Up to Date em Hormonioterapia no Câncer de

Mama Metastático

Aknar Calabrich

• Avaliação do status hormonal

• Novos estudos comparando as opções de

hormonioterapia

• Evolução na reversão de resistência à terapia hormonal

Índice

ASCO 2010

• Tissue confirmation of disease recurrence in patients with breast cancer: Pooled analysis of two large prospective studies.

• Should liver metastases of breast cancer be

biopsied to improve treatment choice?

• Discordance in hormone receptor status in breast cancer during tumor progression.

Amir et al.

Karlsson et al

Locatelli et al

Desenho do Estudo

#1007 Amir et al

#CRA1008 Locatelli et al

#1009 Karisson et al

Número 271 255 486

Desenho Prospectivo Retrospectivo Retrospectivo

Receptores avaliados

RE, RP, HER2 RE, RP, HER2 RE e RP

Sítio metástase qualquer fígado qualquer

Objetivos

#1007 Amir et al

#CRA1008 Locatelli et al

#1009 Karisson et al

Primário % de pcts cuja biópsia modificou

o tratamento

Discordância entre o status do RE, RP e

Her2 entre o primário e a

metástase hepática

Discordância entre o status do RE e RP entre o primário e a

metástase

Secundário Discordância entre o status do RE, RP

e Her2 entre o primário e a

metástase

Potencial impacto no tratamento

-

Resultados: significante taxa de discordância entre o primário e a metástase

Estudos #1007 Amir et al

#CRA1008 Locatelli et al

#1009 Karisson et al

RE + RE - 12% 11% 27%

RE - RE + 14% 25% 8%

Discordância RE 12% 14,5% 35%

Discordância RP 34% 48% 43%

Her2 - Her2 + 4.6% 5.9% n.r.

Her2 + Her2 - 12,5% 31,5% n.r.

Mudança no manejo

15% 12% n.r.

Re-biópsia

PRÓS

• Decisão terapêutica • Informação prognóstica

• Status do receptor define prognóstico

• Diferencial: • Lesão benigna vs

metástase vs novo primário

CONTRAS

• Atraso no início do tratamento

• Riscos do procedimento

• Acurácia do resultado (biópsia óssea)

• Dor e ansiedade

Take Home Message

A biópsia da recidiva do câncer de mama deve ser bastante considerada

em pacientes selecionadas

ASCO 2011- Abstr 622

Hormone therapy versus chemotherapy as first-line treatment for estrogen receptor-positive metastatic breast cancer (MBC)

patients

J Clin Oncol 29: 2011 (suppl; abstr 622)

Racional

• Comparação entre hormonioterapia e

quimioterapia baseada em estudos antigos

• Drogas antigas

• Status hormonal variável

• Não há estudo randomizados em pacientes

com câncer de mama metastático, RH+, com

esquemas atuais

Barrios et al., Ann Oncol. 2009 Jul;20(7):1157-62.

Desenho do Estudo

• Estudo retrospectivo • Registro do National Taiwan University

Hospital de 2001 a 2006 • Paciente com câncer de mama metastático

RH+, HER2- • N=301 • Objetivos: TTF, OS

RESULTADOS

HT QT p HT QT p N 199 102 105 59

TTF (m) 5.03 4.86 0.008 3.17 4.67 0.313

OS (m) 46.80 45.20 0.303 59.53 36.13 0.162

Todo o grupo Presença de metástase visceral

Take Home Message

Hormonioterapia é a opção preferencial de tratamento da paciente com câncer de mama

metastático RH positivo

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With

Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive

Advanced Breast Cancer

Di Leo et al., J Clin Oncol. 2010 28(30):4594-600

Desenho do estudo

F250 (1 injection i.m.) +

Placebo (1 injection i.m.) days 1, 14 (2 placebo

injections), 28 and every 28 days thereafter

Accrual: 736 (Closed)

F500 (2 injections 250 mg i.m.)

days 1, 14, 28, and every 28 days thereafter

Eligibility

Postmenopausal

ER-positive, advanced disease

R

Time to Progression (ITT Analysis)

Proportion of patients progression free

Time (Months)

Fulvestrant 500 Fulvestrant 250 82 85.8 6.5 5.5

Hazard Ratio (95% CI) = 0.80 (0.68 - 0.94) p-value = 0.006

% progressed Median TTP-mos.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Overall Survival (50% events)

Fulvestrant 500 Fulvestrant 250 48.3 54.3 25.1 22.8

% died Median OS-mos.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Proportion of patients alive

Hazard Ratio (95% CI) = 0.84 (0.69 - 1.03) p-value = 0.091

Time (Months)

Objective Response and Clinical Benefit

F500 (n=362)

F250 (n=374)

Odds ratio (95% CI)

Objective response rate (%) Complete response (%) Partial response (%)

