6 PAPERS DE SAN ANTONIO GILBERTO AMORIM - … · Hormonioterapia “Papers” de SABCS Gilberto...
Transcript of 6 PAPERS DE SAN ANTONIO GILBERTO AMORIM - … · Hormonioterapia “Papers” de SABCS Gilberto...
HormonioterapiaHormonioterapia“Papers” de SABCS
Gilberto Gilberto AmorimAmorim
Oncologistas AssociadosOncologistas AssociadosCoordenador do Grupo de Oncologia Mamária
GBECAM – Grupo Brasileiro de Estudos em Câncer de Mama
DeclaraçãoDeclaração de de ConflitoConflito de de InteressesInteresses::
DeDe acordoacordo comcom aa ResoluçãoResolução 15951595//20002000 dodo ConselhoConselho FederalFederal dedeMedicinaMedicina ee RDCRDC 102102//20002000 dada ANVISA,ANVISA, declarodeclaro queque::
� Participo de estudos clínicos patrocinados pelasempresas: Sanofi-Aventis, Roche, Eli-Lilly, Wyeth, Novartis;
� Participo como speaker de eventos das empresas: � Participo como speaker de eventos das empresas: Sanofi-Aventis, Roche, Eli-Lilly, Novartis, AstraZeneca, Pfizer, Glaxo, BMS;
� Sou membro do advisory board das empresas: Roche, Sanofi-Aventis, AstraZeneca, Glaxo, BMS, Schering-Plough, Novartis;
� Não tenho ações de quaisquer companhias.
Hormonioterapia – “papers” de SABCS
(Neo)Adjuvância / ObesidadeZ1031, MA27, ECOG, TEAM, ADEBAR
BisfosfonatoBisfosfonatoAZURE, ABCSG-12
MetastáticoFIRST, TAMRAD, AMG-479
HormonioterapiaHormonioterapia –– “papers” de SABCS“papers” de SABCS
(Neo)Adjuvância / ObesidadeZ1031, MA27, ECOG, TEAM, ADEBAR
BisfosfonatoBisfosfonatoAZURE, ABCSG-12
MetastáticoFIRST, TAMRAD, AMG-479
ACOSOG Z1031: A randomized neoadjuvantcomparison between letrozole, anastrozole and
exemestane for postmenopausal women with ER rich stage 2/3 breast cancer Biomarker outcomes and the predictive value of the baseline PAM50
based intrinsic subtype
+
+
MA27- Emestano X Anastrozol
MA27- Emestano X Anastrozol
Resultados:Exemestane (n = 3789) Anastrozole (n = 3787)
• OS 5.5 5.9 0.93 (0.77-1.13).64• OS 5.5 5.9 0.93 (0.77-1.13).64
• DDFS 4.1 4.3 0.95 (0.76-1.18) .46
• DSS 2.4 2.6 0.93 (0.70-1.24) .62
Phase III MA27: Summary
• No advantage of exemestane over anastrozolein postmenopausal women with hormone receptor–positive primary breast cancer– Clinical events similar between arms
• More vaginal bleeding with anastrazole; more • More vaginal bleeding with anastrazole; more steroidal effects with exemestane
• Treatment discontinuation similar between arms
• Compliance equally poor in each arm but similar to reports of other long-term agents
Goss PE, et al. SABCS 2010. Abstract S1-1.
Obesity at Diagnosis Is Associated with Obesity at Diagnosis Is Associated with Inferior Outcomes in Hormone Receptor Inferior Outcomes in Hormone Receptor Positive Breast CancerPositive Breast Cancer 11
The Impact of Body Mass Index (BMI) on the The Impact of Body Mass Index (BMI) on the Efficacy of Adjuvant Endocrine Therapy in Efficacy of Adjuvant Endocrine Therapy in Postmenopausal Hormone Sensitive Breast Postmenopausal Hormone Sensitive Breast Cancer Patients; Exploratory Analysis from Cancer Patients; Exploratory Analysis from the TEAM Studythe TEAM Study 22
Multivariate Analysis of Obesity and Disease Multivariate Analysis of Obesity and Disease Free Survival in Patients with Nodal Positive Free Survival in Patients with Nodal Positive Primary Breast Cancer Primary Breast Cancer –– The ADEBAR TrialThe ADEBAR Trial 33
1Sparano JA et al. Proc SABCS 2010;Abstract S2-1.2Seynaeve C et al. Proc SABCS 2010;Abstract S2-3.3Hepp P et al. Proc SABCS 2010;Abstract S2-2.
