Neoadyuvancia Luminal B: Podemos identificar a las pacientes que se benefician de Tratamiento con QT? Ana Lluch Hospital Clínico Universitario Valencia
Tratamiento Neoadyuvante Predicción de Beneficio del Tratamiento Facilita la cirugía reduciendo el tamaño tumoral - Aumenta la resecabilidad 1 - Mejora tasa de cirugía conservadora 1 - Reduce las complicaciones de la cirugía 2 Ayuda a predecir el riesgo de recaída temprana de acuerdo con la pcr - La respuesta patológica completa (RpC) está asociada consistentemente con resultados más favorables, en particular en cáncer de mama HRnegativo/HER2-negativo o HER2-positivo 4 Modelo de investigación innovador frente a ensayos tradicionales - N más pequeña; objetivo= pcr; biomarcadores Permitirá un tratamiento ajustado a la respuesta - Modificar el tratamiento en ausencia de respuesta clínico-radiologica - Ajustar terapia adyuvante en función del tumor residual riesgo 1
Goals of neoadjuvant therapy Increase the rate of conservative surgery Accelerate research in systemic treatment
Cáncer de Mama Tumores >/= 2 cm CIRUGIA QUIMIOTERAPIA CANCER DE MAMA INICIAL (I-III) = SUPERVIVENCIA QUIMIOTERAPIA CIRUGIA
No diferencias en OS, DFS y RFS entre quimioterapia Neoadyuvante y Adyuvante en Cáncer de Mama AC AC T J Clin Oncol. 2008; 26: 778
Porcentaje de conversión de Mastectomía a Cirugía Conservadora 40% 16% 23%
Taxanos: estudios aleatorizados comparando diferentes esquemas de Quimioterapía Neoadyuvante TASAS DE RPc ANTRACICLINAS Y TAXANOS SECUENCIALES AC x 4 Txt x 4 31% AC x 4 Txt x 4 vs. 22.4% CVAP x 4 Txt x 4 25.6% wtxl x 12 FAC x 4 28.8% ATxl x 4 CMF x 4 23% 3wTxl x 4 FAC x 4 13.6% 2wE x 3 Txl x 3 vs. 18% COMBINACIONES ANTRACICLINAS/TAXANOS ETxt x 6 18.6% ATxt x 6 12% ETxl x 4 10% 2wATxt x 4 11.5% ETxt x 3 7.7% AC x 6 16% AC x 4 15% CVAP x 8 13.7% Bear, 2001; Gianni, 2002; Smith, 2002 ; Green 2002; Untch, 2002; von Minckwitz, 2002; Evans, 2004 ; Steger, 2004
TRATAMIENTO NEOADYUVANTES. INCORPORACION DE FARMACOS AC-TXT FEC/AC-TXL CMF/AC
Incorporación de Nuevos Farmacos Nab-Paclitaxel Sales de Platino Inhibidores de PARP Otros
Qué pacientes son Candidatas Óptimas para ser tratadas con Quimioterapía Neoadyuvante? Todas las pacientes que van a recibir Quimioterapia Adyuvante son candidatas a Quimioterapia Neoadyuvante Hortobagy 2007
Factores predictores de Respuesta Patológica Completa M.Kauffman Ann Surg Oncol (2012)
pcr como Marcador subrrogado
Cuáles son las ventajas de la RpC? Mayor precisión en la valoración del riesgo de recaída RpC lograda Evaluación de eficacia temprana Posible endpoint para la aprobación de fármacos en cáncer de mama precoz Cortazar, et al. Lancet 2014
Surviving (%) pcr after neoadjuvant therapy is predictive of a good outcome B-18 B-27 100 100 80 80 60 60 40 40 20 Group n Deaths HR No pcr pcr 598 86 266 14 0.32 p Group n Deaths HR p 20 No pcr 1857 490 <0.0001 pcr 397 42 0.36 <0.0001 0 0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 Time after surgery (years) Time after surgery (years) Rastogi P, et al. J Clin Oncol 2008;26:778 85
RCp Válida para todos los Subtipos Moleculares? RE+ 65% 75% Cáncer de Mama HER2+ 15% 20% Triple Neg 15% Fenotipos importantes utilidad Pronóstica y Predictiva
pcr de acuerdo a Subtipos Moleculares
Respuesta a QT Neoadyuvante por Subtipos Moleculares RCp P/FAC x 8 (Rouzier) N = 83 AC-T (Carey) 107 Total 21/83 (26%) 7/46 (15%) Luminal A and B 2/31 (6%) 4/26 (7%) Normal breast-like 0/10 (0%) 0/7 (0%) HER2+/ER- 9/20 (45%) 4/11 (36%) Basal-like 10/22 (45%) 9/34 (26%)
Prognostic impact of pcr on DFS in 4.193 patients according to breast cancer intrinsic subtype LUMINAL A (RH+/g1-2/Her2-) LUMINAL B/HER2 NEG (RH+/g3/Her2-) LUMINAL B HER2+ HER2+/ER- TRIPLE NEGATIVO
