Ana Lluch
Hospital Clínico Universitario Valencia
Luminal B: ¿Podemos identificar a
las pacientes que se benefician de
Tratamiento con QT?
Neoadyuvancia
Tratamiento Neoadyuvante
Predicción de Beneficio del Tratamiento
• Facilita la cirugía reduciendo el tamaño tumoral
- Aumenta la resecabilidad 1 - Mejora tasa de cirugía conservadora1
- Reduce las complicaciones de la cirugía2
• 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 HR-
negativo/HER2-negativo o HER2-positivo4
• 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
CANCER DE
MAMA
INICIAL (I-III)
CIRUGIA → QUIMIOTERAPIA
QUIMIOTERAPIA → CIRUGIA
Cáncer de Mama Tumores >/= 2
cm
= SUPERVIVENCIA
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
16% 23%
40%
Taxanos: estudios aleatorizados comparando
diferentes esquemas de Quimioterapía
Neoadyuvante
AC x 6 16%
AC x 4 15%
CVAP x 8 13.7%
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%
Bear, 2001; Gianni, 2002; Smith, 2002 ; Green 2002; Untch, 2002; von Minckwitz , 2002; Evans, 2004 ; Steger, 2004
FEC/AC-TXL
AC-TXT
TRATAMIENTO NEOADYUVANTES.
INCORPORACION DE FARMACOS
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?
Cortazar, et al. Lancet 2014
Mayor precisión en la valoración del riesgo de recaída
Evaluación de eficacia temprana
Posible endpoint para la aprobación de fármacos en cáncer de mama precoz
RpC lograda
pCR after neoadjuvant therapy is predictive of a good outcome
Su
rviv
ing
(%
)
100
No pCR
pCR
598
86
266
14
Group n Deaths HR
0 2
80
60
40
20
0
4 6 8 10 12 14 16
Time after surgery (years)
0.32
p
<0.0001 <0.0001
100
0
80
60
40
20
0
2 4 6 8
Time after surgery (years)
B-27 B-18
No pCR
pCR
1857
397
490
42
Group n Deaths HR
0.36
p
Rastogi P, et al. J Clin Oncol 2008;26:778–85
Cáncer de Mama
RE+
65%–75%
HER2+
15%–20%
Triple Neg
15%
Fenotipos importantes utilidad Pronóstica y Predictiva
¿RCp Válida para todos los
Subtipos Moleculares?
pCR de acuerdo a 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%)
Respuesta a QT Neoadyuvante por
Subtipos Moleculares
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+
HER2+/ER- TRIPLE NEGATIVO
LUMINAL B/HER2 NEG (RH+/g3/Her2-)
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
Asociación de la RpC con la EFS en los subtipos de Cáncer con receptor HER2+ y RH
HR=0.58, P* = 0,001
HER2+ HR+
pCR (n=247) No pCR (n=839)
1.0
0.8
0.6
0.4
0.2
0.0
0 40 20 60 80 100 120
Meses desde la aleatorización
HR=0.25, P* < 0,001
HER2+ HR-
pCR (n=325) No pCR (n=510)
1.0
0.8
0.6
0.4
0.2
0.0
0 40 20 60 80 100 120
Meses desde la aleatorización
Pro
bab
ilid
ad d
e su
per
vive
nci
a
libre
de
even
tos
Pro
bab
ilid
ad d
e su
per
vive
nci
a
libre
de
even
tos
Cortazar, et al. 2014
• 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
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
Características
AP
Características
clínicas
- Relacionados con
RE
- Relacionados con
proliferación
- Ciclo celular
- RE positivo
- Grado 3
- Ki67 elevado
- Pobre SLE
- 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)
- Receptor estrógenos positivo
- Her2 negativo
- Alguno de los siguientes:
- Receptor progesterona negativo o bajo
- Ki67 alto (> 14%)
- Alto riesgo en perfil génico (Oncotype, Mammaprint)
Luminal B
(Her2 positivo)
- Receptor estrógenos positivo
- Her2 positivo
- Cualquier Ki67 y status de RP
Respuesta completa patológica Factores predictivos relevantes en Luminal B
Von MinckWitz G, JCO 2012
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
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
Von MinckWitz G, JCO 2012
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
Respuesta completa patológica Factores predictivos de respuesta
Association of pCR with EFS in HR+ HER2-Subtype
Meta-análisis de Ensayos Neoadyuvantes
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.
The pooled-analysis could not establish pCR as a surrogate
endpoint for EFS/OS
Role of Ki-67 in distinguishing
luminal A from luminal B
breast cancer
&
of characterizing
molecular subtypes
High Proliferation (luminal B)
ER-/PR-
HER2- HER2+ ER+/HER2-
Low Proliferation (luminal A)
Pro
life
ratio
n
High risk Low risk
Connection between proliferation, and tumor classes…
Ki67 index appears to be able to
discriminate between Luminal A and B
subtypes
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
HER2 expression by HercepTest (Dako)
and amplification by PathVysion FISH
probes (Abbott Molecular)
ASCO/CAP guidelines
All asssays evaluated
by 3 expert
pathologists blinded to
pathological response
The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03,
2006-14
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%
pCR rates and ROC curves
The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03,
2006-14
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
Rate of pCR for breast and axilla by ER status, HER2
status and Ki67 score
The Oncologist 2016;21:1-6.
GEICAM/2002-01, 2003-03, 2006-03,
2006-14
QT neoadyuvante en CM luminal B Selección de pacientes
Edad
< 50 años
Ductal
infiltrante
RP negativo
G 3
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)
Neoadyuvancia en cáncer de mama II Foro de Actualización en áncer de Mama 2015
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)
4x 28d cycles:
Nab-paclitaxel
125 mg/m2 QW 3/4
R
1:1
4x 28d cycles:
Conventional paclitaxel
90 mg/m2 QW 3/4
• 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)
4x 21d cycles:
AC or EC or FEC
4x 21d cycles:
AC or EC or FEC
SURGERY
FOLLOW-UP: 10 years after randomization of last patient
BIOPSY
BIOPSY
BIOPSY
BIOPSY
BIOPSY
BIOPSY
NCT01822314. Available at: www.clinicaltrials.gov
Primary EP : pCR (absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0)
N=632
Recruitment
finished
ASCO 2016
Plataformas Genómicas
Study N Neoadjuvant Chemotherapy
Gianni et al1 89 Doxorubicin/Paclitaxel x 3 cycles
Chang et al2 72 Docetaxel x 4 cycles
Yardley et al3 108 Ixabepalone/Cyclophosphamide x 6 cycles
Study N Neoadjuvant Endocrine Therapy
Akashi-Tanaka et al4
87 Anastrozole or Tamoxifen x 4 months
Masuda et al5 64 Exemestane 16 weeks → 8 weeks more if no progression at 16 weeks
Study N Neoadjuvant Chemotherapy or Endocrine Therapy
Zelnak et al6 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.
N=89 P=0.005
Milan Study
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
61
Results from Neoadjuvant Studies Are Consistent with Adjuvant Studies
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.
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
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 long-
term 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
RP negativo
G 3
Ki67 elevado
QT neoadyuvante en CM luminal B Conclusiones
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