ECOGECOG trials included in the meta-analysis
Trial, (n) E1199 (n = 3,484) E5188 (n = 1,502) E3189 (n = 613)
PopulationNode-positive and high-risk node negative
ER-positive, node-positive;
premenopausal
ER-negative,node-positive
Chemotherapy AC-taxane CAFCAF vs 16-wk
regimen
Endocrine therapy TAM or TAM/AINone vs goserelin
vs goserelin + TAM
None
Median age (years)
52 43 47
Obese (BMI >30) 38% 25% 31%
Sparano JA et al. Proc SABCS 2010;Abstract S2-1.
AI = aromatase inhibitor; BMI = body mass index; DFS = disease-free survival; OS = overall survival; TAM = tamoxifen
Multivariate Analysis (E1199)Multivariate Analysis (E1199)
Obese vs
nonobeseDFS, HR* (95% CI) OS, HR (95% CI)
All patients1.10 (0.96-1.26);
p = 0.141.13 (0.96-1.33);
p = 0.15
HR-positive, 1.23 (1.02-1.49); 1.46 (1.15-1.85); HR-positive, HER2-negative
1.23 (1.02-1.49);p = 0.035
1.46 (1.15-1.85); p = 0.002
HER2-positive1.07 (0.77-1.47);
p = 0.700.89 (0.60-1.31);
p = 0.55
Triple-negative1.01 (0.77-1.33);
p = 0.931.05 (0.77-1.43);
p = 0.75
Sparano JA et al. Proc SABCS 2010; Abstract S2-1.
* HR = hazard ratio. HR > 1 indicates a worse outcome.
Author Conclusions (1)● Obese patients from E1199 who had ER-positive,
HER2-negative disease had inferior outcomes compared to nonobese patients.
● A test for interaction showed obesity and ER-positive/HER2-negative disease to interact significantly for OS but not DFS (data not shown).
● This observation was validated with data from the two ● This observation was validated with data from the two other studies (E5188 and E3189).
Sparano JA et al. Proc SABCS 2010;Abstract S2-1.
● Obesity did not affect the delivery of AC or endocrine therapy (data not shown).
● Lower relative dose intensities were seen for paclitaxel but not docetaxel in obese patients compared to nonobesepatients (data not shown).
The Impact of Body Mass Index (BMI) on the Efficacy of
Adjuvant Endocrine Therapy in Postmenopausal Hormone
Sensitive Breast Cancer Sensitive Breast Cancer Patients; Exploratory Analysis
from the TEAM Study
Seynaeve C et al.Proc SABCS 2010;Abstract S2-3.
Recurrence Rates (from Abstract)
2.75-year
follow-up*Normal weight Overweight Obese
Exemestane 8.1% 6.8% 7.5%
Tamoxifen 9.1% 8.8% 12.5%
HR (95% CI) 0.91 (0.66-1.24) 0.78 (0.55-1.09) 0.57 (0.39-0.84)†HR (95% CI) 0.91 (0.66-1.24) 0.78 (0.55-1.09) 0.57 (0.39-0.84)†
* A total of 41 underweight patients were excluded from this analysis† p = 0.004
Seynaeve C et al. Proc SABCS 2010; Abstract S2-3.
5.1-year follow-up*Normal weight
Overweight Obese
Exemestane 14.8% 15.1% 15.1%
Tamoxifen 17.0% 16.9% 18.3%
Author Conclusions (2)● At 2.75 years, significantly fewer obese patients
treated with exemestane had recurrences compared to obese patients treated with tamoxifen (p = 0.004).
- However, the differences in recurrence rate between the obese treatment groups disappeared by year five. by year five.
● There were no significant differences in overall survival or disease-free survival between the BMI groups for either treatment (data not shown).
● These data suggest that BMI may be an important determinant of recurrence rate between patients treated with tamoxifen vs exemestane.
Seynaeve C et al. Proc SABCS 2010;Abstract S2-3.
Multivariate Analysis of Obesity and Disease Free
Survival in Patients with Nodal Positive Primary Breast
Cancer – The ADEBAR TrialCancer – The ADEBAR Trial
Hepp P et al.Proc SABCS 2010;Abstract S2-2.
