Perfil de paciente para estratégia switch de hormonioterapia

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1 Perfil de paciente para estratégia switch de hormonioterapia Declaração de conflito de interesses ResoluçãoCFM n o 1595/2, 18/5/2 RDC ANVISA n o 12, 3/11/2 Daniele Assad Oncologista Clínica - Centro de Oncologia do Hospital Sírio Libanês Speaker Roche Speaker Pfizer Tratamento endócrino do câncer de mama Benefício de tamoxifen por 5 anos Em até 75% dos casos de câncer de mama, a sinalização de ER é um dos principais causadores da proliferação tumoral O tratamento endócrino adjuvante melhora significativamente os resultados do câncer de mama precoce com ER+ Cleator SJ et al. Clin Breast Cancer. 29;9(Suppl 1):S6 S17. EBCTCG 25 Lancet 25 1

2 Opções de terapia hormonal Mecanismos de ação Mecanismo Bloqueio do ER Supressão da síntese de estrogênio (mulheres na pósmenopausa) Ablação hormonal (mulheres na prémenopausa) Exemplos de modalidades terapêuticas Moduladores seletivos dos receptores de estrogênio (SERMs) Down-regulators seletivos dos receptores de estrogênio (SERDs) Inibidor / inativador da aromatase (AI) Análogos de LHRH, radiação, cirurgia Outros Andrógenos, progesterona Hayes DF et al. In: Robertson et al., eds. Endocrine Therapy of Breast Cancer. 22:3 1. Robertson JF. Clin Ther. 22;24(suppl A):A17 A3. Stephen R.D. Johnston; Nature Reviews. Cancer (Nov 23) Estudos com IA Metanálise de IA x TAM ATAC BIG 1-98/IBCSG Aromatase inhibitors as initial therapy a. postmenopausal ATAC: Arms: tamoxifen vsanastrozole vs combination BIG 1:-98: Arms: tamoxifen vs letrozole MA.27: Arms: anastrozole vs exemestane FACE: Arms: anastrozole vs letrozole b. Premenopausal ABCSG 12: Arms (all with goserelin, ± zoledronic acid): tamoxifen vs OFS + exemestane SOFT: Arms: tamoxifen vs ovarian function suppression (OFS) + tamoxifen vsofs + exemestane TEXT: Arms: OFS + tamoxifen vsofs + exemestane 2. Sequential use of aromatase inhibitors after < 5 years (usually 2-3 years) of tamoxifen vs tamoxifen for a total of 5 years of therapy IES: Arms (after 2-3 years of tamoxifen (5 years) vs tamoxifen (2 years) then anastrozole (3 years) ITA: Arms (after 2-3 yearsof tamoxifen): tamoxifen vs anastrozole ARNO 95: Arms (after 2 years of tamoxifen): tamoxifen vs anastroxole NSAS BC-3: Arms (after 1-4 years tamoxifen): tamoxifen vs exemestane 3. Sequencing of aromatase inhibitors and tamoxifen vs aromatase inhibitor monotherapy for a total of 5 years of therapy BIG 1-98: Arms: tamoxifen to letrozole and letrozole to tamoxifen, both compared with letrozole monotherapy TEAM: Arms: tamoxifen (2.5 to 3 years) then exemestane vsexemestane monotherapy 4. Aromatase inhibitors after about 5 years of tamoxifen MA. 17: Arms: letrozole vsplacebo (both for 5 years) NSABP B33: Arms: exemestane vs placebo (both for 5 years) ABCSG 6ª: Arms: anastrozole (3 years) vsobservation Later: Arms: letrozole vsplacebo (both for 5 years) 5. Duration of aromatase inhibitor therapy (after some period of aromatase inhibitor) NSABP B42: Arms: exemestane vs placebo (both for 5 years) MA. 17R: Arms: letrozole vsplacebo (both for 5 years) ABCSG 16: Arms: anastrozole for 3 yearsvsanastrozole for 5 years 6. Intermittent aromatase inhibitor therapy Sole: Arms: continuous letrozole vs intermittent letrozole Coorte 1: 9856 pacientes TAM 5 anos x IA 5 anos F/U 5.8 years Recaída SG Dowsett JCO 21 2

3 Metanálise de IA x TAM Coorte 2: 915 pacientes TAM 5 anos x TAM 2-3 anos switch IA Recaída Redução de 29% ARNO, IES/BIG 2-97, ITA, ABCSG VIII SG HR.79 (SE.7) reduction 2P =.4 Benefício em SG Visão geral dos estudos de swtich: benefício de sobrevida global Teste IES (Exemestano) 1-3 ARNO 95 (Anastrozol) 4 n Desenho Duplo-cego Aberto QT Sim (32%) Não Nodo + 48% 26% F/U 91 meses 3 meses HR DFS Benefício de sobrevidal global,82 (,73,92) p =,9,86 (,75,99) p =,4,66 (,44 1,) p =,49,53 (,28,99) p =,45 Dowsett JCO Coombes RC et al. Lancet. 27;369: ; 2. Coombes RC et al. N Engl J Med. 24; 35: ; 3. Bliss JM et al. J Clin Oncol. 212; 3: ; 4. Kaufmann M et al. J Clin Oncol. 27; 25: A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer Diagnosis of breast cancer and treatment for primary disease 2 3 yr of tamoxifen therapy Yr after start of tamoxifen therapy A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer 2362 were randomly assigned to switch to exemestane, and 238 to continue to receive tamoxifen. Disease-free Survival Overall Survival Yr after randomization 183 First events 8.4% of patients continue to Randomization receive treatment 2-3 absolutebenefitin termsofdisease-free survivalof4.7 percent Overall survival was not significantly different 2 3 Yr of tamoxifen therapy n= Yr of exemestane therapy n= First events 8.6% of patients continue to receive treatment 183 First events 8.4% of patients continue to receive treatment 5 Exemestane therapy after two to there years tamoxifen therapy significantly improved disease=free survival compared with the standard five years of tamoxifen treatment. Coombes NEJM 24 follow-up of 3.6 months Coombes NEJM 24 3

