Non-Invasive Detection of Genomic Atypia Increases Real-World NPV and PPV of the Melanoma Diagnostic Pathway and Reduces Biopsy Burden

Abstract

Background: Management of pigmented lesions currently relies on visual assessment with surgical biopsy and histopathologic examination for those lesions suspicious for melanoma. A non-invasive genomic assay that detects two melanoma-associated biomarkers (PLA, 2-GEP) has recently been validated as an adjunct to visual assessment for distinguishing high-risk pigmented lesions appropriate for biopsy from those that can be safely monitored via clinical surveillance. Methods: Real-world NPV was determined by following a cohort of 1,233 PLA-negative pigmented lesions for evidence of malignancy for up to 36 months and by re-testing a separate prospective cohort of 302 PLA-negative lesions up to 2 years after initial testing. Real-world PPV was determined by identifying melanoma diagnoses among PLA-positive lesions within a US-based registry of 3,418 PLA-tested cases. Results: Ten early-stage melanomas (4 in situ and 6 pT1a) were identified among 1,233 PLA-negative lesions (0.8%), corresponding to a real-world NPV of 99.2% (CI 95% = 98.5 - 99.6). Of 302 initially PLA- negative lesions subjected to repeat testing an average of 15 months later, 34 were PLA-positive. Biopsy revealed 3 melanomas (all in situ), further confirming an NPV of > 99%. Among 316 PLA-positive cases, 59 were diagnosed as melanoma by histopathology, corresponding to a PPV of 18.7%. Of all PLA-positive lesions, 30.5% had histopathologic diagnoses corresponding to high-risk MPATH-Dx categories (Classes III-V). Conclusions: The PLA has an NPV of >99% within the real-world intended use population. The PLA has a PPV of 18.7% for melanoma and also detects high-risk lesions such as dysplastic nevi with severe/high-grade atypia that are generally targeted for complete excision.