The new Leeds Solid Tumour Molecular Oncology Diagnostics Service. Paul Roberts, Genetics, Leeds

Transcription

1 The new Leeds Solid Tumour Molecular Oncology Diagnostics Service Paul Roberts, Genetics, Leeds

2 Molecular Oncology services pre-2013 DNA lab Germline cancer Cytogenetics lab FISH, cell culture, molecular testing- lung cancer, soft tissue tumours, CNS tumours Molecular Pathology Molecular testing - breast cancer, colorectal cancer, whipples, selected viruses, MSI Cancer Genomics Various molecular testing with molecular pathology, including colorectal cancer

3 Total tumour testing FFPE FISH EGFR KRAS IDH MGMT GIST ALK HER2 MSI Cell culture

4 How to take molecular diagnostics forward with such a split service? Timeline 2011 Dialogue commenced with Pat Harnden, Paul Roberts & Carol Chu Ad hoc meetings to discuss existing services 2012 Request to pathology directorate management to look at molecular oncology SIMP team facilitated molecular oncology meetings Group identified from key stakeholders

5 RCPath model for molecular pathology

6 Upper Normandy somatic genetic tumour platform

7 DH model for molecular diagnostic testing Cancer molecular pathology proposed structure and fit to existing and new groups Existing group New group National Horizon Scanning Centre Royal College Pathologists Clinical Molecular Genetics Society NCRI Clinical Study Groups Topic identification Group NICE Medical Technology Advisory Programme NICE Diagnostics Oversight by Steering Group UK NEQAS NHS Commissioning Board Cancer Registry and NCIN Quality assurance NHS, academic and private labs Test and clinical results Patients Referring Hospitals

8 Stakeholders Genetics Cytogenetics Business manager Molecular Pathology Histopathology Genomics Translation Pathology Management Opps manager Clinical director Medical Oncology Cancer Genomics

9 Remit of group Clive Mulatero chair Discuss existing work Unify services Where to do the work How to bring in new work What technologies Staff roles Business case Dec 2011 business case to PCT rejected May 2013 new business case for LTHT

10 Options for molecular oncology service Option 1 Continue with a piecemeal approach with services offered by different departments Option 2 Send all tumour genetic testing to a provider outside LTHT Option 3 Develop and consolidate a single best in class LTHT diagnostic molecular oncology facility

11 Risk analysis of proposal Option Financial Clinical Other Mitigation 1. Continue with piecemeal approach 2. Outsource to different provider 3. Develop Diagnostic Molecular Oncology facility in LTHT Equipment duplication Several 100K cost to LTHT to send work out. Missed opportunity for additional income Individual staff cost. Increased reagent cost needed in budget Lack of service continuity. Service disjointed. Misses opportunity to consolidate staffing Loss of status as centre of excellence. Loss of R&D partnerships. Less effective MDTs All stakeholders need to sign up No clear contact lead for service users. No clear outward face of the service Detrimental effect on genomic advances, and damages efforts at closer pathology integration Will need to repatriate testing that is delivered outside LTHT. Need to secure mechanism to pay for tests Has worked well so far and enhanced reputations of individual departments involved Some centres are already outsourcing this work Already UK leaders in NGS technology. Molecular Oncology Diagnostic Group already in place, and structure of staffing and Board has been worked out

12 Where are we now? May 2013 HER2 testing moved onto DDISH into histopath Molecular pathology scientific staff & genetics oncology team unify as one oncology team Scientific staff based in genetics Lead scientist for technical development All molecular oncology testing done by same team Sharing of equipment Identification of scientific director, lead pathologist, & operational manager Ongoing NGS validation

13 R&D Trials Molecular Oncology Board Clinical Directors, Oncology leads Histopathology lead, Scientific director, Scientific operational lead Scientific/Technology lead, R&D/Genomics Horizon scanning UKNEQAS Molecular Oncology Operational team Scientific director Scientific operational lead Hisopathology lead Scientific, technical & other staff Sample prep & Quality assessment Technology development & implementation Translational Genomics team Test request & sample production FISH Sequencing (NGS, etc) PCR Referring hospitals (clinicians) Informatics Patients Test results and reports Authorised Integrated into clinical report by histopathology & oncology

14 Staffing Scientific director Paul Lead Histopathologist Heike Operational lead Helen Lead scientist Technical development Dave Scientific team Genetics + Molecular Pathology

15 Create new name Going forward Tests & reports on one LIMS by one team Purchases from single budget Notify service users Update website Educational visits to other Trusts LTHT provider and Yorkshire cancer network solution Repatriate testing Bring in new tests from outside LTHT Develop molecular oncology board Use lessons learned to assist with integration of other molecular services

16 Molecular Oncology board Strategic Horizon scanning Business cases Implementation of new tests & technologies Core members plus ad hoc representation from interested parties Link to LTHT and pathology management for service development & implementation

17 The tasks ahead Resolving issues with data entry Finance Staffing Reporting Histopathologists input Convincing the network Participation in stratified medicine phase 2 Linking with R&D & University Service continuity A new building?

