Genetics, Molecular Profiling & Epidemiology of Early Stage Melanoma Winship Cancer Institute 2016 Melanoma Conference Atlanta, GA, Feb.

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1 Genetics, Molecular Profiling & Epidemiology of Early Stage Melanoma Winship Cancer Institute 2016 Melanoma Conference Atlanta, GA, Feb. 27, 2016 Sancy Leachman, M.D., Ph.D.

2 Disclosures & Conflicts Myriad Genetics Laboratory MSAB (honorarium), Early Access Program for mypath & myrisk (limited number of free tests) Castle Biosciences MSAB (honorarium) Apple Support Research Kit Tools, Thought Leader Meeting, & Marketing NOTE: Mole Mapper is free, open source, and no revenue is being generated from sponsorships.

3 Overview: Early Detection through Genetic & Epidemiologic Tools Genetic tools: Identifying patients at-risk Epidemiologic Tools War on Melanoma Community Registry Mole Mapper iphone App

4 Melanoma Genetics & Genetic Testing Germline Blood tests that tell you how much risk the patient has of developing a melanoma (predisposition testing) Somatic Tests that tell you how likely your patient s tumor has of being a melanoma (diagnostic testing) Somatic Tests that tell you how likely your patient s melanoma has of metastasizing (being a lethal melanoma prognostic testing)

5 Context: Germline Testing of Highest Risk Patients for Early Identification & Screening Risk Level (relative to Gen. Pop.) 30+X Highest/Syndromic Rule of Threes and Other Cancers CDKN2A (p16, ARF), CDK4, TERT, POT1, XP, BAP1, PTEN Proportion of Melanoma Population % 4-8X High-Risk Red hair (MC1R homozygote); > 100 nevi; >5 dysplastic nevi; personal hx MM; AKs, BCCs, SCCs (genes & environment) 15-30% 2X Vulnerable Phenotype Light skin, eyes, hair, family history Freckles, Sunburns, immunosuppression Almost everybody else!? Almost everybody else!?

6 Identifying Hereditary Melanoma: Consider the Rule of Twos & Threes 3 invasive melanomas in blood relatives 3 melanomas in an individual 3 melanoma + pancreatic OR astrocytoma (*2) in FDRs OR unusual associations: Uveal melanoma, lung adenocarcinoma, mesothelioma, paraganglioma, clear cell renal carcinoma *Only 1 criteria needs to be met. Consideration should be given to age at diagnosis, UV exposure, skin type, and ethnicity, as there may be exceptions to the Rule of Twos & Threes. Leachman, et al. JAAD 2009

7 Germline genetic testing: Single genes, panels of genes, o NGS, test sequencing? Single gene when phenotype suggests a particular mutation Gene panel perhaps better, if cost is no object Exome/Genome sequencing interpretation difficult Testing order: based on phenotype, history, cost

8 Navigating the Genetic Testing Options for Hereditary Patients FAMMM Only Melanoma +/- Pancreatic OR +/- Astrocytoma If Negative CDKN2A CDK4 If Negative BAP-1 Pattern Melanoma + Uveal Melanoma OR + Lung Adenocarcinoma OR + Paraganglioma OR + Mesothelioma OR + Clear Cell Renal Carcinoma If Negative BAP1 Melanoma in special context Multiple other cancers/signs including: SCC/BCC Breast, Thyroid, Endometrial Prostate Renal Colon PANEL TEST Work with Genetic Counseling Assure Genes Associated with Observed Cancers Are Contained in the Panel Cutaneous Cancer Syndrome Other Syndrome? Xeroderma pigmentosum Cowden Tumor-specific (e.g. Breast or Colon)

9 The Testing Process Does NOT Desire Testing Identify Candidates Using Rule of Twos & Threes Refer for Genetic Counseling No Mutation Manage Based on Family History Select Family Member with Melanoma Preauthorize Send to a CLIA Lab Desires Testing Mutation of Uncertain Significance Mutation Add Other CA Screening Test 1 st Degree

10 Genetic Diagnostic Testing for Melanoma Fundamentally different than predisposition testing Purpose is to determine if a lesion is melanoma, not if the individual is at risk for melanoma Performed on tissue, not blood Provides adjunctive measure to complement histology in ambiguous cases