Meta-análisis de Ensayos Neoadyuvantes Para llevar a cabo una revisión sistemática de los estudios publicados de quimioterapia neoadyuvante para evaluar exhaustivamente: Asociación global entre pcr con la posterior supervivencia libre de enfermedad (DFS) y supervivencia global (OS) Asociación entre pcr con DFS y OS en cáncer de mama HR+, HER-2+ y triple negativo (TN) CORTAZAR,P Lancet 2014
CORTAZAR,P Lancet 2014
Association of pcr with EFS in HR+ HER2-Subtype
Probabilidad de supervivencia libre de eventos Probabilidad de supervivencia libre de eventos Asociación de la RpC con la EFS en los subtipos de Cáncer con receptor HER2+ y RH HER2+ HR+ HER2+ HR- Existe una fuerte asociación significativa entre la RpC y el pronóstico a largo plazo (SLE y SG) en el subgrupo de pacientes con CM HER2-positivo con independencia del estado de RRHH 1.0 0.8 0.6 0.4 0.2 0.0 HR=0.58, P* = 0,001 pcr (n=247) No pcr (n=839) 0 20 40 60 80 100 120 Meses desde la aleatorización 1.0 0.8 0.6 0.4 0.2 0.0 HR=0.25, P* < 0,001 pcr (n=325) No pcr (n=510) 0 20 40 60 80 100 120 Meses desde la aleatorización Cortazar, et al. 2014
Association of pcr with EFS in Triple Negative Subtype
Marcadores predictivos de respuesta por Fenotipos Moleculares Subtipos moleculares Respuesta Subtipos Basal Like y HER2 [+] Subtipos Luminal A y B [-]
2012 FDA aprueba prc como marcador subrrogado de SV
Cáncer de Mama Subtipo Luminal B
Características del cáncer de mama luminal B Genes sobreexpresados - Relacionados con RE - Relacionados con proliferación - Ciclo celular Características AP - RE positivo - Grado 3 - Ki67 elevado - Pobre SLE Características clínicas - Riesgo elevado de recaída precoz - Predisposición a metástasis óseas y pleurales - Menor hormono-sensibilidad que Luminal A - Menor quimio-sensibilidad que Basal-like y Her2
Cómo reconocer el cáncer de mama luminal B? Definición clínico-patológica subrogada (St Gallen 2013) Luminal B (Her2 negativo) Luminal B (Her2 positivo) - Receptor estrógenos positivo - Her2 negativo - Alguno de los siguientes: - Receptor progesterona negativo o bajo - Ki67 alto (> 14%) - Alto riesgo en perfil génico (Oncotype, Mammaprint) - Receptor estrógenos positivo - Her2 positivo - Cualquier Ki67 y status de RP
Respuesta completa patológica Factores predictivos relevantes en Luminal B Subtipo histológico RCP (%) ypt0/is ypn0 Ductal 21.3 Lobulillar 8.9 Edad RCP (%) ypt0/is ypn0 < 35 30.9 35-39 23.8 40-49 21 50-59 17.1 > 60 16.3 Grado histológico RCP (%) ypt0/is ypn0 1 7.4 2 13.1 3 28.8 Receptor progesterona RCP (%) ypt0/is ypn0 Positivo 10.3 Negativo 29.8 Von MinckWitz G, JCO 2012
Subtipos Moleculares y RCp *Immunohistochemical definition of molecular subtypes
Pathologic Response to Anthracycline/Taxane by Subtype 369 patients from 3 neoadjuvant datasets Modified PAM50 Overall pcr rate = 22% (82/369) Classification Residual dz pcr Basal-like 47 (58%) 34 (42%) Claudin-low 29 (67%) 14 (33%) HER2-enriched 31 (63%) 18 (37%) LumA 110 (98%) 2 (2%) LumB 56 (85%) 10 (15%) Normal-like 13 (76%) 4 (24%) Dr- Segui, Parc Tauli
Respuesta completa patológica según subtipo molecular Subtipo molecular RCP (%) ypt0/is ypn0 Luminal A 8.9 Luminal B Her2-15.4 Luminal B Her2 + (sin T) 17.2 Luminal B Her2 + (con T) 32.3 Her2 + (sin T) 33.1 Her2 + (con T) 51 Triple negativo 35.8 Von MinckWitz G, JCO 2012
Respuesta completa patológica Factores predictivos de respuesta
Meta-análisis de Ensayos Neoadyuvantes Association of pcr with EFS in HR+ HER2-Subtype
The pooled-analysis could not establish pcr as a surrogate endpoint for EFS/OS Possibly due to: low pcr rates small pcr improvements heterogeneous population lack of targeted therapies (except NOAH trial) Larger pcr differences between treatment arms may translate into long-term outcome and may vary according to breast cancer subtype.
