40-Gene Test Validated for High-Risk Squamous Cell Carcinoma

High-risk cutaneous squamous cell carcinoma (SCC) requires accurate stratification to align surveillance and adjuvant therapy with each patient’s risk. Clinicopathologic staging alone may not precisely identify which patients are most likely to recur or metastasize, creating uncertainty for care teams. A newly published multicenter study validates an integrated 40-gene expression profile test that improves prognostic discrimination and may better guide treatment decisions in this population.

Image: DecisionDx-SCC evaluates expression of 40 tumor genes and integrates those data with five clinicopathologic risk factors for high-risk cutaneous squamous cell carcinoma (Image Credit: 123RF)

Castle Biosciences’ (Friendswood, TX, USA) DecisionDx‑SCC integrated test result (i40‑GEP) was validated in a Journal of the American Academy of Dermatology article published online August 24, 2026, using an independent, multi-center cohort of 572 patients with high‑risk disease. The study confirmed the test’s ability to deliver prognostic information and estimate likelihood of adjuvant radiation therapy benefit, supporting risk‑aligned management.

DecisionDx-SCC evaluates expression of 40 tumor genes and integrates those data with five clinicopathologic risk factors: immunosuppression, tumor diameter, histological differentiation, perineural invasion, and anatomic site. Using optimized nested predictive models, the test reports metastatic risk, local recurrence risk, and potential adjuvant radiation benefit. The integrated output can reclassify patients across clinically actionable thresholds to help guide follow-up, imaging, and multidisciplinary referral.

In validation, 44.6% of patients received a Class 1A, or low-risk, result, with a 97.3% negative predictive value for metastasis, supporting de-escalation where appropriate. The algorithm assigned 12.9% of patients to Class 2B, the highest-risk group, which had 66.2% three-year metastasis-free survival compared with 97.3% for Class 1A. In multivariable analysis, Class 2B patients were 10.7 times more likely to develop metastasis than Class 1A patients (p<0.001).

Class 2B also identified patients most likely to benefit from adjuvant radiation, with approximately 50% lower median metastatic progression at five years and significantly delayed progression (p<0.01), while no significant difference was seen for Class 2A. The test outperformed National Comprehensive Cancer Network risk groups and Brigham and Women’s Hospital staging in predicting metastatic risk.

“Managing high-risk SCC patients can be challenging because clinicopathologic staging isn't always precise enough to confidently tailor patients' treatment intensity to their individual level of risk. The ability to more precisely distinguish which patients require less intensive management from those who would benefit from additional treatment can help reduce uncertainty for both patients and physicians,” said Désirée Ratner, M.D., board-certified dermatologist and Mohs micrographic surgeon, and clinical professor of dermatology at NYU Grossman School of Medicine in New York.

“This study showed that the DecisionDx-SCC integrated test result, which evaluates patients' tumor biology in combination with their clinicopathologic risk factors, can provide improved, clinically actionable information to support informed discussions about the most appropriate, risk aligned management approach,” said Dr. Ratner.

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