TheraGuide 5-FU

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(No Transcript)
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Learning ObjectivesAt 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

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Pharmacogenetics

• The study of genetic variation that determines an
  individuals 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

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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.

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DPD DeficiencyMechanism 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.

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TS DeficiencyMechanism 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.

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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 Mar24(2)215-7. Semin
Oncol. 2007 Apr34(2 Suppl 1)S37-40. Ann Oncol.
2005 Dec16(12)1853-4. J. Clin. Onc. 1998 16
3537-3541. Drugs. 2003.63(2)217-36. J Clin Onc.
200321(15)2896-2903.
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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 Mar24(2)215-7.
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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 110(17)5880-8. Clin Cancer Res.
2006 Jul 112(13)3928-34.
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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

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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
• IVS141 GgtA, 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.
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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

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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/capecitabine-related toxicity
• TheraGuide 5-FU is used to determine a patients
  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 Pharmacogenom
ics J 2001.1(1) 65-70.
FDA package warnings http//www.fda.gov/medwatc
h/SAFETY/2003
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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) 289-291Pharmacogenom
ics J 2001.1(1) 65-70Cancer Invest. 2006
Mar24(2)215-7Semin Oncol. 2007 Apr34(2 Suppl
1)S37-40Ann Oncol. 2005 Dec16(12)1853-4J.
Clin. Onc. 1998 16 3537-3541Drugs.
2003.63(2)217-36.
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In Summary

• TheraGuide 5-FU can help predict a patients
  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.