Role of Ki-67 in distinguishing luminal A from luminal B breast cancer & of characterizing molecular subtypes
Proliferation Connection between proliferation, and tumor classes Ki67 index appears to be able to discriminate between Luminal A and B subtypes High Proliferation (luminal B) Low Proliferation (luminal A) ER-/PR- HER2- HER2+ ER+/HER2- Low risk High risk
GEICAM/2002-01, 2003-03, 2006-03, 2006-14 The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03, 2006-14 Patient population 262 patients with available centralized Ki67 IHC determination and pathological response* data, from four neoadjuvant GEICAM trials: 73% of the whole sample size in the four trials (all together) Antracycline and taxane-based chemotherapy Anti-HER2 therapy (trastuzumab or lapatinib) administered for most of patients with HER2 overexpression Clinical Trial N Breast cancer subtypes 2002-01 34 All subtypes 2003-03 32 HER2 overexpressed 2006-03 119 Luminal and Triple Negative 2006-14 77 HER2 overexpressed The Oncologist 2016;21:1-6. *pcr defined on the basis of the Miller and Payne criteria.
GEICAM/2002-01, 2003-03, 2006-03, 2006-14 IHC and/or FISH determination Ki67, ER, PR, HER2 Ki67 mab clone MIB1 (Dako) ER mab clone SP1 or EP1 (Dako) PR mab clone 1A6 (Novocastra), PgR636 (Dako) or Y85 (Vitro) IHC determination by EnVision FLEX system (Dako) ASCO/CAP guidelines All asssays evaluated by 3 expert pathologists blinded to pathological response HER2 expression by HercepTest (Dako) and amplification by PathVysion FISH probes (Abbott Molecular) ASCO/CAP guidelines The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03, 2006-14 pcr rates and ROC curves Results based on ROC curve method showed that the Ki67 cutpoints with the highest S and E values were 60 and 50 Based on this cutpoint (Ki67 > 50%): high Ki67 in 35% of patients Ki67 > 50% 53% of patients with pcrs had tumors with Ki67 > 50% Patients with Ki67 > 50% achieved a pcr rate = 40% Ki67 50% 72% of patients with no pcrs had tumors with Ki67 50% Patients with Ki67 50% achieved a pcr rate = 19% The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03, 2006-14 Rate of pcr for breast and axilla by ER status, HER2 status and Ki67 score The 50% cutpoint of Ki67 predicted better pcrs, specifically in patients with ER-/HER2- (42% high vs 15% low; p=0.0337) and ER-/HER2+(64% high vs 45% low; p= 0.3238) tumors The Oncologist 2016;21:1-6.
QT neoadyuvante en CM luminal B Selección de pacientes Edad < 50 años Ductal infiltrante G 3 RP negativo Ki67 elevado
Cáncer de Mama Subtipo Luminal B Tratamiento
Neoadyuvancia: Quimio versus Endocrinoterapia Porcentajes similares de respuestas objetivas y cirugía conservadora (33 vs 24% - P 0.58)
II Foro de Actualización en áncer de Mama 2015 Neoadyuvancia en cáncer de mama Even in luminal phenotypes, chemotherapy tends to be more effective than hormonal therapy in the neoadjuvant setting Chemotherapy appears to be more effective than hormonal therapy in patients with Ki67 >10%, pre-menopausal and with high Allred score Hormonal therapy appears to have similar efficacy to chemotherapy in patients with Ki67 10% and post-menopausal Alba et al, ASCO 2010
Unplanned analysis Clinical Response and Ki67 CT arm (n=46) HT arm (n=45) p value Ki67 10% 19 19 Response rate 12 (63%) 11 (58%) 0.7 Ki67 >10% 27 26 Response rate 18 (67%) 11 (42%) 0.07
Nab-Paclitaxel. Nuevos datos. NEOADYUVANCIA
