©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation...


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


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?


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

5-Fluorouracil metabolism85%

15%

Nature Reviews Cancer. 2003; 3:330-38.


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.


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


Is toxicity a significant clinical problem?

5-FU(diarrhea)

Meta Analysis Group in Cancer study 1998

31%(5-FU bolus)

Cassidy 2002•Before dose modification

13%(Mayo Clinic regimen)

Goldberg 20069-15%

(FOLFOX4)

Schmoll 200720%

(Mayo and Rosewell Park)

Schwab 20088.6%

(5-FU monotherapy)

JCO 1998 16: 3537-3541.

Ann Oncol. 2002 Apr;13(4):566-75. JCO. 2006:24(25):4085-4091.

JCO. 2007 25:102-109. JCO. 2008;26(13): 2130-2137.

Prevalence Rate: Grade 3-4 diarrhea


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 Apr;13(4):566-75.

FDA WARNINGFDA 2003 warning had been issued stating capecitabine and 5-FU

are contraindicated in patients with a known DPD deficiency

FDA package warnings – http://www.fda.gov/medwatch/SAFETY/2003


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. 2008;26(13):2130-2137.


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. 2008;26(13): 2130-2137.

StudyPatients

(unselected)

Overall

Grade 3-4 toxicity

DPYD and Grade 3-4

toxicity

DPYD and toxicity

relative risk

Morel n = 487 9% 60% 7-fold

Schwab n = 683 16% 50% 3-fold


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 1;10(17):5880-8.Clin Cancer Res. 2006 Jul 1;12(13):3928-34.

J Clin Oncol. 2008;26(13):2130-2137.

StudyPatients

(unselected)

Overall Grade 3-4

toxicity

TYMS and Grade 3-4

toxicity

TYMS Grade 3-4

toxicity relative risk

Meta analysis

n = 200 22% 52% 2.5 fold

Schwab n = 683 16% 22% 1.4 fold


• 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?


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.


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 confers a 1.4-2.5-fold increased

risk for adverse events


How are TheraGuide 5-FUTM 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 patient’s 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): 289-291Pharmacogenomics J 2001.1(1): 65-70.


• 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): 289-291Pharmacogenomics J 2001.1(1): 65-70

Cancer Invest. 2006 Mar;24(2):215-7Semin Oncol. 2007 Apr;34(2 Suppl 1):S37-40

Ann Oncol. 2005 Dec;16(12):1853-4J. Clin. Onc. 1998 16: 3537-3541

Drugs. 2003.63(2):217-36.

How are TheraGuide 5-FUTM results used?


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 improve patient quality of life.


Supplemental Slides


National Cancer Institute Common Toxicity Criteria

Adverse Event Short Name 1 2 3 4 5

Diarrhea Diarrhea

Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline

Increase of 4 – 6 stools per day over baseline; IV fluids indicated <24hrs; moderate increase in ostomy output compared to baseline; not interfering with ADL

Increase of ≥7 stools per day over baseline; incontinence; IV fluids ≥24 hrs; hospitalization; severe increase in ostomy output compared to baseline; interfering with ADL

Life-threatening consequences (e.g., hemodynamic collapse)

Death

Dehydration Dehydration

Increased oral fluids indicated; dry mucous membranes; diminished skin turgor

IV fluids indicated <24 hrs

IV fluids indicated ≥24 hrs

Life-threatening consequences (e.g., hemodynamic collapse)

Death

Mucositis/stomatitis(clinical exam)– Select:– Anus– Esophagus– Large bowel– Larynx– Oral cavity– Pharynx– Rectum– Small bowel– Stomach– Trachea

Mucositis (clinical exam)– Select

Erythema of the mucosa

Patchy ulcerations or pseudomembranes

Confluent ulcerations or pseudomembranes; bleeding with minor trauma

Tissue necrosis; significant spontaneous bleeding; life-threatening consequences

Death


National Cancer Institute Common Toxicity Criteria

Adverse Event Short Name 1 2 3 4 5

Nausea NauseaLoss of appetite without alteration in eating habits

Oral intake decreased without significant weight loss, dehydration or malnutrition; IV fluids indicated <24 hrs

Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN indicated ≥24 hrs

Life-threatening consequences

Death

Vomiting Vomiting 1 episode in 24 hrs 2 – 5 episodes in 24 hrs; IV fluids indicated <24 hrs

≥6 episodes in 24 hrs; IV fluids, or TPN indicated ≥24 hrs

Life-threatening consequences

Death

Rash: hand-foot skin reaction

Hand-foot

Minimal skin changes or dermatitis (e.g.,erythema) without pain

Skin changes (e.g., peeling, blisters, bleeding, edema) or pain, not interfering with function

Ulcerative dermatitis or skin changes with pain interfering with function interfering with function

— —

Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) (ANC <1.0 x 109/L, fever ≥38.5°C)

Febrile neutropenia

— — Present

Life-threatening consequences (e.g., septic shock, hypotension, acidosis, necrosis)

Death


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.

©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation...

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