11 Fluorescent In-Situ Hybridization (FISH) Two clinically available assays based on gene copy number Most studies on unambiguous lesions Sensitivity 87-94%; specificity 95-98% Less sensitivity in ambiguous lesions (43%) Subjective, requires specialized expertise Chromosomes: 6p25 (RREB1), 8q24 (MYC), 9p21 (CDKN2A/p16), 11q13 (CCND1), centromere (CEN9)

12 Comparative Genomic Hybridization (CGH) Also detects chromosomal gains and losses Comparison between tumor DNA & control DNA to evaluate entire genome Sensitivity & specificity not as well-characterized Most studies done on unambiguous cases Some subjectivity, but less than FISH

13 Gene Expression Profiling (GEP): Quantitative Reverse Transcription Polymerase Chain Reaction Evaluates expression of RNA rather than mutations in DNA Panel of 23 genes used Expression algorithm used to generate a score that falls into a benign or malignant range Objective and quantitative

14 Comparison of Diagnostic Genetic Tests for Melanoma Advantages FISH CGH qrt-pcr Minimal tissue required; single-cell resolution; can detect translocations Can assess all 23 chromosomes; no proficiency in fluorescent microscopy required Provides additional diagnostic value in discriminating benign vs malignant lesions Limitations Visualizes tiny fraction of genome; expertise requirement Can t assess intratumoral heterogeneity; dilution by stroma New test, publications in progress; no correlation with outcome

15 Genetic Prognostic Testing for Melanoma Fundamentally different than predisposition or diagnostic testing Purpose is to determine if a lesion is a potentially deadly melanoma Performed on tissue, not blood Provides adjunctive measure to complement histologic (e.g., Breslow depth) and other prognostic (e.g., sentinel node biopsy) data

16 Gene Expression Profiling (GEP): Quantitative Reverse Transcription Polymerase Chain Reaction Evaluates risk of recurrence for cutaneous melanoma patients Separates tumors into Class 1 (less risk) and Class 2 (more risk) High positive predictive value for Class 2 High negative predictive value for Class 1 Allows improved risk stratification that supports consideration of heightened follow-up (maybe adjuvant therapy in future) Hodi, et al. 2010; Joseph, et al. 2014; Lyle, et al. 2014; Menzies, et al. 2014; Nishino, et al. 2014; Steinman, et al. 2014; Del Vecchio, et al. 2015; Kaufman, et al. 2015; Tsai, et al. 2015

17 Gene Expression Profiling (GEP): Class 1 and 2 Discriminates Risk of Recurrence % free of metastasis Distant Metastasis Free Survival 100% Class 1 75% 50% 25% n=217 p< Class 2 0% 5-yr DMFS Class 1 = 100% Class 2 = 58% Gerami, et al. Clin Cancer Res. 2015;21(1), Time (years) Class 1 (n=76) Class 2 (n=141) Events yr DMFS 82% 46% Gerami, et al. J Am Acad Dermatol. 2015;72(5):780-5.e

18 Putting it all together: An integrated approach to choice points in melanoma patients Patient calls with concern New ing Hx? Yes No Expedited Appointment Routine Appointment History Physical Risk assess FBSE Dermoscopy Low/Moderate Risk Education & Appropriate F/U High/Extreme Risk Photography? Biopsy? Referral? Photography? Total body Select nevi Combination Reassured (Monitor) Biopsy? Additional Imaging Confocal OCT Hyperspectral Benign or Equivocal Consider 2 nd Opinion Consider Molecular Dx Referral? *Excise Genetic *Guidelines Counselor *Multidisciplinary Malignant Consider Mol. Prog. Genetic Testing?

