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A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE UK AND IRELAND Simon Ramsden, Nikki Gambhir, Jennifer Higgs, Kay Poulton, William Newman.

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Presentation on theme: "A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE UK AND IRELAND Simon Ramsden, Nikki Gambhir, Jennifer Higgs, Kay Poulton, William Newman."— Presentation transcript:

1 A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE UK AND IRELAND Simon Ramsden, Nikki Gambhir, Jennifer Higgs, Kay Poulton, William Newman

2 Background Imatinib (Glivec/Gleevec) Gastrointestinal stromal tumor (GIST) a is a rare tumor of the gastrointestinal tract resistant to chemotherapy. Due to somatic activating mutations in c-KIT exons 9, 11 13, 17 or PDGFRA exons 12, 14 and 18

3 Current Scope of the UKGTN

4 Molecular testing for acquired changes Published in May labs surveyed 33 responded 22 using molecular tests. FISH (haematology) IHC (CRC, BrCa, haematology) DNA (somatic mutations/MSI/ LOH/arrays )

5 cKIT and PDGFR in GISTS - Imatinib (Glivec) KRAS in colorectal cancer - Cetuximab (Erbitux) EGF receptor in non-small cell lung cancer Erlotinib (Tarceva) None reported characterising tumours for drug response

6 Pharmacogenetics in Australia and NZ 2005 Questionnaires sent to 629 labs (Aus & NZ) – 510 (81%) responses Genotyping – 10 Phenotyping – 18

7 Pharmacogenetics in Australia and NZ Phenotyping: TPMT (Azathioprine/6 mercaptopurine) Pseudocholinesterase suxamethonium/mivacurium) CYP2D6 (Codeine/Perhexiline) Genotyping: TPMT Pseudocholinesterase PGx tests performed rarely in clinical practice.

8 Irinotecan (Camptosar) Chemotherapy agent used is in treatment of colon cancer Extreme suppression of the immune system Particular caution should be exercised ……in patients known to be homozygous for UGT1A1*28 allele.

9 Current prescribing advice “Between 2000 and new drug labels were approved [by the FDA] that contained pharmacogenomic information reflecting 37% of all new approved labels.”

10 Scope of Questionnaire Multidisciplinary: - CMGS HoLs -H&I National Network -RCPath Bulletin UK and Ireland Inherited changes

11 Participants by specialty 10 Genetics 16 Histocompatibility & Immunogenetics 5 Biochemistry 1 Haematology Total 32

12 Accreditation 30/32 labs CPA accredited 100% of all UK NHS labs were

13 Does your laboratory offer any pharmacogenetic test services? 3/10 Genetics 14/16 Histocompatibility & Immunogenetics 4/5 Biochemistry 0/1 Haematology

14 Current pharmacogenetic services GeneticsBiochemH & I Cytochrome P450 2D6 (CYP2D6) (codeine) 121 Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Sirolimus) 1 HLA-B*1502 ( Carbamazepine) 6 HLA-B*5701 ( Abacavir) 14 Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) 113 UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) 1

15 Current pharmacogenetic services GeneticsBiochemH & I Cytochrome P450 2D6 (CYP2D6) (codeine) 121 Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Sirolimus) 1 HLA-B*1502 ( Carbamazepine) 6 HLA-B*5701 ( Abacavir) 14 Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) 1 2 labs >55,000 samples pa 3 UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) 1

16 Current pharmacogenetic services GeneticsBiochemH & I Cytochrome P450 2D6 (CYP2D6) (codeine) 121 Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Sirolimus) 1 HLA-B*1502 ( Carbamazepine) Immune mediated toxic effects 6 HLA-B*5701 ( Abacavir) 14 Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) 113 UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) 1

17 Carbamazepine - Brand names Carbatrol, Equetro, Tegretol, Tegretol XR, Epitol Anticonvulsant/mood stabilizing drug - epilepsy and bipolar disorder Dangerous/fatal skin reactions esp. in patients with HLA-B*1502 HLA-B*1502 almost exclusively in patients South Asian ancestry. Widely prescribed PGx only offered selectively

18 Abacavir - Brand name Ziagen Antiviral reverse transcriptase inhibitor - HIV-1 infection. Hypersensitivity reactions occur in approximately 5% - strongly associated with HLA-B*5701 and can be fatal Prevalence of HLA-B*5701. Highest in India lowest in SE Asia. Widely prescribed PGx widely offered

19 For what reasons does your laboratory not offer pharmacogenetic test services? H & I No Demand Genetics No demand Not previously cost effective No proven clinical validity or utility Lack of guidelines or evidence for clinical benefit or effectiveness

20 Co-ordination of PGx tests Do you believe there is a need for an implementing body whose main function will be to co-ordinate pharmacogenetic laboratory services in the UK (similar to the UK Genetic Testing Network)? Genetics – 10/10 labs voted yes (prevent monopoly) H & I: 8/15 – yes (no: restrictive/protectivist) Biochem: 0/5 – yes Haem: 1/1 - yes

21 Conclusions – The Present Compared to previous surveys - big increase in PGx Many labs across different disciplines Lab offering tests depends on nature of test (ie not to a generic PGx lab)

22 Conclusions – The Future More tests being developed: –Poor response to tamoxifen in BRCA predicted by CYP2D6 –Antibiotic (aminoglycoside) ototoxicity associated with m.1555A>G Setting standards – –American Association of Biochemists practice guidelines –EQA Is there a role for the UKGTN.


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