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©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.