19 Epidemiologic Tools: War on Melanoma Community Registry Walsh Family $$ 25,000 Living Patients Patients, Family, Friends IRB-Approved Collaborative >4800 total >3500 Patients

20 Early Detection: Oregon vs Schleswig-Holstein Similar Populations, Different Health Care System

21 Unsuccessful The War Plan: A Statewide Population Sciences Experiment! Massive Public Education Campaign Providers Skin Care Services Lay Public Grass Roots AND Top-Down Discovery of Suspicious Lesions Experimental Design Baseline Measures: Obstacles Tumor Depth/Stage Cost Comparison to controls Refine & Repeat Screening & Biopsy If Needed Early Stage Removal If Needed Expansion To Other States Repeated Measures Successful

22 A Massive Campaign Requires A Massive Army Melanoma Community Registry Patients Family Friends Education: Symposia Curriculum Outreach Activism: Legislation Community Events Fundraising Research: Questionnaires Imaging Phone Apps New Tests Novel Application Of Volunteerism Tools

23 Pilot Experiment: Skin Cancer Research Expo and Sun Safety Event, May 30, 2015 Over 800 Participants 126 Volunteers 21 Providers 18 from registry

24 Skin Cancer Research Expo and Sun Safety Event May 30, 2015 Melanoma Community Registry 127 New Registrants Enrolled 244 Risk & Phenotype Questionnaires Completed

25 Skin Cancer Research Expo and Sun Safety Event May 30, 2015 Knight BioLibrary 162 blood draws ml vials 2,400 aliquots

26 Skin Cancer Research Expo and Sun Safety Event May 30, 2015 Skin Checks and Sun safety 247 screened 55 recommended biopsies 4 possible melanoma 5 possible SCC 13 possible basal cells 55 toured DermSpectra

27 Skin Cancer Research Expo and Sun Safety Event May 30, 2015 Research Demos/Info Knight Clinical Trials 50 ppl Tan Meter 175 ppl Mole Mapper 20 downloaded app OCTRI 65 healthy controls

28 Skin Cancer Research Expo and Sun Safety Event May 30, 2015 Social Media - 45 social posts on Facebook, Twitter, & LinkedIn - Reached 105,608 users across all Platforms - 15,000 saw our top Post re-engagements (re-tweets, comments, shares, etc.) clicks to our registry & sites YouTube views

29 Preliminary Data: The Registry Wants to Participate Opportunities to Participate: I want to attend educational conferences I want to attend focus groups to provide my opinion about questionnaire development or other documents for participants. I want to attend melanomacentric events

30 Preliminary Data: The Registry Will Participate In Research

31 Where do the patients come from? Q19: HEALTH CARE SYSTEMS THAT HAVE MY ELECTRONIC MEDIAL RECORDS INCLUDE: Kaiser Permanente 11% Legacy Health 9% Other 22% Veterans Administration 2% Other 7% I prefer not to provide access to this information electronically, but I will provide records as hardcopy 2% Providence Health & Systems 20% Oregon Health & Science University (OHSU) 31% I prefer not to privide access to this information 3%

32 War on Melanoma Community Registry: Representative Participants for Research Q26: What was your Stage of Melanoma (n=1162) 1% 3% 7% 3% 24% 62% Representative categories of patients Controls included Eager to participate A tool to better understand melanoma at every level In Situ Stage I or II Stage III Stage III In transit Stage IV Don't know

33 Mole Mapper: A tool within a tool Dream: To make this app OUR app, to facilitate mole tracking and collaboration worldwide! FAQ s: Cannot diagnose melanoma or make recommendations for care Can measure & track nevi Available in itunes Store (NOT PLUS) Part of Apple s ResearchKit Suite of Apps Android version in development

34 Short-Term Goals for the Mole Mapper App For The People: Provide a free, quantitative mole-tracking tool For Providers & Patients: Facilitate productive clinic visits Clinician Participant Researcher For Researchers: Conduct a largescale, crowdsourced, research study

35 Design: Current Work Flow PHI Strip Identifiers OHSU War on Melanoma Cohort De-Identified Data Linkers Sage Bionetwork Consent to Share Data Image Analysis & Challenges Human Research Citizen Science Mole Map Keep Data On Phone No back-up Optimization

36 Challenges for the Development of a Melanoma Research App: Legal & Regulatory Bureau of Consumer Protection

37 Challenges: Clinical Research App Development is Complex Team Effort: OHSU Leadership Knight Leadership Clinical Trials/CTSA Dermatology Strategic Communications Social Media IRB Contracts Legal Affairs ITG Security Technology Transfer Outside consultants Funding OHSU Sage Bionetworks Developer Dan Webster Oct. 15! App Launch Essential Collaborator Back-end Big-data ResearchKit Modification for ResearchKit Specifications Testing Thought Leaders Pre-launch Meetings Guidance Prioritization Publicity

