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

J Clin Aesthet Dermatol. 2024;17(3 Suppl 2):S3–S8.

by Ramesh Gopal, MD, PhD; Michael Marquardt, MD, MPH; Gaurav Singh, MD, MPH; Stanislav N. Tolkachjov, MD; and Sarah T. Arron, MD, PhD

Dr. Gopal is a radiation oncologist and Associate Professor of Radiation Oncology at the New Mexico Comprehensive Cancer Center, in Albuquerque, New Mexico. Dr. Marquardt is a radiation oncologist at Hall-Perrine Cancer Center, in Cedar Rapids, Iowa; Dr. Singh is a Board-certified dermatologist and Mohs surgeon in Wisconsin. Dr. Tolkachjov is a board-certified dermatologist and Mohs micrographic and reconstructive surgeon at Epiphany Dermatology in Lewisville, Texas; Clinical Assistant Professor at the Department of Dermatology at University of Texas at Southwestern in Dallas, Texas; Clinical Associate Professor at the Texas A&M School of Medicine in Dallas, Texas; and a core faculty for the dermatology residency at Baylor University Medical Center in Dallas, Texas. Dr. Arron is a Board-certified dermatologist and Mohs micrographic and reconstructive surgeon at Peninsula Dermatology Medical Group in Burlingame, California. 

FUNDING: Castle Biosciences, Inc., provided funding for the development of this article.

DISCLOSURES: All authors received an honorarium from for their participation in this roundtable supplement. Dr. Tolkachjov is a speaker and  investigator for Castle Biosciences, Inc., and Bioventus/LifeNet. Dr. Marquardt has served as a speaker for Castle Biosciences, Inc.

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,  gene expression profiling, cutaneous squamous cell carcinoma, risk of recurrence, risk stratification, prognosis, adjuvant radiation therapy, consensus

Introduction

Early identification of patients with cutaneous squamous cell carcinoma (cSCC) who are at higher risk of developing metastasis is important so that clinicians can implement timely and effective treatments. Clinical and pathologic tumor features are incorporated into prognostic tools, such as the American Joint Committee on Cancer (eighth edition) (AJCC-8)1 and the Brigham and Women’s Hospital (BWH)2 staging systems, and management guidelines, such as the National Comprehensive Cancer Network® (NCCN) Squamous Cell Skin Cancer guidelines.3 However, clinicopathologic risk factors are incomplete predictors of metastatic risk; some patients with low-stage tumors develop metastasis and might have benefited from more aggressive treatment, while some patients with high-stage tumors may actually be at lower risk of metastasis and experience more risk than benefit from aggressive treatment.2,4–6 This is particularly relevant when considering adjuvant therapies, such as postoperative radiation therapy or immunotherapy, both of which carry significant risk to the patient and burden to the healthcare system. Improved identification of the patients most likely to benefit from these therapies will enable precision medical decision-making.

Gene expression profile (GEP) testing has emerged as an important tool to assist clinicians in identifying patients with cSCC who are at high risk for metastasis. The validated 40-GEP test (DecisionDx®-SCC, Castle Biosciences, Inc.), which is commercially available in the United States, quantifies expression of 40 genes from the primary tumor using reverse transcription-polymerase chain reaction (RT-PCR) and applies a neural-network algorithm to accurately classify patients as low (Class 1), higher (Class 2A), or highest (Class 2B) biological risk of nodal or distant metastasis within three years of diagnosis.7 A patient with a primary cSCC and at least one high-risk feature (Table 1) is eligible for 40-GEP testing. The 40-GEP test is not validated for testing of recurrent tumor tissue. The information provided by 40-GEP testing, combined with information provided by the current cSCC staging systems, improves prognostic precision and risk-appropriate treatment decisions made by the multidisciplinary team and patient.8 

One key decision after surgical clearance of cSCC is whether to recommend adjuvant radiation therapy (ART). Guidance from NCCN on ART is broad: 2024 guidelines recommend multidisciplinary consultation and consideration of ART in high risk cSCC if there is extensive perineural, large, or named nerve involvement, or if there are other poor prognostic features or if the patient is deemed to be at high risk for nodal or distant metastasis.3 The American Academy of Dermatology similarly recommends ART for cSCC with concern for perineural invasion (PNI) or high risk for regional or distant metastasis,9 while the American College of Radiology (ACR) focuses recommendations on extensive perineural and large nerve involvement.10 The American Society for Radiation Oncology (ASTRO) has the most detailed guidelines, recommending ART for cSCC with gross clinical or radiologic PNI, AJCC-8 T3 and T4 tumors, or desmoplastic or infiltrative tumors in chronically immunosuppressed patients.11

