1 Genetic Testing for Melanoma Risk Stratification Sancy Leachman, MD, PhD Assistant Professor Huntsman Cancer Institute and the Department of Dermatology.

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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