Simple SummaryA subset of cutaneous squamous cell carcinoma (cSCC) that is associated with high-risk features carries an increased risk for aggressive disease, local recurrence, and regional metastasis, which leads to significant morbidity and mortality. The current available systems for cSCC risk stratification are considered inadequate and fail to accurately distinguish high-risk cSCC patients who can benefit from aggressive management, emphasizing a great need for an accurate metastatic risk tool for early identification of high-risk cSCC patients. A 40-gene expression profile (40-GEP) was developed to biologically distinguish high-risk tumors that would benefit from more aggressive management. This systematic review and meta-analysis aimed to evaluate the reported prognostic value and clinical utility of the 40-GEP test. The results indicated that the 40-GEP test improved cSCC risk stratification both independently and in combination with other clinicopathologic risk factors.AbstractBackground: The current tumor staging systems for cutaneous squamous cell carcinoma (cSCC) are considered inadequate and insufficient for evaluating the risk of metastasis and for identifying patients at high risk of cSCC. This meta-analysis aimed to assess the prognostic significance of a 40-gene expression profile (40-GEP) both independently and integrated with clinicopathologic risk factors and established staging systems (American Joint Committee on Cancer, eighth edition (AJCC8) and Brigham and Women’s Hospital (BWH)). Methods: Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and Google Scholar, were systematically searched to identify cohort studies and randomized controlled trials on evaluations of the prediction value of 40-GEP in cSCC patients up to January 2023. The metastatic risk analysis of a given 40-GEP class combined with tumor stage and/or other clinicopathologic risk factors was based upon log hazard ratios (HRs) and their standard error (SE). Heterogeneity and subgroup analyses were performed, and data quality was assessed. Results: A total of 1019 patients from three cohort studies were included in this meta-analysis. The overall three-year metastatic-free survival rates were 92.4%, 78.9%, and 45.4% for class 1 (low risk), class 2A (Intermediate risk), and class 2B (high risk) 40-GEP, respectively, indicating a significant variation in survival rates between the risk classification groups. The pooled positive predictive value was significantly higher in class 2B when compared to AJCC8 or BWH. The subgroup analyses demonstrated significant superiority of integrating 40-GEP with clinicopathologic risk factors or AJCC8/BWH, especially for class 2B patients. Conclusions: The integration of 40-GEP with staging systems can improve the identification of cSCC patients at high risk of metastasis, potentially leading to improved care and outcomes, especially in the high-risk class 2B group.