A multidisciplinary panel comprising radiation oncologists and dermatologists/Mohs micrographic surgeons with expertise in cSCC management convened on June 23, 2023, with the objective of establishing guidance to clinicians on the integration of clinicopathologic staging and 40-GEP testing into cSCC clinical decision-making in regard to ART. During the roundtable, the panel members discussed the benefits and limitations of the current staging and treatment systems, reviewed 40-GEP validation and real-world data, and described their real-world experiences, rationales, and scenarios in which they have used 40-GEP testing to improve risk stratification and more accurately identify patients with cSCC who are at high risk of metastasis and may benefit from ART. Based on these discussions, the expert panel developed risk-based clinical recommendations for ART referral in patients with cSCC, integrating 40-GEP testing and AJCC-8 staging into current NCCN guidelines. The aim of this consensus recommendation is to improve precision in recommendations for ART in patients with cSCC.

Current Risk Stratification in cSCC

The two cSCC staging systems primarily utilized in the United States (US) are AJCC-81 and BWH.2 The AJCC-8 staging system classifies T1 tumors as those with diameters 2cm or less and no high risk factors; T2 tumors as those with diameters greater than 2cm but no larger than 4cm, with no high risk factors; and T3 tumors as those with diameters greater than 4cm or a tumor of any size with any one high risk factor (e.g., deep invasion [beyond the subcutaneous fat or >6mm], minor bone erosion, PNI ≥0.1mm). The BWH staging system comprises four risk factors: 1) a tumor diameter of 2cm or greater, 2) tumor invasion beyond subcutaneous fat, 3) PNI 0.1mm or greater, and 4) poor differentiation. A BWH T1 tumor is designated as having no risk factors, a T2a tumor as having one risk factor, a T2b tumor as having 2 to 3 risk factors, and a T3 tumor as having all four risk factors and/or bone invasion. Although patients identified as BWH T1 or T2a are considered to be at low risk for metastasis and those identified as T2b or T3 are considered to be at high risk, external validation studies have shown an average false negative rate of 35.9 percent, suggesting under-staging, and an average false positive rate of 75.3 percent, suggesting over-staging (Table 2).4–6,12–15 Thus, there is an opportunity to improve precision, to spare lower-risk T2b/T3 patients from unnecessary intervention, and to target adjuvant treatment toward higher-risk T1/T2a patients.

The purpose of prognostic staging is to determine risk of poor outcomes, independent of treatment. Staging systems are complemented by NCCN treatment guidelines, which define a broad range of high- and very high-risk features, including those used in staging (Table 1), as well as clinical factors (e.g., rapid tumor growth, neurologic symptoms, selected histologic subtypes) and patient factors (e.g., immunosuppression).3 NCCN guidelines recommend multidisciplinary consultation and consideration of ART for high- or very high-risk cSCC that have been excised with negative surgical margins.3 The 40-GEP test provides independent prognostic data that, when combined with traditional staging and management guidelines, enhances the clinical picture, allowing clinicians to more accurately identify those patients with cSCC who will benefit most from ART.

The 40-GEP Prognostic Test

Validation studies. In the initial development and validation studies,7,16 the 40-GEP test demonstrated a statistically significant ability to stratify regional and distant metastatic risk in patients with cSCC and was used to define three risk groups: Class 1 (low risk), Class 2A (high risk), and Class 2B (highest risk). Kaplan-Meier survival curves show significantly different three-year metastasis-free survival (MFS) rates of 93.9 percent, 80.5 percent, and 47.8 percent among the Class 1, Class 2A, and Class 2B groups, respectively.16 Higher 40-GEP class was associated with a statistically significant increase in risk for metastasis and disease-specific death. When integrated into bivariate prediction models with AJCC and BWH staging systems, 40-GEP Class was confirmed to be an independent and significant predictor of metastatic risk. This combination improved the metastatic risk prediction of AJCC-8 and BWH staging systems (Figure 1).7  In multivariate modeling, the increased hazard for metastasis conferred by a GEP Class 2A or 2B (2.3, p=0.013; 6.9, p<0.001, respectively) was similar or higher than that conferred by other high-risk features, including poor differentiation and PNI.16 

