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