+
+
Author Conclusions (3)● Compared to overweight patients, obese patients had
significantly decreased rates of disease-free survival (p = 0.008) and overall survival (p = 0.014).
● There were no significant differences between treatments (FEC versus EC/Doc) when comparisons were made within each BMI group for disease-free survival and overall survival.survival and overall survival.
● A multivariate analysis of overall survival indicated BMI >30 kg/m2 to be an independent negative prognostic factor (data not shown).● Hazard ratio 1.67, p = 0.008
● This analysis implicates an effect of obesity on disease-free and overall survival in patients with early-stage node-positive breast cancer.
Hepp P et al. Proc SABCS 2010;Abstract S2-2.
HormonioterapiaHormonioterapia –– “papers” de SABCS“papers” de SABCS
(Neo)Adjuvância / ObesidadeZ1031, MA27, ECOG, TEAM, ADEBAR
BisfosfonatoBisfosfonatoAZURE, ABCSG-12
MetastáticoFIRST, TAMRAD, AMG-479
AZURE - BIG 01/04
Stage II to III, node-
positive breast
Standard therapy
Eligibility (N = 3,360)
positive breast
cancer with a
completed primary
resection
* Months 0-6, 6 doses q3-4 wks; Months 7 to 30, 8 doses q3 mos; Months 31 to 60, 5 doses, q6 mos
Standard therapy + Zoledronic acid (ZOL)* 4 mg x 5 yrs
R
Coleman RE et al. Proc SABCS 2010;Abstract S4-5.
AZURE Treatment Effect* on DFS by Menopausal Status
High oestrogenenvironment
N = 2,318505 events
Typical Odds Ratio
Odds reduction (± SD) Menopausal group description
1.13;
With permission from Coleman RE et al. Proc SABCS 2010;Abstract S4-5.
Low oestrogenenvironment
N = 1,041247 events
Total: 0% ± 7%Z = 0.04; P = 0.97
χ21 (heterogeneity) = 5.34; P = 0.02
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0
* Adjusted for imbalances in ER, lymph node status and T stage
0.76; 0.60-0.98
1.13; 0.95-1.35
Distribution of DFS Events by Menopausal Status
N = 1127 N = 1131 N = 551 N = 550Death no recurrence
Other distant
Bone ±±±± other distant
Loco-regional
14
123
83
17
21
With permission from Coleman RE et al. Proc SABCS 2010;Abstract S4-5.
TotalEvents
228 (20.2%) 261 (23.1%) 147 (26.1) 114 (21.1%)
Effects independent of ER
Not menopausal = premenopausal, perimenopausal, unkown age < 60Menopausal = >5 years since menopause or age > 60
Not postmenopausal
Control
Not postmenopausal
ZOL
Postmenopausal Control
Postmenopausal ZOL
78
5645
93
21
68
36
27 16
33
49
21
Overall Survival by Menopausal Status
Pre, peri and unknown menopausal status
>5 years post-menopausal or age >60100
80
60
100
80
60Zoledronic acid N = 550
Control N = 551
Zoledronic acid N = 1,131
Control N = 1,127
% S
urvi
ving
With permission from Coleman RE et al. Proc SABCS 2010;Abstract S4-5.
40
20
00 1 2 3 4 5 6 7
40
20
0
Control N = 551Control N = 1,127
Adjusted HR = 1.0195% CI [0.81, 1.26] p = 0.93157 vs 156 deaths
Adjusted HR = 0.7195% CI [0.54, 0.94] p = 0.01786 vs 120 deaths
No. at risk:ZOL: 1131 1101 1051 993 932 454 70CONT: 1127 1096 1049 1007 940 432 58
0 1 2 3 4 5 6 7
No. at risk:ZOL: 550 532 509 475 448 202 30CONT: 551 536 502 466 424 191 28
Time (years) Time (years)
% S
urvi
ving
Effects independent of ER
Conclusions● The adjuvant use of zoledronic acid did not improve
DFS in this population of patients with stage II/III breast cancer (DFS, P = 0.79; IDFS, P = 0.73)
● A subgroup analysis of post-menopausal (>5 years) patients and those aged >60 years showed significant differences in OS between the control and zoledronic acid groups.zoledronic acid groups.- 120 vs 86 deaths (P = 0.017)
● The adjuvant use of bisphosphonates appears to be dependent on a low estrogen/inhibin concentration within the bone microenvironment.
