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Integrating Molecular Pathology Services in the West Midlands

Integrating Molecular Pathology Services in the West Midlands. Jennie Bell CMGS/ACC Spring meeting 14 th April 2010. Personalised Medicine. The Cancer Cell. Lung cancer cell. Cancer cells acquire the capacity for autonomous and dysregulated proliferation

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Integrating Molecular Pathology Services in the West Midlands

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  1. Integrating Molecular Pathology Services in the West Midlands Jennie Bell CMGS/ACC Spring meeting 14th April 2010

  2. Personalised Medicine

  3. The Cancer Cell Lung cancer cell • Cancer cells acquire the capacity for autonomous and dysregulated proliferation • Uncontrolled production of growth factors • Enhanced expression of growth factor receptors • Proliferation of cancer cells • Induction of angiogenesis • Metastasis

  4. Multiple Genes EGFR KRAS C-KIT

  5. Epidermal Growth Factor Receptor • EGFR is a transmembrane receptor belonging to a family of 4 related proteins • The majority of human epithelial cancers are marked by activation of growth factors and receptors of the epidermal growth factor receptor family

  6. KRAS • KRAS is a gene in the EGFR signaling pathway • Activating mutations impair GTPase activity resulting in constitutive activation • Up to 30% of all human tumours contain a KRAS mutation • Most commonly observed in lung, colon and pancreatic cancer and haematopoietic neoplasm http://www.kras-info.com/

  7. c-KIT (and PDGFRa) • c-KIT is a proto-oncogene and a transmembrane receptor • Ligand binding activates intracellular tyrosine kinase domain • PDGFRa is homologous to KIT and functions in a parallel pathway. • Both genes can be mutated in GIST Gastrointestinal stromal tumours.

  8. Drug Development • EGFR was the first growth factor receptor proposed as a target for cancer therapy. • Development of EGFR antagonists for treatment of metastatic epithelial cancers: • Non-small-cell lung cancer (NSCLC) • Squamous cell carcinoma of head and neck • Colorectal cancer • Pancreatic cancer

  9. Drug Action EGFR inhibitors approved for cancer treatment: Erlotinib Gefitinib Cetuximab Panitumumab

  10. Gefitinib Treatment in NSCLC Gefitinib, a small molecule tyrosine kinase inhibitor, is a targeted therapy for the treatment of patients with non-small cell lung cancer The drug binds to the EGFR TK domain with high specificity and affinity resulting in highly effective inhibition of the aberrant signalling pathways.

  11. Imatinib Treatment in GIST • Imatinib is a synthetic tyrosine kinase inhibitor (Glivec, Novartis Pharmaceuticals UK) successfully used in the treatment of CML • Imatinib can block the activated receptor tyrosine kinase activity of c-kit • Targeted therapeutic approach in GIST.

  12. Patient Response Not all patients respond in the same way to drug treatment The presence or absence of a mutation can influence response The presence of different somatic mutations within each gene can affect the action of the drug at the cellular level

  13. Lung Cancer and EGFR Status • Clinical trials have shown that patients with certain EGFR mutations derive significant benefit from gefitinib treatment while patients without these mutations gain more benefit from standard chemotherapy • Mutations are found in four exons of the EGFR gene (exons 18 to 21). • Deletions in exon 19 and a point mutation in exon 21 (L858R) account for around 90% of all activating mutations

  14. EGFR mutation sites

  15. Effect of Sequence Changes- NSCLC As Gefitinib has been shown to benefit patients with particular somatic sequence changes Essential to identify specific sequence changes in individual patients Match sequence variants with specific patient treatment

  16. Effect of Sequence Changes- GIST • GIST patients with a somatic mutation generally have a higher response to treatment than those that do not. • Exon 11 most commonly mutated in (67% of cases) • Mutations in exon 11 generally respond to treatment with Imatinib better than mutations in other exons. • Exon 9 mutations are less common (17% of cases) • Exon 9 mutations have a lower response rate to Imatinib therapy vsexon 11 mutations (but a better response rate to Imatinib than c-kit "wild-type" GIST)

  17. Molecular Analysis There has been a recent paradigm shift in cancer patient treatment Broad-spectrum cytotoxic therapy molecular targeted treatment The presence of a sequence variant within one of these genes (EGFR, c-Kit, KRAS) can determine a patient’s treatment.

  18. Patient Care Pathway (NSCLC) A patient presents with lung cancer A biopsy is taken A diagnosis of NSCLC should be confirmed by a Consultant Histopathologist Subsequent molecular analysis of the tumour sample is required Identifying patients with an EGFR mutation is a critical part of the patient care pathway Appropriate treatment discussion with patient

  19. Patient Care Pathway Brendan O’Sullivan/Frances Hughes BMS, UHB Jennie Bell/Dr Fiona Macdonald Consultant Clinical Scientists, BWH http://www.egfr-info.com/EGFR-exon Dr Philippe Tanière Consultant Histopathologist UHB

  20. A Distance Apart West Midlands Regional Genetics BWH Department of Cellular Pathology UHB

  21. Sharing of Expertise Partnership established in 2002 Department of Cellular Pathology, University Hospital Birmingham and West Midlands Regional Genetics Laboratory Tumour studies in colon cancer (MSI and IHC in Lynch syndrome/HNPCC)

  22. Available Services • KIT and PDGFRa analysis for GIST • Sequencing exons 9, 11, 13, 17 c-kit and exons 10, 12, 14, 18 PDGFRa • KRAS analysis for lung and colon cancer • Pyrosequencing exon 2 KRAS • EGFR for lung cancer • Analysis of exons 18 to 21 (RQ-PCR, sequencing)

  23. Molecular Analysis All molecular work is performed within the Regional Genetics Laboratory A basic report is issued giving details of any sequence variants identified (or not) The results are integrated into an overall patient summary by Consultant Histopathologist

  24. GIST Reports * Samples reported 1st Jan to 31st March 2010

  25. KRAS Reports Validation * Samples reported 1st Jan to 31st March 2010

  26. EGFR Service validation complete Problem with availability of DxS kit Currently using direct sequencing Reports will be issued from 1st April 2010

  27. Ongoing Developments • BRAF analysis in colorectal cancer • Pyrosequencing based assay • BRAF and KIT in melanoma • KIT mutated in non-skin melanomas • BRAF mutated in sun exposed areas • MGMT methylation in gliomas and endocrine tumours • predictive to alkylant based chemotherapy • ERCC1 expression • RNA based test on paraffin sections • Predictive marker to response to platinum based chemotherapy (lung, pancreas, stomach and colon)

  28. A Successful Partnership Management of results for patients referred with cancer is co-ordinated by Consultant Histopathologist Equipment and molecular expertise is provided by the Genetics Service Molecular testing is performed to accredited standards

  29. The Future More drug targets Improved drug treatments Further expansion of molecular pathology services is anticipated Supported by strong cross-discipline collaboration

  30. Acknowledgements • Molecular Laboratory Staff • Dr Fiona Macdonald jenny.bell@bwhct.nhs.uk • Brendan O’Sullivan • Frances Hughes • Dr Philippe Tanière phillipe.taniere@uhb.nhs.uk

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