2. 2nd Quebec Conference on Therapeutic Resistance in Cancer Bienvenue !!!!!

4. Network and Partners Q-CROC Government FRSQ (research) MDEIE (economic dev.) MSSS (health) Universities Hospitals Pharma (Pfizer, Sanofi and many others) Coalition Priorité Cancer (advocacy group) Members 80 members from Montréal, Québec City and Sherbrooke

5. Prospective Study to Identify Molecular Mechanisms of Clinical Resistance to Standard First-Line Therapy in Patients with Metastatic Colorectal Cancer (Q- CROC-01) Needle core biopsies of liver metastasis at D0 and at acquired resistance Needle core biopsies of liver metastasis at D0 and at acquired resistance Blood samples collected and banked during treatment Blood samples collected and banked during treatment Biopsy-driven study in Non-Hodkins Lymphoma (NHL) using rituximab in combination with a drug involved in epigenetic modifications (Q-CROC-02) Lymph node biopsies D0, D15 and optional at 24 hrs Lymph node biopsies D0, D15 and optional at 24 hrs PBMC isolation at D0 and D15 PBMC isolation at D0 and D15 The genomics and proteomics of Triple Negative Breast Cancer drug resistant breast cancer (Q-CROC-03) Neoadjuvant: Biopsy: breast before treatment and at surgeryNeoadjuvant: Biopsy: breast before treatment and at surgery Metastatic: Biopsy: liver, skin, lung, pleura; before and after treatmentMetastatic: Biopsy: liver, skin, lung, pleura; before and after treatment Ongoing Q-CROC Research Projects

6. ER+ luminal A ER+ luminal A ER+ luminal B ER+ luminal B HER2+ HER2+ Triple negative (ER-PR-HER2-), basal-like Triple negative (ER-PR-HER2-), basal-like normal normal Breast cancer gene expression array phenotyping can guide therapy: This is only a first step.......

7. Predictive markers: WHY? Estrogen receptor: the oldest target and tumor marker Tamoxifen: discovered in 1970s Efficacy in ER+ breast cancers adjuvant Prognostic, biologic factors Resistance

8. Romond E et al. N Engl J Med 2005;353:1673-1684 Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B) HERCEPTIN: effective in breast cancer patients with ERBB2 amplification (approx 15-25% breast cancer patients) Predictive markers: WHY? $ 50000/year

9. Burning questions: WHO can be spared unnecessary treatment? WHO will predictably not benefit? HOW can we overcome resistance? Focus on therapeutic resistance in the metastatic setting

10. FOCUS: Metastatic disease Metastases are ultimately the lethal element They are either initially or inevitably become resistant New treatments are almost always studied in this setting There are opportunties for biology discovery (e.g. discordance between primary and metastatic tumors, etc.) Limited number of annotated biobanks of metastatic tumors linked to specific therapies

11. FOCUS: Therapeutic resistance Clinically resistance is a ‘hard endpoint’…what is stable disease? Scientific opportunities The biology of intrinsic resistance vs. acquired resistance ? Stem cells Novel mechanisms, novel cross-talk between pathways Modifications of drugs to overcome resistance Potential new chemosensitizers Diagnostic tests

12. Personalized medicine Because technology to facilitate it is rapidly developing; Because it is scientifically and conceptually appealing; Because it may be the only way to afford new targeted agents It is best for the patients, since humility requires us to recognize serious limitations in our current approach

13. Thanks to sponsors Canadian Institutes for Health Research: conference grant Canadian Institutes for Health Research: conference grant Gold sponsor: Roche Canada Gold sponsor: Roche Canada Platinum Sponsor: Astra Zeneca Platinum Sponsor: Astra Zeneca And many others And many others