Current and future applications of Molecular Pathology. Kathy Walsh Clinical Scientist NHS Lothian

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1 Current and future applications of Molecular Pathology Kathy Walsh Clinical Scientist NHS Lothian

2 Molecular Pathology in Solid tumours Cancer type Genes tested Purpose Associated treatments Non small cell lung cancer EGFR mutations ALK rearrangements Treatment EGFR Tyrosine Kinase Inhibitors (Erlotinib) ALK inhibitors (Crizotinib) Colorectal adenocarcinoma KRAS and NRAS mutations Treatment EGFR monoclonal antibodies e.g cetuximab Colorectal adenocarcinoma Mismatch repair genes Screening for Lynch syndrome/prognosis/tre atment 5FU Melanoma BRAF mutations Treatment Vemurafenib, Dabrafenib Gliomas and Glioblastoma MGMT methylation IDH1 and 2 mutations Diagnosis and Treatment Temozolomide 1p19q co-deletion Soft tissue and bone tumours EWS1, MDM2, SSX1 and 2, FOXO1 etc Diagnosis Treatment varies with diagnosis GIST KIT PDGFRA Diagnosis and treatment Imatinib Sunitinib Metastatic gastric cancer HER2 (tyrosine kinase receptor) Treatment Herceptin

3 Molecular Pathology tests FISH Karyotyping Methylation Large chromosomal rearrangements RT-PCR Microarray IHC Pyrosequencing PCR HRM MLPA Small mutations Sequencing Real-time PCR Fragment analysis Dako igece.org

4 Molecular Pathology tests FISH Large chromosomal rearrangements Microarray IHC Small mutations Karyotyping Methylation PCR HRM RT-PCR MLPA Pyrosequencing Sequencing Real-time PCR Fragment analysis Dako igece.org

5 Tumour assessment is essential DNA (or RNA) from FFPE tissue. Struggle to obtain enough DNA. Typical limits of detection for PCR based assays 5 to 10% alleles (need 10 to 20% tumour). Insufficient if tumour proportion too low or tissue too small. Can extract from unwanted IHC slides (may be dirty ). Close contacts with pathology departments very important.

6 Colorectal cancer EGFR activation in many colorectal cancers drives tumour cell proliferation via the RAS-RAF- AKT pathway. Anti-EGFR monoclonal antibody therapy, e.g. cetuximab, binds to EGFR and switches off this pathway.

7 Colorectal cancer HOWEVER: Certain RAS mutations (KRAS and NRAS) lead to constitutive activation of RAS and the downstream pathway- regardless of Anti-EGFR therapy. Mut RAS Anti-EGFR monoclonal antibody therapy will not benefit patients with KRAS or NRAS mutations in their tumours.

8 Mismatch repair pathway (MMR) Loss of MMR is one mechanism of CRC development. Can be germline (Lynch syndrome) or sporadic. Patients under the age of 50 screened for MMR defects. + the medullary phenotype is associated with MMR defects. MMR pathway most mutations in MLH1, MSH2, MSH6, and PMS2 genes. MMR defects detected by IHC and/or microsatellite instability. Better prognosis but little benefit from 5FU chemo (Dukes B)

9 Lung cancer nd most diagnosed malignancy in Scotland. Scottish 5 year survival rates of 7.5% and 9.5% for men and women respectively. Surgical resection in only 10% of cases For most disease is too advanced or their health is too poor to benefit from surgery. For the majority of patients only a small biopsy or cytology sample is available. Histological diagnosis to type/ subtype guides treatment multiple IHCs may be required. Many patients will have no histology sample at all.

10 EGFR in Lung adenocarcinoma (ADC) Ligand mediated EGFR activation leads to cell proliferation. In 10% (Caucasian pop n ) of ADC mutated EGFR leads to ligandindependent activation. Mutated rate higher in East Asian ethnicities (40%). Mutations more common in non-smokers. Mutations found in the tyrosine kinase domain (exons 18, 19, 20 and 21)

11 EGFR Tyrosine kinase inhibitors OPTIMAL TRIAL Improved PFS in patients with EGFR mutations Some mutations predict resistance to EGFR TKIs. EGFR WT patients found to benefit more from standard chemotherapy regimes. EGFR mutation status required prior to EGFR TKI therapy. Meta-analysis shows no difference in overall survival. Zhou et al The Lancet Volume 12, No. 8, p , August 2011

12 ALK inhibitors in lung cancer Crizotinib improved OS and PFS in patients with ALK rearrangements. 3 to 5% ADC Impressive tumour response. More common in younger patients and non-smokers.

13 ALK translocations Translocations in chromosome 2 can cause fusion proteins involving the Anaplastic Lymphoma Kinase gene (ALK). Aberrant expression of the ALK gene. Different fusion partners detected by IHC and/or break-apart FISH.