38 Post-Launch Challenges: A Three-Year Plan for Success Intensive & ongoing needs analysis, team building Optimized data flow Nurturing the cohort De-bugging, improved usability Evolving/Adding new features functionality Development & release process, including Android Serving outside collaborators Obtaining preliminary data Writing grants/proposals Business plan for sustainability

39 Progress: What does the App do now? Map, Measure, and Monitor Moles Monthly Monitor Monthly Map Measure Monitor Monthly

40 Informed Consent Is Required Before Data Release Occurs: Novel Process Go through formal consent on app Pass test to demonstrate understanding of risks and benefits (Courtesy of John Wilbanks & Sage Bionetworks)

41 Data: Includes Baseline Demographic and Risk Questions

42 Data: How much interest has been generated for Mole Mapper? 35,000 Mole Mapper Stats 30,000 25,000 20,000 15,000 10,000 5, /23 11/3 11/9 11/16 11/24 12/7 1/7 2/4 2/19 App Store Views Downloads Registrants Moles Measured

43 Data: Building a Cohort of Thousands in Months (4 months) 8,019 App Downloads 2,204 Consented Participants 2,787 Mole Measurements & Mole Photos ~13% of participants are melanoma patients/survivors, ~27% with family history

44 Data: Mole Size Is Consistent with Clinical Experience 225 Mole Measurement Distribution Number of Mole Measurements Mole Diameter (mm) Average Mole Size: 3.83mm 1 std. deviation larger: 5.97mm in keeping with 6mm eraser recommendation for vigilance

45 Data: User Comments The dashboard helped me discover my statistically significant Ugly Duckling : 7.1 mm fried-egg on my back

46 Citizen Science: Patient-Driven Improvements Sometimes it s hard to take pictures and keep the reference next to the mole I don t always have a coin on me for measuring Participant Clinician Researcher

47 Opportunities: Long-Term Goals for the Mole Mapper App Provide a free, melanoma triage tool - maybe a diagnostic tool? Reduce unnecessary patient visits and detect melanoma earlier Clinician Participant Researcher Optimize and automate image analysis for diagnostic purposes? Incorporate advanced imaging tools and algorithms?

48 Opportunities: Data will be open-sourced to qualified researchers worldwide Participant Clinician Researcher 48

49 Opportunities: Cohort will be crowd-sourced to contribute data worldwide Participant Clinician Researcher Chemoprevention Trial?

50 Summary: Germline Genetic Testing to Identify Patients at Highest Risk for Screening Identify the highest risk individuals Unlikely you will find many of these patients Likely the tests will have changed between now and the time you identify them Identify a genetic counselor in your area and refer, work with them to assure appropriate follow-up Refer to a registry: leachmas@ohsu.edu

51 Summary: Diagnostic & Prognostic Genetic Testing to Identify Patients Needing Additional Care Diagnostic genetic testing to assess likelihood that a lesion is malignant FISH, CGH, qrt-pcr available Little outcome data on any Little data on ambiguous lesions Can help to guide surgical removal & treatment Prognostic genetic testing to assess likelihood that a lesion is deadly qrt-pcr available Growing data to support (David Lawson) Can help to guide follow-up

52 Summary: Epidemiologic and Technologic Tools Can Contribute Directly to Research Efforts The next era of cancer care will emphasize prevention and early detection Engaging patients through a registry/app is powerful It takes a village To Join/refer: War on Melanoma Try the App: and provide feedback Contact me: leachmas@ohsu.edu Together we can make this happen!

53 Acknowledgements! Dan & Courtney Webster Berwick Baker Edelson Guild Gershenwald Norris Stephen Friend Edison Eberting Kirkwood Olbricht Swetter Rigel Andrew Trister Divya Nag Lisa Domenico Kashani Kean Tumeh Zone Halpern Geller Weinstock Thought Leaders Jeff Williams