Antonio González H. Universitario Ramón y Cajal Madrid Biología del tumor que sobre-expresa HER2: Implicaciones en el tratamiento adyuvante Antonio González H. Universitario Ramón y Cajal Madrid
Science. 1987 Jan 9;235(4785):177-82. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.
Implicación Pronóstica de HER2 20-30% PACIENTES SOBRE-EXPRESAN O TIENEN AMPLIFICADO HER2 MENOR SUPERVIVENCIA. PERFIL DIFERENCIAL DE RESPUESTA A QUIMIOTERAPIA Y HORMONOTERAPIA 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.
HER1, HER2, HER3, and HER4 (also called epidermal growth factor receptors ErbB-1, ErbB-2, ErB-3, and ErB-4, respectively) are transmembrane tyrosine kinase receptors with partial homology that normally regulate cell growth and survival, as well as adhesion, migration, differentiation, and other cellular responses Each of these receptors consists of an extracellular binding domain, a transmembrane lipophilic segment, and (except for HER3) a functional intracellular tyrosine kinase domain.
The tyrosine kinase domains are activated by both homodimerization and heterodimerization, generally induced by ligand binding. In contrast to the extracellular domains of the three other HER receptors, the extracellular domain of HER2 can adopt a fixed conformation resembling a ligand-activated state, permitting it to dimerize in the absence of a ligand Receptor overexpression or mutation can also induce dimerization HER2 is the preferred dimerization partner for the other HER family members
Figure 1. Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab. As shown in Panel A, the four members of the HER family are HER1, HER2, HER3, and HER4. There are receptor-specific ligands for HER1, HER3, and HER4. An intracellular tyrosine kinase domain exists for HER1, HER2, and HER4. Phosphorylation of the tyrosine kinase domain by means of homodimerization or heterodimerization induces both cell proliferation and survival signaling. HER2 is the preferred dimerization partner for the other HER family members. The phosphorylated (activated) tyrosine residues on the intracellular domain of HER2 activate the lipid kinase phosphoinositide 3-kinase (PI3-K), which phosphorylates a phosphatidylinositol that in turn binds and phosphorylates the enzyme Ak transforming factor (Akt), driving cell survival. In parallel, a guanine nucleotide exchange factor, the mammalian homologue of the son of sevenless (SOS), activates the rat sarcoma (RAS) enzyme that, in turn, activates receptor activation factor (RAF) and then the mitogen-activated protein kinase (MAPK) and mitogen extracellular signal kinase (MEK). MEK phosphorylates, among others, the MAPK, driving cellular proliferation. One of many other downstream effects is the production of vascular endothelial growth factor (VEGF) supporting angiogenesis. The most well-documented potential mechanisms of action are shown in Panels B through F. Cleavage of the extracellular domain of HER2 leaves a membrane-bound phosphorylated p95, which can activate signal-transduction pathways (Panel B). Binding of trastuzumab to a juxtamembrane domain of HER2 reduces shedding of the extracellular domain, thereby reducing p95 (Panel C). Trastuzumab may reduce HER2 signaling by physically inhibiting either homodimerization, as shown, or heterodimerization (Panel D). Trastuzumab may recruit Fc-competent immune effector cells and the other components of antibody-dependent cell-mediated cytotoxicity, leading to tumor-cell death (Panel E). Additional mechanisms such as receptor down-regulation through endocytosis have been postulated (Panel F). 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.
Cell Survival Cell Proliferation Figure 1. Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab. As shown in Panel A, the four members of the HER family are HER1, HER2, HER3, and HER4. There are receptor-specific ligands for HER1, HER3, and HER4. An intracellular tyrosine kinase domain exists for HER1, HER2, and HER4. Phosphorylation of the tyrosine kinase domain by means of homodimerization or heterodimerization induces both cell proliferation and survival signaling. HER2 is the preferred dimerization partner for the other HER family members. The phosphorylated (activated) tyrosine residues on the intracellular domain of HER2 activate the lipid kinase phosphoinositide 3-kinase (PI3-K), which phosphorylates a phosphatidylinositol that in turn binds and phosphorylates the enzyme Ak transforming factor (Akt), driving cell survival. In parallel, a guanine nucleotide exchange factor, the mammalian homologue of the son of sevenless (SOS), activates the rat sarcoma (RAS) enzyme that, in turn, activates receptor activation factor (RAF) and then the mitogen-activated protein kinase (MAPK) and mitogen extracellular signal kinase (MEK). MEK phosphorylates, among others, the MAPK, driving cellular proliferation. One of many other downstream effects is the production of vascular endothelial growth factor (VEGF) supporting angiogenesis. The most well-documented potential mechanisms of action are shown in Panels B through F. Cleavage of the extracellular domain of HER2 leaves a membrane-bound phosphorylated p95, which can activate signal-transduction pathways (Panel B). Binding of trastuzumab to a juxtamembrane domain of HER2 reduces shedding of the extracellular domain, thereby reducing p95 (Panel C). Trastuzumab may reduce HER2 signaling by physically inhibiting either homodimerization, as shown, or heterodimerization (Panel D). Trastuzumab may recruit Fc-competent immune effector cells and the other components of antibody-dependent cell-mediated cytotoxicity, leading to tumor-cell death (Panel E). Additional mechanisms such as receptor down-regulation through endocytosis have been postulated (Panel F). Cell Proliferation Hudis C. N Engl J Med 2007;357:39-51
La vía de PI3k es la más importante para la transformación.
