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Personalized medicine Tumour vs Patient Profile Etienne GC Brain, MD PhD Medical Oncology Hôpital René Huguenin / Institut Curie Saint-Cloud, France

www.siog.org Disclosures

Receipt of grants/research supports: TEVA (Cephalon), HalioDX (Qiagen/Ipsogen), Amgen

Receipt of honoraria or consultation fees: Hospira, TEVA, OBI PHARMA, Roche, Amgen, Celgene, AstraZeneca,

Participation in a company sponsored speaker’s bureau: Hospira, AstraZeneca, Roche, Janssen • Stratified/tailored medicine (precision)  Develop drug in a population defined by a biomarker = companion biomarker

• Personalized medicine  Each patient is unique

• Precision & Personalized medicine - Way that healthcare is moving in the future - Model customizing healthcare based on the individual 's and tumour ’s genetics - Main goal = to make medicine predictive (precision ), preventive , personalized and participatory

Introduction to tumours

• Importance to make a distinction between – Somatic mutation: tumour DNA – Germinal mutation: any detectable and heritable variation in the lineage of germ cells • BRCA 1 & 2: predisposition to breast & ovarian cancer • DPD: pharmacogenomic and metabolism of 5-FU

• Cancer = genetic disease – Succession of genome alterations "Standard" vs "innovative" treatments

Cytotoxic agents Targeted treatments

ADN enzymes tubules

alkylating anti-topo I anti- cisplatin irinotecan microtubules taxane oxaliplatin topotecan vinorelbine

anti- anti-topo II metabolites anthracycline 5-FU etoposide gemcitabine IPILUMUMAB VISMODEGIB IMATINIBGEFITINIB

Targeted therapies

2000 2005 2010 Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy

Targeted Targeted Targeted Targeted Targeted Targeted Targeted therapy therapy therapy therapy therapy therapy therapy c-erbB2 1985-1989

• Oncogene, chromosome 17 (17q12) • Protein 185 kD, tyrosine kinase receptor • EGFR family • No ligand c-erbB2 • Activation = heterodimerization • Signal transduction – Proliferation – Survival – Angiogenesis – Etc. • ~ 20% of breast cancer

Coussens. Science 1985; Slamon. Science 1987 & 1989; Hynes. Biochem Biophys Acta Rev Cancer 1994; Gusterson. J Clin Oncol 1992 1990 = trastuzumab (Herceptin®) 1st humanized antibody (95%) anti-HER2

TGF-α EGF Heregulin Epiregulin (neuregulin-1) Betacellulin Epiregulin HB-EGF Heregulin (neuregulin-1) HB-EGF Amphiregulin Neuregulins-2,3,4 Ligand- binding domain

Trans- membrane

Tyrosine kinase domain Erb-B3 Erb-B1 Erb-B4 HER3 EGFR Erb-B2 HER4 HER1 HER2/ neu Survival Analysis of the Carolina Breast Cancer Study Cases Grouped Using the Refined Breast Tumor Immunohistochemical Intrinsic Subtypes

Carey, L. A. et al. JAMA 2006;295:2492-2502.

Copyright restrictions may apply. Prat, Mol Oncol 2011 Moja. Cochrane Database Syst Rev 2012 CLEOPATRA docetaxel + trastuzumab ±

Baselga. N Engl J Med 2012 Targets Targeted theapy Tumour type Biomarker EGFR Erlotinib/ Lung Mutation EGFR Cetuximab/Panitumumab Colon Mutation KRAS Cetuximab H&N - HER-2 Trastuzumab/TDM-1 Breast Amplification HER2 Lapatinib/Pertuzumab Breast Amplification HER2 Trastuzumab Stomach Amplification HER2 mTOR Temsirolimus/Everolimus Kidney - Everolimus Endocrine tumours - c-Kit GIST Over expression c-Kit SMO Vismodegib Basocellularcarcinoma - VEGF(R) Bevacizumab Breast, kidney, colon, lung - Sunitinib Kidney, endocrine tumours - Sorafenib Kidney, hepatocarcinoma - HDAC Vorinostat Cutaneouslymphoa - NF-κB Bortezomib Multiple myeloma - CTLA4 Ipilumumab Melanoma - RAF Vemurafenib Melanoma Mutation V600E BRAF ALK Crizotinib Lung Translocation ALK RET Vandetanib/ Thyroidmedullarycarcinoma - Lung adenocarcinoma – HER2 mutation V659E – Lapatinib

Melanoma – KIT mutation – Imatinib Serra Cancer Discov 2013 Hodi J Clin Oncol 2013 Molecular profile

Molecular abnormality

Thérapie ciblée Thérapie ciblée Thérapie ciblée Thérapie ciblée Thérapie ciblée Thérapie ciblée Thérapie ciblée

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