Incorporating a Prognostic Gene Expression Profile Test into the Management of Cutaneous Squamous Cell Carcinoma: An Expert Consensus Panel Report

February 2024 | Volume 23 | Issue 2 | 54 | Copyright © February 2024


Published online November 16, 2023

Danny Zakria MD MBAa, Nicholas Brownstone MDb, Brian Berman MDc, Roger Ceilley MDd, Terrence A. Cronin Jr. MDc, James Q. Del Rosso DOe, Laura K. Ferris MD PhDf, Gary Goldenberg MDa, Daniel Siegel MDg

aDepartment of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY
bDepartment of Dermatology, Temple University Health, Philadelphia, PA
cDepartment of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
dDepartment of Dermatology, The University of Iowa, Iowa City, IA
eDepartment of Dermatology, Touro University, Henderson, NV
fDepartment of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA
gDepartment of Dermatology, SUNY Downstate, Brooklyn, NY

had a negative predictive value of 91.1% compared to 87.7%, 86.3%, and 90.5% for the AJCC, BWH, and NCCN low-risk groups, respectively. Similarly, Ibrahim et al found that the PPV for a Class 2B result in their cohort was 52.2% compared with 30.0% and 33.9% for high-stage AJCC8 and BWH tumors, respectively.11 Likewise, in a cohort of cSCCs on the head and neck, Arron et al found that the sensitivity of a Class 2 result for metastasis was significantly greater than high-stage AJCC8 T3/T4 and BHW T2b/T3 results and the specificity of a Class 2B result was significantly greater than the high-stage AJCC8 and BWH results.29

Statement 4: Adding 40-GEP data to the AJCC8 and BWH staging systems enhances the prognostic assessment of cSCC. (SORT Level A)

Not only does the literature support the independent prognostic value of the 40-GEP test, but it also establishes that incorporating these results into current staging systems and guidelines further improves prognostic assessment. Patients classified as NCCN high risk and very high risk that also received a 40-GEP result of Class 2B had a metastasis occurrence rate of 37.5% and 60.0% respectively, compared to a rate of 9.8% for NCCN high risk and a rate of 23% for NCCN very high risk alone.11

Statement 5: The 40-GEP test results can increase the precision and confidence in cSCC management decisions. (SORT Level A)

As previously noted, applying 40-GEP test results has the potential to re-categorize NCCN-defined high-risk cSCC patients into lower intensity management groups.11,28 This can have a large impact on management decisions, such as frequency of follow-up, method of nodal assessment (ie, palpation vs biopsy), use of advanced imaging, and use of adjuvant therapy. The NCCN guidelines for high-risk cSCC are broad and have the potential to lead to overtreatment, as 63.0% of the high-risk NCCN cases in the original 40-GEP validation cohort were identified as low-risk Class 1.28 By incorporating additional data from 40-GEP testing into management decisions, clinicians can better adjust their management intensity based on risk. In a survey of 162 dermatologists, Litchman et al showed that a 40-GEP Class 1 result caused clinicians to substantially increase their avoidance of additional interventions while a Class 2B result led clinicians to choose a higher intensity management plan with increases in recommendations for sentinel lymph node biopsy, adjuvant radiation, adjuvant chemotherapy, and shorter follow-up intervals.34 Hooper et al also conducted a clinical utility study by surveying 34 clinicians who ordered 10 or more 40-GEP tests in its first year of availability. Using 6 real-world cases spanning the spectrum of risk levels, they found that clinicians were overall well-aligned regarding the baseline risk levels and subsequent management changes based on 40-GEP results.33 Farberg et al analyzed a cohort of 300 NCCN-defined high-risk cSCC patients and found that 40-GEP test results, after adjusting for AJCC8 or BWH tumor stage, were able to recommend low management intensity for 53.0% or 57.7% of patients, respectively.14

Statement 6: The 40-GEP test should be considered for use on cSCC tumors with at least 1 high-risk feature per AJCC8 and/or BWH and/or NCCN guidelines. (SORT Level A)

The validation study for the 40-GEP test consisted of a cohort of patients with at least 1 high-risk feature as defined by these staging systems and NCCN guidelines.28 Additional studies demonstrating the test's accuracy and clinical validity also utilized similar inclusion criteria.11,14 Therefore, the panel recommends considering the test for cSCC cases with at least 1 high-risk feature in order to maximize prognostic accuracy and utility.

Statement 7: The 40-GEP test is not recommended to be used on cSCC in situ or invasive cSCC without high-risk features, or for patients that are not candidates for additional procedures or therapies. (SORT Level C)

Similarly, the available literature does not support the use of the test for in situ cSCC or cSCC without high-risk features. Until further studies are completed on these tumors, the use of the test would result in unnecessary healthcare costs that outweigh the benefits of the results. Additionally, if a patient is not a candidate for additional procedures or therapies, the panel believes that there is limited value in the test's results, as it will not lead to an alteration in management.

CONCLUSION

cSCC is a growing health concern with a rapidly rising incidence and poor survivability in cases of metastatic disease.1-5,8,9,11 Existing clinicopathologic staging systems have significant limitations in their ability to predict which patients will experience a metastasis, as only 14% to 17% of patients with AJCC8 T3/T4 tumors and 24% to 38% of patients with BWH T2b/T3 tumors develop one.16,21,22 A more accurate method of assessing this risk is critical to reduce the morbidity and mortality associated with both cSCC and unnecessary interventions. This comprehensive review demonstrated that the 40-GEP test has been validated as an independent predictor of cSCC risk of metastasis beyond AJCC8 and BWH staging systems. Furthermore, when 40-GEP testing is used in conjunction with these systems, multiple studies have shown that more accurate prognostic assessment is possible.11,14,28 These consensus recommendations put forth by the panel can help guide dermatology clinicians on appropriate test usage to make better risk-aligned management decisions, thereby ultimately improving patient outcomes.

DISCLOSURES

DZ and NB have participated in a research fellowship partially funded by Castle Biosciences. BB has served as a consultant for Castle Biosciences. RC, TAC, JQDR, LKF, and GG have no conflicts of interest. DS has served as a consultant to DermTech.

Funding: This study was funded in part by an unrestricted educational grant from Castle Biosciences.

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