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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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slide2
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:
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

Pharmacogenetics
5 fluorouracil capecitabine mechanism of action
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.
dpd deficiency mechanism of action
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.
ts deficiency mechanism of action
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.
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

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.

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.

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.

what are the risks9
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.

slide10

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
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

TheraGuide 5-FUTM includes full sequencing of DPYD

Mol Cancer Ther 2006. 5(11): 289-291.

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

TheraGuide 5-FUTM includes analysis of TYMS
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 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

how are theraguide 5 fu tm 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

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.

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.

In Summary