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Learning Objectives A t 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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Learning Objectives A t the conclusion of this presentation participants should understand the following:

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  1. 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 Learning ObjectivesAt the conclusion of this presentation participants should understand the following:

  2. 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 Pharmacogenetics

  3. 5-fluorouracil/capecitabineMechanism 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.

  4. 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.

  5. 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.

  6. 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 Who benefits from TheraGuide 5-FU™? 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.

  7. 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. What are the risks? Mol Cancer Ther 2006. 5(11): 289-291. PharmacogenomicsJ 2001.1(1): 65-70. Cancer Invest. 2006 Mar;24(2):215-7.

  8. 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 What are the risks? PharmacogenomicsJ 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.

  9. 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

  10. 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 TheraGuide 5-FUTM includes full sequencing of DPYD Mol Cancer Ther 2006. 5(11): 289-291.

  11. TYMS variations 2R/2R 2R/3R 3R/3R 4R variations have also been described The 2R/2R variation is considered high-risk TheraGuide 5-FUTM includes analysis of TYMS

  12. As many as 1 in 4 individuals have a variation in DPYD or TYMS that increases the risk for5-FU/capecitabine-related 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 How are TheraGuide 5-FUTM results reported? Mol Cancer Ther 2006. 5(11): 289-291 PharmacogenomicsJ 2001.1(1): 65-70. FDA package warnings – http://www.fda.gov/medwatch/SAFETY/2003

  13. Identifies high risk patients before beginning their chemotherapy Allows for personalized treatment options for cancer therapy enhanced patient monitoring dose reduction considerations alternate chemotherapies How are TheraGuide 5-FUTM results used? Mol Cancer Ther 2006. 5(11): 289-291PharmacogenomicsJ 2001.1(1): 65-70Cancer Invest. 2006 Mar;24(2):215-7Semin Oncol. 2007 Apr;34(2 Suppl 1):S37-40Ann Oncol. 2005 Dec;16(12):1853-4J. Clin. Onc. 1998 16: 3537-3541Drugs. 2003.63(2):217-36.

  14. 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. In Summary

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