1 genetic testing for melanoma risk stratification sancy leachman, md, phd assistant professor...
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Genetic Testing for Melanoma Risk Stratification
Sancy Leachman, MD, PhDAssistant Professor
Huntsman Cancer Institute and the Department of Dermatology
University of Utah Health Sciences Center
Pacific Dermatologic AssociationAugust 9, 2008
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Hereditary Melanoma Nevus Phenotype: Lots and Atypical
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Hereditary MelanomaNevus Phenotype: Many, Mainly Small
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Hereditary MelanomaNevus 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 EstimationFamily History is Greatest Risk
• Member of melanoma family 35 – 70
• Previous primary melanoma 8.5
• Multiple nevi/atypical nevi 2 – 12
• Red hair 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
FactorFactor Relative RiskRelative Risk
Kefford RF, et al. J Clin Oncol. 1999;17:3245-3251.
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*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.
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
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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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≥3 melanomas in a family (any degree of relationship) 12%-41%
≥3 melanomas in an individual 5%-23%
≥3 “cancer events” in a family (any combination of melanoma and pancreatic cancer) ~68%
Candidates for p16 Testing:“Rule of Threes”
*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 melanomain 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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Adapted from ASCO.
True negativeInconclusive
Answer: NoInterpreting a Negative Result Not Possible
MM
MM
MM
MM
p16 mutation
MM MM
MM
(-) p16 mutation
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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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-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
p16- NoMelanoma History
p16+ NoMelanoma History
p16+ MelanomaHistory
Baseline
1 Month
Underscreeners
1 SSE/Month (On Target)
Overscreeners
Receipt of Positive p16 Results Increases Screening
P < .0003
P < .023
n.s.
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