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. 2024 Mar;14(3):593-612.
doi: 10.1007/s13555-024-01111-5. Epub 2024 Mar 1.

Integrating the 40-Gene Expression Profile (40-GEP) Test Improves Metastatic Risk-Stratification Within Clinically Relevant Subgroups of High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients

Ashley Wysong  1 , Ally-Khan Somani  2   3 , Sherrif F Ibrahim  4 , Javier Cañueto  5   6   7 , Alison L Fitzgerald  8 , Jennifer J Siegel  8 , Anesh Prasai  8 , Matthew S Goldberg  8   9 , Aaron S Farberg  10 , Christie Regula  11 , Anna Bar  12 , Julia Kasprzak  13 , David G Brodland  14 , Shlomo A Koyfman  15 , Sarah T Arron  16
Affiliations

Integrating the 40-Gene Expression Profile (40-GEP) Test Improves Metastatic Risk-Stratification Within Clinically Relevant Subgroups of High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients

Ashley Wysong et al. Dermatol Ther (Heidelb). 2024 Mar.

Abstract

Introduction: The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old.

Methods: This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP.

Results: Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models).

Conclusion: The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.

Keywords: 40-GEP; Cutaneous squamous cell carcinoma; Metastasis; Prognostic; Risk assessment.

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Conflict of interest statement

Ashley Wysong and Anna Bar receive research funding from CBI. Christie Regula, Ally-Khan Somani, and Sherrif Ibrahim are speakers and principal investigators for CBI. Aaron Farberg is consultant for CBI and has funding from Regeneron, Replimune, Enspectra Health, Gerson Lehrman Group. Alison Fitzgerald, Jennifer Siegel, Anesh Prasai, and Matthew Goldberg are employees, stock and options holders for CBI. Shlomo Koyfman is a consultant for CBI, Merck, BMS, Regeneron and Galera therapeutics; has research support from Merk, BMS and Regeron and honoraria from UpToDate and Varian. Sarah Arron is a paid consultant for Enspectra Health, CBI, and WorldCare Clinical; paid speaker bureaus for Regeneron and CBI; paid expert testimony from Forensis, Inc, and Muro & Lampe; travel expenses paid by CBI; paid participation on a data safety monitoring board for Replimune; paid advisory board participation for Regeneron, Dermatology Times/Multimedia Medical, and Matrix Medical; leadership in the International Transplant Skin Cancer Collaborative; stock holding in Rakuten Medical and Enspectra Health, with stock held by spouse in Genentech and 23andMe. All remaining authors participated as investigators for CBI during this study.

Figures

Fig 1
Fig 1
Flow chart describing final patient cohort and attrition due to study eligibility. *Did not meet protocol inclusion criteria, lacked sufficient material to be run under clinical standard operating procedures, did not meet clinical testing inclusion criteria. ART adjuvant radiation therapy
Fig 2
Fig 2
Kaplan-Meier plot based on metastasis-free survival (MFS) for the combined cohort, demonstrating significant stratification by 40-GEP results (log-rank test). The table below the plot indicates the number of patients at risk annually for each 40-GEP risk class. The bottom table demonstrates 3-year MFS rates for each 40-GEP class and associated metastatic event rates, in addition to overall survival metrics for the cohort
Fig 3
Fig 3
Kaplan-Meier survival analysis subset by the National Comprehensive Cancer Network (NCCN, v1.2024) risk classification system demonstrated statistically significant 3-year metastasis-free survival (MFS) between all 40-GEP classes. A NCCN high risk, B NCCN very high risk; Tables as described in Fig. 2, p values indicate log-rank tests
Fig 4
Fig 4
Kaplan-Meier survival analysis of Brigham and Women’s Hospital (BWH) lower risk stages demonstrated statistically significant 3-year metastasis-free survival (MFS) between all 40-GEP classes. (A) BWH T1; (B) BWH T2a; Tables as described in Fig. 2, p values indicate log-rank tests
Fig 5
Fig 5
Kaplan-Meier survival analysis of the ≥ 65 (25th quartile) and ≥ 80 (75th quartile) years of age at diagnosis subsets demonstrated statistically significant 3-year metastasis-free survival (MFS) between all 40-GEP classes. Tables as described in Fig. 2; p value indicates log-rank tests
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