18 Service delivery Generic referral form Test request per tumour type FFPE new currency Test panels for affordability Working to 5 day TATs Integration to histopathology Technology development Cancer Genomics?R&D

19 Cytogenetics website Home A-Z of Services Cytogenetics Cytogenetics What we do Postnatal Microarrays Prenatal Haematological Disorders Solid Tumours Molecular Oncology Molecular Pathology (other) Referral Cards Ordering Medium Frequently asked questions Contact us

20 Total solid tumour testing tests

21 Estimated unmet need for molecular testing Tumour type Non-small cell lung cancer Colorectal cancer Gastrointestinal tumour Gene mutation Associated drug treatment No. tests EGFR Gefitinib 7,300 (+/- 10%) KRAS Cetuximab 4,380 (+/- 5%) KIT and Imatinib 465 PDGFRA (+/- 5%) No. patients requiring test/year 12,500 (+/- 20%) 3,525 12,800 Less than 500 Estimated unmet need (tests/year) c. 5,000 0 c8,600 Uncertain Breast cancer HER2 Herceptin 7,500 (+/- 20%) 8,000 None

22 Present tests Breast Cancer type Example of tests performed Number of tests performed in England Estimated cost ( million) Reliability of data HER2 ISH to determine eligibility for targeted anti-her2 drug therapy 7.5k 1.1 Medium (+/- 20%) Lung EGFR mutation testing to determine eligibility for targeted drug therapy e.g. EGFR inhibitors 7.3k 1.1 High ( 90%) Bowel Other childhood cancers Muscle, bone and soft tissue Mutation testing to determine eligibility for targeted drug therapy e.g. KRAS mutation and KIT inhibitors 4.8k KRAS: 4380 KIT: High (+/-5%) Mutation detection to aid diagnosis and guide chemotherapy 1.0k 0.2 Medium to high Mutation testing to aid pathologists in making the diagnosis 1.0k 0.3 unknown Other (including brain, melanoma of the eye) Mutation detection to guide chemotherapy 1.4k 0.4 unknown Total 22.9k 3.8

23 Costs of testing Tumour Site Molecular test Associated treatment Tests 2010/11 Upper estimate of total demand Estimated Cost/test ( ) Total cost ( ms) NSCL Colorectal Cancer Gastrointestinal stromal tumour Breast Cancer EGFR Gefitinib 7,300 12, KRAS Cetuximab 4,380 12, KIT & PDGFRA Imatinib HER2 Herceptin 7,500 8, TOTAL 5.0

24 Molecular targets Imatinib (Gleevec/Glivec) Gastrointestinal stromal tumour KIT (CD117) Vemurafenib (Zelboraf) Malignant melanoma Advanced melanoma with BRAF V600E mutation Panitumumab (Vectibix) Colorectal cancer EGFR expressing, metastatic colorectal carcinoma, non-mutated (wild-type) KRAS Crizotinib (Xalkori) Lung cancer Advanced non-small cell lung cancer (NSCLC) with an ALK gene translocation Cetuximab (Erbitux) Colorectal cancer EGFR+ metastatic colorectal cancer with wild-type KRAS, advanced head/neck cancer Erlotinib (Tarceva) Lung cancer Advanced NSCLC (EGFR+ in the EU), advanced pancreatic cancer Gefitinib (Iressa) Lung cancer Advanced NSCLC (EGFR mutation positive in the EU) Trastuzumab (Herceptin) Breast cancer HER2+ breast cancer, advanced gastric or gastro-oesophageal junction adenocarcinoma EMA Approved EMA approved EMA Approved Under review by EMA EMA Approved NICE Approved for a subset of patients with metastatic colorectal cancer EMA Approved EMA Approved NICE approved EMA Approved NICE approved

25 Emerging therapies Cancer type Therapy class Associated gene test(s) Colorectal EGFR inhibitor KRAS/BRAF mutations Malignant melanoma Drug Erlotinib* IGF1R inhibitor IGF1R mutations Dalotuzumab (MK- 0646) Cixutumumab (IMC-A12) C-MET inhibitor EGFR/KRAS mutation OSI-906 ARQ-197 MEK inhibitor BRAF MSC B I/II mtor inhibitor PI3KCA / PTEN mutations Everolimus (Afinitor)* BRAF inhibitor BRAF / NRAS GSK III MEK inhibitor BRAF mutations GSK III c-kit inhibitor KIT mutations Imatinib mesylate* II Pancreatic IGF1R inhibitor IGF1R mutations Ganitumab (AMG- 479) Gastric mtor Inhibitor PTEN / PIK3CA / Akt mutations Everolimus* Phase of current clinical trials III II I II II II III

