Neoadyuvancia en Cáncer de - Doctaforum · •Inicio precoz del tto sistémico •Downstaging (operabilidad, qx conservadora) •Test in vivo del efecto antitumoral •Valor pronóstico

Neoadyuvancia en Cáncer de Mama

E. Ciruelos

Servicio de Oncología Médica

Hospital 12 de Octubre

- Excelentes tasas de respuestas en CM localmente avanzado

e inflamatorio (tratamiento estándar) Chia S, JCO 2008; 26: 786

Tasa alta de respuesta clínica (60-70%)

Tasa baja de respuesta patológica (20%)

- Mayor tasa de cirugía conservadora (resultado estético)

- Supervivencia equivalente a la quimioterapia

adyuvante (SLE, SG)

Justificación

Tratamiento neoadyuvante

del cáncer de mama

VENTAJAS

• Inicio precoz del tto sistémico

• Downstaging (operabilidad, qx conservadora)

• Test in vivo del efecto antitumoral

• Valor pronóstico de pCR*

• Oportunidad de marcadores surrogados

• Desarrollo nuevos fármacos

Tratamiento neoadyuvante

del cáncer de mama

DESVENTAJAS

• Diagnóstico inicial según biopsia/cilindro

(no refleja heterogeneidad del tumor)

• No estadiaje histopatológico

• Riesgo de enfermedad multifocal residual

• Requiere Unidad Multidisciplinar

EBCTCG, Sept 2006

Mieog JS, Cochrane Database Syst Rev 2007; CD005002

Tipos de Marcadores Subrogados

del Tratamiento Neoadyuvante

Diagnostico Neoadyuvancia Cirugía

Marcadores

Tempranos

-Ki 67

-Imagen

-Otros

Marcadores

Tardíos

-PEPI score

-RCp

-Enf Residual

NSABP B-18

Operable breast cancer (n 1523)

Randomization

AC x 4 Surgery

SurgeryAC x 4

Fisher B, J Clin Oncol 1998; 16: 2672-2685

Wolmark N, J Natl Cancer Inst 2001; 96-102

pCR 13%

NSABP B-18

Rastogi P, J Clin Oncol 2008; 26: 778-785.

16 años seguimiento

NSABP B-18


NSABP B-27

Operable breast cancer

Randomization

I II III

AC x 4 AC x 4 AC x 4

Surgery Docetaxel x 4 Surgery

Surgery Docetaxel x 4

n=784 n=777n=783

AC – 60/600/m2

Tam – 20mg/day

x 5yr

Taxotere –

100mg/m2

Bear HD, J Clin Oncol 2006; 24: 2019-2027.

NSABP B-27: pathological

complete responses in breast

12.8%*

26.1%*

14.3%*

9.1

3.7 18.9

7.2

9.9

4.4

0%

5%

10%

15%

20%

25%

30%

Group I

(n=764)Group II

(n=767)Group III

(n=775)

DCIS onlyNo tumor

Bear HD, J Clin Oncol 2006; 24: 2019-2027.

NSABP B-27: OS, DFS, RFS


16 años seguimiento


NSABP B-27: overall survival –pCR vs non-pCR patients

Definiciones de pCR

• Ausencia de tumor invasivo en mama (NSABP)• Ausencia de tumor invasivo en mama y axila (MDA)• Ausencia de tumor invasivo y no invasivo

en mama y axila (GBG)• Symmans (MDA; GEICAM)

Von Minckwitz, JCO 2012

CTNeoBC Selected Trials

– 12 neoadjuvant

randomized

controlled trials

– pCR clearly defined

with all necessary

data collected

– Long-term follow-up

EFS and OS data

collected

GBG: 7 trials 6243

NSABP: 2 trials 3171

EORTC: 1 trial 1856

ITA: 2 trials 685

Total # patients 11955

GBG, NSABP, AGO-B, EORTC, BIG, Fondazione Michelangelo, SweBCG, UNC, NCI, FDA

CTNeoBCFDA, SABCS 2012

Considerations FDA For Future

Trials:

pCR Definition

A pCR definition that includes the

assessment of the axillary nodes

(ypT0ypN0 or ypT0/isypN0) should be

used in future trials.

pCR=ypT0/is ypN0

HR=0.48, P* < 0.001 HR=0.36, P* < 0.001

* Nominal p-value

Association of pCR with EFS and OS

CTNeoFDA, SABCS 2012

Molecular classification in breast cancer:

