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 2008 50 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 2005 43 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.