26 Emerging therapies Breast mtor inhibitor PIK3CA / PTEN mutation PARP inhibitor BRCA1 / BRCA2 mutation PI3K inhibitor PI3KCA / PTEN / Akt mutations NSCLC EGFR inhibitor EGFR / KRAS mutations c-met Inhibitor EGFR / KRAS mutations Everolimus (Afinitor)* Ridaforolimus Temsirolimus (CCI- 779) Iniparib Veliparib (ABT-888) AG XL-147 BEZ-235 PX-866 BIBW-2992 (Tovok, Afatinib) ARQ-197 MetMAb (RG-3638) IGF1R inhibitor IGF1R mutations Dalotuzumab (MK- 0646) Ovarian PARP inhibitor BRCA1 / BRCA2 mutations Iniparib (BSI-201) PARP inhibitor EGFR mutations Erlotinib III III II I/II III II I/II III III II II II

27 Are we ready to meet the demand?

28 ALK and lung cancer 6,709 patients (approx 20%) diagnosed with small cell lung cancers 32, 546 lung cancer patients per annum 26,836 patients (80%)with non small cell lung caner 7,811 (approx 30%) patients present with locally/regionally advanced disease 7,811 (approx 30%) present with locally advanced disease 10,414 (approx 40%) patients with advanced metastatic disease 3,905 (approx 50%) of these patients will have surgery Tested for ALK status for prescription of crizotinib

29 Estimated US cost for cancer testing

30 Disease Test type and method Tissue Test with targeted treatments Lung cancer EGFR Mutation analysis - RQPCR P ALK gene rearrangement - FISH GISTs Mutation analysis ckit, PDGFRA Sanger sequencing P Colorectal cancer KRAS Mutation analysis - Pyrosequencing P Sarcoma diagnostics Alveolar rhabdomyosarcoma Ewing s sarcoma tumours FOXO1 gene rearrangement FISH FOXO1 - PAX gene f u s i on FISH MYCN amplification FISH PAX7 & PAX3 rearrangements - FISH EWSR1 gene rearrangement FISH EWSR1 - FLI1 gene fusion FISH EWSR1 - ERG1 gene fusion - FISH DSRCT EWSR1 gene rearrangement - FISH Clear cell sarcoma EWSR1 gene rearrangement - FISH Angiomatoid fibrous histiocytoma EWSR1 gene rearrangement - FISH Extraskeletal myxoid chondrosarcoma EWSR1 gene rearrangement - FISH Other tumours with EWSR1 rearrangements EWSR1 gene rearrangement - FISH Myoepitheloid tumour Occasional myxoid liposarcoma Synovial sarcoma SYT gene rearrangement - FISH Liposarcoma MDM2 amplification FISH FUS - CHOP gene rearrangement FISH 13q deletion (spindle cell variant) - FISH P or f resh Spindle cell lipoma 13q14 loss - FISH Alveolar soft part tumour TFE3 gene rearrangement - FISH DFSP /giant cell fibroblastoma COLIA1 - PDGFB rearrangement - FISH Low grade fibromyxoid sarcoma FUS gene rearrangement - FISH Inflammatory myofibroblastic tumour ALK gene rearrangement - FISH Glioma diagnostics Grade II and III glioma IDH1 mutation analysis pyrosequencing 1p/19q dosage - FISH P P Grade IV glioma IDH1 mutation analysis pyrosequencing MGMT methylation analysis MS - MLPA P Other tests on request PTEN loss FISH EGFR amplification FISH RB1 loss FISH P16 loss - FISH Pilocytic astrocytoma KIAA BRAF fusion FISH or RT - PCR (in preparation) Other CNS tumours ATRT SMARCB1 deletion FISH or MLPA Medulloblastoma CMYC and MYCN amplification FISH P53 deletion/17q gain - FISH Meningioma 22q, 1p and 14q deletion - FISH Other tumour diagnostics Neuroblastoma MYCN amplification, 1p deletion, 11q deletion & 17q gain FISH Mesoblastic nephroma/congenital fibrosarcoma ETV6 gene rearrangement Other carcinomas Papillary renal cell carcinoma TFE3 gene rearrangement - FISH Mucoepidermoid carcinoma/hidradenoma MAML2 gene rearrangement - FISH Present testing

31 How to deliver multiple tests Gene panels Single platform Sample multiplexing Multiple cancers Other test types, eg germline Leeds solution NGS Mix germline & somatic cancer tests Speed up process Develop software solutions

32 It s complicated