Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma

Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis. To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management. Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study. A GEP signature was developed using a discovery cohort (n = 202) and validated in a separate, nonoverlapping, independent cohort (n = 324). A prognostic 40-GEP test was developed and validated, stratifying patients with high-risk cSCC into classes based on metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk). For the validation cohort, 3-year metastasis-free survival rates were 91.4%, 80.6%, and 44.0%, respectively. A positive predictive value of 60% was achieved for the highest-risk group (class 2B), an improvement over staging systems, and negative predictive value, sensitivity, and specificity were comparable to staging systems. Potential understaging of cases could affect metastasis rate accuracy. The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC.