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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