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Molecular profiling of colorectal cancers Dr Angela Silmon 12th September 2014 Colorectal NSSG Audit Day Outline • • • • Brief introduction to NewGene Personalised Medicine Molecular testing in colorectal cancer Horizon scanning NewGene Ltd A pioneer in developing, validating and delivering molecular diagnostics using the latest high throughput sequencing and genotyping technologies Technology platforms Genotyping • Sequenom MassARRAY 4 – MALDI TOF mass spectrometer – Low cost – Rapid turn around – Targeted mutations Sequenom Mass Array 4 SAP clean PCR Extension reaction Resin Spotting MALDI TOF Data analysis Detector F 5’end 3’end 3’end 5’end R Time of flight 5800Da extension into SNP site 5500Da Laser Allele 1 6100Da Allele 2 Sequenom chip Sequenom Mass Array 4 5500Da 7000Da Wild type allele only (TT) 7000Da Wild type and mutant allele present (TC) 7000Da Mutant allele only (CC) Personalised medicine portfolio Gene Mutations Non-small cell lung cancer EGFR 17 point mutations Indels exon 19 and 20 Inclds T790M Metastatic colorectal cancer KRAS, BRAF, NRAS 23 mutations in each RAS gene Inclds BRAF V600E Melanoma BRAF GIST cKIT, PDGFRA Two step process Funding Gene Mutations EGFR Astra Zeneca until Oct 2010 CCGs ALK* Pfizer 2015, likely change Metastatic colorectal cancer KRAS, BRAF, NRAS Merck Serono until May 2014 NHS England Melanoma BRAF Roche 2015, TBD GIST cKIT, PDGFRA Referring Trust Non-small cell lung cancer * IHC carried out at Cellular Pathology, RVI, FISH test carried out by Cytogenetics Referral pathway Request CDF number Refer for testing incld CDF number Automatic unregistration from CDF T176 Refer for testing Check T176 box Test result Test result Therapy decision CDF number if req Funding: CDF Therapy decision Funding: NHS England Molecular testing in mCRC • Mutation in the RAS genes offer prognostic value with patients with a mutation in the KRAS or NRAS gene having lower overall survival rates compared to wild type • Mutations predict lack of benefit from EGFR targeted therapies such as Cetuximab and Panitumumab • Mutations in codons 12 and 13 of KRAS most common, ~40% of mCRC patients • Mutations in RAS genes found in ~ 50% of patients Association of Clinical Pathologists Molecular Pathology and Diagnostics Group • Targeted mutations – KRAS codons 12, 13, 59, 61, 117 and 146 – NRAS codons 12, 13, 59 and 61 • Interpretation – Therapy license - wild type RAS genes only – BRAF prognostic indicator but guidelines may change Wong NACS, Gonzalez D, Salto-Tellez M, et al. J Clin Pathol 2014 Association of Clinical Pathologists Molecular Pathology and Diagnostics Group • Primary or metastatic CRC tissue can be used • Biopsy or resection specimen tissue can be used • The minimum neoplastic cell content tested should be at least two times the assay’s LOD. • Audit – TAT ≤7 working days for >90% of samples – Incident rates – Failure rates Wong NACS, Gonzalez D, Salto-Tellez M, et al. J Clin Pathol 2014 NewGene Audit 2014 • Turn around time – – – – • Failure rate Target 5 working days – < 1% Range 2 - 11 days • EQA Average 3.4 days – Participation since 2010 90% of reports issued within – All genotyping maximum 5d marks, no poor performance • Incidence rate Wild type samples 42% Mutation positive samples 58% Gene NewGene Reported KRAS 42.7% 40% NRAS 6% 5% BRAF 9.3% 10% Jan – June 2014 N = 500 Horizon scanning • Require a comprehensive joined up approach to molecular testing – Funding mechanism – Testing mechanism Gene Horizon Non-small cell lung cancer EGFR KRAS Metastatic colorectal cancer KRAS, BRAF, NRAS Melanoma BRAF NRAS Horizon scanning • OncoFocus – Comprehensive test for actionable mutations • UltraSeek – Circulating tumour DNA – 1% tumour content GeneAA ABL1 AKT1 ALK BRAF EGFR FLT IDH1 IDH2 JAK2 KRAS NRAS PIK3CA T3151 E17K F1174L V600E, V600K, V600R G719S, T790M, L861Q, E746A750del 1836del R132H R140Q, R172K V617F G12A, G12D, G12V, G12C, G12S, G13D Q61K, Q61R E545K, E542K, H1047R Horizon scanning • Pilot data generation – OncoFocus – UltraSeek – Business case for service delivery – Phase I Clinical trials – Clinical implementation Thank you Contact: [email protected] 0191 242 1923 www.newgene.org.uk
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