4 A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer Subgroup Analysis of Disease-free Survival Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study Subgroup (no.) Favors Exemestane Favors Tamoxifen Hazard Ratio Hormone-receptor status Estrogen-receptor positive (3853).64 (.52.79) Progesterone-recept or positive (2619).66 (.51.87) Progesterone-receptor negative (735).58 (.38.9) Progesterone-receptor status unknown (499).67 ( ) Estrogen-receptor status negative or unknown (889).85 ( ) Nodal status Negative (2422).68 (.48.95) 1 3 Positive nodes (1421).71 (.51.98) 4 Positive nodes (651).58 (.42.81) Previous hormone-replacement therapy Yes (1124).63 (.4.99) No (347).69 (.56.85) Previous chemotherapy Yes (1531).69 (.51.92) No (3171).67 (.52.86) All patients (4742) (.56.82) median follow-up was 91 months Hazard Ratio (log scale) Coombes NEJM 24 Bliss, JCO 212 Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study Events by Treatment Group in the ER-Positive/ER-Unknown Population Death from other know cause Other cancer Vascular Cardiac Other ER-Positive/ER-Unknown Population Exemestane (n = 2,294) Tamoxifen (n = 2,35) Total (N = 4,599) Conclusion No. % No. % No. % The protective effect of switching to exemestane Overall survival compared with continuing on tamoxifen on risk of Breast cancer death relapse or death was maintained for at least 5 Death from unknown cause years post-treatment and was associated with a continuing beneficial impact on overall survival Bliss, JCO 212 Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 81 years median follow-up A B A B C D T wo-arm option (1998 2) T amoxifen Letrozole T amoxifen Letrozole Four-arm option ( ) T amoxifen Letrozole Letrozole Tamoxifen Years Trial profile n=911 n=917 n=1548 n=1546 n=1548 n=154 n=1828 n=6182 Sequential treatment analysis n=4922 Monotherapy analysis n=81 Regan, Lancet 211 4

5 Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 81 years median follow-up Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 81 years median follow-up Sequential treatment analysis follow-up of 8.1 years Regan, Lancet 211 Interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient s risk of recurrence and treatment tolerability. Regan, Lancet 211 Toxicidades Josefsson. The Breast 21; 19:

6 Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study Visita (meses desde a randomização) Coluna Lombar EOT EOT+12 EOT+24 -,29 -,179-2,689-3,147 -,622 -,925-3,933-4,166-2,774-2,637-3,132-3, EOT EOT+12 EOT+24 -,18-1,359 Quadril Visita (meses desde a randomização) -,179 -,994-1,531-2,34-2,882-2,976-3,11-3,132-2,989-3, Exemestano Tamoxifeno 26 patients Josefsson. The Breast 21; 19: Coleman RE et al. Breast Cancer Res Treat. 21; 124: (Exemestane[E] = 11, Tamoxifen[T] = 15) Transição entre os estados normal, osteopenia e osteoporose 24m após fim do tratamento IES: Eventos ginecológicos Evento Ginecológico grave (incluindo a histerectomia e D&C uterina) Sangramento vaginal Favorece o exemestano População Chave Todas Durante Após Favorece o tamoxifeno E%* v T%**; valor p 6,8 v 1,4; <,1 4,9 vs 7,2;,1 Hiperplasia endometrial / pólipos e miomas uterinos,2,4,8 1, 1,7 Razão de possibilidade (99% de CI) 1,5 v 3,9; <,1 Coleman, Breast Can Res Treat 21 *N = 2319 **N = 2338 p/ sangramento vaginal; *N = 238 **N = 259 para outros eventos Coombes RC et al. ECCO15/ESMO Resumo

7 Relação entre eventos adversos e a eficácia do exemestano Ondas de calor: HR,39, 95% de CI,19,81 p =,12 Músculo-esqueletico: HR,68, 95% de CI,39 1,17 p =,16 Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation Ferramentas usadas: FACT-B trimestralmente por um ano ES semestralmente por 5 anos 582 pacientes de oito países Conformidade de 84,5% com o questionário Meta primária: O índice de resultado de teste (TOI), que é a soma da subescala referente a preocupações físicas, funcionais e do câncer de mama. Fontein DB et al. Ann Oncol. 212; 23: QoL qualidade de vida Fallowfield LJ et al. Br J cancer. 212; 16: Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation Mean change from baseline Exemestane Tamoxifen End of treatment Mean change from baseline TOI scores within treatment groups. Sem diferença QOL Months from randomisation Fallowfield British Journal of Cancer, 212 IAs e Tamoxifeno Riscos e benefícios potenciais Câncer de mama contra-lateral Risco de osteoporose Mialgia Hiperlipidemia Tamoxifeno Neurocognição Função sexual Doença cardiovascular Ondas de calor Tromboembolias Câncer endometrial Efeitos adversos no trato geniturinário Câncer de mama contra-lateral Trombose venosa profunda Câncer endometrial Ondas de calor AI Artralgia / mialgia Risco de osteoporose Riscos cardiovasculares? Burstein HJ et al. J Clin Oncol. 21; 28: Amir E et al. J natl Cancer Inst. 211; 13: Phillips KA et al. Breast Cancer Res. 211; 13: 23 7

8 Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials Lancet 215; 386: Lancet 215; 386: HT pós menopausa: Algoritmo da ASCO Considerações finais Journal of Clinical Oncology, Vol31, No 11 (April 1), 213: pp