Transcript Melanoma Symposium - Pacific Dermatologic Association

Genetic Testing for Melanoma
Risk Stratification
Sancy Leachman, MD, PhD
Assistant Professor
Huntsman Cancer Institute and the
Department of Dermatology
University of Utah Health Sciences Center
Pacific Dermatologic Association
August 9, 2008
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Hereditary Melanoma
Nevus Phenotype: Lots and Atypical
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Hereditary Melanoma
Nevus Phenotype: Many, Mainly Small
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Hereditary Melanoma
Nevus Phenotype: Few, Few/No Atypical
Phenotype ≠ Genotype
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Other Phenotypic Markers
“Constitutional” Risk
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Wild-Type and Homozygous “R”
Variant MC1R
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Heterozygous for MC1R Variants
Phenotype ≠
Genotype
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Risk Estimation
Family History is Greatest Risk
Factor
Relative Risk
• Member of melanoma family
35 – 70
• Previous primary melanoma
8.5
• Multiple nevi/atypical nevi
• Red hair
2 – 12
2.4 – 4
• Family history of melanoma
2–3
• History of blistering sunburn
2–3
• Freckling
2-3
• Blue eyes
1.6
• Skin type I
1.4
Kefford RF, et al. J Clin Oncol. 1999;17:3245-3251.
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p16 Mutation Carriers:
Melanoma and Pancreatic Adenocarcinoma
● p16 Tumor Suppressor controlling the cell cycle
● Higher lifetime risk of melanoma*
– United Kingdom: 58%
– United States: 76%
– Australia: 91%
● Increased risk of pancreatic cancer†
– (11%-17% in some families)
● Red hair increases risk
*Bishop DT et al. J Natl Cancer Inst. 2002;94:894-903.
†Rulyak SJ et al. Cancer. 2003;98(4):798-804; and Paker JF et al. Arch Dermatol. 2003;139:1019-1025.
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Few Melanomas Are Hereditary
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Case Presentation
● A dermatologist from Kentucky contacted our genetic
counseling group to discuss how to
perform genetic testing on a patient:
– 64 y/o nurse practitioner with dysplastic nevus syndrome,
a personal history of melanoma, no children
– No known family history of melanoma or pancreatic
cancer
– Patient wishes to have p16 genetic testing performed on
a self-pay basis
– Patient is interested in participating in available research
protocols for melanoma
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Should Clinical Genetic Testing
be Offered to This Patient?
1. Yes
2. No
3. Maybe
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Issues for Consideration
● Statistically, the patient has only between a 0.2%-2.0% risk of carrying
a p16 mutation (Aitken et al, and Begg et al)
● The patient does NOT have features suggestive of elevated risk
for carriage of a p16 mutation (Hansen et al. Lancet Oncology. 2004)
– Multiple primary melanomas
– Two or more other family members with melanoma
– Family member with pancreatic cancer
● Because she has already had melanoma, there is little chance
that a positive or negative test result will alter prevention,
early detection, management, or follow-up recommendations
● She expressed the desire for testing and willingness to pay
● Knowledge of status may provide psychological benefit to her
because of her curiosity and professional background
● If p16-positive (unlikely), other family members could be tested and
pancreatic cancer screening (if available) could be offered
● Research protocols are available to p16 mutation-tested individuals
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Candidates for p16 Testing:
“Rule of Threes”
≥3 melanomas in a
family (any degree of
relationship) 12%-41%
≥3 “cancer events” in a
family (any combination of
melanoma and pancreatic
cancer) ~68%
≥3 melanomas in an individual 5%-23%
*Only 1 criteria needs to be met. Consideration should be given to age of diagnosis, UV exposure,
skin type, and ethnicity, as there may be exceptions to the “Rule of Threes.”
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Should Clinical Genetic Testing
be Offered to This Patient?
1.
Yes
2.
No
3.
Maybe
Answer: Based on typical criteria used to evaluate
a patient for genetic testing, the answer is “NO.”
However, as with all areas of medicine, there is
“art” involved.
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Case Presentation
● 32 y/o woman with numerous clinically atypical nevi
● No personal history of melanoma
● Confirmed family history of invasive melanoma
in 2 of 6 siblings, and 2 paternal uncles.
● Her father died from metastatic pancreatic carcinoma
● She has 3 children (ages 10, 8, and 6 years)
● Two children have clinically atypical nevi
● She is NOT interested in participating in an available
research protocol for familial melanoma
● She wishes to have p16 genetic testing performed
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Should Clinical Genetic Testing
be Offered to This Patient?
1.
Yes
2.
No
3.
Maybe
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Answer: No
Interpreting a Negative Result Not Possible
MM
 p16
mutation
MM
MM
MM
MM
MM
(-) p16
mutation
MM
Inconclusive
True negative
Adapted from ASCO.
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Should an Affected Member
of the Family be Tested?
1.
Yes
2.
No
3.
Maybe
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Issues for Consideration
● Statistically, the patient’s family has a greater than 50% risk of
carrying a p16 mutation
● Carriers in her family are also likely to be predisposed to
pancreatic cancer
● She expressed the desire for testing
● If she is not interested in clinical research, there will be little
change in management
● Knowledge of status may provide psychological benefit,
especially if negative
● Knowledge of status may permit lifestyle change and rigorous
adherence to prevention and early detection strategies in her
children if positive
● Summary: Benefit of knowledge, little to no risk
● A family member would be tested in our institution if desired
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p16 Test Reporting Study
● 45 members of p16 families received test
results
● 19 non-carriers, 26 carriers
● 23 female, 22 male
● 43/45 reported benefits or positive aspects
to testing
● 40/45 reported no downside or negative
aspects
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Receipt of Positive p16 Results
Increases Screening
Overscreeners
1
P < .0003
0.8
n.s.
0.6
0.4
0.2
1 SSE/Month
(On Target)
P < .023
Baseline
0
1 Month
-0.2
-0.4
-0.6
-0.8
Underscreeners
-1
p16- No
p16+ No
Melanoma History Melanoma History
p16+ Melanoma
History
Aspinwall et al. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1510-1519.
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How Should it be Done?
● Identify high-risk patients
● Get Help First Time Around!!
 Refer to a research protocol
 Consult a clinical genetic testing center
• Find a local center: www.nsgc.org
• www.cancer.gov/ (National Cancer Institute)
• Huntsman Cancer Institute:
[email protected]
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Where is Testing Performed?
● Clinical U.S. genetic laboratories offering
p16 genetic testing (some will assist with
obtaining insurance approvals)
 Find details at www.genetests.org
 Current CLIA certified laboratories
• GeneDX (USA)
• Myriad Genetic Laboratories (USA)
• Yale University School of Medicine (USA)
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How Much Does it Cost?
● Approximately $750 for first test
● Site-specific testing about $385
● 70% who go through pre-authorization
receive 90% coverage on average
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Conclusions for Genetic Testing
● It is difficult to perform clinical genetic testing in the
average outpatient setting
● Patient selection for candidacy is crucial
● Informed consent and pre- and post-test counseling
is important
● Enrollment of patients in a research protocol for
hereditary melanoma is preferable whenever possible,
though patients may wish to choose protocols that
report results
● Special situations may arise in which clinical genetic
testing is appropriate for a given individual, but
should never replace the standard criteria for testing
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