9.1 1.1 8.0

10.2 0.3 9.9

0.94 (0.57 – 1.55) — —

Clinical benefit rate (%) 45.6 39.6 1.28 (0.95 – 1.71)

Progressive disease (%) 38.7 44.7 —

Median duration of clinical benefit (months)

16.6 13.9 —

Pre-specified Adverse Events*

F500 (n=361) F250 (n=324)

All (%)

≥ Grade 3 (%)

All (%)

≥ Grade 3 (%)

Gastrointestinal disturbances 20.2 2.2 20.3 0.2

Joint disorders 18.8 2.2 18.7 2.1

Injection site reactions 13.6 0.2 13.4 0

Hot flashes 8.3 0 6.1 0

Urinary tract infections 2.2 0.2 2.1 0.2

Ischemic cardiovascular disorders 1.4 0 1.9 0.8

Thromboembolic events 0.8 0.5 1.6 1.0

* Shown are only those adverse events with an incidence of ≥1%.

Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the

FIRST study.

Robertson JF, et al. J Clin Oncol. 2009;27:4530-4535 . Robertson JFR, et al. SABCS 2010. Abstract S1-3.

FIRST: Study Design

• Randomized, open-label phase II trial • Primary endpoint: CBR, defined as CR, PR, or SD for

≥ 24 wks

Postmenopausal women with

previously untreated hormone receptor–positive advanced

breast cancer

(N = 205)

Fulvestrant 500 mg by IM injection on 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: Comparable Clinical Benefit Rate Observed in Primary Analysis

Robertson JF, et al. J Clin Oncol. 2009;27:4530-4535.

Outcome Fulvestrant (n = 102)

Anastrozole (n = 103)

OR (95% CI)

P Value

Absolute Difference, %

(95% CI) Clinical benefit rate, %

72.5 67.0 1.30 (0.72-2.38) .386 5.6

(-7.8 to 15.8)

TTP after 36% progressed

FIRST: Fulvestrant Significantly Increased TTP in Secondary Analysis

Robertson JFR, et al. SABCS 2010. Abstract S1-3.

Parameter Fulvestrant (n = 102)

Anastrozole (n = 103)

Patients progressing, n (%) 63 (61.8) 79 (76.7) Median TTP, mos 23.4 13.1 HR (95% CI) 0.66 (0.47-0.92); P = .01

TTP after 69% progressed

Take Home Message

Fulvestranto na dose de 500 mg é superior à dose de 250 mg no controle da doença

metastática RH+ sem impacto na sobrevida e pode ser considerada uma opção de

tratamento

A Qualitative Systematic Review of the Evidence Base for Non-Cross-Resistance

Between Steroidal and Non-steroidal Aromatase Inhibitors in Metastatic Breast

Cancer

Clin Oncol. 2011 Apr 1;23(3):209-215

M Beresford, I Tumur, J Chakrabarti, J Barden, N Rao, A Makris

Desenho do Estudo

• Paciente com câncer de mama metastático RH+ • Progressão/falência ao tratamento com inibidor

de aromatase na adjuvância, primeira ou segunda linha

• Tratamento subsequente com pelo menos dois regimes contendo aminoglutethimide, anastrozole, letrozole and/or exemestane

• 9 estudos reportaram uso de exemestano após IA não esteroidal

Resultados

Benefício Clínico

Resposta Completa

Resposta Parcial

Doença Estável

TTP

12-55% 0-6% 2-13% 10-35% 3,7-5,2 m

Eficácia do exemestano após falha de IA não esteroidal

Fatores favoráveis: resposta a hormônio prévio, RH fortemente positivo, ausência de doença visceral

Take Home Message

O uso de exemestano após falha inicial ao inibidor de aromatase não esteroidal está

associado a benefício clínico modesto

Where Do mTORs Act in the Cell?

PTEN

mTOR

PI3-Kinase Akt/PKB

Growth factors Nutrients Amino acids

ENERGY

MTOR Inh FKBP-12

Signal Transduction and ER Pathway Crosstalk: An Opportunity for Combination Therapy

ER signaling

Anti-E2 Resistance Prognosis

Nuclear events

mTOR = mammalian target of rapamycin.

TAMRAD: A Gineco Randomized phase II trial of everolimus in combination with tamoxifen

versus tamoxifen alone in patents with hormone-receptor positive, HER2 negative

metastatic breast cancer with prior exposure to aromatase inhibitors.

Bachelot T, Bourgier C, Cropet C, et al. 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010

TAMRAD Phase II Study Schema

Primary endpoint: Clinical benefit rate (CBR) at 6 months; a gain of 20% in CBR required to warrant further study of tamoxifen/everolimus combination. Secondary endpoints: Time to progression (TTP), overall survival, objective response rate, toxicity.

