A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE

A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE

A SURVEY OF CURRENT PHARMACOGENETIC TESTING IN THE UK AND IRELAND Simon Ramsden, Nikki Gambhir, Jennifer Higgs, Kay Poulton, William Newman 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 Current Scope of the UKGTN 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) None reported characterising tumours for drug response cKIT and PDGFR in GISTS - Imatinib (Glivec) KRAS in colorectal cancer - Cetuximab (Erbitux) EGF receptor in non-small cell lung cancer Erlotinib (Tarceva) Pharmacogenetics in Australia and NZ

2005 Questionnaires sent to 629 labs (Aus & NZ) 510 (81%) responses Genotyping 10 Phenotyping 18 Pharmacogenetics in Australia and NZ Phenotyping: PGx tests performed

rarely in clinical practice. TPMT (Azathioprine/6 mercaptopurine) Pseudocholinesterase suxamethonium/mivacurium) CYP2D6 (Codeine/Perhexiline) Genotyping: TPMT Pseudocholinesterase

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

Participants by specialty 10 Genetics 16 Histocompatibility & Immunogenetics 5 Biochemistry 1 Haematology Total 32 Accreditation 30/32 labs CPA accredited 100% of all UK NHS labs were Does your laboratory offer any

pharmacogenetic test services? 3/10 Genetics 14/16 Histocompatibility & Immunogenetics 4/5 Biochemistry 0/1 Haematology Current pharmacogenetic services Genetics Biochem Cytochrome P450 2D6 (CYP2D6) (codeine) Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Siroli

mus) 1 2 1 1 HLA-B*1502 (Carbamazepine) 6 HLA-B*5701 (Abacavir)

Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) H&I 14 1 1 1 3

Current pharmacogenetic services Genetics Cytochrome P450 2D6 (CYP2D6) (codeine) Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Siroli mus) 1 Biochem H & I 2

1 HLA-B*1502 (Carbamazepine) 6 HLA-B*5701 (Abacavir) Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) 1

14 1 1 2 labs >55,000 samples pa 3 Current pharmacogenetic services Genetics Biochem Cytochrome P450 2D6 (CYP2D6) (codeine) Cytochrome P450 3A4

(CYP3A4)(Cyclosporin/Siroli mus) HLA-B*1502 (Carbamazepine) HLA-B*5701 (Abacavir) Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP) UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan) 1 2 H&I

1 1 Immune mediated toxic effects 1 1 1 6 14 3

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 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 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 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 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) 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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