Precision Oncology: Experience at UW

Transcription

1 Precision Oncology: Experience at UW Colin Pritchard MD, PhD University of Washington, Department of Lab Medicine WSMOS Meeting November 1, 2013

2 Conflict of Interest Disclosures I declare the following, real or perceived conflict(s) of interest: I am an employee of the University of Washington I have no financial stake in the tests I will discuss

3 Precision Oncology

4 Emerging Model of Cancer Treatment Tumor tissue routinely acquired for molecular diagnostics All/or all actionable mutations assessed Therapy selected based on molecular characteristics

5 Validated Markers Cancer Lung (non-small cell) Colon Melanoma Gastrointestinal stromal tumor (GIST) Acute Myeloid Leukemia (AML) Molecular Tests Commonly Used EGFR, KRAS, ALK, ROS1 KRAS, BRAF, MSI BRAF, KIT, NRAS KIT, PDGFRA FLT3, NPM1, CEBPA

6 Much More on the Horizon Target Number of Trials Target Number of Trials BRAF PI3K KRAS MEK C-MET EGFR PDGFR C-KIT MSI PTEN

7 Colin Pritchard, UW Lab Medicine

8 Precision Oncology Gene Panels Theoretical advantages: Comprehensive testing High hit rate for actionable mutations Drive research, discovery Cost-effective +

9 Precision Oncology Gene Panels Potential disadvantages: Incidental findings Information overload Turnaround time Not universally accepted by payers -

10 Regulatory Framework Licensing CLIA Accreditation CAP Laboratory Developed Tests (LDT)

11 Regulatory/Ethical Issues Role of FDA Proficiency testing (CAP) Use of data for research Ethics of incidental findings

12 Challenges/Approach to Solution Challenge Reimbursement Rapidly evolving knowledge Complexity of Service Potential Solution Work with payers, demonstarte what is billed has clinical utility Consortium to share clinical interpretations of mutations, assays designed to allow rapid updates of new genes Develop multidisciplinary teams, effectively integrate clinical and lab personnel

13 Cost Effectiveness Profiling panels often more cost effective than individual assays after ~3 markers are tested

14 Facilitates Research Patients eligible for clinical trials based on clinical gene panel results Oncology clinics can become trial site for new targeted inhibitor trials

15 Precision Oncology Gene Panels at UW Risk Identification BROCA 50 genes, focus on breast/ovarian cancer risk Developed by Tom Walsh/Mary-Claire King lab ColoSeq 19 genes, colon cancer risk Tumor Sequencing to Guide Therapy UW-OncoPlex 194 genes

16 BROCA Cancer Risk Panel

17 UW-OncoPlex Background Clinical assay designed to identify actionable alterations in tumors to guide therapy Collaborative effort of faculty at UW and SCCA Developed by Colin Pritchard and Tom Walsh Offered at UW since August 2012 through Department of Lab Medicine Available to order regionally and nationally

18 UW-OncoPlex Background Highly comprehensive clinically-validated test Detects all types of mutations in 194 genes including gene copy number changes and structural changes This is in contrast to many other multi-gene panels which detect only hotspots

