CENTER FOR INDIVIDUALIZED MEDICINE Precision Oncology: Current Applications of omics ACP Arizona Chapter Scientific Meeting, 2014 Arizona State University in Tempe, Arizona Alan Bryce, MD 2012 MFMER slide-1
None Disclosures 2012 MFMER slide-2
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NSCLC Pao W. The Lancet Oncology Volume 12, Issue 2 2011 175-180 2012 MFMER slide-5
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 2012 2012 MFMER slide-6
Study Design Two parallel protocols were opened Institutionally funded protocol for rare cancers (Stewart) Self Pay protocol (Borad) Patients must have Advanced Malignancy refractory to standard therapy Biopsiable lesion Life Expectancy >3 months 2012 MFMER slide-7
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-8
2012 MFMER slide-9 Cholangiocarcinoma Graphical Overview
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ERRFI1 (Mig6) inactivating mutation 2012 MFMER slide-11
ERRFI1 mutation treated with erlotinib Baseline 3 months 2012 MFMER slide-12
Detected fusions in cholangiocarcinomas A B C 2012 MFMER slide-13
FGFR2 and FGFR3 IHC 2012 MFMER slide-14
FGFR2:MGEA5 fusion and FGFR3 amplification treated with ponatinib Baseline 6 weeks 2012 MFMER slide-15
2012 MFMER slide-16 Cervical Cancer Graphical Overview
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HPV 18 integration 2012 MFMER slide-18
2012 MFMER slide-19 Extramedullary Myeloma Graphical Overview
Extramedullary Myeloma British Journal of Haematology Volume 161, Issue 5, pages 748 751, 11 MAR 2013 DOI: 10.1111/bjh.12291 http://onlinelibrary.wiley.com/doi/10.1111/bjh.12291/full#bjh12291 fig 0001 2012 MFMER slide-20
Precision Oncology at MCA Challenges Cost and Time of testing Bioinformatics Staff- Medical Geneticists and Genetic Counselors Drug Acquisition Need new Paradigms for Trials RAPID Number Needed to Screen Routine Testing of all patients is needed 2012 MFMER slide-21
Eroom s Law 2012 MFMER slide-22
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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-24
RAPID (Modular Design) GENOMIC PROFILING TARGET ID CLINOMICS BOARD Treatment Plan CIM GENOMIC OUTCOMES DATABASE Sponsor 1 Drug 1 Sponsor 1 Drug 2 Sponsor 2 Drug 1 Sponsor 2 Drug 2 Sponsor N Drug n Sponsor N Drug n+1 EFFICACY OUTCOME AND SAFETY OUTCOME 2012 MFMER slide-25 MODULAR DESIGN
CIM at MCA today Oncology 1. Genomic Oncology Clinic 2. BEAUTY- Breast Cancer Pharmcagenomics Trial 3. PROMOTE- Prostate Cancer PGX Trial 4. SU2C- Randomized trial of genome directed therapy versus chemotherapy 2012 MFMER slide-26
BEAUTY Old Model Surgery First tumor surgery disease free chemo observe outcome known here New Model response / outcome known here tumor chemo nothing surgery disease free observe 2012 MFMER slide-27
Von Minckwitz G. et al. JCO 2012; 30: 1796-1804 2012 MFMER slide-28
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-29
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-30
CIM at MCA Non Oncology 1. Service Line 2 - Diagnostic Odyssey 2. TAILOR-PCI - Clopidogrel Pharmacogenomics 3. Pharmacogenomics Task Force- Development of EMR based tools 2012 MFMER slide-31
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-32
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-33
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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-35
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