The intrinsec subtypes

Sorlie, T et al. PNAS, 2001

Perou, CM et al. Nature, 2000

Perreard, L et al. Breast Cancer Res, 2006


N 6377


Luminal ALuminal B HER2 - Luminal B HER2+

HER2+ RE-TN

pCR=ypT0/is ypN0

HR=0.49, P* < 0.001 HR=0.63, P* = 0.07 HR=0.27, P* < 0.001

* Nominal p-value

Association of pCR with EFS in

HR+ HER2-SubtypeHR+ HER2-

Subtype

FDA, SABCS 2012


Her2-positive Subtype

pCR=ypT0/is ypN0

HR=0.39, P* < 0.001 HR=0.58, P* = 0.001 HR=0.25, P* < 0.001

* Nominal p-value

CTNeoFDA, SABCS 2012

HR=0.24, P* < 0.001

pCR=ypT0/is ypN0 * Nominal p-

value


Triple Negative Subtype

FDA, SABCS 2012

Breast Cancer Intrinsic Subtypes: A Spectrum

Endocrine Dependent

Chemo Resistant

Endocrine Independent

Chemo Sensitive

Pathways

ER HER Family

SurvivalProlif’n ER SurvivalProlif’nHER Family

Lum A Lum B HER2-rich Basal-like Others

Hayes D J. Clin. Oncol. 2012 30; 1264-7

7

16

0

10

20

30

40

50

60

18

30 31

50

.

Grade 1-2 Grade 3

HR+

No Tras Yes Tras

HER2+ HR+

No Tras Yes Tras

HER2+ HR- TRIPLE NEG

34

pCR Rates by Tumor Subtypes

FDA, SABCS 2012

Higher OncotypeDX Recurrence Score

Associated with Higher Likelihood of pCR

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 10 20 30 40 50 60 70 80 90 100

Recurrence Score

Pro

ba

bility

of

pC

R

Low risk Int. risk High risk

Gianni L et al., JCO 2005

HER2+

MDAOperable breast cancer

HER2+, n 282

2007-2011

T x 12 > FEC

+ Trastuzumab/s

SurgerySurgery

FEC > Taxol x 12 +

Trastu

pCR breast 56% 54%

pCR

breast+nod

es

48% 46%

pCR si ER- 72% 76%

Buzdar AU, ASCO 2013

CMFq4w x 3 cycles

NOAH study

design

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation;

H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2);

q3w, every 3 weeks; T, paclitaxel (175 mg/m2); q4w, every 4 weeksaHormone receptor-positive patients will receive adjuvant tamoxifen

HER2-positive LABC

(IHC 3+ or FISH+)

ATq3w x 3 cycles

Tq3w x 4 cycles

H + ATq3w x 3 cycles

H + T

q3w x 4 cycles

H q3w x 4 cycles+ CMF q4w x 3 cycles

H continued q3wto week 52

(n=115) (n=113

) ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

HER2-negative LABC

(IHC 0/1+)

Surgery followed byradiotherapya

(n=99)



19 crossed over to H

Patients (%)

43%

(38%)

22%

(19%) 16%

0

10

20

30

40

50

With H Without H HER2 negative

HER2 positive

pCR

p=0.002

p=0.43

pCR breast (+ nodes) rates in the NOAH trial

Gianni, Lancet 2010

DFS and OS: HER2-positive population

Median follow-up is 5,4 years

Gianni, ASCO 2013

• DFS - HR 0,64 (p 0,01) a favor de trastuzumab• OS - HR 0,66 (p 0,05) a favor de trastuzumab

• DFS en pCR: HR 0,29• DFS en no pCR: HR 0.92

E90C600 x 4

Paclitaxel 175 + Trastu6 mg/kg x 4

Cirugía

Trastu x 1 año

N 217

pCR: ypT0 38,7%

ypT0N0 22,6%

E90C600 x 4

Paclitaxel 175 + Trastu6 mg/kg x 4

Cirugía

Trastu x 1 año

N 217

pCR: ypT0 38,7%

ypT0N0 22,6%

HER2+: Doble bloqueo

5 FU 600 mg/m2

Epi 75 mg/m2

CTX 600 mg/m2

Paclitaxel 80 mg/m2Trastuzumab 2 mg/kg

R

A

N

D

O

M

I

Z

A

T

I

O

NLapatinib 1000 mg CDD

Lapatinib 1500 mg continuous daily dose (CDD)

C

O

R

E

B

I

O

P

S

Y

S

U

R

G

E

R

Y

A

B

C

LVEF

CHERLOB trial (Guarnieri V, ASCO 2011)

