Biología del tumor que sobre-expresa HER2: Implicaciones en el tratamiento adyuvante

Antonio González

H. Universitario Ramón y Cajal

Madrid

Berger et al. Cancer Res. 1988;48:1238. Chazin et al. Oncogene. 1992;7:1859. Hynes and Stern. Biochim Biophys Acta. 1994;1198:165. O’Reilly et al. Br J Cancer. 1991;63:444. Paik et al. J Clin Oncol. 1990;8:103. Press et al. J Clin Oncol. 1997;15:2894. Slamon et al. Science. 1987;235:177. van de Vijver et al. N Engl J Med. 1988;319:1239.

Implicación Pronóstica de HER2

20-30% PACIENTES SOBRE-EXPRESAN O TIENEN AMPLIFICADO HER2

MENOR SUPERVIVENCIA.

PERFIL DIFERENCIAL DE RESPUESTA A QUIMIOTERAPIA Y HORMONOTERAPIA

Hudis C. N Engl J Med 2007;357:39-51

Dimerización La dimerización ocurre por contacto de

los dominios II y IV HER2 tiene una conformación abierta

que favorece la dimerización espontánea.

Los heterodímeros de EGFR o ErbB3 con HER2 son los más estables compañero preferido de dimerización.

Hudis C. N Engl J Med 2007;357:39-51

Cell Proliferation

Cell Survival

Survivin Interfiere con caspasas actuando como inhibidor

de apoptosis Afecta la formación del huso mitótico e interfiere

en la citoquinesis Sobre-expresión de survivina causa aneuploidia

IHC scoring: semi-quantitativeinterpretation of HER2 expression

‘1+’ (negative)

‘2+’ (equivocal) ‘3+’ (positive)

‘0’ (negative)

Dual-colour FISH scoring No amplification HER2 negative

Increased HER2 genecopy number

Normal HER2 genecopy number

Amplification HER2 positive

Approximately 20% of current HER2 testing may be inaccurate.

When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy.

Targeting HER2 by monoclonal antibodies

HERCEPTIN™ (TRASTUZUMAB): ANTICUERPO HUMANIZADO ANTI-HER2

Fragmento de anticuerpo murino con capacidad de reconocimiento de HER-2

IgG1Humana

Figura . Estructura de trastuzumab

Pietras et al 1998

Control

Herceptin

Se suspendeHerceptin

Volumen tumoral (mm3)

Tumorvuelve a crecer

Días

Xenoinjerto humano de mama positivo para HER2 (MCF-7)

2000

1500

1000

500

0706050403020100

Adaptado con autorización de Macmillan Publishers Ltd Oncogene 17; 2235-2249, copyright 1998

Hudis C. N Engl J Med 2007;357:39-51Mechanisms of Action of Trastuzumab

Burstein H. N Engl J Med 2005;353:1652-1654

Intracellular Effects

• Induction of apoptosis

• Decrease proliferation

• HER2 down regulation

• Decrease VGEF production

• Potentiation of chemotherapy

• Altered cross talk with others sgnal path

• 3968 pts; 619 events; 258 deaths• 2,9 year median follow-up• 21% crossover to trastuzumab concurrently or sequentially but they are analysed in the control group as “intent to treat”

E. Perez. ASCO 2007

•HR 0.48 (95% CI 0.41-0.57) at 4 years. E. Perez. ASCO 2007

HR 0.65 (95% CI 0.51-0.84) at 4 y.E. Perez. ASCO 2007

HER2+FISH

4 x AC60/600mg/m2

4 x docetaxel100mg/m2

6 x docetaxel and carboplatin75mg/m2 AUC 6

1-year Herceptin®

n=3,150N+, high-risk N– (29%)

1-year Herceptin®

AC T

AC TH

DCH

BCIRG 006

Crossover 1.6 % Slamon. SABCS 2006

Median Follow-up 36 months462 DFS events

HR 0·64 (0·54–0·76; p<0·0001)

HR 0·66 (0·47–0·91; p=0·0115)

FinHer (Finland Herceptin)N Enlg J Med 23 Feb 2006

1.8%

B-31

HERA

BCIRG 006

E. Perez. ASCO 2007

15% recaída

Overcoming Trastuzumab resistanceBlock the HER-2 pathway at other points (RKT, AKT, mTOR): RAD001, CCI-779

Block other growth factor receptor pathways (HER-1, IGF-R1): lapatinib, NVP-AEW541

Block angiogenesis (trastuzumab + bebacizumab)

Pertuzumab

• Protects against receptor shedding

• Has no effect on role of HER2 as a

coreceptor

• Inhibits HER2-mediated signaling pathways

• Applicable to breast cancer tumors thatoverexpress HER2

• Does not prevent receptor shedding

• Has a major effect on role of HER2 as a coreceptor

• Inhibits multiple HER-mediated signaling pathways

• Potentially applicable across a wide range of tumor types

Trastuzumab

Pertuzumab and Trastuzumab bind distinct epitopes on HER2

Phase II trial combining pertuzumab and trastuzumab in HER2+ MBC after progression on trastuzumab: Response and Toxicity Results

42 patients evaluable for toxicity and 33 evaluable for efficacy

Toxicity Diarrhea of any grade most common adverse

event (57% of patients)

Diarrhea only adverse event ≥ grade 3 (1 patient)

Only 1 patient with decrease in LVEF

Efficacy Measure, nPatients(N = 33)

CR 1

PR 5

SD for 6 mos 7

PD 10

Baselga J, et al. ASCO 2007. Abstract 1004.

WO20697Neoadjuvant Treatment

R

Trastuzumab & Docetaxel

Trastuzumab & Pertuzumab &

Docetaxel

Trastuzumab & Pertuzumab

Study dosing q3wks Cycles 1 – 4

Trastuzumab q3wks until Cycle 17

Adjuvant Treatment

S

U

R

G

E

R

Y

5-Fluorouracil, Epirubicin,

Cyclophosphamide (FEC) q3wk

Docetaxel 75mg x C5, 100mg C6 –

C8

FEC q3wk

Study dosing Cycles 5-17

A

B

C

A

B

C

MCF-7/HER2 Xenografts:Chemotherapy + Trastuzumab + Bevacizumab Pre-Clinical

Synergy

Epstein. Breast Cancer Res Treat. 2002;76:S143. Abstract S70.

1201008060402000

1000

2000

3000

Days

Tu

mor

Vol

um

e (m

m3 )

Paclitaxel

Paclitaxel + bevacizumab + trastuzumab

Paclitaxel +trastuzumabPaclitaxel + bevacizumab

Control

NSABP B44 CIRG011

Resected and centrally confirmed HER-2 + node + or high risk node negative BC

ESTRATIFICATION

• Number of nodes (0, 1-3, 4+)

•Hormone receptor (ER or PR +ve vs ER/PR –ve)

RANDOMIZATION

Chemotherapy*

+

Trastuzumab 1 year

Chemotherapy*

+

Trastuzumab 1 year

+

Bevacizumab 1 year*TCHH or THFECH

ConclusionesHER2 está sobre-expresado en 20-30% de pacientes con cáncer de mama y le confiere una menor supervivencia

La administración de trastuzumab en el tratamiento adyuvante reduce el riesgo de recaída en un 40-50%

Nuevos estudios en adyuvancia de pacientes HER2 asociando inhibidores de tirosin-kinasa (lapatinib) o anticuerpos frente a otro dominio extracelular (pertuzumab) o anti-VGEF (bevacizumab)

Muchas Gracias