Quimioterapia Adjuvante. Fatores Atuais de Decisão

Transcrição

1 Quimioterapia Adjuvante. Fatores Atuais de Decisão Dr Antonio C. Buzaid Chefe Geral

2 Breast Cancer Subtypes ER-/PR-/HER2-: Largely overlaps with Basaloid Type ER+ and PR+/HER2-/low Ki67: Largely overlaps with Luminal A ER+ and/or PR+/HER2+ or neg/high Ki67: Mostly Luminal B tumors ER-/PR-/HER2+: Mostly HER2-type

3 Recurrence (%) EBCTCG 2012: Recurrence Rate Chemo vs no Chemo 8575 women: any anth-based regimen (82% N+) 34.6% 26.1% No CTX 47.4% 39.4% Anthracycline 5253 women: standard CMF (or near-standard CMF) (34% N+) 30.2% 20.3% No CTX 39.8% 29.6% CMF 10 0 RR 0.73 (95%CI ) Log-rank 2P< year gain 8.0% (SE 1.2) Recurrence (%/year) and log-rank analyses RR 0.70 (95%CI ) Log-rank 2P< year gain 10.2% (SE 1.4) Recurrence rates (%/year) and log-rank analyses Allocation Years 0-4 CTX 6.14 (1179/19190) No CTX 9.06 (1259/13899) Rate ratio 0.69 SE 0.04 (0-E)/V /489.8 Years (487/11981) 4.56 (365/8011) 0.89 SE /174.7 Years (161/5530) 3.87 (159/4104) 0.72 SE /65.5 Years (549/11357) 7.20 (748/10385) 0.61 SE /277.0 Years (207/8038) 2.93 (210/7158) 0.84 SE /95.9 Years (116/6155) 1.90 (100/5260) 0.99 SE /48.7

4 Meta-analysis of the EBCTCG 2012 COMPARISONS HR of death 2P value Adding 4 cycles of a taxane to a fixed anthracycline (e.g AC X 4 - Taxane vs AC X 4) Adding a taxane compared with an equivalent # of anthracycline cycles (e.g FEC X 8 vs AC X 4 T X 4) AC X 4 equivalent to CMF X CAF or CEF X 6 cycles superior to CMF CAF X 6 vs no chemo AC X 4 vs no chemo EBCTCG. The Lancet 379:432, 2012

5 Meta-analysis of the EBCTCG 2012 In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. EBCTCG. The Lancet 379:432, 2012

6 Impacto da Terapia Adjuvante 100 Sobrevida Livre de Doença % Sem benefício Benefício com terapia Anos Sobrevida Terapia não necessária % Sem benefício Benefício com terapia Terapia não necessária Anos

7 Percentage of Patients that Accept Chemothehrapy % of Patients that Accept Chemo Coates Ravdin Lindley Percent Gain of Overall Survival

8 RiskReductionof30% ofdeath Lymph Node Positivo 50% risk of death Nº de Pacientes Adj. Obs. %OS at 5 year Adj. Obs. % absolute difference Nº total Nº of death (325/500) (250/500) (65-50) (0.7 X 250) Lymph Node Neg - 10% risk of death Nº total Nº of death (465/500) (450/500) (93-90) (0.7 X 50)

9 Tests that Help Determine Prognosis and Chemo Benefit OncotypeDx Risk of recurrence in the presence of adjuvant tamoxifen Chemo benefits only high risk Mammaprint Risk of recurrence with NO therapy (natural history) Chemo not necessary for low risk

10 Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC BAG1 RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0 100) Low risk RS < 18 Intermed risk RS 18 and < 31 High risk RS 31 Paik S, NEJM 351(27):2817, 2004

11 DRFS B-14 Benefit of Tam vs Placebo By Oncotype-DX Recurrence Score Risk Low risk (RS<18) Int risk (RS 18-30) 0.4 DRFS Placebo Tamoxifen Years Placebo Tamoxifen Years DRFS High risk (RS 31) Placebo Tamoxifen Years Paik S, et al. E Engl J Med 351:2817,

12 DRFS B-20: Tam alone vs. Tam + Chemotherapy in Node Negative ER+ P = 0.76 Low risk patients (RS < 18) Tam + Chemo Tam By Oncotype-DX Recurrence Score Risk Low risk (RS<18) Intermediate risk (RS = 18-30) N Events Years DRFS DRFS High risk (RS 31) P = Int Risk Patients (RS 31) Tam + Chemo Tam Years N P = 0.71 Int Risk (RS 18-30) Tam + Chemo Tam N Events Years Events Paik et al. J Clin Oncol. 2006;24:

