Sequenciamento hormonal na doença metastática na mulher pós-menopáusica.

Transcrição

1 Sequenciamento hormonal na doença metastática na mulher pós-menopáusica. Sergio D Simon Hospital Israelita Albert Einstein Centro Paulista de Oncologia(CPO)

2 Câncer de Mama RH+/HER2 avançado Tratamento após progressão em primeira linha Inibidorda Aromatase Progressão em tratamento adjuvante em adjuvância/doença metastática Resistência Endócrina Fulvestranto 500 mg Everolimo + exemestano Quimioterapia Apenaspara pacientescom necessidadede rápido controle NCCN 1 ABC-1 2 Atualização do ABC2 3 Recomenda 3 tratamentos endócrinos consecutivos antes de encaminhar a paciente para quimioterapia NÃO SIM Sem consenso após IA inicial. Opções incluem: Tamoxifeno Outro IA Fulvestranto Acetato de Megestrol Primeira linha recomendada é IA ou TAM, dependendo do tipo e duração da adjuvância. Fulvestranto é também uma opção. *Guidelines refer to postmenopausal HR+ advanced breast cancer, and recommend endocrine therapy for patients who are not in visceral crisis. The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis. 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V ; 2. Cardoso F, et al. Breast. 2012;21(3): ; 3. Cardoso F, et al. Ann Oncol. 2014;25(10):

3 OPÇÕESDE HORMONIOTERAPIA EMPRIMEIRALINHA

4 Estudo FIRST Randomização (1:1), Fase II, aberto, de primeira linha, RH+, pós-menopausa com câncer de mama avançado (N=205), sem tratamento prévio Fulvestranto 500 mg (500 mg i.m. nos Dias 0, 14 e 28 e a cada 28 dias a partir de então) N=102 Progressão Acompanhamento Anastrozol 1 mg (1 mg p.o. diariamente) N=103 Progressão Acompanhamento Desfecho primário Taxa de benefício clínico Desfechos secundários Tempo até a progressão Taxa de resposta objetiva Duração da resposta Duração do benefício clínico Segurança Desfechos exploratórios Melhor resposta para a terapia subsequente Resultado clínico subsequente em participantes da pesquisa que demonstrarem alterações nos marcadores tumorais séricos Robertson JFR et al. J Clin Oncol 2009; 27: Proprietary and Confidential AstraZeneca 2012 FOR INTERNAL USE ONLY

5 Tempo até a progressão (conjunto de análise completo) Proporção de 1,0 participantes da Fulvestranto 500 mg Anastrozol 1 mg pesquisa vivos e 0,8 livres de progressão HR = 0,66; 95% IC: 0,47, 0,92; p=0,01 0,6 0,4 0,2 0, Tempo (meses) Participantes da pesquisa em risco: Fulvestranto 500 mg Anastrozol 1 mg Após o primeiro corte dados primário, a progressão foi determinada por parecer do investigador Adaptado de: Robertson JFR et al. Cancer Res 2010; 70 (Suppl 2): abstract S1-3 O estudo FIRST é um estudo de Fase II e fulvestranto não é indicado nesta população de participantes da pesquisa Exclusivo Proprietary e Confidencial and Confidential AstraZeneca AstraZeneca 2012 EXCLUSIVO 2012 FOR PARA INTERNAL USO USE INTERNO ONLY 0 0

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7 FALCON: Ongoing Confirmatory Phase 3 Study of Fulvestrant in First-Line MBC Phase 3 randomized, double-blind, parallel-group study ELIGIBILITY CRITERIA Postmenopausal women with ER+ and/or PR+ ABC No prior ET for advanced disease 1 lesion suitable for repeated assessment N=450* 1:1 RANDOMIZATION Fulvestrant 500 mg + Anastrozole placebo PO, QD Anastrozole 1 mg PO, QD + Fulvestrant placebo Primary endpoint: PFS Secondary endpoints: OS, ORR, DOR, CBR *Estimated enrollment. ABC=advanced breast cancer; CBR=clinical benefit rate; DOR=duration of response; ER=estrogen receptor; ET=endocrine therapy; ORR=objective response rate; OS=overall survival; PO=by mouth; PR=progesterone receptor; PFS=progression-free survival; QD=every day. 1. ClinicalTrials.gov. NCT Accessed April 17, 2015.

