PowerPoint Presentation Non-Invasive Genomic Profiling of Pigmented Lesions – an Interim Registry Analysis Greg Stevens DMSc Fellow, PA-C1, Burkhard Jansen, MD1, Terry Arnold, MBA, PA-C1, James Rock, MS1, Jennifer Wood, DMSc, PA-C1, Mark Hyde, PhD, PA-C1, Loren Clarke, MD1 Presented at the Fall Clinical Dermatology Conference October 20th – 23rd, 2022 1. DermTech, 11099 North Torrey Pines Road, Suite 150 La Jolla, CA 92037, USA Background: Pigmented lesion analysis remains a challenging aspect of dermatology. The DermTech Melanoma Test (‘the test’) is a non-invasive gene-expression test designed to rule-out melanoma. It consists of the pigmented lesion assay, which detects RNA products of Long Intergenic Non-Coding RNA 00518 (LINC00518) and Preferentially Expressed Antigen in Melanoma (PRAME), and an add-on assay for DNA promoter mutations in telomerase reverse transcriptase (TERT). In previous studies, the test was found to have a negative predictive value ≥99%. This registry study examines the real-world correlation of genomically atypical (test-positive) lesions with histopathologic diagnoses. Methods: Between April 2021 and March 2022, multiple geographically diverse sites throughout the US submitted data to a registry to assess real-world use of the test. Approximately 8,000 clinically atypical lesions were tested. After receiving the test result, providers followed their clinical judgement for biopsy decision. Histopathologic diagnoses for biopsied lesions were correlated with test results. Results: Among the approximately 8000 tests performed,1033 (12.9%) were positive. Thirty-six did not have histopathologic diagnoses or confirmed test results available. Of the 997 complete cases, 134 (13.4%) were diagnosed as melanoma; 89 (66.4%) were in situ and 45 (33.6%) were invasive. Only 7 (5.2%) melanomas were beyond stage T1a. In addition, 73 (7.3%) positive lesions exhibited severe cytologic atypia or atypical junctional melanocytic hyperplasia histopathologically. Conclusions: Over 20% of lesions that tested positive were severely dysplastic, melanoma in situ, or invasive melanoma by histopathology. Nearly 87% of clinically atypical lesions tested negative. Almost all lesions diagnosed as melanoma were in situ or pT1a. This study demonstrates that the test guides appropriate biopsy decisions in real-world settings. Abstract Introduction and Objective Methods Between April 2021 and March 2022, approximately 8000 lesions were entered into a nationwide registry from 63 unique sites. Sites were encouraged to enter all results, including corresponding histopathology. Histopathologic diagnoses were categorized first into melanoma and non- melanoma. The melanomas were subcategorized into in situ and invasive, with the latter characterized by AJCC tumor size staging. Among non-melanomas, the number of SDN/AJMH was determined. All uncertain cases were reviewed by a board-certified dermatopathologist. Furthermore, correlation between number of genomic markers present to histopathologic diagnoses was calculated. The gene expression test is designed to rule out melanoma by analyzing non- invasively collected skin tissue from pigmented lesions for genomic atypia (LINC00518, PRAME, and/or TERT). The results of the test are designed to guide biopsy decisions on clinically suspicious lesions. This approach improves pigmented lesion management beyond visual inspection with a negative predictive value of ≥99% and a sensitivity of 91-97%, and by enriching melanoma among biopsied lesions almost 5-fold.1-3 The real-world performance of the test and its impact on clinical practice has been addressed in a previously completed 2020 patient registry, and summarized in 2 peer reviewed publications.3,4 The objective of this study was to better understand the real-world utility of the test using a nationwide registry. An interim analysis of this registry is presented here. 1. Gerami P, Yao Z, Polsky D, et al. Development and validation of a noninvasive 2-gene molecular assay for cutaneous melanoma. J Am Acad Dermatol. 2017;76(1):114-120.e2. 2. Jackson SR, Jansen B, Yao Z, Ferris LK. Risk Stratification of Severely Dysplastic Nevi by Non-Invasively Obtained Gene Expression and Mutation Analyses. SKIN The Journal of Cutaneous Medicine. 2020;4(2):105-110. 3. Brouha B, Ferris LK, Skelsey, MK, et al. Genomic Atypia to Enrich Melanoma Positivity in Biopsied Lesions: Gene Expression and Pathology Findings From a Large U.S. Registry Study. SKIN. 2021;5(1),13–18. 4. Brouha B, Ferris LK, Skelsey MK, et al. Real-World Utility of a Non-Invasive Gene Expression Test to Rule Out Primary Cutaneous Melanoma: A Large US Registry Study. J Drugs Dermatol. 2020;19(3):257-262. 5. Skelsey MK, Brouha B, Rock J, et al. Non-Invasive Detection of Genomic Atypia Increases Real-World NPV and PPV of the Melanoma Diagnostic Pathway and Reduces Biopsy Burden. SKIN. 2021;5(5), 512–523. References Results Genomic markers present 1 2 3 n % n % n % Non-melanoma (excl. SDN/AJMH) 627 87.8% 157 64.6% 6 15.0% SDN/AJMH 45 6.3% 22 9.1% 6 15.0% Melanoma 42 5.9% 64 26.3% 28 70.0% Total 714 243 40 Table 1. Figure 1 Of the approximately 8000 lesions entered into the registry from April 2021 to March 2022, 1033 (12.9%) were positive for at least one genomic biomarker. Thirty-six of these lesions did not have histopathologic diagnoses or confirmed test results available. Of the 997 complete cases, 134 (13.4%) were diagnosed as melanoma; 89 (66.4%) were in situ and 45 (33.6%) were invasive. Only 7 (5.2%) melanomas were beyond stage T1a. In addition, 73 (7.3%) positive lesions exhibited severe cytologic atypia or atypical junctional melanocytic hyperplasia histopathologically. These results are depicted in the Figure. As the number of genomic markers present increased, so did the percentage of both SDN/AJMH and melanomas. Of note, the triple-positive cases (n=40) had a high likelihood of being either melanoma (n=28, 70%) or SDN/AJMH (n=6, 15%). These data are included in the Table. ~8000 tests performed 1033 (12.9%) positive test results 997 (96.5%) records available 790 (79.2%) non-melanomas, excluding SDN/AJMH 134 (13.5%) melanomas 89 (66.4%) in situ 45 (33.6%) invasive 38 (84.4%) T1a 7 (15.6%) T1b – T2b 73 (7.3%) SDN/AJMH Funding/disclaimer: all study sites were reimbursed by DermTech for the collection of data; the authors are employed by DermTech. Conclusion This interim registry analysis demonstrates the real-world rate of positivity along with histopathologic correlation for this genomic test. Over 20% of lesions that tested positive for any number of genomic markers were diagnosed histopathologically as melanoma or SDN/AJMH. The correlation increases markedly as more genomic markers are present (12.2% for one, 35.4% for two, and 85% for three). As SDN/AJMH are often treated similarly to early melanomas, this is data that can help clinicians with their management plans. SDN = severely dysplastic nevus AJMH = atypical junctional melanocytic hyperplasia Scan QR code for additional peer-reviewed publications regarding this genomic test When paired with the previously shown negative predictive value of >99%,1,2,5 this study demonstrates the test’s clinical utility. The evidence suggests that the ideal use for this test is on clinically indeterminate lesions, where the tests addition adds the greatest value with minimal risk.