Wysong, AshleyNewman, Jason G.Covington, Kyle R.Kurley, Sarah J.Ibrahim, Sherrif F.Farberg, Aaron S.Bar, AnnaCleaver, Nathan J.Somani, Ally-KhanPanther, DavidBrodland, David G.Zitelli, JohnToyohara, JenniferMaher, Ian A.Xia, YangBibee, KristinGriego, RobertRigel, Darrell S.Plasseraud, Kristen MeldiEstrada, SarahSholl, Lauren MeldiJohnson, ClareCook, Robert W.Schmults, Chrysalyne D.Arron, Sarah T.2020-06-252020-06-252020Wysong, A., Newman, J. G., Covington, K. R., Kurley, S. J., Ibrahim, S. F., Farberg, A. S., Bar, A., Cleaver, N. J., Somani, A.-K., Panther, D., Brodland, D. G., Zitelli, J., Toyohara, J., Maher, I. A., Xia, Y., Bibee, K., Griego, R., Rigel, D. S., Plasseraud, K. M., … Arron, S. T. (2020). Validation of a 40-Gene Expression Profile Test to Predict Metastatic Risk in Localized High-Risk Cutaneous Squamous Cell Carcinoma. Journal of the American Academy of Dermatology. https://doi.org/10.1016/j.jaad.2020.04.088https://hdl.handle.net/1805/23089Background: Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value (PPV) for identifying patients who will experience metastasis. Objective: 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. Methods: 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, non-overlaping, independent cohort (n=324). Results: A prognostic, 40-gene expression profile (40-GEP) test was developed and validated, stratifying high-risk cSCC patients 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 (MFS) rates were 91.4%, 80.6%, and 44.0%, respectively. A PPV of 60% was achieved for the highest-risk group (Class 2B), an improvement over staging systems; while negative predictive value, sensitivity, and specificity were comparable to staging systems. Limitations: Potential understaging of cases could affect metastasis rate accuracy.Conclusion: The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC.enPublisher Policycutaneous squamous cell carcinomagene expression profileprognosticationArticle