8 FALCON: KEY INCLUSION / EXCLUSION CRITERIA Postmenopausal women with histologically confirmed ER+ and / or PgR+, HER2- locally advanced or metastatic breast cancer WHO performance status measurable and / or non-measurable lesion(s) Key exclusion criteria: Prior endocrine treatment for breast cancer Systemic estrogen-containing hormone-replacement therapy use 6 months prior to randomisation Presence of life-threatening metastatic visceral disease Prior systemic treatment for breast cancer except one line of chemotherapy, radiotherapy completed 28 days prior to randomisation (except radiotherapy for control of bone pain) Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

9 FALCON: BASELINE PATIENT CHARACTERISTICS Fulvestrant (N=230) Anastrozole (N=232) Median age, years (range) 64.0 (38 87) 62.0 (36 90) Race, n (%) White 175 (76.1) 174 (75.0) Any prior chemotherapy, n (%) 79 (34.3) 81 (34.9) Advanced disease 36 (15.7) 43 (18.5) Adjuvant / neoadjuvant 35 / 11 (15.2/ 4.8) 27 / 16 (11.6/ 6.9) WHO performance status, n (%) 0 / 1 / / 106 / 7 (50.9/ 46.1 / 3.0) 115 / 105 / 12 (49.6/ 45.3 / 5.2) Receptor status, n (%) ER+ / PgR+ 175 (76.1) 179 (77.2) ER+ / PgR- 44 (19.1) 43 (18.5) ER+/ PgR unknown 10 (4.3) 7 (3.0) ER-/ PgR+ 1 (0.4) 3 (1.3) ER-/ PgR- 0 0 Overall disease classification, n (%) Locally advanced disease 28 (12.2) 32 (13.8) Metastatic disease 202 (87.8) 200 (86.2) Visceral disease, n (%) 135 (58.7) 119 (51.3) Measurable disease, n (%) 193 (83.9) 196 (84.5) Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

10 FALCON: PRIMARY ENDPOINT: PFS Proportion of patients alive and progression free HR (95% CI 0.637, 0.999); p= Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months Number of patients at risk: Time (months) Fulvestrant Anastrozole Fulvestrant (n=230) Anastrozole (n=232) A circle represents a censored observation Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

11 FALCON: FOREST PLOT FOR PFS BY PATIENT SUBGROUP All patients Breast cancer type Locally advanced Metastatic Prior chemotherapy Yes No Geographic region US and Canada Non-US or Canada Asia Non-Asia Measurable disease Measurable Non-measurable ER+ and PgR+ at baseline Yes No Prior systemic estrogen containing HRT Yes No Bisphosphonate use at baseline Yes No Visceral disease Yes No HR (95% CI) Number of patients with event Fulvestrant Anastrozole 143 / 230 (62.2%) 11 / 28 (39.3%) 132 / 202 (65.3%) 31 / 36 (86.1%) 112 / 194 (57.7%) 16 / 25 (64.0%) 127 / 205 (62.0%) 19 / 34 (55.9%) 124 / 196 (63.3%) 124 / 193 (64.2%) 19 / 37 (51.4%) 103 / 175 (58.9%) 40 / 55 (72.7%) 3 / 3 (100.0%) 140 / 227 (61.7%) 44 / 61 (72.1%) 99 / 169 (58.6%) 92 / 135 (68.1%) 51 / 95 (53.7%) 166 / 232 (71.6%) 14 / 32 (43.8%) 152 / 200 (76.0%) 33 / 43 (76.7%) 133 / 189 (70.4%) 19 / 24 (79.2%) 147 / 208 (70.7%) 22 / 33 (66.7%) 144 / 199 (72.4%) 143 / 196 (73.0%) 23 / 36 (63.9%) 127 / 179 (70.9%) 39 / 53 (73.6%) 3 / 5 (60.0%) 163 / 227 (71.8%) 53 / 62 (85.5%) 113 / 170 (66.5%) 87 / 119 (73.1%) 79 / 113 (69.9%) HR (95% CI) (0.637, 0.999) (0.360, 1.731) (0.621, 0.991) (0.659, 1.771) (0.585, 0.967) (0.338, 1.304) (0.640, 1.029) (0.438, 1.501) (0.622, 1.005) (0.599, 0.971) (0.534, 1.818) (0.561, 0.944) (0.669, 1.621) NC (0.622, 0.977) (0.455, 1.032) (0.626, 1.073) (0.740, 1.331) (0.419, 0.837) Global interaction test p=0.106 NC, not calculable Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

