6 PAPERS DE SAN ANTONIO GILBERTO AMORIM - … · Hormonioterapia “Papers” de SABCS Gilberto Gilberto Amorim Amorim Oncologistas Associados Coordenador do Grupo de Oncologia Mamária

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




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.





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


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


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)


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)


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).






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


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


� 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


� 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]

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6 PAPERS DE SAN ANTONIO GILBERTO AMORIM - … · Hormonioterapia “Papers” de SABCS Gilberto Gilberto Amorim Amorim Oncologistas Associados Coordenador do Grupo de Oncologia Mamária