● The AZURE data are strikingly different than those observed in the ABCSG XII trial.
Coleman RE et al. Proc SABCS 2010;Abstract S4-5; Gnant M et al. Proc ASCO 2010;Abstract 522.
Eligibility (N = 1,803)
Primary surgery
ABCSG 12 -Carry-Over Effect62m FUP
TAM1 x 3 yrs
TAM1 + ZOL2 x 3 yrs
RTreatment with
goserelin x 3 yrs
1 Tamoxifen 20 mg/day2 Zoledronic acid (ZOL) 4 mg q 6 mos3 Anastrozole (ANA) 1 mg/day
ANA 3 x 3 yrs
ANA 3 + ZOL2 x 3 yrs
R
Gnant M et al. Proc SABCS 2010;Abstract P5-11-02.
Efficacy Results: ZOL versus Endocrine Therapy Alone
Endpoint ZOL No ZOLHR
(p-value)
Disease-free survival
48 mos (n = 899; 904)
62 mos (n = 900; 903)
94%
92%
91%
88%
0.64 (p = 0.01)
0.68 (p = 0.008)
Overall survival
48 mos (n = 899; 904)
62 mos (n = 900; 903)
98%
97%
97%
95%
0.60 (p = 0.10)
0.67 (p = 0.143)
Gnant M et al. Proc SABCS 2010;Abstract P5-11-02.
Efficacy Results: ZOL versus Efficacy Results: ZOL versus Endocrine Therapy Alone Endocrine Therapy Alone in TAM and ANA Groupsin TAM and ANA Groups
Subgroup ZOL No ZOL HR (95% CI)
Disease-free survival
TAM (n = 450; 450)
ANA (n = 450; 453)
92%
91%
88%
87%
0.67 (0.44, 1.03)
0.68 (0.45, 1.02)
Gnant M et al. Proc SABCS 2010;Abstract P5-11-02.
Conclusions - ABCSG12
● The addition of ZOL to endocrine therapy for 3 years was associated with a durable benefit in disease-free survival in the ANA and TAM groups.
● At 62 months, the benefits of ZOL were decreased bone metastases, decreased contralateral breast cancer, decreased locoregional and distant cancer, decreased locoregional and distant metastases and improved disease-free survival.
● ZOL did not increase the incidence of serious adverse events compared with endocrine therapy alone.
● ESMO 2010 guidelines now recommend that ZOL may be appropriate for premenopausal women receiving aromatase inhibitor therapy (Ann Oncol 2010;21[suppl5]:v9-14).
Gnant M et al. Proc SABCS 2010;Abstract P5-11-02.
HormonioterapiaHormonioterapia –– “papers” de SABCS“papers” de SABCS
(Neo)Adjuvância / ObesidadeZ1031, MA27, ECOG, TEAM, ADEBAR
BisfosfonatoBisfosfonatoAZURE, ABCSG-12
MetastáticoFIRST, TAMRAD, AMG-479
FIRST: Study Design
• Randomized, open-label phase II trial– Primary endpoint: CBR, defined as CR,
PR, or SD for ≥ 24 wksPostmenopausal
women with previously
Fulvestrant 500 mg by IM injection onDays 0, 14, 28, and every previously
untreated hormone receptor–positive
advanced breast cancer
(N = 205)
Days 0, 14, 28, and every 28 days thereafter
(n = 102)
Anastrozole 1 mg/day PO(n = 103)
Until disease progression or
other event requiring
discontinuation
Robertson JFR, et al. SABCS 2010. Abstract S1-3.
FIRST• TTP benefits for fulvestrant 500 mg were significantly
greater than those of anastrozole 1 mg with longer follow-up.
– Patients experiencing disease progression: 61.8%61.8%vs 76.7%76.7% (p = 0.01)
– Median TTP: 23.423.4 months vs 13.113.1 months (p = – Median TTP: 23.423.4 months vs 13.113.1 months (p = 0.01)
• TTP benefit of fulvestrant 500 mg was consistent in allpredefined subgroups (data not shown).
• Patients who experience disease progression on either fulvestrant or anastrozole remain sensitive to subsequent endocrine treatments.
Robertson JFR et al. Proc SABCS 2010;Abstract S1-3.