12 FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE Proportion of patients alive and progression-free HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Without visceral disease Fulvestrant (n=95) Anastrozole (n=113) Proportion of patients alive and progression-free HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months With visceral disease Fulvestrant (n=135) Anastrozole (n=119) Time (months) Time (months) Post hoc interaction test p<0.01 A circle represents a censored observation Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

13 FALCON: OS (31% MATURITY) Fulvestrant (N=230) Anastrozole (N=232) 0.8 Proportion of patients alive Number of patients at risk: Fulvestrant Anastrozole HR 0.88 (95% CI 0.63, 1.22); p= Time (months) Median follow up 25.0 months A circle represents a censored observation Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

14 FALCON: SECONDARY ENDPOINTS Endpoint Fulvestrant (N=230) Anastrozole (N=232) ORR a 46.1% (89 / 193) CBR 78.3% (180 / 230) a In patients with measurable disease at baseline 44.9% (88 / 196) 74.1% (172 / 232) Odds ratio(95% CI) 1.07 (0.72, 1.61); p=0.729 Odds ratio(95% CI) 1.25 (0.82, 1.93); p=0.305 Median DoR 20.0 months 13.2 months - Median DoCB 22.1 months 19.1 months - EDoR 11.4 months 7.5 months EDoCB 21.9 months 17.5 months Median time to deterioration in FACT- B total score 13.8 months 11.1 months Ratio (95% CI) 1.52 (1.23, 1.89); p<0.001 Ratio (95% CI) 1.26 (1.13, 1.39); p<0.001 HR (95% CI) 0.84 (0.66, 1.07); p=0.159 Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

15 FALCON: AEs IN ANY CATEGORY (SAFETY ANALYSIS POPULATION) AE category Fulvestrant (N=228) Number (%) of patients Anastrozole (N=232) SAEs 30 (13.2) 31 (13.4) Consideredrelated to treatment 4 (1.8) 3 (1.3) Discontinuations due to AEs 16 (7.0) 11 (4.7) AEs Grade 3 or worse 51 (22.4) 41 (17.7) Deaths due to AEs 6 (2.6) 7 (3.0) Considered related to treatment 0 0 Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

16 FALCON: CONCLUSIONS The Phase III FALCON study met its primary endpoint Statistically significant improvement in PFS for fulvestrant vs. anastrozole The primary analysis was supported by secondary efficacy endpoints Treatment effects were largely consistent across pre-specified patient subgroups, with the largest treatment effect seen in patients without visceral disease The AE profile was generally consistent with known profiles Overall, HRQoL was maintained and was similar in both treatment groups These results are consistent with data from the FIRST study and confirm that fulvestrant is more efficacious than anastrozole in postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have not received prior endocrine therapy Presented at the European Society for Medical Oncology (ESMO) 2016 Congress; October 7-11, 2016; Copenhagen, Denmark.

17 Molecular Targets in Advanced Breast Cancer HR+ HER2 neg 1-5 Estradiol Aromatase inhibitors Growth factor receptor (eg, EGFR) Estrogen receptor downregulator SOS GRB2 Shc PI3K Ras Raf Src p53 ER AKT MEK CDK4/6 p21 mtor Cyclin D p16 P P MAPK CDK4/6 P ER P CoA P P ER CoA AP-1 TFs P CoA P P P Rb E2F P P Cyclin D E2F M G1 Cell cycle G2 S EREs AP-1/SP-1 TFs-REs Gene transcription Data from 1. Yardley DA, et al. ASCO BC 2011, Abstract 268; 2. Osborne CK, et al. Annu Rev Med. 2011;62: ; 3. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 4. Zardavas D, et al. Nat Rev Clin Oncol. 2013;10(4): ; 5. Infante JR, ASCO 2014, Abstract