These findings were recently confirmed in an independent external validation cohort of 534 patients.17  Combining the two cohorts to approximately 900 patients enabled a subgroup analysis of those with T1 stage tumors. The all-comer T1 population had a 6.5-percent three-year metastasis rate, but one in five patients tested had a 40-GEP Class 2A or 2B biologic risk. These 40-GEP Class 2A and 2B tumors had significantly increased metastatic rates of 11.3 percent and 33.3 percent, respectively.18 The T1/Class 2B population represents a group that may benefit from escalated treatment, even at a low prognostic stage. 

The combined cohort population also enabled an evaluation of which patients with high-risk cSCC would benefit most from postoperative ART. Patients were given a propensity score matched on clinical risk factors, and bootstrap resampled cohorts were analyzed using survival methods stratified by 40-GEP test results and ART status.19 This study demonstrated a median 50-percent improvement in MFS rates for 40-GEP Class 2B patients who received ART compared to those who did not.19 

Real-world studies. Summary metrics from the first year of clinical orders of the 40-GEP test (n=7,317) demonstrated that clinicians ordered the test for the intended use population (i.e., those with at least one of the risk factors listed in Table 1).20 Nearly all patients (99.9%) had one or more risk factors that would be classified by NCCN as high risk or very high risk, 75 percent of the patients had two or more risk factors, and the median number of risk factors per patient was three. Results from this initial 40-GEP real-world study also determined 71.1 percent of patients received a Class 1 result, 25.9 percent received a Class 2A result, and 2.9 percent received a Class 2B result.20 

Consensus Risk-based Clinical Workflow for Art in cSCC

The primary goal of ART is local control and to reduce the risk of locoregional recurrence and, ultimately, distant metastasis. As noted above, NCCN guidelines recommend that if there is extensive perineural, large, or named nerve involvement or if other poor prognostic features are present, multidisciplinary consultation and ART should be considered. The authors of the current article convened to discuss the existing data and recommendations for integrating the 40-GEP test into clinical decision-making for ART. All agreed that NCCN guidelines and staging systems currently guide decision-making, with the radiation oncologists favoring the AJCC-8 staging system and dermatologists using both AJCC-8 and BWH staging systems. 

Three clinical practice gaps emerged during the discussion for which the panel members agreed that the addition of 40-GEP testing has significant utility: 1) in escalation of care for lower-stage patients with high-risk tumors; 2) in de-escalation of care for patients for whom the risks of ART may outweigh the benefits; 3) and in decision-making regarding elective radiation to the nodal basin.

The expert panelists agreed that ART should be recommended for AJCC-8 T3-staged cSCC, particularly those with extensive PNI. They concurred with the report from a recent survey of members of the multidisciplinary Skin Cancer Outcomes (SCOUT) consortium, which recommended that ART be considered when risk of metastasis is 20 percent or higher.21 Panelists noted that the data are less clear for tumors with other high-risk features listed by the NCCN guidelines. For example, the panelists agreed that location on the head and neck alone is not sufficient to prompt a referral to radiation in the absence of other risk factors. They also acknowledged other significant risk factors that would support a recommendation for ART that are not included in current staging systems, such as lymphovascular invasion and sarcomatoid, infiltrative, or poorly differentiated cSCC.  

In this context, the panelists agreed that the 40-GEP Class 2A or 2B result in each AJCC-8 stage of tumor serves as a high- or very high-risk feature for consideration in recommendation for ART, as the increased metastatic risk conferred by a Class 2A or 2B result is similar to those of poor differentiation and PNI.19 Panelists agreed that dermatologists should image these patients and refer them to radiation oncology, with a recommendation for multidisciplinary tumor board discussion for patients with 40-GEP Class 2B results. Panelists agreed that radiation oncologists should discuss individual risks and benefits of radiation with all of their patients and integrate the high risk 40-GEP class 2 into the context of other high-risk clinicopathologic factors when considering raduation, with a stronger recommendation to those with a 40-GEP Class 2B result.

