Gene Expression tools: Diagnostic Prognostic

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1 Disclosures & Conflicts Applying Technology to Dermatologic Diagnosis 2016 Fall Clinical Dermatology Conference October 23, 2016; Wynn Encore in Las Vegas Sancy Leachman, M.D., Ph.D. 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. Overview: Early Detection through Genetic & Epidemiologic Tools Genetic Diagnostic Testing for Melanoma Gene Expression tools: Diagnostic Prognostic Epidemiologic Tools: War on Melanoma Community Registry Mole Mapper iphone App Other Technologies 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 Fluorescent In-Situ Hybridization (FISH) Comparative Genomic Hybridization (CGH) 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) Also detects chromosomal gains and losses Comparison between tumor DNA & control DNA to evaluate entire genome Sensitivity & specificity not as wellcharacterized Most studies done on unambiguous cases Some subjectivity, but less than FISH 1

2 Gene Expression Profiling (GEP): qrtpcr Comparison of Diagnostic Genetic Tests for Melanoma 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 Advantages Limitations FISH CGH qrt-pcr Minimal tissue required; singlecell resolution; can detect translocations Visualizes tiny fraction of genome; expertise requirement Can assess all 23 chromosomes; no proficiency in fluorescent microscopy required Can t assess intratumoral heterogeneity; dilution by stroma Provides additional diagnostic value in discriminating benign vs malignant lesions New test, publications in progress; no correlation with outcome Genetic Prognostic Testing for Melanoma Gene Expression Profiling (GEP): qrtpcr Fundamentally different than predisposition or diagnostic testing Purpose is to determine if a lesion is likely to metastasize Performed on tissue, not blood Provides adjunctive measure to complement histologic (e.g. Breslow depth) and other prognostic (e.g. sentinel node biopsy) data 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 Gene Expression Profiling (GEP): Class 1 & 2 and Risk of Recurrence Distant Metastasis Free Survival 100% 75% 50% Class 1 Putting It Together: An Integrated Approach for Melanoma Patients New ing Patient calls with concern 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? 5-yr DMFS Class 1 = 100% Class 2 = 58% Gerami et al, Clin Cancer Res; 21(1), 2015 % free of metastasis 25% 0% 0 n=217 p< Time (years) Class 2 Class 2 Class 1 (n=76) (n=141) Events yr DMFS 82% 46% Gerami et al, J Am Acad Dermatol 72(5):780-5.e3, Photography? Total body Select nevi Combination Reassured (Monitor) Biopsy? Additional Imaging Confocal OCT Hyperspectral Referral? *Excise *Guidelines *Multidisciplinary Benign or Equivocal Malignant Consider 2 nd Opinion Consider Consider Molecular Dx Mol. Prog. Genetic Counselor Genetic Testing? 2

3 Epidemiologic Tools: War on Melanoma Community Registry Early Detection: Oregon vs Schleswig-Holstein Walsh Family $$ 25,000 Living Patients Patients, Family, Friends IRB-Approved Collaborative >4800 total >3500 Patients Similar Populations, Different Health Care System Waldman, A; Brit J Cancer (2012) 106: ; Katalinic A; Dtsch Arztebl Int. (2015) 112(38): The War Plan: A Statewide Population Sciences Experiment A Massive Campaign Requires A Massive Army Massive Public Education Campaign Providers Skin Care Services Lay Public Grass Roots AND Top-Down Discovery of Suspicious Lesions Screening & Biopsy If Needed Early Stage Removal If Needed Expansion To Other States Experimental Design Baseline Measures: Obstacles Tumor Depth/Stage Cost Comparison to controls Refine & Repeat Unsuccessful Repeated Measures Successful Education: Symposia Curriculum Outreach Melanoma Community Registry Patients Family Friends Activism: Legislation Community Events Fundraising Research: Questionnaires Imaging Phone Apps New Tests Novel Application Of Volunteerism Tools 2015: 800 s;126 Volunteers; 21 Providers 2016: 1500 s; 200 Volunteers; 30 Providers Melanoma Community Registry 2015: 127 New Registrants Enrolled 2016: 317 New Registrants Enrolled 3