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19 Paloma1: Progression-free Survival PFS 20.2 months 10.2 months

20 Paloma1: Progression-free Survival by cohort

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23 PALOMA-2: Phase III Study Design in Postmenopausal Patients with ER+, HER2 Advanced Breast Cancer Postmenopausal ER+, HER2 advanced breast cancer No prior systemic treatment for advanced disease Prior (neo)adjuvant treatment with anastrozoleor letrozolewas allowed if the disease free interval was 12 months from completion of therapy Measurable disease according to RECIST v1.1 or boneonly disease ECOG PS 0 2 Adequate organ function No advanced, symptomatic visceral spread at risk of short-term life-threatening complications N=666 a Phase III, randomized, double-blind trial at 186 centers in 17 countries Palbociclib (125 mg QD, 3/1 schedule b ) + letrozole (2.5 mg QD) Placebo (3/1 schedule) + letrozole (2.5 mg QD) Treatment continued until objective disease progression, unacceptable toxicity, or withdrawal of consent. Crossover was not allowed Palbociclib/placebo dose reductions were allowed per protocol. Letrozole dose reductions were not permitted 2:1 RANDOMIZATION a Randomization stratified by disease site (visceral/non-visceral), disease-free interval, and prior (neo)adjuvant hormonal therapy. ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER+, estrogen receptor-positive; HER2, human epidermal growth factor receptor 2- negative; NSAI, non-steroidal aromatase inhibitor; QD, once a day; RECIST, Response Evaluation Criteria In Solid Tumors b 3 weeks on/1 week off of a 4-week cycle 23 clinicaltrials.gov NCT ; Finn RS, et al. N EnglJ Med 2016 Nov 17;375(20):

24 PALOMA-2: Demographics and Baseline Characteristics (ITT Palbociclib + letrozole Placebo + letrozole Population) (N=444) (N=222) Age, n (%) Median (range) 62 (30 89) 61 (28 88) <65 years 263 (59.2) 141 (63.5) 65 years 181 (40.8) 81 (36.5) Race, n (%) White 344 (77.5) 172 (77.5) Asian 65 (14.6) 30 (13.5) Black 8 (1.8) 3 (1.4) Other 27 (6.1) 17 (7.7) ECOG PS, n (%) (57.9) 102 (45.9) (40.1) 117 (52.7) 2 9 (2.0) 3 (1.4) Disease site, n (%) Visceral a 214 (48.2) 110 (49.5) Non-visceral 230 (51.8) 112 (50.5) Bone-only 103 (23.2) 48 (21.6) No. of disease sites (31.1) 66 (29.7) (26.4) 52 (23.4) (25.2) 61 (27.5) 4 77 (17.3) 43 (19.4) Disease-free interval, b n (%) Newly metastatic disease 167 (37.6) 81 (36.5) 12 months 99 (22.3) 48 (21.6) >12 months 178 (40.1) 93 (41.9) a Visceral disease was defined as: any lung (including pleura) and/or liver involvement b Timesince completion of (neo)adjuvant therapy and onset of recurrence; percentage calculated based on number of patients who received (neo)adjuvant therapy Patients who progressed while receiving or 12 months from completion of prior anastrozoleor letrozole were excluded Finn RS, et al. N EnglJ Med 2016 Nov 17;375(20):

