Up to Date em Hormonioterapia no Câncer de Mama Metastático. Aknar Calabrich

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2 Up to Date em Hormonioterapia no Câncer de Mama Metastático Aknar Calabrich

3 Índice Avaliação do status hormonal Novos estudos comparando as opções de hormonioterapia Evolução na reversão de resistência à terapia hormonal

4 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? Amir et al. Locatelli et al Discordance in hormone receptor status in breast cancer during tumor progression. Karlsson et al

5 Desenho do Estudo #1007 Amir et al #CRA1008 Locatelli et al #1009 Karisson et al Número Desenho Prospectivo Retrospectivo Retrospectivo Receptores avaliados RE, RP, HER2 RE, RP, HER2 RE e RP Sítio metástase qualquer fígado qualquer

6 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 -

7 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 - Her % 5.9% n.r. Her2 + Her2-12,5% 31,5% n.r. Mudança no manejo 15% 12% n.r.

8 Re-biópsia PRÓS CONTRAS Decisão terapêutica Informação prognóstica Status do receptor define prognóstico Diferencial: Lesão benigna vs metástase vs novo primário Atraso no início do tratamento Riscos do procedimento Acurácia do resultado (biópsia óssea) Dor e ansiedade

9 Take Home Message A biópsia da recidiva do câncer de mama deve ser bastante considerada em pacientes selecionadas

10 ASCO Abstr 622 Hormone therapy versus chemotherapy as first-line treatment for estrogen receptorpositive metastatic breast cancer (MBC) patients J Clin Oncol 29: 2011 (suppl; abstr 622)

11 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 Jul;20(7):

12 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

13 RESULTADOS Todo o grupo Presença de metástase visceral HT QT p HT QT p N TTF (m) OS (m)

14 Take Home Message Hormonioterapia é a opção preferencial de tratamento da paciente com câncer de mama metastático RH positivo

15 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 (30):

16 Desenho do estudo Accrual: 736 (Closed) Eligibility Postmenopausal ER-positive, advanced disease R F250 (1 injection i.m.) + Placebo (1 injection i.m.) days 1, 14 (2 placebo injections), 28 and every 28 days thereafter F500 (2 injections 250 mg i.m.) days 1, 14, 28, and every 28 days thereafter

17 Time to Progression (ITT Analysis) % progressed Median TTP-mos. Fulvestrant 500 Fulvestrant Proportion of patients 0.5 progression 0.4 free 0.3 Hazard Ratio (95% CI) = 0.80 ( ) p-value = Time (Months)

18 Overall Survival (50% events) 1.0 % died Median OS-mos. Fulvestrant 500 Fulvestrant Hazard Ratio (95% CI) = 0.84 ( ) p-value = Proportion of patients alive Time (Months)

19 Objective Response and Clinical Benefit F500 (n=362) F250 (n=374) Odds ratio (95% CI) Objective response rate (%) Complete response (%) Partial response (%) ( ) Clinical benefit rate (%) ( ) Progressive disease (%) Median duration of clinical benefit (months)

20 Pre-specified Adverse Events* F500 (n=361) F250 (n=324) All (%) Grade 3 (%) All (%) Grade 3 (%) Gastrointestinal disturbances Joint disorders Injection site reactions Hot flashes Urinary tract infections Ischemic cardiovascular disorders Thromboembolic events * Shown are only those adverse events with an incidence of 1%.

21 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: Robertson JFR, et al. SABCS Abstract S1-3.

22 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 Abstract S1-3.

23 FIRST: Comparable Clinical Benefit Rate Observed in Primary Analysis Outcome Fulvestrant (n = 102) Anastrozole (n = 103) OR (95% CI) P Value Absolute Difference, % (95% CI) Clinical benefit rate, % ( ) (-7.8 to 15.8) TTP after 36% progressed Robertson JF, et al. J Clin Oncol. 2009;27:

24 FIRST: Fulvestrant Significantly Increased TTP in Secondary Analysis Parameter Fulvestrant (n = 102) Anastrozole (n = 103) Patients progressing, n (%) 63 (61.8) 79 (76.7) Median TTP, mos HR (95% CI) 0.66 ( ); P =.01 TTP after 69% progressed Robertson JFR, et al. SABCS Abstract S1-3.

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26 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

27 A Qualitative Systematic Review of the Evidence Base for Non-Cross-Resistance Between Steroidal and Non-steroidal Aromatase Inhibitors in Metastatic Breast Cancer M Beresford, I Tumur, J Chakrabarti, J Barden, N Rao, A Makris Clin Oncol Apr 1;23(3):

28 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

29 Resultados Eficácia do exemestano após falha de IA não esteroidal Benefício Clínico Resposta Completa Resposta Parcial Doença Estável TTP 12-55% 0-6% 2-13% 10-35% 3,7-5,2 m Fatores favoráveis: resposta a hormônio prévio, RH fortemente positivo, ausência de doença visceral

30 Take Home Message O uso de exemestano após falha inicial ao inibidor de aromatase não esteroidal está associado a benefício clínico modesto

31 Where Do mtors Act in the Cell?

32 Signal Transduction and ER Pathway Crosstalk: An Opportunity for Combination Therapy Growth factors Nutrients Amino acids ER signaling PTEN ENERGY Nuclear events PI3-Kinase Akt/PKB mtor MTOR Inh FKBP-12 Anti-E2 Resistance Prognosis mtor = mammalian target of rapamycin.

