INDIVIDUALIZED MEDICINE

Transcription

1 Genomics in Oncology CENTER FOR INDIVIDUALIZED MEDICINE Alan Bryce, MD American College of Osteopathic Internists October 9-13, 2013 Renaissance Esmeralda Resort and Spa, Indian Wells, CA 2012 MFMER slide-1

2 Objectives Discuss the What, Why, and How of Individulaized Medicine Present Results from Genome Guided Oncology Studies at MCA Introduce Existing Initiatives Currently Active at MCA Discuss the Role of Individualized Medicine in Oncology 2012 MFMER slide-2

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5 Cost per genome $100,000,000 $10,000,000 Moore s Law $1,000,000 $100,000 $10,000 $1,000 Jan 2002 Jan 2004 Jan 2006 Jan 2008 Jan 2010 Jan MFMER slide-5

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8 NSCLC Pao W. The Lancet Oncology Volume 12, Issue MFMER slide-8

9 Clinical Application of NGS Real time application of NGS to clinical practice is challenging Time from biopsy to return of results Development of Bioinformatic infrastructure for interpretation of results Acquisition of drugs Pilot study was begun in the third quarter of 2010 to address these challenges Genomic Tumor Board for return results begun May MFMER slide-9

10 Genetic Counselor visit Four 18 gauge core biopsy samples Serum for germline DNA Whole genome, exome and RNA sequencing Clinical Genomics Tumor Board CLIA validation Consensus recommendation to treating physician Results discussed with patient, physician and genetic counselor 2012 MFMER slide-10

11 Cholangiocarcinoma Graphical Overview 2012 MFMER slide-11

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13 ERRFI1 (Mig6) inactivating mutation 2012 MFMER slide-13

14 ERRFI1 mutation treated with erlotinib Baseline 3 months 2012 MFMER slide-14

15 Detected fusions in cholangiocarcinomas A B C 2012 MFMER slide-15

16 FGFR2 and FGFR3 IHC 2012 MFMER slide-16

17 FGFR2:MGEA5 fusion and FGFR3 amplification treated with ponatinib Baseline 6 weeks 2012 MFMER slide-17

18 Eroom s Law 2012 MFMER slide-18

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20 New Paradigms Target Discovery/Validation through Genome directed therapy studies FGFR inhibitor studies being initiated at MCA (Borad) Histology Specific trials of multiple molecular aberrations Basket Studies of tumor agnostic aberration specific therapy RAPID 2012 MFMER slide-20

21 BEAUTY Project Breast Cancer Genome Guided Therapy Women with invasive breast cancer HER2+ HER2- Tumor biopsy Magnetic Resonance Imaging Molecular Breast Imaging Mouse avatars (xenografts) Paclitaxel + Trastuzamab Paclitaxel Tumor biopsy Magnetic Resonance Imaging Molecular Breast Imaging AC or FEC AC or FEC MRI MBI Surgery Tumor tissue Mouse avatars (xenografts) 5 year observation 2012 MFMER slide-21

22 Tumor Biopsies from BEAUTY Patients Breast Tumor samples Baseline (before chemotherapy), during and after chemotherapy All 3 biopsies go for sequencing Baseline biopsy and any residual disease goes for xenografts Tumor DNA Exome Sequence Germline DNA Exome Sequence Determine functional implications of genetic alterations Multiple sequencing approaches Tumor RNA-Seq Germline SNP Array Xenografts Tumor Methylation 450K Ilumina RPPA Study new drugs, and drug combinations, to identify best regimens to move forward in specific tumor subtypes 2012 MFMER slide-22

23 Pharmacogenomics Program Ensure we give the right drug at the right dose at the right time based on the individual patient Abacavir Carbamazepine Interferon Thiopurines Embed in EMR Educate physicians Improve care Reduce costs 2012 MFMER slide-23

24 Phenotype: Metabolizer Group Ultrarapid Metabolizer Genotype and Examples Two or more copies of functional alleles or two copies of increased function alleles *1/*1xN *2A/*2AxN (*1/*2A)xN *2A/*2A Effect on CYP2D6 activity Increased Effect on Codeine metabolism Increased morphine formation leading to increased risk of toxicity Recommended Action Avoid Codeine due to toxicity Consider alternatives that are not similarly CYP2D6 dependant- i.e. avoid Tramadol Extensive Metabolizer Intermediate Metabolizer Two functional alleles*1/*1 One functional and one absent functional allele or 2 reduced function alleles Normal Reduced Normal morphine formation Reduced morphine formation and possible insufficient pain relief Standard dosing Standard dosing Monitor for lack of efficacy If no response use alternative that that is not similarly CYP2D6 dependant- i.e. avoid Tramadol *1/*4 *10/*10 Increased dosing is not recommended. Poor Metabolizer No functional alleles *4/*4 *4/*5 Absent Minimal morphine formation and insufficient pain relief. Side effects of codeine are reported. Avoid Codeine due to lack of efficacy Consider alternatives that are not similarly CYP2D6 dependant- i.e. avoid Tramadol 2012 MFMER slide-24

25 CIM Gianrico Farrugia Richard Caselli Dick Weinshilboum Scott Beck Keith Stewart Rafael Fonseca Sharon Levey Jennifer McCormick Kostas Lazaridis Rob McWilliams Acknowledgements MCA TGEN Mitesh Borad Jeff Trent Katherine Hunt Dan Van Hoff Jan Egan David Craig Mia Champion John Carpten Ann McCullough Steve Mastrian Rick Valdez Winnie Liang James Hernandez Aleks Sekulic Raoul Tibes Rachel Condjella 2012 MFMER slide-25

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