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-quantitative interpretation of HER2 expression ‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)
Dual-colour FISH scoring No amplification HER2 negative Amplification HER2 positive Normal HER2 gene copy number Increased HER2 gene copy number
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 IgG1 Humana Figura . Estructura de trastuzumab
Xenoinjerto humano de mama positivo para HER2 (MCF-7) Volumen tumoral (mm3) 2000 Control Herceptin 1500 1000 Tumor vuelve a crecer Se requieren niveles sostenidos de Herceptin para lograr inhibición tumoral Se suspende Herceptin 500 10 20 30 40 50 60 70 Días Adaptado con autorización de Macmillan Publishers Ltd Oncogene 17; 2235-2249, copyright 1998 Pietras et al 1998
Mechanisms of Action of Trastuzumab The most well-documented potential mechanisms of action are shown in Panels B through F. Cleavage of the extracellular domain of HER2 leaves a membrane-bound phosphorylated p95, which can activate signal-transduction pathways (Panel B). Binding of trastuzumab to a juxtamembrane domain of HER2 reduces shedding of the extracellular domain, thereby reducing p95 (Panel C). Trastuzumab may reduce HER2 signaling by physically inhibiting either homodimerization, as shown, or heterodimerization (Panel D). Trastuzumab may recruit Fc-competent immune effector cells and the other components of antibody-dependent cell-mediated cytotoxicity, leading to tumor-cell death (Panel E). Additional mechanisms such as receptor down-regulation through endocytosis have been postulated (Panel F). Promote tretameric forms which become internalized Mechanisms of Action of Trastuzumab Hudis C. N Engl J Med 2007;357:39-51
Intracellular Effects Induction of apoptosis Decrease proliferation HER2 down regulation Decrease VGEF production Potentiation of chemotherapy Altered cross talk with others sgnal path Interactions between Trastuzumab and Tumor Cells. HER2 serves as a coreceptor with related members of the HER family of tyrosine kinase-associated growth factors. Acquired amplification of the HER2/neu gene on chromosome 17 in HER2-positive breast cancer leads to marked overexpression of HER2 on the cell surface, which alters normal signaling function. Trastuzumab is a humanized monoclonal antibody that binds to HER2 and inhibits tumor-cell growth through a variety of intracellular, and possibly extracellular, mechanisms. Burstein H. N Engl J Med 2005;353:1652-1654
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
BCIRG 006 AC T AC TH DCH 4 x AC 60/600mg/m2 4 x docetaxel HER2+ FISH AC TH n=3,150 N+, high-risk N– (29%) 1-year Herceptin® 6 x docetaxel and carboplatin 75mg/m2 AUC 6 DCH 1-year Herceptin® Crossover 1.6 % Slamon. SABCS 2006
Median Follow-up 36 months 462 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
B-31 HERA 1.8% BCIRG 006
15% recaída E. Perez. ASCO 2007
Overcoming Trastuzumab resistance Block 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 and Trastuzumab bind distinct epitopes on HER2 Omnitarg and Herceptin bind to different and nonoverlapping regions (epitopes) on the extracellular domain of the HER2 receptor protein. The mechanism of action of Omnitarg is inhibition of HER dimerization; Herceptin does not affect HER dimerization. Omnitarg is potentially more broadly applicable than Herceptin across a number of tumor types, including tumors that do not overexpress HER2 or show HER2 gene amplification. Protects against receptor shedding Has no effect on role of HER2 as a coreceptor Inhibits HER2-mediated signaling pathways Applicable to breast cancer tumors that overexpress 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
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, n Patients (N = 33) CR 1 PR 5 SD for 6 mos 7 PD 10 LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer; CR, Complete response; PR, Partial response; SD, Stable Disease; PD Progressive disease Baselga J, et al. ASCO 2007. Abstract 1004. 49 49
WO20697 Neoadjuvant Treatment Adjuvant Treatment A S Trastuzumab q3wks until Cycle 17 A Trastuzumab & Docetaxel S U R G E Y 5-Fluorouracil, Epirubicin, Cyclophosphamide (FEC) q3wk A Trastuzumab & Pertuzumab & Docetaxel B B R Docetaxel 75mg x C5, 100mg C6 –C8 FEC q3wk Trastuzumab & Pertuzumab C C Study dosing q3wks Cycles 1 – 4 Study dosing Cycles 5-17
MCF-7/HER2 Xenografts: Chemotherapy + Trastuzumab + Bevacizumab Pre-Clinical Synergy 3000 Paclitaxel Paclitaxel + bevacizumab + trastuzumab Paclitaxel +trastuzumab Paclitaxel + bevacizumab Control 2000 Tumor Volume (mm3) 1000 20 40 60 80 100 120 Days Epstein. Breast Cancer Res Treat. 2002;76:S143. Abstract S70.
Resected and centrally confirmed HER-2 + node + or high risk node negative BC NSABP B44 CIRG011 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
Conclusiones HER2 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