33 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

34 TAMRAD Phase II Study Schema Eligibility Metastatic breast cancer Menopausal condition Hormone receptor-positive; HER2-negative Prior exposure to aromatase inhibitor (AI) R Tamoxifen 20 mg/day (n = 57) Everolimus 10 mg/day + Tamoxifen 20 mg/day (n = 54) Primary endpoint: Stratified by primary vs secondary hormone resistance* 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.

35 TAMRAD: Treatment History and Hormone Resistance Patients, % Tamoxifen (n = 57) Tamoxifen + Everolimus (n = 54) Previous adjuvant tamoxifen Previous chemotherapy Adjuvant setting Metastatic setting Hormone resistance Primary Secondary Bachelot T, et al. SABCS Abstract S1-6.

36 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 TTP, all pts with primary hormone resistance 1 (n = 54) 3.9 mos 5.4 mos 0.53 ( ) 0.74 ( ) TTP, all pts with secondary hormone resistance 2 (n = 56) 5.0 mos 17.4 mos 0.38 ( ) Overall survival (n = 57; 54) 0.32 ( ) 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

37 Results Primary hormone resistance (n = 54) TAM: 3.9 months TAM + RAD: 5.4 months HR = 0.74 ( ) Secondary hormone resistance (n = 56) TAM: 5.0 months TAM + RAD: 17.4 months HR = 0.38 ( ) HR = hazard ratio; RAD = RAD001; TAM = tamoxifen Probability of survival Probability of survival TAM TAM + RAD Months Months

38 TAMRAD: Significant Increase in Clinical Benefit Rate With TAM + RAD vs TAM Alone P =.045* 61.1 TAM + RAD (n = 54) TAM (n = 57) Patients (%) *Exploratory analysis. Clinical Benefit Rate

39 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% % 11.1% Rash 5.3% 1.8% 38.9% 5.6% Anorexia 17.5% 3.5% 44.4% 9.3% Diarrhea 8.8% % 1.9% Dose reduction due to AE 0 28% Treatment discontinuation due to AE 7.0% 5.6%

40 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, Abstract: 9LBA

41 BOLERO-2 Desenho do estudo Postmenopausal ER+, Her2-, unresectable locally advanced or metastatic breast cancer refractory to letrozole or anastrozole R N = 724 2:1 (everolimus:placebo) Everolimus 10 mg PO daily Exemestane 25 mg PO daily (N=485) Placebo PO daily Exemestane 25 mg PO daily (N=239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over

42 BOLERO-2: Prior Therapy Therapy Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Sensitivity to prior hormonal therapy Last treatment: LET/ ANA Last treatment Adjuvant Metastatic Prior tamoxifen Prior fulvestrant Prior chemotherapy for metastatic BC Number of prior therapies: Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

43 BOLERO-2 Primary Endpoint: PFS Local Assessment 100 HR = 0.43 (95% CI: ) Log rank P value = 1.4 x Probability of Event (%) Everolimus + Exemestane (E/N=202/485) Placebo + Exemestane (E/N=157/239) Time (weeks) EVE + EXE: 6.9 months PBO + EXE: 2.8 months

44 BOLERO-2 Primary Endpoint: PFS Central Assessment 100 HR = 0.36 (95% CI: ) Log rank P value = 3.3 x Probability of Event (%) Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) Time (weeks) EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months

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

46 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

47 BOLERO-2: Most Common G3/4 AEs Everolimus + Exemestane (N = 482), % All Grades Grade 3 Grade 4 Placebo + Exemestane (N = 238), % All Grades Grade 3 Grade 4 Stomatitis Fatigue 33 3 < Dyspnea <1 Anemia 16 5 <1 4 <1 <1 Hyperglycemia 13 4 <1 2 <1 0 AST 13 3 < Pneumonitis

48 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

49 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

50 Deacetylation of Histones by HDAC Can Prevent Gene Expression HAT Acetylation by histone acetyltransferases (HATs) allows transcription and gene expression Transcription factors Ac HISTONE ACETYLATION Ac Deacetylated Histone Closed chromatin Transcription factors cannot access DNA HISTONE DEACETYLATION Ac Acetylated Histone Open chromatin Transcription factors can access DNA Deacetylation by histone deacetylases (HDACs) can prevent transcription and gene expression HDAC Ac: acetyl group HDAC depicts a class I deacetylase

51 Increased HDAC Activity In Tumor Cells, Imbalanced HAT and HDAC Activity Can Result in Deregulated Gene Expression Decreased HAT Activity HAT HDAC HDAC HDAC TF Ac Ac Decreased Tumor Suppressor Gene Activity (p21, p27) Unchecked Cell Growth and Survival Tumor Cell Ac: acetyl group TF: transcription factors HDAC depicts a class I deacetylase

52 HDAC Inhibition Restores Gene Expression in Tumor Cells HDAC HDAC HDAC DAC Inhibition Increases Acetylation of Histones HAT DAC Inhibitor Ac TF Ac Ac 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

53 Mecanismo de resistência aos inibidores de aromatase

54 Desenho do Estudo 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 Exemestano + Etinostat 5 mg PO week N=57 Exemestano + Placebo 5 mg PO week N=57 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)

55 Resultados

56 PFS Greatest in Exemestane+Entinostat in Subjets Who Hyperacetylate

57 Sobrevida Global

58 Eventos Adversos Mais Frequentes Exemestan0 + Placebo (N = 66), % Todos os Grau Grau 3 Grau 4 Exemestano + Entinostat (N = 63), % Todos os Graus Grau 3 Grau 4 Fadiga Náuseas Neutropenia Vômito Trombocitopenia Anemia Dispnéia

59 Take Home Message Inibidores da histona deacetilase (HDAC) são drogas promissoras na reversão da resistência à terapia hormonal

60 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+

61 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

62 OBRIGADA