ETNA: Phase III study design (Michelangelo /GEICAM) ASCO 2016 HER2-negative non metastatic unilateral breast cancer at risk of disease recurrence ECOG PS 0-1 No prior radiotherapy, chemotherapy, biotherapy and/or hormonal therapy for current BC One of the following stages: T2, T3, T4 disease, triple negative (HER2, ER, PgR) T2, T3, T4 disease, ER or PgR positive and moderately /poorly differentiated (G II-III) BIOPSY 4x 28d cycles: R Nab-paclitaxel 125 mg/m 2 QW 3/4 1:1 4x 28d cycles: Conventional paclitaxel 90 mg/m 2 QW 3/4 BIOPSY BIOPSY BIOPSY 4x 21d cycles: AC or EC or FEC N=632 Recruitment finished 4x 21d cycles: AC or EC or FEC BIOPSY SURGERY BIOPSY FOLLOW-UP: 10 years after randomization of last patient Primary EP : pcr (absence of invasive disease in breast and nodes (ypt0/yptis, ypn0) NCT01822314. Available at: www.clinicaltrials.gov
Plataformas Genómicas
Study N Neoadjuvant Chemotherapy Gianni et al 1 89 Doxorubicin/Paclitaxel x 3 cycles Chang et al 2 72 Docetaxel x 4 cycles Yardley et al 3 108 Ixabepalone/Cyclophosphamide x 6 cycles Study N Neoadjuvant Endocrine Therapy Akashi-Tanaka 87 Anastrozole or Tamoxifen x 4 months et al 4 Masuda et al 5 64 Exemestane 16 weeks 8 weeks more if no progression at 16 weeks Study N Neoadjuvant Chemotherapy or Endocrine Therapy Zelnak et al 6 46 Recurrence Score result 10 Exemestane Recurrence Score result 11-24 Exemestane OR Docetaxel Cyclophosphamide x 6 cycles Recurrence Score result 25 Docetaxel Cyclophosphamide x 6 cycles 1. Gianni et al. J Clin Oncol. 2005. 4. Akashi-Tanaka et al. Breast. 2009. 2. Chang et al. Breast Cancer Res Treat. 2008. 5. Masuda et al. ASCO 2011. Abstract 558. 3. Yardley et al. SABCS 2011. Abstract P5-13-09. 6. Zelnak et al. ASCO 2013. Abstract 562.
Milan Study N=89 P=0.005 Gianni et al. J Clin Oncol. 2005.
N=72 Chang et al. Breast Cancer Res Treat. 2008.
RC<18: Tratamiento neoadyuvante con HORMONOTERAPIA. RC>25: Tratamiento neoadyuvante con QUIMIOTERAPIA
Results from Neoadjuvant Studies Are Consistent with Adjuvant Studies In both the adjuvant AND neoadjuvant settings The lower the Recurrence Score result The lower the benefit of chemotherapy The greater the benefit of endocrine therapy The higher the Recurrence Score result The greater the benefit of chemotherapy The lower the benefit of endocrine therapy Paik et al. N Engl J Med. 2004. Paik et al. J Clin Oncol. 2006. Gianni et al. J Clin Oncol. 2005. Chang et al. Breast Cancer Res Treat. 2008. 61
62
Conclusiones Generales In selected patients, neoadjuvant therapy can provide an increased breast conserving surgery, prognostic information, and access to clinical trials investigating novel agents. Management involves a coordinated multidisciplinary team Even though pcr was not validated as a surrogate endpoint for longterm outcomes, its strong association with substantially improved outcome in patients with more agressive BC subtypes (TN, Her2 +, high grade HR +) supported the opening of an acelerated approval pathway. Future clinical trials of targeted therapies in more homogeneus BC subtypes with larger differences in pcr rates will help elucidate if prc may be a surrogate for improved EFS and OS.
Despite the weakness of pcr as a surrogate for OS and DFS in the detection of a treatment effect, preoperative chemotherapy is a model to investigate biology and impact of therapy Perhaps order of therapy does not change outcome, but changes knowledge
Overall response rate appears similar for CT and HT pcr rate is very low for both modalities pcr may not be a robust predictive factor in this population
QT neoadyuvante en luminal B Conclusiones Opción en pacientes que consideremos claramente indicada la QT adyuvante Hay que seleccionar pacientes: jóvenes, ductal, Ki67 elevado, grado 3 y/o receptor de progesterona negativo La HT es menos eficaz que la QT, pero puede ser una alternativa en postmenopáusicas con Ki67 bajo La adición de terapias dirigidas podría mejorar en un futuro el resultado de la QT neoadyuvante en CM luminal B
QT neoadyuvante en CM luminal B Selección de pacientes Edad < 50 años Ductal infiltrante G 3 RP negativo Ki67 elevado
QT neoadyuvante en CM luminal B Conclusiones