13 Oncotype DX TransATAC LN- LN+, ER+ Anastrozol vs Tamoxifeno N=1231 blocos disponíveis para RS do Oncotype DX 872 N0, 306 N+, 53 N desconhecido Dowsett et al., J Clin Oncol 28:

14 Sobrevida Livre de Meta à Distância Linfonodo Negativo, Ambos os Braços n=872 9 anos SLMD Logrank p<0.001 Baixo Interm Alto N (%) Eventos 513 (59%) (26%) (15%) 28 Grupo IR HR* 95%CI Alto vs Baixo 5.2 ( ) Int vs Baixo 2.5 ( ) 96% 88% 75% Anos Dowsett et al., J Clin Oncol 28: *Hazard ratio para grupo IR ajustado para tamanho do tumor, grau, idade e tratamento

15 Sobrevida Livre de Meta à Distância Linfonodo Positivo, Ambos os Braços Logrank p<0.001 n=306 9 anos 83% 72% 51% SLMD Baixo Int Alto N (%) 160 (52%) 94 (31%) 52 (17%) Eventos Grupo IR HR* 95%CI Alto vs Baixo 2.7 ( ) Int vs Baixo 1.8 ( ) Dowsett et al., J Clin Oncol 28:1829,2010 anos *Hazard ratio para grupo IR ajustado para tamanho do tumor, grau, idade e tratamento

16 Sobrevida Livre de Meta à Distância de Acordo com Número de LNDs+ e RS Predicted 9-year risk of distant recurrence Mean 95% CI Predicted score 4+ positive Nodes n = 63; 31 events 1-3 positive Nodes n = 243; 43 events Node Negative n = 872; 72 events Dowsett et al., J Clin Oncol 28:

17 Intergroup TAILORx Trial Trial Assigning IndividuaLized Options for Treatment LND neg ER+ e/ou PR+ HER2 neg (IHC 0-1+ or FISH [-]) Oncotype DX Assay RS < 11 HT* (Braço A) (29%) RS Randomiza HT* (Braço B) vs. QT+ HT* (Braço C) (44%) RS > 25 QT+ HT* (Braço D) (27%) *Escolha de terapia a critério do investigador Total de pts

18 Sugestão de Quando Pedir Oncotype DX em Paciente N0 Carcinoma invasivo RE+, HER-2 neg, N0 Grau de Nottingham Grau 1 Grau 2 Grau 3 RP alto* e Ki67 <10% RP baixo RP alto RP baixo e Ki67 >10% Tratar como RS baixo Mandar para Oncotype DX Tratar como RS alto *Allred > 5 Allison et al. Breast Cancer Res Treat 131:413, 2012

19 Mammaprint: Good and Poor Signature Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25):

20 Mammaprint: Node Negative Patients Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25):

21 Mammaprint: Node Positive Patients Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25):

22 TRANSBIG - Validation Probability N=307 LN negativo, Sem tratamento adjuvante Patients Events Risk group Genetic low risk Genetic high risk SV10a = 88% (81%-95%) SV10a = 71% (63%-78%) Year GLR GHR Number at risk Marc Buyse, et al, J Natl Cancer Inst 2006; 98:1183

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24 EORTC-BIG MINDACT: Desenho do estudo n = mulheres LN negativo Avaliação do risco Clínico-Patológico risk e assinatura 70-genes N=3.300 Ambos de ALTO risco Quimioterapia ± 4000 pacientes 55% 35% 10% Usar risco Clin-Path para decidir QT ou não Casos discordantes N=2.100 Clin-Pat ALTO 70-genes BAIXO Clin-pat BAIXO 70-genes ALTO R1 Usar risco 70-genes para decidir Qt ou não N=6.00 Ambos de BAIXO risco Sem QT, só HT Se QT Trerapia endócrina ± 3500 pacientes R2 Base em Taxana R3 Sequência 2a Tam 5a Letrozol Base em Antraciclina 7a Letrozol Cardoso F, et al. J Clin Oncol 2008; 26(5):

25 TakeHome Message The relative risk reduction depends on the breast cancer subtype. Greaterbenefit is observed in HER-2 enriched, basal subtypes followed by luminal B tumors. Low gain in luminal A tumors Two testsmay help selecting patientsfor chemotherapy Oncotype Dx Mammaprint

26 TakeHome Message The final decisionmust include Patient s age Comorbidities Risk of recurrence Absolute risk reduction

27 OBRIGADO