Everolimus 10 mg/day + Tamoxifen 20 mg/day

(n = 54)

Tamoxifen 20 mg/day (n = 57)

Eligibility

Metastatic breast cancer Menopausal condition Hormone receptor-positive; HER2-negative Prior exposure to aromatase inhibitor (AI)

R

Stratified by primary vs secondary hormone resistance*

TAMRAD: Treatment History and Hormone Resistance

Bachelot T, et al. SABCS 2010. Abstract S1-6.

Patients, % Tamoxifen (n = 57)

Tamoxifen + Everolimus (n = 54)

Previous adjuvant tamoxifen 40.4 31.5 Previous chemotherapy Adjuvant setting 56.1 46.3 Metastatic setting 26.3 24.1 Hormone resistance Primary 49.1 49.1 Secondary 50.9 50.9

Results

Tamoxifen Tamoxifen + Everolimus

Hazard Ratio

(95% CI) p-value

CBR (n = 57; 54) 42.1% 61.1% — —

Median TTP (n = 57; 54) 4.5 mos 8.6 mos 0.53 (0.35-0.81) 0.0026

TTP, all pts with primary hormone resistance1 (n = 54) 3.9 mos 5.4 mos 0.74

(0.42-1.3) —

TTP, all pts with secondary hormone resistance2 (n = 56) 5.0 mos 17.4 mos 0.38

(0.21-0.71) —

Overall survival (n = 57; 54) — — 0.32 (0.15-0.68) 0.0019

1 Patients who received no benefit from hormone therapy, experiencing either relapse during adjuvant AI or progression within six months of starting AI in the metastatic setting 2 Patients who relapsed later, either after AI discontinuation in the adjuvant setting or after responding, experiencing progression later in the metastatic setting

Results

• Primary hormone resistance (n = 54)

• TAM: 3.9 months • TAM + RAD: 5.4 months • HR = 0.74 (0.42-1.3)

• Secondary hormone resistance (n = 56)

• TAM: 5.0 months • TAM + RAD: 17.4 months • HR = 0.38 (0.21-0.71)

HR = hazard ratio; RAD = RAD001; TAM = tamoxifen

TAM TAM + RAD

Months

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Prob

abili

ty o

f su

rviv

al

0 6 12 18 24 30

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Prob

abili

ty o

f su

rviv

al

Months 0 6 12 18 24 30

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

61.1

Clinical Benefit Rate

70

60

50

40

30

20

10

0

*Exploratory analysis.

Eventos adversos

Adverse event (AE)

Tamoxifen (n = 57) Tamoxifen + everolimus

(n = 54)

Any grade Grade 3/4 Any grade Grade 3/4

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 due to AE 0 28%

Treatment discontinuation due to AE 7.0% 5.6%

Everolimus in Combination with Exemestane for Postmenopausal Woen with Advanced

Breast Cancer Who Are Refractory to Letrozole or Anastrozole: Results of the BOLERO-2

Phase III Trial

Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011.

Abstract: 9LBA

BOLERO-2 – Desenho do estudo

Placebo PO daily Exemestane 25 mg PO daily (N=239)

Everolimus 10 mg PO daily Exemestane 25 mg PO daily

(N=485) Postmenopausal ER+, Her2-, unresectable locally advanced or metastatic breast cancer refractory to letrozole or anastrozole

R

N = 724 2:1

(everolimus:placebo)

PFS

OS ORR

Bone Markers Safety

PK

Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease

No cross-over

BOLERO-2: Prior Therapy

Therapy

Everolimus + Exemestane (N=485), %

Placebo + Exemestane (N=239), %

Sensitivity to prior hormonal therapy 84 84

Last treatment: LET/ ANA 74 75

Last treatment Adjuvant 21 16 Metastatic 79 84

Prior tamoxifen 47 49

Prior fulvestrant 17 16

Prior chemotherapy for metastatic BC 26 24

Number of prior therapies: ≥3 54 53

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

BOLERO-2 Primary Endpoint: PFS Local Assessment

Time (weeks) 0 12 6 18 24 30 36 48 60 42 54 72 66 78

80

60

40

20

100

0

Pro

babi

lity

of E

vent

(%)

Everolimus + Exemestane (E/N=202/485) Placebo + Exemestane (E/N=157/239)

HR = 0.43 (95% CI: 0.35–0.54)

EVE + EXE: 6.9 months PBO + EXE: 2.8 months

Log rank P value = 1.4 x 10 -15

BOLERO-2 Primary Endpoint: PFS Central Assessment

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months

Log rank P value = 3.3 x 10 -15

0 12 6 18 24 30 36 48 60 42 54 72 66 78

80

60

40

20

100

0

Pro

babi

lity

of E

vent

(%)

Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239)

BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment

P < 0.0001

P < 0.0001

BOLERO-2: Overall Survival

As of PFS interim analysis: 83 deaths 10.6% in everolimus arm 13.0% in placebo arm

