Transcript TheraGuide 5-FU

©2007 Myriad Genetic Laboratories, Inc.
Learning Objectives
At the conclusion of this presentation
participants should understand the following:
• Use of pharmacogenetics in understanding patient
susceptibility to 5-FU/capecitabine toxicity
• Toxicity risk associated with variations in DPYD and
TYMS
– DPYD = DPD deficiency
– TYMS= TS deficiency
• Use of genetic test results in medical management
©2007 Myriad Genetic Laboratories, Inc.
Pharmacogenetics
• The study of genetic variation that determines an
individual’s response to drugs
• Pharmacogenetic testing can be beneficial in oncology
because it can help determine
– How a patient will respond to chemotherapy
• Example: cytochrome P450 2D6 (CYP2D6) genotype
and ability to metabolize Tamoxifen
– The likelihood that a patient will experience severe
side effects
• Example: TheraGuide 5-FU
©2007 Myriad Genetic Laboratories, Inc.
5-fluorouracil/capecitabine
Mechanism of Action
• The majority of 5-FU is rendered inactive by the
DPD enzyme.
• The remaining 5-FU is sufficient for cancer therapy
and binds TS enzyme.
©2007 Myriad Genetic Laboratories, Inc.
DPD Deficiency
Mechanism of Action
• Variations in DPYD can lead to DPD insufficiency.
• This results in an inability to inactivate 5-FU leading to
increased levels of active drug in the system that can
result in toxicity.
©2007 Myriad Genetic Laboratories, Inc.
TS Deficiency
Mechanism of Action
• Variations in TYMS can lead to TS deficiency.
• This results in lower amounts of the TS enzyme being
available to bind with the active 5-FU.
• This results in increased levels of active drug in the
system that can result in toxicity.
©2007 Myriad Genetic Laboratories, Inc.
Who benefits from
TheraGuide 5-FU™?
• Up to 1 in 3 patients will experience an adverse reaction to
5-FU/capecitabine based chemotherapy
– Dependant on drug administration and regimen
– Meta Analysis Group in Cancer study (JCO 1998)
• 6 randomized 5-FU clinical trials
• Assessment in toxicity is key to determining treatment
modality
• 31% of patients had grade 3 or 4 toxicity when given
5-FU bolus
– Andre, et al JCO 2003
• 11% of patients had grade 3 or 4 toxicity with 5-FU and
leucovorin semi-monthly
Cancer Invest. 2006 Mar;24(2):215-7.
Semin Oncol. 2007 Apr;34(2 Suppl 1):S37-40.
Ann Oncol. 2005 Dec;16(12):1853-4.
J. Clin. Onc. 1998 16: 3537-3541.
Drugs. 2003.63(2):217-36.
J Clin Onc. 2003:21(15):2896-2903.
©2007 Myriad Genetic Laboratories, Inc.
What are the risks?
• Variations in DPYD and TYMS are associated with up to
a 60% risk of severe to life-threatening toxicity to
5-FU/capecitabine.
– Morel et al. study (Mol Cancer Ther 2006)
• 187 out of 487 patients had DPYD variations
– 44 had grade 3 or 4 toxicity
– 12 had grade 1 or 2 toxicity
– 3 specific variations caused level 3 or 4 toxicity in 60% of
carriers
• Approximately ½ of highly toxic reactions to 5-FU in
patients are due to DPD deficiency.
Mol Cancer Ther 2006. 5(11): 289-291.
Pharmacogenomics J 2001.1(1): 65-70.
Cancer Invest. 2006 Mar;24(2):215-7.
©2007 Myriad Genetic Laboratories, Inc.
What are the risks?
• TYMS gene variations are associated with a 2.5-fold
increased risk of severe toxicity
– Meta analysis (Lecomte, Pullarkat, Ichikawa)
• 200 unselected patients treated with 5-FU
• 43 patients (22%) had grade 3 to 4 toxicity
• 52% of patients with TYMS high risk genotype
had grade 3 to 4 toxicity
Pharmacogenomics J 2001.1(1): 65-70.
Clin Cancer Res.. 2004 Sep 1;10(17):5880-8.
Clin Cancer Res. 2006 Jul 1;12(13):3928-34.
©2007 Myriad Genetic Laboratories, Inc.
What is included in
TheraGuide 5-FU™ analysis?
• The only clinical test that performs:
– Full sequencing of the DPYD gene and
– Analysis of the TYMS gene promoter region
©2007 Myriad Genetic Laboratories, Inc.
TheraGuide 5-FUTM includes
full sequencing of DPYD
• DPYD (DPD deficiency)
– Three common variations account for the majority of
known 5-FU toxicity to date
• IVS14+1 G>A, D949V, and I560S
– More than 40 different variations in DPYD have
been identified as causing DPD deficiency
– Full sequencing is the “gold standard” for identifying
mutations
Mol Cancer Ther 2006. 5(11): 289-291.
©2007 Myriad Genetic Laboratories, Inc.
TheraGuide 5-FUTM includes
analysis of TYMS
• TYMS variations
– 2R/2R
– 2R/3R
– 3R/3R
– 4R variations have also been described
• The 2R/2R variation is considered high-risk
©2007 Myriad Genetic Laboratories, Inc.
How are TheraGuide 5-FUTM
results reported?
• As many as 1 in 4 individuals have a variation in DPYD
or TYMS that increases the risk for 5-FU/capecitabinerelated toxicity
• TheraGuide 5-FU™ is used to determine a patient’s
likelihood of 5-FU toxicity
– High Risk (up to 60% risk for Grade 3 or Grade 4 toxicity)
– Low Risk
– Indeterminate
• FDA 2003 warning had been issued stating capecitabine
and 5-FU are contraindicated in patients with a known
DPD deficiency
Mol Cancer Ther 2006. 5(11): 289-291
Pharmacogenomics J 2001.1(1): 65-70.
FDA package warnings – http://www.fda.gov/medwatch/SAFETY/2003
©2007 Myriad Genetic Laboratories, Inc.
How are TheraGuide 5-FUTM
results used?
• Identifies high risk patients before beginning their
chemotherapy
• Allows for personalized treatment options for cancer
therapy
• enhanced patient monitoring
• dose reduction considerations
• alternate chemotherapies
Mol Cancer Ther 2006. 5(11): 289-291
Pharmacogenomics J 2001.1(1): 65-70
Cancer Invest. 2006 Mar;24(2):215-7
Semin Oncol. 2007 Apr;34(2 Suppl 1):S37-40
Ann Oncol. 2005 Dec;16(12):1853-4
J. Clin. Onc. 1998 16: 3537-3541
Drugs. 2003.63(2):217-36.
©2007 Myriad Genetic Laboratories, Inc.
In Summary
• TheraGuide 5-FU™ can help predict a patient’s risk of
toxicity to 5-FU.
• Patient management can be personalized based
on results.
• Avoiding adverse events can help physicians save
time, money, and patient quality of life.
©2007 Myriad Genetic Laboratories, Inc.