QHow does the 40-GEP test add value when you are already using NCCN risk groups and BWH staging for CSCC?

Carlson P.  Nguyen¹, Harrison P. Nguyen, MD, MBA, MPH^1,2,3

¹Harrison Dermatology & Research Group, Houston, TX

²University of Houston College of Medicine, Houston, TX

³Baylor College of Medicine, Houston, TX

For patients with cutaneous squamous cell carcinoma (cSCC), certain subgroups have an increased risk for metastasis and local recurrence, even after surgical treatment – making accurate risk-stratification necessary to help inform the selection of proper interventions. Risk assessment strategies such as the National Comprehensive Cancer Network (NCCN) guidelines or staging criteria like the Brigham & Women’s Hospital (BWH) aim to stratify cSCC patients into risk levels based on their clinicopathologic risk factors but have been shown to have low positive predictive value for adverse outcomes.¹ [CN1] This raises the question: What steps can clinicians take to better inform their clinical decision-making for cSCC patients?

A key step is the integration of molecular diagnostics to provide a personalized assessment of a tumor’s biological risks. The DecisionDx-SCC is a 40-gene expression profile (40-GEP) test that helps fill that gap by using biological risk factors to provide prognostic, predictive information about cSCC patient outcomes. However, until recently, it had not been shown how the 40-GEP added value beyond BWH staging within NCCN risk groups.

To address this, a recent retrospective study, involving a multi-center cohort of 1,412 patients with ≥1 GEP-40 high-risk factors, demonstrated that the GEP-40 added prognostic value beyond the typical clinicopathologic features used by the NCCN. The study excluded patients that received adjuvant radiation therapy (ART) and used Kaplan-Meier survival analysis to estimate 3-year metastasis-free survival (MFS) and Cox regression models to compare the metastatic risk prediction of BWH staging alone versus BWH combined with the 40-GEP test.

In the study, the 40-GEP test further stratified 3-year MFS rates for both NCCN High Risk (HR) and Very High Risk (VHR) groups, which made up 56.0% and 36.1% of the patient cohort, respectively. Among VHR patients, the test identified distinct outcomes at a 95% confidence interval, with MFS rates of 87.3% for Class 1 (low), 74.9% for Class 2A (high), and 58.0% for Class 2B (highest). A similar, powerful stratification was seen in the HR group, where MFS rates were 97.4% for Class 1, 90.5% for Class 2A, and 71.4% for Class 2B. In both HR and VHR groups, incorporating 40-GEP data with BWH staging significantly improved the models’ predictive performance compared to BWH-staging alone: χ2=17.32; P<0.001 and χ2=26.62; P<0.001.²

These results suggest that incorporation of the 40-GEP metric help to paint a more accurate and complete image of cSCC patients’ risk of metastasis and adverse outcomes – helping to guide short-term clinician decision making in areas where traditional clinicopathological features fall short. For dermatologists, this additional stratification represents a step forward in terms of early detection and the proper selection of treatment options that are ultimately more cost efficient or beneficial for patient outcomes and quality of life.

References:

1. Farberg AS, Fitzgerald AL, Ibrahim SF, et al. Current Methods and Caveats to Risk Factor Assessment in Cutaneous Squamous Cell Carcinoma (cSCC): A Narrative Review. Dermatol Ther. 2022;12(2):267-284. doi:10.1007/s13555-021-00673-y
2. CLO25-055: Metastasis-Free Survival Prediction With the 40-Gene Expression Profile Test in Patients With Cutaneous Squamous Cell Carcinoma Risk Stratified According to the National Comprehensive Cancer Network Guidelines in: Journal of the National Comprehensive Cancer Network Volume 23 Issue 3.5 (2025). Accessed August 18, 2025. https://jnccn.org/view/journals/jnccn/23/3.5/article-CLO25-055.xml?content=fullhtml-7350