Clinical Utility of the 40-Gene Expression Profile (40-GEP) Test for Improved Patient Management Decisions and Disease-Related Outcomes when Combined with Current Clinicopathological Risk Factors for Cutaneous Squamous Cell Carcinoma (cSCC): Case Series

While cutaneous squamous cell carcinoma (cSCC) has an overall favorable prognosis, a subset of patients will develop metastases and die from their disease. Even with a low fatality rate, the high (~1.8 million cases/year [1]) and increasing incidence of cSCC will perpetuate the occurrence of poor outcomes. Once nodal metastasis is detected, 5-year survival rates have been reported to be 50–70% [2, 3] even after appropriate treatments, and once distant metastasis has been identified, 5-year survival is rare [4]. Deaths from this disease are estimated to surpass those from melanoma, making the management of cSCC an increasingly significant clinical issue [5].

The National Comprehensive Cancer Network (NCCN) classifies cSCC patients as high risk for local recurrence or very high risk for metastasis or death by the presentation of selected risk factors and presents a range of downstream management approaches [6]. Tumor staging systems, such as the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition (AJCC-8) [7] and Brigham and Women’s Hospital (BWH) system [8], help determine recurrence and metastatic risk by translation of high-risk factors into tumor (T) stages. However, these systems can fail to fully assess patient risk, leading to low accuracy when identifying metastasis [9]. The subset of cSCC patients classified as high risk commonly require a more aggressive treatment regimen, but guidelines are vague and staging criteria has been noted as limited and lacking homogeneity [10‐12], creating a burden for clinicians when establishing an appropriate treatment plan.

A 40-gene expression profile (40-GEP) test was recently developed to assess the biology of primary archival formalin-fixed paraffin-embedded (FFPE) cSCC tissue, and has been validated to significantly improve metastasis risk prediction when compared with the current staging systems listed above [9]. The 40-GEP test classifies patients into three groups based on risk for regional and/or distant metastasis (Class 1: low risk; Class 2A: moderate risk; Class 2B: high risk). As national guidelines for high-risk cSCC patients are unclear on which patients warrant additional follow-up and management, treatment of high-risk cSCC often relies on risk assessment based on individual risk factors weighted by physician judgement, leading to management intensity heterogeneity and highlighting the critical need for an unbiased method of risk assessment. The purpose of developing the 40-GEP test was to identify high-risk cSCC early in the disease state, such that its result could complement current risk assessment methods for development of more personalized management plans to reduce the risk of poor outcomes for cSCC patients. The cases discussed herein highlight the utility of 40-GEP to provide additional information to guide treatment decisions and improve outcomes.

We present two cases that highlight the utility of the 40-GEP test as an adjunct to enhance cSCC risk stratification. Each case was similar in patient background and tumor characteristics and had the same initial BWH and AJCC-8 staging, yet there were distinctively different outcomes between them (Table 1). Case 1 highlighted a biologically less aggressive tumor (with a retrospective 40-GEP Class 1 result) that did not recur despite incomplete surgical clearance. Case 2 highlighted a biologically aggressive tumor (with a retrospective 40-GEP Class 2B result) that developed regional metastasis despite clear surgical margins obtained through MMS. Adjuvant treatment might have been appropriate for this patient earlier in the disease course and thus altered his prognosis.

Although the majority of cSCC tumors are associated with a favorable outcome, patients presenting with clinicopathologic high-risk factors show a higher risk of local recurrence, as well as regional and distant metastasis, which are associated with high levels of cSCC mortality [12]. Unfortunately, an unclear agreement on what factors are most influential in determining a high-risk cSCC tumor that may most benefit from a particular adjuvant therapy, as seen in the ambiguity concerning treatment recommendations (as governed by the NCCN) and the diversity of risk factors considered high risk by staging criteria (i.e., AJCC-8 and BWH), has led to a wide range of and variation in patient management decisions [13, 14]. These inconsistencies have a profound effect on the accuracy of applying staging to risk assessment [9] and emphasize the need for an objective tool to complement these systems.

Effective molecular prognostic assays provide reproducible and reliable risk assessment (analytical and clinical validity) to alter decision making (clinical utility). The advancement of gene expression profiling signatures for use in clinical management make them a powerful prognostic tool, when complementing staging, for many other tumor types [15‐19]. A recent publication from Ibrahim et al. [20] demonstrated how combining both clinicopathologic features with molecular testing for cSCC can augment stratification of metastatic risk. This may reduce expanding health care costs by focusing more intense treatments (i.e., therapeutics, surgeries, and/or imaging) toward patients who will see the utmost benefit, while reducing unnecessary procedures for those who would be appropriately deemed low risk for metastatic disease. With this study, we demonstrate that the integration of novel molecular prognostication for cSCC in combination with traditional clinicopathologic risk factors, has the potential to improve stratification of high-risk cSCC patients and posits selection of risk-appropriate treatment and surveillance strategies aligned with a patient’s biological risk for poor outcomes.