
• Prämenopause: 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 überlegen• Abhängigkeit 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. für Patientinnen mit sekundärer 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?
- Stör-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 (prä-/posttherapeutisch)• PEPI score 0 (ER+/T1/2N0/Ki67<2,7%):
- Gute Langzeitprognose, kein CHT benefit- 3,2x häufiger LuminalA
• Unabhängig von ER/pT/N/Her2, Ki67v10%vs>10%
• ANA vs LET vs EXE: Therapeutische Wirksamkeit (cPR/ cPR) und Veränderungen 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 Prädiktor von- Wirksamkeit (breast cancer free survival)- Hitzewallungen (kein Prädiktor der therapeutischen Wirksamkeit)
• Rae et al: ATAC:
CYP2D6 spielt keine relevante Role in der Selektion endokriner TherapieCYP2D6*SNP: keine Prädiktion 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
• Ungeklärte Fragen- Cyp2D6 und CYP3A4: Bessere Prädiktion?- Welche Tam- Metabolit-konzentrationen sind relevant?- Interaktion Tam metabolite ↔ ERß/Her2neu
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