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Molecular profiling of colorectal cancers
Dr Angela Silmon 12th September 2014 Colorectal NSSG Audit Day
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Outline Brief introduction to NewGene Personalised Medicine
Molecular testing in colorectal cancer Horizon scanning
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NewGene Ltd A pioneer in developing, validating and delivering molecular diagnostics using the latest high throughput sequencing and genotyping technologies
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Technology platforms
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Genotyping Sequenom MassARRAY 4 MALDI TOF mass spectrometer Low cost
Rapid turn around Targeted mutations Rapid cost effective clinical personalised medicine Greater sensitivity Bench top, reliability MALDI TOF mass spec
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Sequenom Mass Array 4 Sequenom chip Detector Time of flight Laser PCR
Extension reaction MALDI TOF Data analysis SAP clean Resin Spotting Detector F 5’end 3’end [C/G] [G/C] R [C/G] [G/C] G C Allele 1 Allele 2 Time of flight extension into SNP site 5500Da Laser C 5800Da G 6100Da Sequenom chip
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Sequenom Mass Array 4 Wild type allele only (TT)
5500Da 7000Da 7000Da 7000Da Rapid cost effective clinical personalised medicine Greater sensitivity Bench top, reliability MALDI TOF mass spec Wild type allele only (TT) Wild type and mutant allele present (TC) Mutant allele only (CC)
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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
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Funding Gene Mutations Non-small cell lung cancer 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 * IHC carried out at Cellular Pathology, RVI, FISH test carried out by Cytogenetics
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Referral pathway Request CDF number T176
Refer for testing incld CDF number Refer for testing Check T176 box Automatic un-registration from CDF Test result Test result Therapy decision Therapy decision CDF number if req Funding: NHS England Funding: CDF
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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
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Targeted mutations Interpretation
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
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Primary or metastatic CRC tissue can be used
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
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NewGene Audit 2014 Turn around time Failure rate EQA Incidence rate
Target 5 working days < 1% Range days EQA Average 3.4 days Participation since 2010 90% of reports issued within 5d All genotyping maximum 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
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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
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Horizon scanning OncoFocus UltraSeek
Comprehensive test for actionable mutations UltraSeek Circulating tumour DNA 1% tumour content Gene AA ABL1 T3151 AKT1 E17K ALK F1174L BRAF V600E, V600K, V600R EGFR G719S, T790M, L861Q, E746- A750del FLT 1836del IDH1 R132H IDH2 R140Q, R172K JAK2 V617F KRAS G12A, G12D, G12V, G12C, G12S, G13D NRAS Q61K, Q61R PIK3CA E545K, E542K, H1047R
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Horizon scanning Pilot data generation OncoFocus UltraSeek
Business case for service delivery Phase I Clinical trials Clinical implementation
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Contact: Angela.silmon@newgene.org.uk 0191 242 1923 www.newgene.org.uk
Thank you Contact:
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