NeoSphere: study design

THP (n=107)docetaxel +

trastuzumab +pertuzumab

HP (n=107)trastuzumab +

pertuzumab

TP (n=96)docetaxel + pertuzumab

S

U

R

G

R

Y

docetaxel q3w x 4→FEC q3w x 3

trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17



Study dosing: q3w x 4

TH (n=107)docetaxel + trastuzumab

Patients with

operable or

locally

advanced

/inflammatory*

HER2-positive BC

Chemo-naïve &

primary tumors

>2cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide

*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0

H, trastuzumab; P, pertuzumab; T, docetaxel3

NeoAltto Neosphere GeparQuinto

Pac-L Pac-H Pac-

HL

Doc-H Doc-

HP

HP Doc-P ED

H

ED

L

pCR

B

24,7% 29,5% 51,3% 29% 45,8% 16,8% 24% 50,4% 35,2%

pCR

B+N

20% 27,6% 46,9% 21,5% 39,3% 11,2% 17,7% 45% 29,9%

pCR

RE-

33,8% 36,5% 61,3% 36,8% 63,2% 29,1% 30% - -

0

10

20

30

40

50

60

70

TH THP HP TP

ER or PR pos

ER and PR neg

NeoSphere: pCR and hormone

receptors status

20.0

26.0

17.4

36.8

29.1 30.0

63.2

5.9

pC

R, %

9

5%

CI

H, trastuzumab; P, pertuzumab; T, docetaxel

7

HER2+: Doble bloqueo Opción sin antraciclinas

Tryphaena (Schneeweiss, SABCS 2011)

HER2-positive

EBC

centrally confirmed

(n = 225)

FEC

Trastuzumab

to complete

1 year

S

u

r

g

e

r

y

• All 3 arms were experimental

• Study dosing q3w:− FEC: 500 mg/m2, 100 mg/m2, 600 mg/m2

− Carboplatin: AUC 6− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Pertuzumab: 840 mg loading dose, 420 mg maintenance− Docetaxel: 75 mg/m2 (escalating to 100 mg/m2 if tolerated, in Arms A and B only)

Docetaxel

Cycles 1‒3 4‒6

Pertuzumab+ trastuzumab

Pertuzumab + trastuzumab

FECDocetaxel

Carboplatin

Docetaxel

Pertuzumab + trastuzumabC

B

A

Pathologic complete response by hormone

receptor status

ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; PR,

progesterone receptor; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

Pa

tho

log

ic c

om

ple

te r

esp

on

se (

%)

ER- and PR-negative ER- and/or PR-positive

79.4

65.0

46.248.6

83.8

50.0

ypT0/is

FEC+H+P x3 T+H+P x3

(n = 73)

FEC x3 T+H+P x3

(n = 75)

TCH+P x6(n = 77)

Neoadyuvancia en HER2+

• Doble bloqueo HER2 + QT (excepto B41)

• Antraciclinas excepto en casos seleccionados

(Tryphaena)

• Reexplorar la combinación antiHER2 + HT

(Pamela)

• Relevancia de pCR como marcador surrogado?

Neoaltto: no diferencias en DFS y OS

Piccart M, SABCS 2013

Fenotipo Triple Negativo

7

16

0

10

20

30

40

50

60

18

30 31

50

.

Grade 1-2 Grade 3

HR+

No Tras Yes Tras

HER2+ HR+

No Tras Yes Tras

HER2+ HR- TRIPLE NEG

34

pCR Rates by Tumor Subtypes

FDA, SABCS 2012

Basal-like 1: cell cycle, DNA repair and

proliferation genes

Basal-like 2: Growth factorsignaling (EGFR, MET, Wnt,

IGF1R)

IM: immune cellprocesses (medullary

breast cancer)

M: Cell motility and differentiation, EMT

processes

MSL: similar to M butgrowth factor signaling, lowlevels of proliferation genes

(metaplastic cancers)

LAR: Androgen receptor and downstream genes,

luminal featuresLehmann, Bauer, Chen, et al.,

J Clin Invest doi:10.1172/JCI45014.

Identification of Human TNBC Subtypes

GEPARSIXTO (von Minckwitz, ASCO 2013)

•Adición de carbo a tto neoadyuvante en TN y HER2+

•pCR 46 vs 37% en global58 vs 38% en TN (< 0,05)33 vs 36 % en HER2+ (ns)

•en TN, si pT0/is N0, pCR de 64% (la mayor reportada en TN)

•Apoya estudios futuros con platinos en neoadyuvancia

CALGB 40603 (Sikov, SABCS 2013)

•Adición de carbo y bevacizumab a tto neoadyuvante en TN •Paclitaxel semanal +/-beva +/- carboplatino

seguido ACX4 (dd)•pCR mama y axila:

- 41 vs 54% a favor de carboplatino (p 0,0029)- 44 vs 52% tendencia a favor de beva (NS)

•Junto a datos de Geparsixto, valorar adición de carboplatino

•Necesario mayor seguimiento (SLE)

