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©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation participants should understand the following: Use.

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Presentation on theme: "©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation participants should understand the following: Use."— Presentation transcript:

1 ©2007 Myriad Genetic Laboratories, Inc.

2 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

3 ©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

4 ©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.

5 ©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.

6 ©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.

7 ©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 % of patients had grade 3 or 4 toxicity with 5-FU and leucovorin semi-monthly Cancer Invest Mar;24(2): Semin Oncol Apr;34(2 Suppl 1):S Ann Oncol Dec;16(12): J. Clin. Onc : Drugs (2): J Clin Onc. 2003:21(15):

8 ©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 (11): Pharmacogenomics J (1): Cancer Invest Mar;24(2):215-7.

9 ©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 (1): Clin Cancer Res Sep 1;10(17): Clin Cancer Res Jul 1;12(13):

10 ©2007 Myriad Genetic Laboratories, Inc. The only clinical test that performs: –Full sequencing of the DPYD gene and –Analysis of the TYMS gene promoter region What is included in TheraGuide 5-FU™ analysis?

11 ©2007 Myriad Genetic Laboratories, Inc. TheraGuide 5-FU TM 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 (11):

12 ©2007 Myriad Genetic Laboratories, Inc. TheraGuide 5-FU TM 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

13 ©2007 Myriad Genetic Laboratories, Inc. How are TheraGuide 5-FU TM 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 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 FDA package warnings – Mol Cancer Ther (11): Pharmacogenomics J (1):

14 ©2007 Myriad Genetic Laboratories, Inc. 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 (11): Pharmacogenomics J (1): Cancer Invest Mar;24(2):215-7 Semin Oncol Apr;34(2 Suppl 1):S37-40 Ann Oncol Dec;16(12): J. Clin. Onc : Drugs (2): How are TheraGuide 5-FU TM results used?

15 ©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.


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