Non-invasive Gene Expression Analysis Rules Out Melanoma with High Negative Predictive Value Regardless of Skin Phototype

Abstract

Non-invasive assessment of clinically atypical, pigmented skin lesions to rule out melanoma with a negative predictive value (NPV) of 99% by detecting expression of LINC00518 and PRAME (2-GEP assay) is gaining adoption. These melanomaassociated biomarkers are not known to differ by skin type, race, or ancestry. However, since the test was initially validated in cohorts comprised predominantly of patients with Fitzpatrick skin types I-III, we sought to identify any differences in performance in skin types IV-VI. In the study presented here, we compared 2-GEP assay performance in patients with Fitzpatrick skin types I-III (n=4152) to that in patients with Fitzpatrick skin types IV-VI (n=130) using real-world clinical follow-up data. Median follow-up of over one year was available for approximately 60% of the patients in both groups. Consistent with prior published results, the assay’s NPV for Fitzpatrick I-III patients was 0.9989. Sensitivity and specificity were 0.943 and 0.909, respectively, and positive predictive value (PPV) was 0.15. Among Fitzpatrick IVVI subjects, all three  melanomas diagnosed by histopathology were correctly identified by the assay as positive (higher probability of melanoma). NPV in this smaller cohort was 1.0, sensitivity was 1.0, specificity was 0.94, and PPV was 0.3. The 95% confidence intervals for the NPVs in the Fitzpatrick I-III and IV-VI groups (calculated using the Clopper-Pearson Exact Binomial Test) were 0.9972-0.9997 and 0.9697-1.0000, respectively. The 95% confidence interval for the difference between the groups includes 0 (-0.0299 to 0.0028) which indicates that there is no significant difference in the NPVs. Median follow-up times for the Fitzpatrick I-III and IV-VI groups were 368 days and 378 days, respectively. Among patients with Fitzpatrick skin type I-III and negative test results, one patient was diagnosed with melanoma in situ at a 5-month follow-up visit. No melanomas were diagnosed in patients with Fitzpatrick skin type IV-VI whose lesions tested negative.
Additionally, analytical PCR performance in Fitzpatrick I-III and Fitzpatrick IV-VI samples was indistinguishable. These findings indicate that performance of the 2-GEP assay in patients with Fitzpatrick skin types IV-VI does not differ from its performance in patients with Fitzpatrick skin types I-III. During a median follow-up period of over one year, only one melanoma (in situ) was diagnosed among patients whose lesions initially tested negative, further supporting the test’s ability to appropriately guide biopsy decision-making for ambiguous pigmented skin lesions of all skin phototypes.