Integrating 40-GEP Testing to Improve Clinical Recommendations for Adjuvant Radiation for Cutaneous Squamous Cell Carcinoma: Multidisciplinary Consensus Guidelines

Abstract

Early identification and intervention in patients with cutaneous squamous cell carcinoma (cSCC) who are at high risk for metastasis is important for optimal outcomes. Prognostic tools (e.g., American Joint Committee on Cancer, 8th edition [AJCC-8]) and management guidelines (National Comprehensive Cancer Network® [NCCN]) are useful in helping to identify high-risk patients with cSCC who might benefit from adjuvant therapies, such as radiation and/or immunotherapies; however, traditional staging and management guidelines rely on clinicopathologic risk factors to predict risk, which limits their prognostic accuracy. Gene expression profiling (GEP) is a clinically available, objective metric that can be used in conjunction with traditional clinicopathological staging to help clinicians stratify risk in patients with cSCC. The validated 40-GEP test can accurately classify patients with at least one high-risk feature as being at low (Class 1), higher (Class 2A), or highest (Class 2B) biological risk of nodal or distant metastasis within three years of diagnosis. A multidisciplinary panel comprising radiation oncologists and dermatologists/Mohs micrographic surgeons with expertise in cSCC management convened in June 2023 to discuss the utility of 40-GEP testing in cSCC clinical decision-making in regard to adjuvant radiation therapy (ART). The panel identified gaps in clinical practice in which 40-GEP testing has particular utility: in escalation of care for lower-stage patients with high-risk tumors; in de-escalation of care for patients for whom the risks of ART may outweigh the benefits; and in decision-making regarding elective radiation to the nodal basin. The expert panel developed a risk-based clinical workflow for ART in patients with cSCC, utilizing 40-GEP testing within NCCN management guidelines and AJCC-8 staging.

Keywords: 40-GEP; adjuvant radiation therapy; consensus; cutaneous squamous cell carcinoma; gene expression profiling; prognosis; risk of recurrence; risk stratification.

FIGURE 1.

Metastatic risk prediction of AJCC-8 and BWH staging systems is significantly improved when 40-GEP is included. When the performance of staging-alone models was compared to multivariate models that included the 40-GEP, a significant improvement in predictive accuracy of metastatic events was observed. Inclusion of interaction terms revealed no significant interactions (p>0.05), verifying the 40-GEP as contributing independent prognostic value to the prediction of metastatic risk relative to staging alone.GEP: gene expression profile; AJCC-8: American Joint Commission on Cancer Staging Manual, eighth edition; BWH: Brigham and Women’s Hospital cancer staging system SOURCE: Wysong A, Newman JG, Covington KR, et al. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2021;84(2):361–369.

FIGURE 2.

A risk-based clinical workflow for ART in patients with cSCC, integrating AJCC-8 staging and 40-GEP testing into current NCCN guidelines