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 toxicity
• Toxicity risks associated with variations in the
  genes DPYD and TYMS
• DPYD DPD (Dihydropyrimidine Dehydrogenase)
• TYMS TS (Thymidylate Synthase)
• Use of genetic test results in medical management

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Cancer Genetic Testing

• Hereditary Cancer testing
• What is the likelihood that my patient will
  develop a future cancer?
• Example Hereditary Breast and Ovarian Cancer
  Syndrome
• Tumor Characteristic testing
• Are there characteristics about this tumor that
  would dictate treatment options?
• Example HER2/neu testing
• Pharmacogenetic testing
• Does my patient have something innate that will
  cause him/her to respond differently to treatment?

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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 metabolism
85
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Nature Reviews Cancer. 2003 3330-38.
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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 greater toxicity

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TS DeficiencyMechanism of Action

• Variations in TYMS can lead to altered TS
  expression
• Lower levels of the TS enzyme can lead to
• Increased levels of active 5-FU
• Toxicity

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Is toxicity a significant clinical problem?
Prevalence Rate Grade 3-4 diarrhea
JCO 1998 16 3537-3541. Ann Oncol. 2002
Apr13(4)566-75. JCO. 200624(25)4085-4091. JCO
. 2007 25102-109. JCO. 200826(13) 2130-2137.
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Is toxicity a significant clinical problem?

• Cassidy study several patients discontinued
  treatment due to related side effects
• -6.7 of 5-FU patients
• Of patients who continued treatment following
  dose modification (reduced by 25-50), several
  continued to have side effects
• 45/138 Hand Foot Syndrome
• 21/89 Diarrhea
• 6/30 Stomatitis

Ann Oncol. 2002 Apr13(4)566-75.
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FDA WARNING

• FDA 2003 warning had been issued stating
  5-FU is contraindicated in patients with a known
  DPD deficiency

FDA package warnings http//www.fda.gov/medwatc
h/SAFETY/2003
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Who benefits from TheraGuide 5-FU?

• 5-FU therapy candidates
• About 1 in 14 (7) patients treated with 5-FU
  have Grade 3-4 toxicity associated with a DPYD or
  TYMS gene variation

Mol Cancer Ther 2006. 5(11) 289-291. J Clin
Oncol. 200826(13)2130-2137.
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What are the risks?

• DPYD gene variations are associated with a 7-fold
  (or up to a 60) risk of severe toxicity .

Mol Cancer Ther 2006. 5(11) 289-291.
Pharmacogenomics J 2001.1(1) 65-70. JCO.
200826(13) 2130-2137.
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What are the risks?

• TYMS gene variations are associated with a 1.4 to
  2.5-fold (or 22-52) increased risk of severe
  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. J Clin Oncol.
200826(13)2130-2137.
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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-FU 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-FU includes analysis of TYMS

• TYMS variations
• 2R/2R
• 2R/3R
• 3R/3R
• 4R variations have also been described
• The 2R/2R variation confers a 1.4-2.5-fold
  increased risk for adverse events

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How are TheraGuide 5-FU results reported?

• As many as 1 in 4 individuals have a variation
  that increases the risk for 5-FU related toxicity
• DPYD 5
• TYMS 15-20
• TheraGuide 5-FU is used to determine a patients
  likelihood of 5-FU toxicity
• High Risk
• 7-fold (or up to 60) risk for Grade 3 or Grade 4
  toxicity
• Moderate Risk
• 1.4 to 2.5-fold (or 23-53) risk for Grade 3 or
  Grade 4 toxicity
• Low Risk
• Common causes of 5FU toxicity is ruled out
• Indeterminate

Mol Cancer Ther 2006. 5(11) 289-291. Pharmacogeno
mics J 2001.1(1) 65-70.
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How are TheraGuide 5-FU results used?

• Identifies patient risk for 5-FU toxicity
• Allows for personalized treatment options for
  cancer therapy
• More informed discussion regarding toxicity risk
• Enhanced patient monitoring
• Dose reduction considerations
• Alternate chemotherapies

Mol Cancer Ther 2006. 5(11) 289-291.Pharmacogeno
mics J 2001.1(1) 65-70.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.
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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 improve patient quality of life

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Supplemental Slides
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National Cancer Institute Common Toxicity Criteria
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National Cancer Institute Common Toxicity Criteria
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Metastatic Breast Cancer PatientLow Risk Result

• 68 yo female
• Presented with recurrent breast cancer and
  lymphangitic lung disease after 3 years of being
  disease free
• TheraGuide 5-FU was ordered due to the previous
• life threatening toxicity
• effectiveness of 5-FU in treating her cancer
• Patient was found to have a low risk result
• Proceeded with a 5-FU regimen
• Currently on treatment with marked improvement
  and has no 5-FU related toxicities