25 PALOMA-2: Demographics and Baseline Characteristics (ITT Palbociclib + letrozole Population) (N=444) Placebo + letrozole (N=222) Disease stage at initial diagnosis, n (%) I 51 (11.5) 30 (13.5) II 137 (30.9) 68 (30.6) III 72 (16.2) 39 (17.6) IV 138 (31.1) 72 (32.4) Unknown 36 (8.1) 12 (5.4) Other or data missing a 10 (2.3) 1 (0.5) Recurrence type, n (%) Locoregional 2 (0.5) 2 (0.9) Loca 6 (1.4) 3 (1.4) Regional 3 (0.7) 1 (0.5) Distant 294 (66.2) 145 (65.3) Newly diasgnosed 139 (31.3) 71 (32.0) Prior neoadjuvant therapy, n (%) Chemotherapy 213 (48.0) 109 (49.1) Neoadjuvant 54 (12.2) 32 (14.4) Adjuvant 180 (40.5) 89 (40.1) Adjuvant hormonal therapy b 249 (56.1) 126 (56.8) Tamoxifen 209 (47.1) 98 (44.1) Anastrozole 56 (12.6) 29 (13.1) Letrozole 36 (8.1) 16 (7.2) Exemestant 30 (6.8) 13 (5.9) Goserelin 5 (1.1) 6 (2.7) Toremifene 7 (1.6) 1 (0.5) Other 3 (0.7) 4 (1.8) a Other was an option for the site to select on the clinical report form if none of the other available options were applicable; data missing means that the site did not complete that field because the information was not available. b Patientswho received anastrozole or letrozole as a component of their adjuvant or neoadjuvant therapy were excluded from the study if they had disease progression while receiving the therapy or within 12 months after completing thetherapy. Finn RS, et al. N EnglJ Med 2016 Nov 17;375(20):

26 PALOMA 2 PFS Subgroup Analysis (ITT, Investigator Assessment) Subgroup n (%) Hazard Ratio (95% CI) All randomized patients 666 (100) ( ) Age <65 y 404 (60.7) ( ) 65 y 262 (39.3) ( ) Race White 516 (77.5) ( ) Asian 95 (14.3) ( ) Site of metastatic disease Visceral Nonvisceral 324 (48.6) 342 (51.4) ( ) ( ) Prior hormonal therapy Yes 375 (56.3) ( ) No 291 (43.7) ( ) Disease-free interval De novo metastases 12 months >12 months 248 (37.2) 147 (22.1) 271 (40.7) ( ) ( ) ( ) Region ECOG performance status Bone-only disease at baseline Measurable disease Prior chemotherapy Most recent therapy Number of disease sites North America Europe Asia/Pacific 0 1/2 Yes No Yes No Yes No Aromatase inhibitor Antiestrogen (40.1) 307 (46.1) 92 (13.8) 359 (53.9) 307 (46.1) 151 (22.7) 515 (77.3) 509 (76.4) 157 (23.6) 322 (48.3) 344 (51.7) 135 (20.3) 229 (34.4) 204 (30.6) 462 (69.4) In favor of PAL+LET In favor of PCB+LET ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Confidential. Pfizer Inc. Do Not Distribute. Finn RS, et al. N Engl J Med 2016 Nov 17;375(20):

27 PALOMA-2: PFS Let+ Palb= 24.8 m Let = 14.5 m Let+ Palb= 30.5 m Let = m Finn R et al. NEJM, Nov17, 2016

28 MONALEESA-2

29 Kaplan Meier Analysis of Progression-free Survival. Hortobagyi GN et al. N Engl J Med 2016;375:

30 OPÇÕESDE HORMONIOTERAPIA EMSEGUNDALINHA

31 Molecular Targets in Advanced Breast Cancer HR+ HER2 neg 1-5 Estradiol Aromatase inhibitors Growth factor receptor (eg, EGFR) Estrogen receptor downregulator SOS GRB2 Shc PI3K Ras Raf Src p53 ER AKT MEK CDK4/6 p21 mtor Cyclin D p16 P P MAPK CDK4/6 P ER P CoA P P ER CoA AP-1 TFs P CoA P P P Rb E2F P P Cyclin D E2F M G1 Cell cycle G2 S EREs AP-1/SP-1 TFs-REs Gene transcription Data from 1. Yardley DA, et al. ASCO BC 2011, Abstract 268; 2. Osborne CK, et al. Annu Rev Med. 2011;62: ; 3. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 4. Zardavas D, et al. Nat Rev Clin Oncol. 2013;10(4): ; 5. Infante JR, ASCO 2014, Abstract

32 BOLERO-2: Phase III dtudy of Exemestane ± Everolimus in patients with ABC progressing after NSAIs N = 724 PMW with HR+, HER2 ABC refractory to LET or ANA, defined as Recurrence during or within 12 months after end of adjuvant treatment, or Progression during or within 1 month after end of treatment for advanced disease Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Placebo + Exemestane 25 mg/day (n = 239) Stratification 1. Sensitivity to prior endocrine therapy 2. Presence of visceral disease No crossover Primary endpoint PFS Secondary endpoints OS, ORR, CBR, safety, QOL, bone markers NSAI, nonsteroidal aromatase inhibitor. Baselga J, et al. N Engl J Med. 2012;366(6):