14 Melanoma BRAF inhibitors (e.g. Vemurafenib and Dabrafenib) give improved OS and PFS in melanoma patients whose tumours have BRAF mutations. Approx 40% melanomas carry mutations in BRAF codon 600 Getting tissue is usually not difficult but melanin can inhibit PCR. BRIM3

15 Brain Tumours 1p19q co-deletion gliomas: Good prognostic Improved response to chemotherapy IDH1 and 2 mutations in gliomas: Usually concurrent with 1p19q deletions Good prognostic indicator MGMT methylation in primary glioblastomas: Methylation of the mismatch repair protein MGMT decreases expression. Low MGMT expression is thought to reduce a tumours ability to repair the damage done by chemotherapy Methylated tumours respond better to alkylating chemotherapy. Usually requires bisulfite treatment of DNA before testing

16 Radiopaedia.org Soft tissue and bone tumours Histological diagnosis of soft tissue and bone tumours very difficult. Recurrent chromosomal rearrangements with particular disease types. Molecular assays (chiefly FISH) used to confirm. Tumour Translocation Fusion gene Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FKHR t(1;13)(p36;q14) PAX7-FKHR Alveolar soft-part sarcoma t(x;17)(p11.2;q25) ASPL-TFE3 Clear cell sarcoma t(12;22)(q13;q12) ATF1-EWS Dermatofibrosarcoma protuberans (giant-cell t(17;22)(q22;13) COL1A1-PDGFB fibroblastoma) Desmoplastic small round cell tumour t(11;22)(p13;q12) WT1-EWS Ewing sarcoma and MPNET t(21;22)(q22;q12) EWS-ERG t(7;22)(p22;q12) EWS-ETV1 t(17;22)(q12;q12) EWS-E1AF t(2;22)(q33;q12) FEV-EWS t(11;22)(q24;q12) FLI1-EWS Etc.etc.etc. (Hahn et al Current Diagnostic Pathology, 2005, vol 11 (6), )

17 Gastrointestinal stromal tumour 85% have KIT mutations, 5% have PDGFRA mutations. Mutations can be used confirm a diagnosis of GIST. Imatinib effective in tumours with CD117 (KIT) expression KIT exon 11 mutations have strongest response to imatinib others have lesser response. Some mutations indicate response if primary mutation but resistance if secondary. Similar situation with PDGFRA mutations Sunitinib available after failure on imatinib, followed by regorafenib. Implications of mutations different for sunitinib.

18 Challenges Fragmented DNA Very small tissue- minimise IHC if possible Turnaround times- delays in getting blocks from other sites Fixation not good in all samples Algorythms becoming more complex. DNA contamination in plasma used to make cell blocks.

19 Plasma-thrombin cell blocks Excellent for histology But plasma contains DNA The amount of DNA is highly variable Problem for molecular testing Working on DNA free plasma with SNBTS file.scirp.org file.scirp.org

20 New and Future biomarkers

21 Herceptin for gastric cancer Recently approved by SMC OS vs standard therapy alone 13.8 vs months Liscenced for HER2 overexpression IHC and/or FISH Similar to breast cancer only equivocal require FISH Performance of IHC not good IHC difficult to validate on low sample numbers Currently Lothian is testing all by FISH

22 Therapies for resistant disease Approx. 50% of Erlotinib resistant lung ADC have developed a second EGFR mutation- T790M 3rd generation tyrosine kinase inhibitors indevelopment. Will require a second sample- increased workload for pathology OR Liquid biopsy Cell free DNA in plasma Poor sensitivity (70% compared to histology sample) Could be used for patients with no other tissue. Requires highly sensitive molecular biology methods. Rapid processing of blood samples.

23 Olaparib Not yet approved PARP-1 inhibitor effective in BRCA1 and 2 mutant tumours (germline or somatic) PARP-1 repairs single stranded breaks in DNA BRCA1 and 2 involved in repair of double stranded breaks. If double stranded breaks not repaired cell dies. Most likely in High grade Serous ovarian cancer Future use prostate cancer. Will need to test for BRCA1/2 in tumour tissue. INHIBITION MUTATION

24 PD-1 and PD-L1 Not yet approved Interaction supresses T cell activation By expressing PD-L1 tumour cells can escape cytotoxic T cells. Anti-PD1 and PD-L1 therapies block the interactionallows T cells to target tumour cells. GOOD NEWS Therapies seem effective in a wide range of diseases including lung cancer and melanoma Stratification based on IHC BAD NEWS IHC scoring system required- intraobserver variation Scoring system varies between drug and disease type. Going to be complex

25 Next challenges for MolPath Validate Next generation sequencing Highly multiplexed High sensitivity Several patients DNA in a single run Could be cheap compared to testing multiple genes individually. Long validation. Data storage!! Bioinformatics!!

26 Thank you

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