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A2 -Personalized Medicines: Challenges and opportunities from bench to patients: clinician researcher perspective - Dancey - Salon C
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A2 -Personalized Medicines: Challenges and opportunities from bench to patients: clinician researcher perspective - Dancey - Salon C

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  • 1. Personalized medicines: Challenges andopportunities from bench to patients:clinician researcher perspectiveJanet Dancey, MD FRCPCOntario Institute for Cancer ResearchNCIC Clinical Trials Group
  • 2. Personalized Medicine –One concept, a multitude of meanings and perspectivesPatient:I want my doctor to know aboutmy life, to understand me and myfamily and to help me reachdecisions that are best for me.I did not want to lose my hair ontreatment so we found an optionfor me that would spare my hair.Clinician:Which patient or diseasefeatures will alter myapproach toprevention, screening, ortreatment?Scientist:Each patient’s cancer has geneticchanges and each patient hasgenomic variations that makethem unique. We are looking forthose changes that will allow theright patient to receive the righttreatments matched to theirgenetic fingerprint.Courtesy of E Eisenhauer 2013Current status: A few successes – potential far from beingrealized
  • 3. Personalized medicine and cancer:A disease of the genomeChallenge in treating cancer:• Every tumour is different• Every cancer patient is different
  • 4. International Cancer Genome ConsortiumProjects as of April 2013High rate of abnormalities (driver vs. passenger);Multiple clones that evolve under the selectionpressures including systemic therapySample type, quality and timing matterMethods of analysis matter
  • 5. 0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%APC BRAF CTNNB1 EGFR KRAS NRAS PIK3CA PTEN RB1 STK11 TP53Lung carcinoma (all subtypes)Prostate adenocarcinomaBreast carcinoma (all subtypes)Colon adenocarcinomaPancreatic ductal adenocarcinomaOvarian carcinoma (all subtypes)Hepatocellular carcinomaGastric adenocarcinomaRenal cell carcinomaMalignant melanomaSurveys of mutation databases indicate that mostmutations are found in many tumour typesSanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54Release (Forbes et al., 2011).
  • 6. Gene Event Type Frequency, %FGFR1 Amplification 20-25FGFR2 Mutation 5PIK3CA Mutation 9PTEN Mutation deletion 18CCND1 Amplification 8CDKN2A Deletion/mutation 45PDGFRA Amplificationmutation9EGFR Amplification 10MCL1 Amplification 10BRAF Mutation 3DDR2 Mutation 4ERBB2 Amplification 2Emerging “Druggable” Targets inNSCLC-Squamous SubtypeLung Cancer Molecular Consortium LungAdenocarcinomasKris MG, et al. ASCO 2011. CRA7506. JohnsonBE, et al. IASLC WCLC 2011. Abstract O16.01Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1Many potential targets and biomarkersMET AMPMutations found in 54% (280/516)No mutationdetected KRAS22%EGFR17%NRASDoublemutants 3%AKT1BRAF 2%MEK1HER2PIK3CA 2%EML4-ALK7%
  • 7. • Need for rapid, accurate and comprehensive profiling ofcancer relevant molecular abnormalities• Need for repeated testing at critical management decisionpointsGenetic heterogeneity & emergence ofresistance
  • 8. CMAJ 2012. DOI:10.1503
  • 9. • Smith G, Pell JP. Parachute use to prevent death and major trauma related togravitational challenge: systematic review of randomised controlled trials.BMJ 2003;327: 1459–61.Personalized medicine: role of phase III trials
  • 10. Crizotinib trials and regulatory approval• Two single arm trials of 255 patients with locally advanced or metastaticALK-positive NSCLC• Crizotinib 250 mg po twice daily• No data available to show improvement in patient reported outcomes orsurvival• 5 of 19 ALK-negative lung carcinoma patients responded; ORR = 26.3%(95% CI 9.1%, 51.2%); 2 additional patients had a single assessment of PR• Approval of drug and diagnostic testStudy Patients (N) ORR % 95%CI Duration wks.A 136 50 42%, 59% 42B 119 61 52%, 70% 48http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202570s000ltr.pdf1-yr OS: 74% 2-yr OS: 54%
  • 11. Personalized medicine: Integration of information
  • 12. The challenge is not just limited to increasing theknowledge about targeted therapies. A practicalframework for clinicians and patients is needed.Personalized medicine & health careDancey et al., Cell 2012