Quimioterapia Adjuvante. Fatores Atuais de Decisão Dr Antonio C. Buzaid Chefe Geral
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
Recurrence (%) 50 40 30 20 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 0.68-0.79) Log-rank 2P<0.00001 10-year gain 8.0% (SE 1.2) Recurrence (%/year) and log-rank analyses RR 0.70 (95%CI 0.63-0.77) Log-rank 2P<0.00001 10-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 -185.2/489.8 Years 5-9 4.06 (487/11981) 4.56 (365/8011) 0.89 SE 0.07-20.0/174.7 Years 10+ 2.91 (161/5530) 3.87 (159/4104) 0.72 SE 0.11-21.2/65.5 Years 0-4 4.83 (549/11357) 7.20 (748/10385) 0.61 SE 0.05-135.5/277.0 Years 5-9 2.58 (207/8038) 2.93 (210/7158) 0.84 SE 0.09-16.9/95.9 Years 10+ 1.88 (116/6155) 1.90 (100/5260) 0.99 SE 0.14-0.7/48.7
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) 0.86 0.0005 0.94 0.33 AC X 4 equivalent to CMF X 6 0.98 0.67 CAF or CEF X 6 cycles superior to CMF 0.78 0.0004 CAF X 6 vs no chemo 0.64 0.0001 AC X 4 vs no chemo 0.78 0.01 EBCTCG. The Lancet 379:432, 2012
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
Impacto da Terapia Adjuvante 100 Sobrevida Livre de Doença % 90 80 70 Sem benefício Benefício com terapia 60 50 0 Anos 5 8 100 Sobrevida Terapia não necessária % 90 80 70 60 Sem benefício Benefício com terapia Terapia não necessária 50 0 5 8 Anos
Percentage of Patients that Accept Chemothehrapy % of Patients that Accept Chemo 100 50 0 Coates Ravdin Lindley 1 2 3 4 10 15 25 Percent Gain of Overall Survival
RiskReductionof30% ofdeath Lymph Node Positivo 50% risk of death Nº de Pacientes Adj. Obs. %OS at 5 year Adj. Obs. % absolute difference Nº total 500 500 65 50 15 Nº of death 175 250 (325/500) (250/500) (65-50) (0.7 X 250) Lymph Node Neg - 10% risk of death Nº total 500 500 93 90 3 Nº of death 35 50 (465/500) (450/500) (93-90) (0.7 X 50)
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
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 = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68-0.08 x GSTM1-0.07 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
DRFS 1.0 0.8 0.6 0.4 B-14 Benefit of Tam vs Placebo By Oncotype-DX Recurrence Score Risk 142 171 Low risk (RS<18) Int risk (RS 18-30) 0.4 DRFS 1.0 0.8 0.6 69 85 0.2 0.0 Placebo Tamoxifen 0 2 4 6 8 10 12 14 16 Years 1.0 0.2 0.0 Placebo Tamoxifen 0 2 4 6 8 10 12 14 16 Years DRFS 0.8 0.6 0.4 0.2 0.0 High risk (RS 31) Placebo Tamoxifen 0 2 4 6 8 10 12 14 16 Years Paik S, et al. E Engl J Med 351:2817, 2004 99 79
DRFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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 218 11 135 5 0 2 4 6 8 10 12 Years DRFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 DRFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 High risk (RS 31) P = 0.001 Int Risk Patients (RS 31) Tam + Chemo Tam 0 2 4 6 8 10 12 Years N P = 0.71 Int Risk (RS 18-30) Tam + Chemo Tam N Events 89 9 45 8 0 2 4 6 8 10 12 Years Events 117 13 47 18 Paik et al. J Clin Oncol. 2006;24:3726-3734.
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 28:1829 2010
Sobrevida Livre de Meta à Distância Linfonodo Negativo, Ambos os Braços n=872 9 anos SLMD - 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Logrank p<0.001 Baixo Interm Alto N (%) Eventos 513 (59%) 20 229 (26%) 24 130 (15%) 28 Grupo IR HR* 95%CI Alto vs Baixo 5.2 (2.7-10.1) Int vs Baixo 2.5 (1.3-4.5) 96% 88% 75% 0 1 2 3 4 5 6 7 8 9 Anos Dowsett et al., J Clin Oncol 28:1829 2010 *Hazard ratio para grupo IR ajustado para tamanho do tumor, grau, idade e tratamento
1.0 0.9 0.8 0.7 0.6 0.5 0.4 Sobrevida Livre de Meta à Distância Linfonodo Positivo, Ambos os Braços Logrank p<0.001 n=306 9 anos 83% 72% 51% SLMD 0.3 0.2 0.1 0.0 Baixo Int Alto N (%) 160 (52%) 94 (31%) 52 (17%) Eventos 25 25 24 Grupo IR HR* 95%CI Alto vs Baixo 2.7 (1.5 5.1) Int vs Baixo 1.8 (1.0-3.2) 0 1 2 3 4 5 6 7 8 9 Dowsett et al., J Clin Oncol 28:1829,2010 anos *Hazard ratio para grupo IR ajustado para tamanho do tumor, grau, idade e tratamento
Sobrevida Livre de Meta à Distância de Acordo com Número de LNDs+ e RS Predicted 9-year risk of distant recurrence 100 80 60 40 20 Mean 95% CI 0 10 20 30 40 50 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 28:1829 2010
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 11-25 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 10.000 pts
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
Mammaprint: Good and Poor Signature Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25): 1999-2009
Mammaprint: Node Negative Patients Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25): 1999-2009
Mammaprint: Node Positive Patients Van de Vijver MJ, et al.. N Engl J Med 2002; 347(25): 1999-2009
TRANSBIG - Validation Probability 0.0 0.2 0.4 0.6 0.8 1.0 N=307 LN negativo, Sem tratamento adjuvante Patients Events Risk group 109 16 Genetic low risk 182 59 Genetic high risk SV10a = 88% (81%-95%) SV10a = 71% (63%-78%) 0 2 4 6 8 10 12 14 Year 109 108 101 95 84 65 44 16 GLR 182 175 160 140 116 92 65 23 GHR Number at risk Marc Buyse, et al, J Natl Cancer Inst 2006; 98:1183
EORTC-BIG MINDACT: Desenho do estudo n = 6.000 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): 729-35
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
TakeHome Message The final decisionmust include Patient s age Comorbidities Risk of recurrence Absolute risk reduction
OBRIGADO