OS interim analysis after 173 events

OS final analysis at 392 events

80% power to detect 26% reduction in hazard ratio (0.74)

46

BOLERO-2: Most Common G3/4 AEs

Everolimus + Exemestane (N = 482), %

Placebo + Exemestane (N = 238), %

All Grades

Grade 3 Grade 4

All Grades

Grade 3

Grade 4

Stomatitis 56 8 0 11 1 0

Fatigue 33 3 <1 26 1 0

Dyspnea 18 4 0 9 1 <1

Anemia 16 5 <1 4 <1 <1

Hyperglycemia 13 4 <1 2 <1 0

AST 13 3 <1 6 1 0

Pneumonitis 12 3 0 0 0 0

Take Home Message

Em pacientes com câncer de mama metastático RE+ que progrediram após IA, everolimus é capaz de aumentar o benefício clínico da terapia hormonal, sendo mais uma

opção de tratamento neste contexto

Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in

postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast

cancer progressing on a nonsteroidal aromatase inhibitor (AI).

Yardley et al. ASCO 2011, abstr 268

Deacetylation of Histones by HDAC Can Prevent Gene Expression

Acetylation by histone acetyltransferases (HATs) allows transcription and gene expression

Deacetylation by histone deacetylases (HDACs) can prevent

transcription and gene expression

HAT

HISTONE ACETYLATION

HISTONE DEACETYLATION

HDAC

Acetylated Histone Open chromatin Transcription factors can access DNA

Deacetylated Histone Closed chromatin Transcription factors cannot access DNA

Ac: acetyl group HDAC depicts a class I deacetylase

Transcription factors –Ac

Ac–

Ac–

In Tumor Cells, Imbalanced HAT and HDAC Activity Can Result in Deregulated Gene Expression

Tumor Cell Unchecked Cell

Growth and Survival

Decreased Tumor Suppressor Gene Activity (p21, p27)

Increased HDAC Activity

Decreased HAT Activity

HDAC

HDAC HDAC

HAT

Ac: acetyl group TF: transcription factors HDAC depicts a class I

deacetylase

TF –Ac Ac–

HDAC Inhibition Restores Gene Expression in Tumor Cells

HDAC

HDAC HDAC DAC Inhibition Increases Acetylation of Histones HAT

DAC Inhibitor

Increased Tumor Suppressor Gene Activity (p21, p27)

Cell-Cycle Arrest and Differentiation

Normalized Cell

Ac: acetyl group TF: transcription factors HDAC depicts a class I

deacetylase

–Ac

Ac–

Ac–

TF

Mecanismo de resistência aos inibidores de aromatase

Desenho do Estudo

Exemestano + Placebo 5 mg PO week

N=57

Exemestano + Etinostat 5 mg PO week

N=57

Eligibility Pos-menopausalwomen with advanced ER+ breast cancer Progressing on a non-steroidal AI (letrozole or anastrozole)

Stratification factors

Adjuvant vs metastatic Bone disease yes vs no Geografhic region

R

Randomized, double-blinded, placebo controlled Endpoint: 1° PFS, 2° ORR and CBR. Exploratory endpoint: OS 1-sided significance level of 0.10 (P<0.10 statistically significant)

Resultados

PFS Greatest in Exemestane+Entinostat in Subjets Who Hyperacetylate

Sobrevida Global

Eventos Adversos Mais Frequentes

Exemestan0 + Placebo (N = 66), %

Exemestano + Entinostat (N = 63), %

Todos os Grau Grau 3 Grau 4

Todos os Graus Grau 3 Grau 4

Fadiga 26 3 0 46 11 2

Náuseas 15 2 0 40 5 0

Neutropenia 0 0 0 25 11 2

Vômito 5 0 0 21 5 0

Trombocitopenia 6 0 0 17 0 0

Anemia 12 2 2 19 2 0

Dispnéia 11 0 0 19 3 0

Take Home Message

Inibidores da histona deacetilase (HDAC) são drogas promissoras na reversão da resistência

à terapia hormonal

Take Home Message

• A biópsia da recidiva do câncer de mama para

avaliação do status hormonal deve ser bastante

considerada em pacientes selecionadas

• Hormonioterapia é a opção preferencial do

tratamento da paciente com câncer de mama RH

positivo

• Fulvestranto na dose de 500 mg é uma opção de

tratamento na doença metastática RH+

Take Home Message

• O uso de exemestano após falha inicial de inibidor

de aromatase não esteroidal está associado a

benefício clínico modesto

• Everolimus é uma opção de tratamento na reversão

da resistência à terapia hormonal

• Inibidores da histona deacetilase (HDAC) são

drogas promissoras no reversão da resistência à

terapia hormonal

OBRIGADA