Transcript Slide 1

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 H & I
Cytochrome P450 2D6 (CYP2D6)
(codeine)
Cytochrome P450 3A4
(CYP3A4)(Cyclosporin/Sirolimus)
1
2
1
1
HLA-B*1502 (Carbamazepine)
6
HLA-B*5701 (Abacavir)
14
Thiopurine methyltransferase
(TPMT) (Azathioprine/6-MP)
UDP-glucuronosyltransferase 1A1
(UGT1A1) (Irinotecan)
1
1
1
3
Current pharmacogenetic services
Cytochrome P450 2D6 (CYP2D6)
(codeine)
Cytochrome P450 3A4
(CYP3A4)(Cyclosporin/Sirolimus)
Genetics
Biochem
H&I
1
2
1
1
HLA-B*1502 (Carbamazepine)
6
HLA-B*5701 (Abacavir)
14
Thiopurine methyltransferase
(TPMT) (Azathioprine/6-MP)
UDP-glucuronosyltransferase 1A1
(UGT1A1) (Irinotecan)
1
1
2 labs >55,000
samples pa
3
Current pharmacogenetic services
Genetics Biochem H & I
Cytochrome P450 2D6 (CYP2D6)
(codeine)
Cytochrome P450 3A4
(CYP3A4)(Cyclosporin/Sirolimus)
HLA-B*1502 (Carbamazepine)
HLA-B*5701 (Abacavir)
Thiopurine methyltransferase
(TPMT) (Azathioprine/6-MP)
UDP-glucuronosyltransferase 1A1
(UGT1A1) (Irinotecan)
1
2
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
6
No of labs
5
4
3
2
1
0
0-19
20-39
No of tests per year
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
3.5
2.5
2
1.5
1
0.5
0
119
20
-3
9
40
-5
9
60
-7
9
80
10 -99
01
20 9 9
02
30 9 9
03
40 9 9
04
50 9 9
05
60 9 9
06
70 9 9
07
80 9 9
08
90 9 9
099
>1 9
00
0
No of labs
3
No of tests
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.