50
60
70
80
What monthly dose of fulvestrant do you try to use in metastatic BC, regardless of
whether you use a loading dose?
n = 213
67%
0
10
20
30
40
50
Research To Practice Premeeting Survey, Real-Life Decisions: Practical Perspectives on the Management of Early and Advanced Breast Cancer, held at SABCS 2010.
250 mg 500 mg
33%
TAMRAD: Study Design• Randomized, controlled phase II trial
– Primary endpoint: CBR at 6 mos (CR + PR + SD)
Patients with HER2-negative, hormone
Everolimus 10 mg/day +
Stratified by primary vs secondary hormone resistance*
negative, hormone receptor–positive metastatic breast
cancer with previous AI exposure
(N = 111)
Tamoxifen 20 mg/day(n = 54)
Tamoxifen 20 mg/day(n = 57)
*Primary resistance: relapse during adjuvant AI therapy or progression during first 6 mos of initiating AI for metastatic disease. Secondary resistance: late relapse (at or after 6 mos) or previous response to AI therapy for metastatic breast cancer and subsequent progression.
Bachelot T, et al. SABCS 2010. Abstract S1-6.
TAMRAD: Significant Increase in Clinical Benefit Rate With TAM + RAD
vs TAM Alone
TAM + RAD (n = 54)TAM (n = 57)
Pat
ient
s (%
)P = .045*
42.1
61.170
60
50
Bachelot T, et al. SABCS 2010. Abstract S1-6.
Pat
ient
s (%
)
42.1
Clinical Benefit Rate
50
40
30
20
10
0
*Exploratory analysis.
TAMRAD: Significant Increase in TTP, OS With TAM + RAD vs TAM Alone
Outcome, % TAM Alone(n = 57)
TAM + RAD(n = 54)
HR(95% CI)
P Value*
Median TTP, mos 4.5 8.60.53
(0.35-0.81).0026
� Primary 0.74
Bachelot T, et al. SABCS 2010. Abstract S1-6.
� Primary hormone resistance
3.9 5.40.74
(0.42-1.30)NR
� Secondary hormone resistance
5.0 17.40.38
(0.21-0.71)NR
Median OS, mos ~ 24† Not reached0.32
(0.15-0.68).0019
*Exploratory log rank test.†Estimate based on Kaplan-Meier curve.
TAMRAD: Safety, Dose Reductions, and Treatment Discontinuations
Patients, % Tamoxifen(n = 57)
Tamoxifen + Everolimus
(n = 54)Adverse events All Grades Grade 3/4 All Grades Grade 3/ 4
� Fatigue 52.6 10.5 74.1 5.6
Bachelot T, et al. SABCS 2010. Abstract S1-6.
� Fatigue 52.6 10.5 74.1 5.6
� Stomatitis 7.0 0 51.9 11.1
� Rash 5.3 1.8 38.9 5.6
� Anorexia 17.5 3.5 44.4 9.3
� Diarrhea 8.8 0 38.9 1.9
Dose reduction for toxicity 0 27.8
Discontinuation for toxicity 7.0 5.6
AMG 479AMG 479ANTICORPO MONOCLONAL HUMANIZADO QUE
ANTAGONIZA IGF1R• Bloqueia a ligação do IGF1 e IGF2 ao IGFR
RACIONAL DO ESTUDORACIONAL DO ESTUDO• A resistência à Hormonioterapia pode ocorrer
pelo aumento do IGF1R. A estimulação da via de IGF está presente na resistência ao tamoxifeno
• A inibição do RE e IGF1R resulta em grande supressão da proliferação
AMG 479AMG 479
Resultados
- Efeitos colaterais:Trombocitopenia, hiperglicemia e neutropenia no braço da combinação
Clinical Benefit Rate 35 31
CR 0 0
PR 8 13
PD 35 34
Response, % AMG 479 + Endocrine Therapy (n = 63) Placebo + Endocrine Therapy (n = 32)
½ ½ MaratonaMaratona de de Miami, EUA Miami, EUA
30 de Janeiro 30 de Janeiro 2011201120112011
3a 3a MeiaMeia, 1a , 1a foraforado Brasil!do Brasil!
Obrigado!Obrigado!Obrigado!Obrigado!Obrigado!Obrigado!Obrigado!Obrigado!gilberto.amorim@[email protected]@[email protected]@[email protected]@[email protected]
[email protected]@[email protected]@[email protected]@[email protected]@gmail.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.comwww.oncologistas.com