Os Mais Importantes Estudos de Quimioterapia Neo-adjuvante O que ha de novo? Carlos H. Barrios Professor, PUCRS School of Medicine Director, Oncology Research Center, Hospital São Lucas Director, Instituto do Câncer Sistema de Saúde Mãe de Deus Grupo Latinoamerican do Investigação Clínica em Oncologia GLICO Porto Alegre, Brazil
Disclosures for this Presentation Consulting, Advisor, Honorarium and Research Support: Roche, GSK
Road Map Neoadjuvância na doença HER2 positiva. bloqueio duplo? concomitância de RH? curabilidade? Seleção de pacientes de acordo com a resposta inicial. Definição de Resposta Patológica Completa. Resultados de sobrevida a longo prazo. de acordo com doença residual de acordo com subtipo molecular
NEO-ADJUVANT TRIALS IN HER2 POSITIVE DISEASE DOUBLE BLOCKADE? HORMONAL RECEPTOR STATUS? Can we cure metastatic breast cancer?
Neo-adjuvant Anti-HER2 MTA in Breast Cancer Strategy Neo ALTTO N=450 Neo-Sphere N=417 Tryphaena N=225 Trastuzumab Chemotherapy Regimen Trastuzumab Paclitaxel pcr 29% Regimen Trastuzumab Docetaxel pcr 29% Regimen pcr Single MTA Chemotherapy Lapatinib Paclitaxel 25% Pertuzumab Docetaxel 24% Combo MTA Trastuzumab Pertuzumab 17% Combo MTA Chemotherapy Trastuzumab Lapatinib Docetaxel 51% Trastuzumab Pertuzumab Docetaxel 46% Trastuzumab Pertuzumab Doce/Carbo 66% Combo MTA Chemotherapy Trastuzumab Pertuzumab FEC-Docetax Sequential Concomitant 57% 62%
Dual HER2 blockade alone or with chemotherapy (or with more chemotherapy?) (Neo-Sphere, Neo-Altto, Tryphaena) 100 80 % pcr Rate 60 40 20 17% Dual HER2 blockade alone 50% Dual HER2 blockade Taxane 63% Dual HER2 blockade Taxane Other agent (anthrac., carbo)
Dual HER2 blockade alone or with chemotherapy Hormone Receptor Negative Disease (Neo-Sphere, Neo-Altto, Tryphaena) 100 80% % pcr Rates 80 60 40 20 29% Dual HER2 blockade alone 62% Dual HER2 blockade Taxane Dual HER2 blockade Taxane other agent (Anthra, Carbo) 7.2 28.8
Dual HER2 blockade alone or with chemotherapy Hormone Receptor Positive Disease (Neo-Sphere, Neo-Altto, Tryphaena, Chang s Trial) 100 80 These somewhat less impressive results could still translate into excellent DFS rates % pcr Rates 60 40 20 6% Dual HER2 blockade alone 26% Trastuzumab Pertuzumab Taxane 42% Trastuzumab Lapatinib Taxane 47% Trastuzumab FEC and Taxane Trastuzumab Pertuzumab Docetaxel Carboplatin 7.2 50% 28.8 21% Trastuzumab Lapatinib A.I.
Câncer de mama metastático é curável? 30/09/2009 15/10/2009 11/11/2009
REVISITING PATIENT SELECTION ACCORDING TO THE INITIAL RESPONSE TO THE NEO-ADJUVANT THERAPY?
