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Genetic Testing for Melanoma Risk Stratification

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Title: Genetic Testing for Melanoma Risk Stratification


1
Genetic Testing for Melanoma Risk Stratification
  • Sancy Leachman, MD, PhD
  • Assistant ProfessorHuntsman Cancer Institute and
    the Department of DermatologyUniversity of Utah
    Health Sciences Center
  • Pacific Dermatologic AssociationAugust 9, 2008

2
Hereditary Melanoma Nevus Phenotype Lots and
Atypical
3
Hereditary MelanomaNevus Phenotype Many, Mainly
Small
4
Hereditary MelanomaNevus Phenotype Few, Few/No
Atypical
Phenotype ? Genotype
5
Other Phenotypic MarkersConstitutional Risk
6
Wild-Type and Homozygous R Variant MC1R
7
Heterozygous for MC1R Variants
Phenotype ? Genotype
8
Risk EstimationFamily History is Greatest Risk
Factor
Relative 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

Kefford RF, et al. J Clin Oncol.
1999173245-3251.
9
p16 Mutation CarriersMelanoma 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.
200294894-903. Rulyak SJ et al. Cancer.
200398(4)798-804 and Paker JF et al. Arch
Dermatol. 20031391019-1025.
10
Few Melanomas Are Hereditary
11
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

12
Should Clinical Genetic Testing be Offered to
This Patient?
  1. Yes
  2. No
  3. Maybe

13
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

14
Candidates for p16 TestingRule of Threes
3 cancer events in a family (any combination
of melanoma and pancreatic cancer) 68
3 melanomas in a family (any degree of
relationship) 12-41
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.
15
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.
16
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

17
Should Clinical Genetic Testing be Offered to
This Patient?
  • Yes
  • No
  • Maybe

18
Answer NoInterpreting a Negative Result Not
Possible
True negative
Inconclusive
Adapted from ASCO.
19
Should an Affected Member of the Family be
Tested?
  1. Yes
  2. No
  3. Maybe

20
Issues for Consideration
  • Statistically, the patients 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

21
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

22
Receipt of Positive p16 Results Increases
Screening
Overscreeners
P lt .0003
n.s.
P lt .023
1 SSE/Month (On Target)
Underscreeners
Aspinwall et al. Cancer Epidemiol Biomarkers
Prev. 200817(6)1510-1519.
23
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 wendy.kohlmann_at_hci.utah
    .edu

24
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)

25
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

26
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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