DNA Repair and synthetic lethality

Adapted from Carey L. Oncologist 2010

Chemo, XRT and Other Insults

DNA DAMAGE

Normal cell BRCA loss PARP

deficient

BRCA loss +

PARP

deficient

VIABLE VIABLE VIABLE DEAD

HR BER HR BER HR BER HR BER

HR: Homologous Recombination

BER: Base Excision Repair




DNA DAMAGE


deficient

BRCA loss +

PARP

deficient





X




DNA DAMAGE


deficient

BRCA loss +

PARP

deficient





X X




DNA DAMAGE


deficient

BRCA loss +

PARP

deficient





X X X X




DNA DAMAGE


deficient

BRCA loss +

PARP

deficient





X X X X

“Synthetic

Lethality”

That which does not kill you…

sets you up so that the next blow will be lethal

PRECOG 0105: (ML Telli, ASCO 2013)

• Neoadyuvancia fase II gem y carbo y iniparib en TN y BRCA ½ mutados

• I-IIIA, T> 1cm. TN o mutación BRCA ½

•Carbo AUC2 d1,8 + Gem 1000 d1,8 + iniparib 5,6 mg (x4) cada 3sem, x 6 ciclos

•N80

•pCR 36% en global

•pCR 33% si BRCAwt47% si BRCA mut56% si TN y BRCA mut

•PAM50 subtipos :Subtipo inmunomodulador con 79% de pCR

Fenotipo Triple Negativo

• Quimioterapia convencional basada

en antraciclinas y taxanos

• Posible papel para platinos e inhibidores

de PARP

• Subtipos intrínsecos (7)

• Papel dudoso de bevacizumab

Tratamiento hormonal neoadyuvante

- pCR poco habitual (< 10%)

- Respuestas clínicas frecuentes, más cirugía conservadora

- Duración indeterminada (>16 semanas; respuestas 12-24m)

- Descenso de Ki67: marcador pronóstico a largo plazo

(estudio IMPACT, Dowsett M, J Natl Cancer Inst 2007; 99: 167-170)

- Ensayo clínico / No candidatas a QT neoadyuvante

(postmenopaúsicas, edad, comorbilidad asociada)

Tratamiento endocrino

neoadyuvante cáncer de mama (CM)

ACOSOG Z-1031

Ellis M, SABCS 2010

Tratamiento hormonal adyuvante vs neoadyuvante

Estudio

adyuvante

Resultados Estudio

neoadyuvante

Resultados

BIG 1-98

Thurlimann 2005

Let > Tam

N 8010

P024

Ellis 2003

Let > Tam

N 185

ATAC

Baum 2002

Ana > Tam

N 9366

IMPACT

Dowsett 2005

Ana > Tam

N 147

MA 27

Goss 2010

Ana = Exe

N 9000

Z1031

Ellis 2010

Ana = Exe

N 165

FACE

?

Ana vs Let ?

N 4000

Z1031

Ellis 2010

Ana = Let

N 161

Ellis M, SABCS 2010

Ellis MJ, et al. JNCI 2008

Preoperative Endocrine Prognostic Index

Basado en pT, N, ER score, y Ki-67 tras 3-4 meses de Tto

Hormonoterapia Neoadyuvante

Información Pronóstica

PEPI Score

Aspectos de manejo

Careful physical and radiological examination at diagnosis

- measuring of primary tumor size

- bilateral mammography, US, MRI

- core needle biopsy in all suspected lesions

- radiopaque clips placed within all lesions at biopsy

- careful assessment of regional lymph nodes:

- Physical exam

- US +/- FNA

- consider sentinel node biopsy before / after tx

Neoadjuvant chemotherapy:

How to optimize locoregional tx?

Symmans WF, J Clin Oncol 2007; 25: 4414-4422

Necesidad de trabajar en Unidades Multidisciplinares

Aspectos regulatorios

ACCELERATEDAPPROVAL

NEOADJUVANTTRIAL

PATHOLOGICAL COMPLETE

RESPONSEpCR

EFSOS

REGULARAPPROVAL

META-ANALISIS EN JUNIO 2012

RESULTADOS MA EN DIC 2012

GUIA DISEÑO EC APROB ACELERADA

FDA: Aprobación Acelerada en base a RCp

(pertuzumab)

Possibly due to:

• low pCR rates

• small pCR improvements

• heterogeneous population

• lack of targeted therapies

Larger pCR differences between treatment

arms may translate into long-term outcome

and may vary according to breast cancer

subtype (more agressive.: TN, HER2+)

FDA pooled-analysis could not establish

pCR as a surrogate endpoint for EFS/OS

Neoadyuvancia en Cáncer de - Doctaforum · •Inicio precoz del tto sistémico •Downstaging (operabilidad, qx conservadora) •Test in vivo del efecto antitumoral •Valor pronóstico

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