GeparTrio Trial Design N=2072 NX Core Biopsy: Uni/bilateral BC ct2-4a-d cn0-3 size 2 cm* NC Sonography CR/ PR R R TACx6 TACx6 Response-guided Arms Conventional Arms TACx8 *low risk patients were excluded (T2 ER/PR pos. cno G1/2 > 35 yrs) von Minckwitz et al, JNCI 100: 542, 2008 von Minckwitz et al. JNCI 100; 552, 2008
Short Term Efficacy (pcr = ypt0 ypn0) 30% Responder N=1344 P=0.27 Non-Responder N=604 P=0.73 20% 10% 21.0 23.5 0 TACx6 TACx8 5.3 TACx6 6.0 TAC-NX PRIMARY CONCLUSION No difference in pcr among the arms! von Minckwitz et al, JNCI 100: 542, 2008 von Minckwitz et al. JNCI 100; 552, 2008
DFS and OS after Conventional (TACx6) vs. Response-guided Rx (TACx8/TAC-NX) Median follow up 62 months PATIENT SELECTION ACCORDING TO INITIAL RESPONSE!!! (independent if pcr or not) Response-guided arms: better DFS and OS
LONG TERM SURVIVAL ENDPOINTS (DFS AND OS) IN NEO-ADJUVANT TRIALS WHAT CAN WE LEARN FROM THIS? von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
LONG TERM SURVIVAL ENDPOINTS (DFS AND OS) IN NEO-ADJUVANT TRIALS DEFINITION OF pcr DFS and OS according to residual disease von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
DFS and OS According to Residual Disease Definition (ypt0 ypn0) no residual tumor in breast and nodes (yptis ypn0) non-invasive residual only in breast (ypt"1 or ypn#) invasive residual in breast and/or nodes von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
LONG TERM SURVIVAL ENDPOINTS ACCORDING TO pcr AND INTRINSIC SUBTYPE von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
GEPAR-TRIO: pcr Rates by Subtype 40 35 pcr (%) 30 25 20 15 10 5 0 Luminal A (N=572) Luminal B (HER2-) (N=211) Luminal B (HER2) (N=281) HER2 (non-luminal) (N=178) Triple-negative N=362) Courtesy of G. von Minckwitz. SABCS 2011
Luminal A Luminal B HER2 DFS by pcr 4.193 patients pcr not prognostic in Luminal A 7 and neo-adjuvant Luminal B HER2 RCTs Luminal B HER2- Luminal B HER2 Retrospective intrinsic subtype classification pcr prognostic in Luminal B HER2- but not in Luminal B HER2 (this needs an explanation!!) HER2 Positive Triple Negative pcr prognostic in HER2 and TNBC von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
LONG TERM SURVIVAL ENDPOINTS (DFS AND OS) IN NEO-ADJUVANT TRIALS DFS IN PATIENTS WITH pcr ACCORDING TO INTRINSIC SUBTYPE
DFS in Patients with pcr According to the Instrinsic Subtype von Minckwitz G, et al. JCO May 2012 10.1200/JCO.2011.38.8595
LONG TERM SURVIVAL ENDPOINTS (DFS AND OS) IN NEO-ADJUVANT TRIALS OS according to pcr (or not pcr)
n= 662 HER2 with trastuzumab n= 3060 HER2 negative n= 665 HER2; no trastuzumab OS analysis by pcr No pcr pcr vs vs p=0.295 p=0.384 Log-rank vs vs p=0.058 p=0.134 Virtually no deaths in pts reaching pcr Arm N Events Arm N Events HER2 w/trast 481 35with a trastuzumab-containing regimen! HER2 w/trast 181 1 pcr HER2 without Trastuzumab seems to do worse than pcr with Trastuzumab HER2 w/o trast 546 75 HER2 w/o trast 119 9 HER2 Negative 2606 310 HER2 Negative 454 14 A Loibl S, Von Minckwitz G, Blohmer J, et al. pcr as a surrogate in HER2-positive patients treated with trastuzumab. Cancer Research. 2011;71(24 suppl 3). Abstract S5-4.
Conclusões Definição adequada da resposta (pcr) é importante. Considerar o subtipo molecular é fundamental: HER2, TNBC, Luminais A e B Doenças com tratamentos diferentes. O que fazer com o resultado inicial ao tratamento? (ainda uma pergunta sem resposta definitiva) Trocar ou prolongar o tratamento neo-adjuvante? (GeparTrio)
Conclusões Diferente da adjuvância, a neoadjuvância permite selecionar as pacientes de acordo com a resposta ao tratamento (pcr vs. não pcr). Reconhecer que as pacientes com doença HER2 positiva (não luminal) e TN que não obtém uma pcr após a neoadjuvância como um subgrupo que necessita uma abordagem terapêutica complementar é fundamental para melhorar o prognóstico destas pacientes. 1. Ou melhoramos o tratamento aumentando a pcr 2. Ou oferecemos mais tratamento (?) para as que não obtém pcr...