Surexpression de HER2 un diktat? Paul COTTU Jean-Yves PIERGA Institut Curie Paris

Transcription

1 Surexpression de HER2 un diktat? Paul COTTU Jean-Yves PIERGA Institut Curie Paris 1 - -

2 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 : isolement et description du RE RE alpha et beta Récepteurs nucléaires Variants et régulation : description de HER2/neu/c-erbB : Portraits moléculaires Sous type «HER2 enriched» 2 - Dr Cottu SFSPM 2011 La longue marche de la caractérisation biologique des cancers du sein HER2 est une étape clé

3 3 - Dr Cottu SFSPM 2011

4 Identification des carcinomes basal-like par les analyses des profils d expression des carcinomes canalaires infiltrants Récepteurs Oestrogènes Basal-like ERBB2 Récepteurs Oestrogènes + Luminal A, B, C Pronostic défavorable 4 - Dr Cottu SFSPM 2011 Sorlie et al, PNAS 2001

5 Séries rétrospectives 5 - Dr Cottu SFSPM 2011 Cheang, JNCI 2009

6 6 - Dr Cottu SFSPM 2011

7 Impact du traitement sur l histoire naturelle du cancer du sein métastatique Dawood JCO 2009

8 Profil d expression des cancers invasifs «LUMINAL» «HER2 +» KRT 8/18 + ESR1 +++ ESR genes regulated BCL2 + ESR1 + ESR1 - GRB7 TP53 * 71% RAS pathway «Normal like» «BASAL» TOP2A MYC KIT pathways ESR1- KRT5/17 + HER2 TP53 * 82% «BRCA1» BCL2 EGFR Perou et al, Sorlie et al, Bertucci et al, Sotiriou et al, Hedenfalk et al, West et al Van de Rijn et al Am J Pathol 2002, Abd El Rehim et al J Pathol Dr Cottu SFSPM 2011

9 Pronostic hétérogène au sein du cluster HER2 9 - Dr Cottu SFSPM 2011 Staaf, JCO, 2010

10 Amplification hétérogène Essai N9831 : survie sans rechute en fonction du traitement par trastuzumab (amplification focale - AF versus amplification diffuse - AD) AF + tras AD + tras AD AF Années Sukov et al., ASCO 2010, abstract 520 actualisé 10 - Dr Cottu SFSPM 2011

11 T1abN0 M0 données Curie 4 TZM P=0.02 NO TZM Kaplan-Meier Disease-Free Survival (months) 11 - Dr Cottu SFSPM 2011 Rodrigues MJ & P. Cottu Ann Oncol 2011 Message : HER2 est FORTEMENT pronostique!

12 HER2 est oncogénique 12 - Dr Cottu SFSPM 2011 Hudis, NEJM 2007

13 Crosstalks 13 - Dr Cottu SFSPM 2011 Pietras, CCR 2007

14 HER2 et RE 14 - Dr Cottu SFSPM 2011 Hurtado, Nature 2008

15 Ciblage HER2 : trastuzumab 15 - Dr Cottu SFSPM 2011 Hudis, NEJM 2007

16 Phase métastatique Hudis, NEJM Dr Cottu SFSPM 2011

17 Phase métastatique (2) 17 - Dr Cottu SFSPM 2011

18 Phase précoce 18 - Dr Cottu SFSPM 2011 Hudis, NEJM 2007

19 19 - Dr Cottu SFSPM 2011

20 Dual Targeting of HER2 Receptor May Have Enhanced Efficacy Trastuzumab T 1 1 L 2 L 2 L 1 L 2 L L Lapatinib Downstream signaling pathways Cell proliferation Cell survival 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.

21 Double ciblage 21 - Dr Cottu SFSPM 2011 Blackwell, JCO 2010

22 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSphere: study design and objectives Patients with operable or locally advanced / inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) Study dosing: q3w x 4 S U R G E R Y Phase II design Primary endpoint: comparison of pcr rates TH vs THP TH vs HP THP vs TP Secondary endpoints: Clinical response DFS Breast conservation rate Biomarker evaluation 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, docetaxel This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. L. Gianni 4 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

23 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSphere: pcr and hormone receptors status 70 pcr, % ± 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. ER or PR pos ER and PR neg 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.

24 HER2 dans les référentiels 24 - Dr Cottu SFSPM 2011

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26 HER2 dans les référentiels 26 - Dr Cottu SFSPM 2011

27 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 27 - Dr Cottu SFSPM 2011

28 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 28 - Dr Cottu SFSPM 2011