PHARMACOGENOMICS IN SOLID TUMOUR

Dr Dzul Azri Mohamed Noor

 OBJECTIVES
• Describe gene functions in solid tumour therapy
• Explain the effect of gene polymorphism towards
solid tumour therapy
• Give recommendation based on pharmacogenomic
data
UGT1A1 IN IRINOTECAN
THERAPY
 WHAT IS IRINOTECAN?
• Camptothecin class of topoisomerase inhibitor
• Indications: 1) colorectal cancer
• 2) small cell lung cancer
• Side effects: diarrhea, neutropenia, vascular
syndromes
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 UGT1A1 FUNCTION
• Converted into SN-38, an active metabolite by
carboxyesterase
• SN-38 inactivated by glucuronidation by UGT1A1
into SN-38G
• SN-38G is excreted through the bile
• In the gut, bacterial glucuronidase may convert
back SN-38G into its active form SN-38 which
add to the incidence of diarrhea
 UGT1A1
Polymorphis Changes
POLYMORPHISM
UGT1A1 fx Incidence
m
*6 G71R (211G>A) Reduce 13-32% Asian

*27 P229Q (686 C>A) Reduce <3% Asian

*28 (TA)6  (TA)7 Reduce Majority in white

and African, 9-16%
in Asian
*36 (TA)6  (TA)5 Increase Majority in African

*37 (TA)6  (TA)8 Reduce Majority in African

*60 -3279 T>G Reduce >30% in White

*93 -3156 G>A Reduce ~83% Japanese

UGT1A1 TA REPEATS
• Related to tandem repeats in
the promoter regions
• WT have 6 (TA) followed by TAA
• Implicated polymorphism (UGT
1A1*28) have 7 (TA) followed
by TAA
• Those with 7 (TA) have less
expression of UGT1A1 (less
function) leads to low
conversion into inactive
metabolite
• Assoc. with reduced clearance
of SN-38 and
hyperbilirubinemia
 CLINICAL IMPLICATIONS
• Toxicity & Efficacy

 *28 have higher risk of side effects but higher chances of

tumour response vs WT
 PHARMACOGENOMIC
TEST DEBATE
• PRO • CONS
Only 30-40% UGT1A1*28 suffer
Polymorphism have toxicities – is it cost-benefit?
strong correlation with Reduce dose as recommended
toxicities may reduce efficacy
Available assay Recommended 20% dose
reduction has not been
Common polymorphism prospectively studied
(in Caucasian) Studies use higher dose (200-
350mg/m2) vs dose commonly
FDA include used (100-125mg/m2) – do the
recommendation in toxicities observed due to high
package insert doses used in the study?
 UGT1A1 AND MAXIMUM
TOLERATED DOSE
• Standard dose of FOLFIRI regimen is 180mg/m2
• Assume that study using this dose also include
*28 genotype.
• If *28 genotype were excluded, will the MTD be
different?
• MTD for UGT1A1 *1/*1 = 370mg/m2
• MTD for UGT1A1 *1/*28 = 310 mg/m2
• Current dose are lower than the MTD
• Is it beneficial to screen for UGT1A1 genotype?
 TESTING
RECOMMENDATION
• Based on Evaluation of Genomic Application in
Practice and Prevention (EGAPP) working group:
- lack of evidence to suggest whether to test or
not
- no trials have shown that dosing adjustment
based on UGT1A1 genotyping can reduce toxicity
5-FLUOROURACIL,
CAPECITABINE
AND DPYD
 5-FLUOROURACIL &
CAPECITABINE
• Fluorinated pyrimidine
(fluoropyrimidines analogue)
• Capecitabine is a prodrug for
5-fluorouracil
• Acts as an irreversible
thymidylate synthase inhibitor
• Blocks the formation of
thymidine required for DNA
replication
• Leads to cell death
POLYMORPHISMS
POLYMORPHISMS
POLYMORPHISMS
POLYMORPHISMS
 METABOLISMS
• 80% inactivated by dipyrimidine dehydrogenase
 DPYD POLYMORPHISM
Allele Nucleotide change DPYD function Notes
*1 WT Normal
*2A 1905+1 G>A Reduce aka IVS14+1
G>A
*2B 1905+1 G>A Reduce With *5
1627 T>C
*3 1898delC Reduce rare
*4 1601 G>A Reduce rare
*5 1627 T>C Reduce WT 1905+1 G,
10-30% White,
African, Asian
*6 2194 C>T Reduce 1-7% White,
African, Asian
*9A 85 A>G Reduce 20-40% White,
African
3-5% Asian
 CLINICAL IMPLICATION
• Polymorphism reduce the DPTD enzyme function,
more active metabolite
• Higher risk of side effects eg neutropenia,
mucositis and diarrhea
(homozygous>heterozygous)
• Association studies still not clear
• Genetic testing is not warranted
 RECOMMENDATION
Based on CPIC guidelines 2013*