The expert panelists acknowledged that recommendations for ART in patients with cSCC are not based on local recurrence or metastatic risk alone. In some cases, there is concern for risk outweighing benefit. Patient age, medical comorbidities, location of the tumor, ability to tolerate the treatment course, patient preference, access to care, and other factors are all part of the treatment decision-making process. For example, ART for tumors on the face may cause damage to the eye, resulting in vision loss, or to salivary glands, impacting dental health, swallowing, and nutrition. An elderly, frail patient with multiple comorbidities will have a higher adverse event profile than a young, healthy person, and may not have the social support for travel and/or home care. Panelists noted that, in these nuanced discussions, the additional information provided by the 40-GEP test can assist in personalized decision-making. A 40-GEP Class 1 result informs a reduced metastatic risk at each AJCC-8 stage, which is reassuring when opting to defer ART, whereas a 40-GEP Class 2A or 2B result would provoke additional support for the benefit of ART. Panelists noted that the option of a hypofractionated radiation schedule may be considered for a patient with a Class 2A tumor in the context of other comorbidities.

Panelists discussed the role of the 40-GEP in decision-making regarding elective nodal radiation. The current American College of Radiation guidelines10 are vague in terms of when to give elective nodal radiation in the head and neck area. Elective nodal radiation can increase the side effect profile (e.g., alopecia, pain, difficulty with swallowing, worsening skin reactions, dry mouth, taste changes). While there may be value in treating the nodes prophylactically, the panel agreed that radiating nodes in the head and neck increases the risk of these side effects. Panelists acknowledged that some radiation oncologists defer treating the nodal basin unless there is pathologic nodal involvement. They discussed that if the nodal basin is close enough to the primary site that exposure to radiation is unavoidable, then treating the entire area might be beneficial to the patient. Significantly extending the treatment field to include a relatively remote nodal basin as a prophylactic measure, however, might cause more harm than benefit to the patient. Panelists agreed that the 40-GEP test would help the radiation oncologist determine a more precise risk-benefit ratio for elective nodal radiation. They recommended stronger consideration of elective nodal radiation for a Class 2B tumor, given the dramatically increased risk of nodal metastasis. 

Based on consideration of validation and real-world data supporting clinical utility of 40-GEP testing, NCCN guidelines, AJCC-8 and BWH staging criteria, an existing case-series based algorithm integrating 40-GEP into current treatment approaches,1-3, 7–11,16–22 and the current roundtable discussions, expert panel members developed a risk-based clinical workflow for ART in patients with cSCC, integrating AJCC-8 staging and 40-GEP testing into current NCCN guidelines (Figure 2). Panel members highlighted that there are no absolutes in risk assessment and emphasized the importance of considering risks versus benefits of ART in the context of a multidisciplinary treatment team. 

Additional Considerations

Panelists acknowledged that the primary aim of ART is locoregional control, whereas 40-GEP testing is validated to predict nodal and distant metastasis and is not currently intended for prediction of local recurrence. However, the panelists noted that early identification and intervention in high-risk patients are beneficial, and that local control is key to preventing nodal metastasis. Though the primary discussion of the panel focused on ART, the expert panelists also noted that patients who are referred for radiation should also be imaged for nodal staging, particularly in cSCC of the head or neck. Panelists recommended imaging by the physician’s choice of preferred modality in cSCC patients with 40-GEP Class 2A or 2B results. Panelists also agreed that imaging is preferred over sentinel lymph node biopsy, given the absence of clear benefit and the possible morbidity of that procedure. 

Conclusion

Combining clinicopathologic staging with the 40-GEP test allows for more accurate prognostic staging of cSCC tumors; this, in turn, improves precision in multidisciplinary treatment recommendations, including the use of ART. The utility of 40-GEP testing has been demonstrated in low-, higher-, and highest-stage cSCC tumors. Additionally, 40-GEP testing has shown greater specificity than current clinicopathologic guidelines in identifying patients at highest risk of nodal or distant metastasis who would most likely benefit from ART, as well as lower risk patients who would benefit less from such therapy. Appropriate use of 40-GEP testing involves a shared decision-making model between the multidisciplinary team and the patient with cSCC, taking into consideration many factors, such as the patient’s risk of metastasis, tumor and nontumor characteristics, and individual preferences. 

References

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