19 UW-OncoPlex v2 Tier 1: Currently Actionable Tier 2: Actionable in the Near Future Tier 3: Frequently Mutated Germline Pharmacogenomics ABL1 ALK BCR BCL2L11 BRAF RET CDK4 CEBPA KIF5B DDR2 EML4 EGFR ERBB2 FLT3 IDH1 IDH2 JAK2 RARA KIT KRAS MPL NPM1 NF2 NRAS PDGFRA PML RICTOR ROS1 TSC1 TSC2 ABL2 AKT1 AKT2 AKT3 ASXL1 ATM AURKA AURKB BAP1 BCOR CBL CBLB CDK6 CDK8 CHEK1 CHEK2 DNMT3A EPHB2 ERBB3 ERBB4 FGFR1 FGFR2 FGFR4 FLT1 FLT4 GATA2 GNA11 GNAQ GRM3 HDAC4 HIF1A HRAS IGF1R JAK3 KDM6A KDR MAP2K1 MAP2K2 MAPK1 MC1R MCL1 MEN1 MET MLH1 MLL MRE11A MSH2 MSH6 MYC MYCN NOTCH1 PAX5 PDGFRB PIK3CA PIK3R1 PMS2 PTEN RAF1 NKX2-1 SMO SRSF2 SUZ12 TET2 TYR VHL MITF ERCC2 APC BAK1 BCL2 CCND1 CCNE1 CDH1 CDKN2A CREBBP CRLF2 CSF1R CTNNB1 EPHA3 EPHA5 EPHB6 ETV6 EZH2 FBXW7 FGFR3 GAB2 GATA1 GNAS GRIN2A HNF1A IKZF1 IL7R JAK1 MAP2K4 MDM2 MDM4 MUTYH MYCL1 NF1 STK11 NOTCH2 PBRM1 PRPF40B PTCH1 PTPN11 PTPRD RB1 RPS14 RUNX1 SF1 SF3B1 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SPRY4 SRC TFG TGFBR2 TP53 TRRAP U2AF1 U2AF65 WT1 ZRSR2 ABCB1 ABCC2 ABCC4 ABCG2 C1orf144 COMT CYP1B1 CYP2C19 CYP2C8 CYP2D6 CYP3A4 CYP3A5 DPYD EIF3A ESR1 ESR2 FCGR1A UMPS FCGR2A FCGR3A GSTP1 GUCY1A2 ITPA LRP2 MAN1B1 MTHFR NQO1 NRP2 SLC19A1 SLC22A2 SLCO1B3 SOD2 SULT1A1 TPMT TYMS UGT1A1 Genes Targeted: 194 DNA Sequenced: >850,000 bp >500X Coverage Colin Pritchard, UW Lab Medicine

20 UW-OncoPlex Sequencing Strategy 200bp Prepare Genomic Libraries Capture Genes of Interest Molecular Bar Coding (up to 16 per lane) Sonicate (3μg DNA) Millions of 101 bp reads HiSeq or MiSeq

21 Copy Number Changes (detected directly by UW-OncoPlex sequencing) 8 4 MDM2 Gene Copies 2 1 CDKN2A 0

22 Gene Fusions Detected by UW-OncoPlex ALK EML4

23 Clinical Reporting Data Analysis and Mutation Identification Sequencing Board Review Report Written by Lab Director Reporting in Medical Record Feedback on treatment and response

24 Independent Multi-Director Review of Raw Data Short list of variants selected by each member of interpretation team Combined lists reviewed together by interpretation group Decisions made on interpretation

25 Decision Support

26 OncoWiki

27

28 UW-OncoPlex Case 1 Male lifetime non-smoker, in his 50s with metastatic lung adenocarcinoma Tumor EGFR mutation negative and ALK negative by FISH at an outside lab On clinical trial of anti-pd-l1 antibody UW-OncoPlex ordered

29 Case 1: Gene Fusion ALK-EML4 fusion identified by UW-OncoPlex deep sequencing which was missed by FISH ALK EML4

30 Case 1 Follow Up Patient switched to crizotinib Complete symptomatic and radiographic response

31 UW-OncoPlex Case 2 Female smoker, in her 50s with metastatic lung adenocarcinoma Initially stage IIIA, treated with resection, cisplatin+pemetrexed+radiation Radiation was very poorly tolerated Now has brain mets UW-OncoPlex ordered

32 Case 2 UW-OncoPlex identifies DDR2 mutation in tyrosine kinase domain Suggests response to dasatinib Patient started on dasatinib with continued stable disease at 6 months

33 Summary Precision oncology panels increasingly used Risk prediction Tumor sequencing to guide therapy Panels more cost-effective than one-at-a-time approach Early experience supports patient benefit Many cases have actionable mutations Expands patient access to clinical trials Education needed to facilitate more widespread adoption and help with reimbursement

34 Acknowledgements UW Lab Medicine John Tait Steve Salipante David Wu Brent Wood Noah Hoffman Christy Smith Karen Koehler Angie Jacobson Sheena Scroggins Brian Shirts UW Pathology Suzy Dintzis Rodney Schmidt Yajuan Liu UW Medical Genetics Tom Walsh Mary-Claire King Ming Lee SCCA and FHCRC Renato Martins Keith Eaton Kari Stricker Bill Grady Kim Margolin John Thompson Pete Nelson Heather Cheng Robin Jones Ed Lin Tony Blau