Genetic Testing for Melanoma Risk Stratification

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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

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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 MarkersConstitutional 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
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.
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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.
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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 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.
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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?

• Yes
• No
• Maybe

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Answer NoInterpreting a Negative Result Not
Possible
True negative
Inconclusive
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 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

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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
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.
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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 wendy.kohlmann_at_hci.utah
  .edu

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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