Genotype Implications Recommendation

Homozygous WT Normal enzyme Use recommended
activity dose
Heterozygous Decrease enzyme Start at least50%
activity, increase risk reduction in starting
of toxicity dose, titrate according
to response
Homozygous variant Complete eenzyme Select alternative drug
deficiency and higher
risk of toxicity

Recommendation only for *2A and *13

EGFR INHIBITOR & KRAS
 EPIDERMAL GROWTH
FACTOR RECEPTOR (EGFR)

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 EPIDERMAL GROWTH
FACTOR RECEPTOR (EGFR)
 EPIDERMAL GROWTH
FACTOR RECEPTOR (EGFR)
 EPIDERMAL GROWTH
FACTOR RECEPTOR (EGFR)
• A cell surface protein that binds
to epidermal growth factors
• Binding of the protein to a
ligand will induce receptor
dimerization, activate
downstream genes (including
KRAS) and tyrosine
autophosphorylation
• This will stimulate cell
proliferation
• By giving EGFR inhibitor
(cetuximab, panitumumab), it
will block this pathway and
inhibit cell proliferation.
 KRAS
• Kirsen (K) Ras is a downstream effector of EGFR
• It is an oncogene
• KRAS signaling pathway thought to control cell
proliferation, differentiation and apoptosis survival.
• When KRAS have activating mutations, it will resist
the inhibition of cell surface tyrosine kinase eg EGFR
and continue sending signal for cell proliferation
• Prevalence of KRAS activating mutation are 27-43%
 CLINICAL IMPLICATIONS
• CRC patient who have KRAS activating mutation is
expected to not responding to EGFR therapy
• According to American Society of Clinical Oncology
(ASCO):
- all metastatic CRC patient who are candidate for
anti-EGFR therapy should be tested for KRAS mutation
- if patient have KRAS mutation at codon 12 or 13,
patient should not receive anti-EGFR therapy
• No published data on KRAS mutation effect on toxicity
and dosing selection.
TAMOXIFEN AND CYP2D6
 TAMOXIFEN
• Selective estrogen receptor modulator
• Tamoxifen is converted to its active metabolite 4-OH N-
desmethyl-tamoxifen (Endoxifen) by CYP2D6. This active
metabolite of tamoxifen compete with estrogen for estrogen
receptor binding. Once bind it decrease DNA synthesis and
inhibit estrogen effects. It will cause cells to remain in G0
and G1 phase of cell cycle but will not cause cell death.
• Indications:
-gold standard for estrogen receptor or progesterone
receptor positive breast cancer
- metastatic and adjuvant therapy in breast cancer
- preventative therapy in pt high risk for breast ca.
 CYP2D6
• Involves in endoxifen formation
• Highly polymorphic
Allele – 74 variants has been
Enzyme activity
*1 identified Normal
*10, *17,*41 Decrease
*3,*4,*5,*6 Null
*17x2, *10x2, *41x2 Increase
Genotype Phenotype Example

functional allele METABOLIZER STATUS

More than 2 copies of Ultrarapid
metabolizers (UM)
*1x2/*1

2 fully functional Extensive *1/*1 or *1/*17

copies or reduced metabolizers
function copies (EM) OR
OR
1 fully functional copy *1/*17x2 or *1/*4
plus 1 multiple copies
of reduced or 1 non-
functional copy OR
OR *4/*17x2
1 multiple copies of
reduced function plus
1 copy non-functional
1 reduced plus 1 non- Intermediate *17/*4
functional allele metabolizer (IM)
2 copies of non- Poor metabolizer (PM) *4/*4
functional allele
PREVALENCE
CLINICAL IMPLICATIONS
• Efficacy
No association between CYP2D6*4 on overall survival
Contradictory data regarding CYP2D6*4 association
with disease recurrence
CYP2D6*4 associated with decrease in disease free
survival

• Toxicity
Variable incidence with hot flashes in CYP2D6*4/*4
 RECOMMENDATION
• Genotyping
- Should include *3,*4,*5,*6,*9,*10,*17,*41
- FDA recommend label update to reflect
increased risk but no formal recommendation on
genetic testing
- Recent data suggest the use of both normal and
tumour tissue sample for genotyping
 RECOMMENDATION

• Alternative therapy
Post-menopausal women:
- change to aromatase inhibitor eg anastrozole,
lestrozole OR
- increase dose of tamoxifen
Pre-menopausal women
- no alternatives therefore may need to
increase tamoxifen dose