4 Knight BioLibrary 2015: 162 blood draws; 2,400 aliquots 2016: 279 blood draws, 10,040 aliquots; 501 saliva samples for genetic testing Skin Checks and Sun safety 2015: 247 Screened; 55 Recommended Biopsies; 4 possible melanoma; 5 possible SCC; 13 possible basal cells 2016: 363 Screened; 80 Biopsies Recommended; 6 Melanoma; 7 SCC, 15 BCC Event, May 30, 2015 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 6 Research Tables 7 Education Tables Social Media 2015: 105,608 OHSU Social Reach (15,000 saw top Post); 1500 Engagements; 1400 clicks to our registry & sites; 600 YouTube views 2016: 106,384 OHSU Social Reach; 8,549 Engagements; 312,000 Redhead Event Social Reach; 166,000 Engagements Preliminary Data: The Registry Wants to Participate Preliminary Data: The Registry Will Participate In Research 66% 53% 76% 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 4

5 Where do the patients come from? Mole Mapper: A tool within a tool for screening our population Kaiser Permanente 11% Providence Health & Systems 20% Q19: HEALTH CARE SYSTEMS THAT HAVE MY ELECTRONIC MEDIAL RECORDS INCLUDE: Legacy Health 9% Other 22% Other 7% Oregon Health & Science University (OHSU) 31% Veterans Administration 2% I prefer not to provide access to this information electronically, but I will provide records as hardcopy 2% I prefer not to privide access to this information 3% 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 Short-Term Goals for the Mole Mapper App Design: Current Work Flow For Providers & Patients: Facilitate productive clinic visits For The People: Provide a free, quantitative mole-tracking tool For s: Conduct a largescale, crowdsourced, research study PHI Strip Identifiers OHSU War on Melanoma Cohort De-Identified Data Linkers Consent to Share Data Mole Map Keep Data On Phone No back-up Sage Bionetwork Optimization Image Analysis & Challenges Human Research Citizen Science Progress: What does the App do now? Map, Measure, and Monitor Moles Monthly 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 Monitor Monthly (Courtesy of John Wilbanks & Sage Bionetworks) Map Measure Monitor Monthly 5

6 Data: Includes Baseline Demographic and Risk Questions Data: Building a Cohort of Thousands in Months (4 months) 8,019 App Downloads 2,204 Consented s 2,787 Mole Measurements & Mole Photos ~13% of participants are melanoma patients/survivors, ~27% with family history Data: Mole Size Is Consistent with Clinical Experience Data: User Comments Number of Mole Measurements Mole Measurement Distribution Average Mole Size: 3.83mm 1 std. deviation larger: 5.97mm in keeping with 6mm eraser recommendation for vigilance The dashboard helped me discover my statistically significant Ugly Duckling : 7.1 mm fried-egg on my back Mole Diameter (mm) Citizen Science: Patient-Driven Improvements Opportunities: Long-Term Goals for the Mole Mapper App 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 Reduce unnecessary patient visits and detect melanoma earlier Provide a free, melanoma triage tool - maybe a diagnostic tool? Optimize and automate image analysis for diagnostic purposes? Incorporate advanced imaging tools and algorithms? 6

7 Opportunities: Data will be open-sourced to qualified researchers worldwide Opportunities: Cohort will be crowd-sourced to contribute data worldwide 37 Chemoprevention Trial? Technologies to Improve Diagnosis Summary: Diagnostic & Prognostic Genetic Testing to Identify Patients Needing Additional Care Photography equipment & packages Dermoscopy & Multi-spectral Imaging Hyperspectral imaging Optical Coherence Tomography In vivo confocal imaging Electrical impedence technology Tape stripping & expression profiling 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 (local resource David Lawson) Can help to guide follow-up Summary: Epidemiologic and Technologic Tools Can Contribute Directly to Research Efforts Acknowledgements! 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! Berwick Baker Edelson Guild Gershenwald Norris Edison Eberting Olbricht Rigel Kirkwood Swetter Kashani Tumeh Kean Geller Zone Halpern Weinstock Dan & Courtney Webster Stephen Friend Divya Nag Andrew Trister Lisa Domenico Thought Leaders Jeff Williams 7