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 responded22 using molecular tests.

• FISH (haematology)• IHC (CRC, BrCa, haematology)• DNA (somatic mutations/MSI/ LOH/arrays)

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

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:

• TPMT (Azathioprine/6 mercaptopurine)• Pseudocholinesterase suxamethonium/mivacurium)• CYP2D6 (Codeine/Perhexiline)

Genotyping:

• TPMT • Pseudocholinesterase

PGx tests performed rarely in clinical

practice.

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 H & I

Cytochrome P450 2D6 (CYP2D6) (codeine)

1 2 1

Cytochrome P450 3A4 (CYP3A4)(Cyclosporin/Sirolimus)

1

HLA-B*1502 (Carbamazepine) 6

HLA-B*5701 (Abacavir) 14

Thiopurine methyltransferase (TPMT) (Azathioprine/6-MP)

1 1 3

UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan)

1

Current pharmacogenetic services

Genetics Biochem H & I

Cytochrome P450 2D6 (CYP2D6) (codeine)

1 2 1

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

Current pharmacogenetic services

Genetics Biochem H & I

Cytochrome P450 2D6 (CYP2D6) (codeine)

1 2 1

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)

1 1 3

UDP-glucuronosyltransferase 1A1 (UGT1A1) (Irinotecan)

1

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.