©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation...
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Transcript of ©2007 Myriad Genetic Laboratories, Inc.. Learning Objectives At the conclusion of this presentation...
©2007 Myriad Genetic Laboratories, Inc.
©2007 Myriad Genetic Laboratories, Inc.
Learning ObjectivesAt the conclusion of this presentation
participants should understand the following:
• Use of pharmacogenetics in understanding patient susceptibility to 5-FU/capecitabine 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
©2007 Myriad Genetic Laboratories, Inc.
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?
©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
5-Fluorouracil metabolism85%
15%
Nature Reviews Cancer. 2003; 3:330-38.
Nature Reviews Cancer. 2003; 3:330-38.
Capecitabine metabolism
©2007 Myriad Genetic Laboratories, Inc.
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.
©2007 Myriad Genetic Laboratories, Inc.
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/capecitabine− Toxicity
©2007 Myriad Genetic Laboratories, Inc.
Is toxicity a significant clinical problem?
Capecitabine(diarrhea)
5-FU(diarrhea)
Meta Analysis Group in Cancer study 1998
--- 31%(5-FU bolus)
Cassidy 2002•Before dose modification
11% 13%(Mayo Clinic regimen)
Goldberg 2006--- 9-15%
(FOLFOX4)
Schmoll 200719%
(XELOX)
20%(Mayo and Rosewell Park)
Schwab 2008 ---8.6%
(5-FU monotherapy)
J Clin Oncol. 1998 16:3537-3541.
Ann Oncol. 2002 Apr;13(4):566-75. J Clin Oncol. 2006:24(25):4085-4091.
J Clin Oncol. 2007 25:102-109. J Clin Oncol. 2008;26(13): 2130-37.
Prevalence Rate: Grade 3-4 diarrhea
©2007 Myriad Genetic Laboratories, Inc.
Is toxicity a significant clinical problem?
• Cassidy study: several patients discontinued treatment due to related side effects– 9.6% of capecitabine patients– 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
©2007 Myriad Genetic Laboratories, Inc.
Who benefits from TheraGuide 5-FU™?
• 5-FU and capecitabine therapy candidates
• About 1 in 14 (7%) patients treated with 5-FU or capecitabine 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):2130-37.
©2007 Myriad Genetic Laboratories, Inc.
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.
J Clin Oncol. 2008;26(13): 2130-37.
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
©2007 Myriad Genetic Laboratories, Inc.
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):2130-37.
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
©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?
©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 confers a 1.4-2.5-fold increased
risk for adverse events
©2007 Myriad Genetic Laboratories, Inc.
How are TheraGuide 5-FUTM results reported?
• As many as 1 in 4 individuals have a variation that increases the risk for 5-FU/capecitabine-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/capecitabine toxicity is ruled out
– Indeterminate Mol Cancer Ther 2006. 5(11): 289-291.Pharmacogenomics J 2001.1(1): 65-70.
©2007 Myriad Genetic Laboratories, Inc.
• Identifies patient risk for 5-FU/capecitabine 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): 289-291.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.
How are TheraGuide 5-FUTM results used?
©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 improve patient quality of life.
©2007 Myriad Genetic Laboratories, Inc.
Supplemental Slides
©2007 Myriad Genetic Laboratories, Inc.
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
©2007 Myriad Genetic Laboratories, Inc.
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
©2007 Myriad Genetic Laboratories, Inc.
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.
Metastatic Breast Cancer PatientDPYD High Risk Result
• 60 yo female• Stage IV colon cancer
– Multiple liver metastases, lymph node involvement including supraclavicular nodes, and possible bone and lung metastases.
– Right hemicolectomy followed by a capecitabine/oxaliplatin regimen.
• After the first cycle, she presented with grade 2-3 toxicities.• Capecitabine dose was reduced by half and her symptoms
continued.• TheraGuide 5FUTM was ordered and confirmed that a DPYD
mutation was playing a role.• Her treatment was then changed to an irinotecan/cetuximab
containing regimen.• Patient responded well to the regimen and a subsequent
PET/CT scan showed complete remission.