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 MelanomaNevus Phenotype: Lots and Atypical

3. Hereditary MelanomaNevus Phenotype: Many, Mainly Small

4. Hereditary MelanomaNevus Phenotype: Few, Few/No Atypical Phenotype ≠ Genotype

5. Other Phenotypic Markers“Constitutional” Risk

6. Wild-Type and Homozygous “R” Variant MC1R

7. Heterozygous for MC1R Variants Phenotype ≠ Genotype

8. Risk EstimationFamily History is Greatest Risk Relative Risk Factor • 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. 1999;17:3245-3251.

9. 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.

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? Yes No 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. Candidatesfor p16 Testing:“Rule 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? Yes No 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 MM MM  p16 mutation MM MM MM MM (-) p16 mutation MM True negative Inconclusive Adapted from ASCO.

19. Should an Affected Member of the Family be Tested? Yes No Maybe

20. 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

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 < .0003 n.s. P < .023 1 SSE/Month (On Target) Underscreeners Aspinwall et al. Cancer Epidemiol Biomarkers Prev. 2008;17(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@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