©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 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
©2007 Myriad Genetic Laboratories, Inc.
5-Fluorouracil metabolism
85%
15%
Nature Reviews Cancer. 2003; 3:330-38.
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 greater toxicity
©2007 Myriad Genetic Laboratories, Inc.
TS Deficiency
Mechanism 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
©2007 Myriad Genetic Laboratories, Inc.
Is toxicity a significant
clinical problem?
Prevalence Rate: Grade 3-4 diarrhea
5-FU
(diarrhea)
Meta Analysis Group in
Cancer study 1998
Cassidy 2002
•Before dose modification
Goldberg 2006
Schmoll 2007
Schwab 2008
31%
(5-FU bolus)
13%
(Mayo Clinic regimen)
9-15%
(FOLFOX4)
20%
(Mayo and Rosewell Park)
8.6%
(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.
©2007 Myriad Genetic Laboratories, Inc.
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.
©2007 Myriad Genetic Laboratories, Inc.
FDA WARNING
FDA 2003 warning had been issued stating 5-FU is
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.
©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 .
Study
Overall
DPYD and
Patients
Grade 3-4 Grade 3-4
(unselected)
toxicity
toxicity
DPYD and
toxicity
relative risk
Morel
n = 487
9%
60%
7-fold
Schwab
n = 683
16%
50%
3-fold
Mol Cancer Ther 2006. 5(11): 289-291.
Pharmacogenomics J 2001.1(1): 65-70.
JCO. 2008;26(13): 2130-2137.
©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
TYMS and
Grade 3-4
toxicity
TYMS
Grade 3-4
toxicity
relative risk
Study
Patients
(unselected)
Overall
Grade 3-4
toxicity
Meta
analysis
n = 200
22%
52%
2.5 fold
Schwab
n = 683
16%
22%
1.4 fold
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.
©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-FU 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-FU 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-FU
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): 289-291.
Pharmacogenomics J 2001.1(1): 65-70.
©2007 Myriad Genetic Laboratories, Inc.
How are TheraGuide® 5-FU
results used?
• 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): 289-291.
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 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
Diarrhea
Dehydration
Mucositis/stomatitis
(clinical exam)
– Select:
– Anus
– Esophagus
– Large bowel
– Larynx
– Oral cavity
– Pharynx
– Rectum
– Small bowel
– Stomach
– Trachea
Short Name
1
Diarrhea
Increase of <4
stools per day
over baseline; mild
increase in ostomy
output compared
to baseline
Dehydration
Increased oral
fluids indicated;
dry mucous
membranes;
diminished skin
turgor
Mucositis
(clinical exam)
– Select
Erythema of the
mucosa
2
3
4
5
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
IV fluids indicated
<24 hrs
IV fluids indicated
≥24 hrs
Life-threatening
consequences
(e.g.,
hemodynamic
collapse)
Death
Patchy ulcerations
or
pseudomembranes
Confluent
ulcerations or
pseudomembrane
s; bleeding with
minor trauma
Tissue necrosis;
significant
spontaneous
bleeding; lifethreatening
consequences
Death
©2007 Myriad Genetic Laboratories, Inc.
National Cancer Institute Common Toxicity Criteria
Adverse Event
Nausea
Vomiting
Rash: hand-foot skin
reaction
Febrile neutropenia
(fever of unknown
origin without
clinically or
microbiologically
documented
infection) (ANC <1.0
x 109/L, fever
≥38.5°C)
Short Name
2
3
Loss 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
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
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
—
—
Present
Life-threatening
consequences
(e.g., septic shock,
hypotension,
acidosis, necrosis)
Death
Nausea
Febrile
neutropenia
1
—
—
4
5
©2007 Myriad Genetic Laboratories, Inc.
Metastatic Breast Cancer Patient
Low 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.