33 BOLERO-2: PFS at 18 Months / Median FUP 55% reduction in the risk of progression or death (local analysis) 62% reduction in the risk of progression or death (central analysis) 33 Probability (%) of Event HR = 0.45 (95% CI = 0.38, 0.54) Log-rank P value: <.0001 Everolimus + Exemestane: 7.8 mo Placebo + Exemestane: 3.2 mo Probability (%) of Event HR = 0.38 (95% CI = 0.31, 0.48) Log-rank P value: <.0001 Everolimus + Exemestane: 11.0 mo Placebo + Exemestane: 4.1 mo Time, wk Number of patients still at risk EVE+EXE PBO+EXE Local Assessment Time, wk Number of patients still at risk EVE+EXE PBO+EXE Central Assessment (independent blind radiology committee) Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival.. Piccart M, et al. ASCO 2012; abstract 559 (poster). Yardley DA, et al. Adv Ther. 2013;30:

34 Beck, JT, Breast Can Res Treat, 2014

35 Abstract LBA502 <br /><br /> A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2- negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy<br />(PALOMA3 Study) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

36 PALOMA3 Study Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting

37 Study Endpoints Presented By Nicholas Turner at 2015 ASCO Annual Meeting

38 Treatment Summary Presented By Nicholas Turner at 2015 ASCO Annual Meeting

39 Adverse Events All Cause Presented By Nicholas Turner at 2015 ASCO Annual Meeting

40 Primary Endpoint: PFS (ITT Population) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

41 PFS: Central Blinded Review Audit (n=211) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

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43 Conclusions Presented By Nicholas Turner at 2015 ASCO Annual Meeting

44 Câncer de Mama RH+/HER2 avançado Tratamento após progressão em primeira linha Inibidorda Aromatase FULVESTRANTO Progressão em500 tratamento adjuvante em LETROZOL+PALBOCIBLIBE adjuvância/doença metastática Resistência Endócrina Fulvestranto 500 mg Everolimo + exemestano Quimioterapia Apenaspara pacientescom necessidadede rápido controle NCCN 1 ABC-1 2 Atualização do ABC2 3 Recomenda 3 tratamentos endócrinos consecutivos antes de encaminhar a paciente para quimioterapia NÃO SIM Sem consenso após IA inicial. Opções incluem: Tamoxifeno Outro IA Fulvestranto Acetato de Megestrol INIBIDOR DA AROMATASE FULVESTRANTO PALBOCIBLIBE Primeira linha recomentada é IA ou TAM, dependendo do tipo e duração da adjuvância. Fulvestranto é também uma opção. *Guidelines refer to postmenopausal HR+ advanced breast cancer, and recommend endocrine therapy for patients who are not in visceral crisis. The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis. 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V ; 2. Cardoso F, et al. Breast. 2012;21(3): ; 3. Cardoso F, et al. Ann Oncol. 2014;25(10):

45 Sequenciamento hormonal na pós-menopausa: Conclusões Manejo padrão no Brasil ainda é de inibidor de aromatase em primeira linha. Fulvestranto 500 é melhor opção para pacientes sem nenhum tratamento prévio. Letrozol + Palbociclibe é melhor opção para pacientes com tratamento adjuvante prévio Fulvestranto + Palbociclibe e Exemestano-Everolimo (BOLERO-2) são opções apropriadas após progressão com IA não há comparação direta entre os 2 esquemas. Tamoxifeno, inibidor de aromatase, acetato de megestrol, continuam como opções para linhas subsequentes. O cenário estará mudando nos próximos anos, com chegada de novas drogas.

46 O futuro do tratamento da doença RH+ Estrogen Letrozol Anastrozol Exemestano Buparlisibe Taselisibe Alpelisibe Lucitanibe Growth Factor Signaling Fulvestranto GDC0810 Entinostat Everolimo Palbociclibe Ribociclibe Abemaciclibe Yamamoto-Ibrusuki, M, et al. BMC Medicine. 2015;12:137.