Surexpression de HER2 un diktat - senologie.tvsenologie.tv/_2011/pdf/J3/COTTU.pdf · 1 - -...
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1 - - Surexpression de HER2 un diktat ? Paul COTTU Jean-Yves PIERGA Institut Curie Paris
Transcript of Surexpression de HER2 un diktat - senologie.tvsenologie.tv/_2011/pdf/J3/COTTU.pdf · 1 - -...
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Surexpression de HER2un diktat ?
Paul COTTUJean-Yves PIERGA
Institut CurieParis
2 - Dr Cottu – SFSPM 2011
Biologie du cancer du sein
• Beatson 1896 : l’ovariectomie a un effet antitumoral chez les femmes non ménopausées atteintes de cancer du sein avancé
• Années 1960-70 : isolement et description du RE RE alpha et beta Récepteurs nucléaires Variants et régulation
• 1987-1989 : description de HER2/neu/c-erbB2
• 2000 : Portraits moléculaires Sous type « HER2 enriched »
La longue marche de la caractérisation biologique des cancers du seinHER2 est une étape clé
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Identification des carcinomes basal-likepar les analyses des profils d’expression
des carcinomes canalaires infiltrants
RécepteursOestrogènes -
RécepteursOestrogènes +
Basal-like ERBB2 Luminal A, B, C
Pronostic défavorable
Sorlie et al, PNAS 2001
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Séries rétrospectives
Cheang, JNCI 2009
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Impact du traitement sur l’histoire naturelle du cancer du sein métastatique
Dawood JCO 2009
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« Normal like »
« BRCA1 »
BCL2EGFR
« LUMINAL»
KRT 8/18 +ESR1 +++ESR genes regulatedBCL2 +
« HER2 + »
ESR1 -GRB7
TP53 * 71%RAS pathway
«BASAL»ESR1-
KRT5/17 +HER2 –
TP53 * 82% TOP2A
MYC KIT pathways
ESR1 +
Profil d’expressiondes cancers invasifs
Perou et al, Sorlie et al, Bertucci et al, Sotiriou et al, Hedenfalk et al, West et alVan de Rijn et al Am J Pathol 2002, Abd El Rehim et al J Pathol 2004
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Pronostic hétérogène au sein du cluster HER2
Staaf, JCO, 2010
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Amplification hétérogène
100
80
60
400 1 2 3 4 5 6
Années
Essai N9831 : survie sans rechuteen fonction du traitement par trastuzumab(amplification focale - AF versus amplification diffuse - AD)
Sukov et al., ASCO 2010, abstract 520 actualisé
AFAD
AD + tras
AF + tras
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T1abN0 M0données Curie
4
Kaplan-Meier Disease-Free Survival (months)
TZM
NO TZMP=0.02
Rodrigues MJ…& P. Cottu Ann Oncol 2011
Message : HER2 est FORTEMENT pronostique !
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HER2 est oncogénique
Hudis, NEJM 2007
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Crosstalks
Pietras, CCR 2007
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HER2 et RE
Hurtado, Nature 2008
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Ciblage HER2 : trastuzumab
Hudis, NEJM 2007
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Phase métastatique
Hudis, NEJM 2007
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Phase métastatique (2)
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Phase précoce
Hudis, NEJM 2007
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1 2
Downstream signaling pathways
Cell proliferation Cell survival
Dual Targeting of HER2 Receptor May Have Enhanced Efficacy
21 1 2
TrastuzumabT
LapatinibL L L L L L
The HER family of surface receptors, when dysregulated, constitute an important prognostic marker, offer tumors a growth advantage, and in the case of HER2 in breast cancer, have a secured role as a proven therapeutic target.A number of targeting strategies are available against HER family members including monoclonal antibodies against the extracellular domain of the receptor, small molecule inhibitors against the intracellular kinase domain, targeting strategies that link a toxic agent with an antibody against the receptor, and molecules, such as heat shock protein inhibitors, that downregulate expression of the receptor.Trastuzumab, a monoclonal approach, offers the advantage of specific targeting against the HER2 receptor and has proven survival benefits when combined with chemotherapy in the treatment of early stage and metastatic breast cancer.Lapatinib, a small molecule inhibitor approach, offers the advantage of targeting multiple receptors, in this case both HER1 and HER2, and does not require a specific extracellular binding domain. When combined with chemotherapy in the treatment of metastatic breast cancer, lapatinib has demonstrated an imroved PFS over chemotherapy alone.As both approaches have demonstrated clinical and biologic benefits, a strategy of optimal HER2 inhibition combining two inhibitory strategies is highly attractive approach in the treatment of breast cancer that is HER2 driven.
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Double ciblage
Blackwell, JCO 2010
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010
This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
NeoSphere: study design and objectives
THP (n=107)docetaxel (75→100 mg/m2) trastuzumab (8→6 mg/kg) pertuzumab (840→420 mg)
HP (n=107)trastuzumab (8→6 mg/kg) pertuzumab (840→420 mg)
TP (n=96)docetaxel (75→100 mg/m2) pertuzumab (840→420 mg)
TH (n=107)docetaxel (75→100 mg/m2)trastuzumab (8→6 mg/kg) S
UR
GERY
• Phase II design
• Primary endpoint:comparison of pCR rates TH vs THPTH vs HP THP vs TP
• Secondary endpoints:Clinical responseDFSBreast conservation rateBiomarker evaluation
Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417)
Study dosing: q3w x 4
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, M0H, trastuzumab; P, pertuzumab; T, docetaxel
4L. Gianni
Today I will present results of the primary analysis of the neoadjuvant portion of the NeoSphere that had a Phase II design with the primary objective f comparing rates of pCR n the breast among the different arms of the study.The doses of the two monoclonal antbodies and of docetaxel are indicated in the box illustrating each arm of the NeoSphere
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010
This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR posER and PR neg
NeoSphere: pCR and hormone receptors status
20.026.0
17.4
36.8
29.1 30.0
63.2
5.9
pCR
, % ±
95%
C
IH, trastuzumab; P, pertuzumab; T, docetaxel
7
In the NeoSphere patients were stratified according thìo the hormone receptor status of their tumors, and an exploratory subset analysis showed, as expected from other trials as well, the eradication of a consistently higher proportion of tumors in the ER and PR negative than in the ER or PR positive cases. This trend could be seen also in women receiving the doublet of the two monoclonals.
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HER2 dans les référentiels
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HER2 dans les référentiels
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Conclusions (1)
• la description de HER2 a fait faire un bond à la connaissance de la biologie des cancers du sein
• la surexpression de HER2 Contribue à la classification des cancers du sein Est fortement pronostique
• HER2 est une cible thérapeutique majeure Le ciblage de HER2 a transformé l’histoire naturelle des cancers du sein
HER2+ L’exploration des voies de résistance génère le progrès thérapeutique
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Conclusions (2)
• Donc, apprécier la surexpression de HER2 est un « diktat »
• A court terme, cette surexpression sera détaillée P95 Hétéro- et homodimères Activation des voies de résistance : PI3K, PTEN, etc
