Aaron Farberg M.D.

Borman, S., Wilkinson, J., Meldi-Sholl, L., Johnson, C., Carter, K., Covington, K. R., Fitzgerald, A. L., Kurley, S. J., Farberg, A. S., Goldberg, M. S., Monzon, F. A., Oelschlager, K. and Cook, R. W. (2022). “Analytical validity of DecisionDx-SCC, a gene expression profile test to identify risk of metastasis in cutaneous squamous cell carcinoma (SCC) patients.” Diagn Pathol 17(1): 32.

Full text of this article.

BACKGROUND: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis. The primary objective of this study was to validate the analytical performance of the 40-gene expression signature. METHODS: The repeatability and reproducibility of the 40-GEP test was evaluated by performance of inter-assay, intra-assay, and inter-operator precision experiments along with monitoring the reliability of sample and reagent stability for class call concordance. The technical performance of clinical orders from September 2020 through July 2021 for the 40-GEP test was assessed. RESULTS: Patient hematoxylin and eosin (H&E) stained slides were reviewed by a board-certified pathologist to assess minimum acceptable tumor content. Class specific controls (Class 1 and Class 2B) were evaluated with Levey-Jennings analysis and demonstrated consistent and reproducible results. Inter-assay, inter-operator and intra-assay concordance were all ≥90%, with short-term and long-term RNA stability also meeting minimum concordance requirements. Of the 2586 orders received, 93.5% remained eligible for testing, with 97.1% of all tested samples demonstrating actionable class call results. CONCLUSION: DecisionDx-SCC demonstrates a high degree of analytical precision, yielding high concordance rates across multiple performance experiments, along with exhibiting robust technical reliability on clinical samples.

Farberg, A. S., Fitzgerald, A. L., Ibrahim, S. F., Tolkachjov, S. N., Soleymani, T., Douglas, L. M., Kurley, S. J. and Arron, S. T. (2022). “Current Methods and Caveats to Risk Factor Assessment in Cutaneous Squamous Cell Carcinoma (cSCC): A Narrative Review.” Dermatol Ther (Heidelb) 12(2): 267-284.

Full text of this article.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, and the number of deaths due to cSCC is estimated to be greater than the number attributed to melanoma. While the majority of cSCC tumors are resectable with clear margins by standard excision practices, some lesions exhibit high-risk factors for which there is evidence of their association with recurrence, metastasis, and disease-specific death. The most commonly used staging systems and guidelines in the USA for cSCC are based on these clinical and pathologic high-risk factors; however, these are limited in their ability to predict adverse events, thus posing a challenge for implementing risk-directed patient management. Since the development of local recurrence and/or metastasis has a profound impact on the survival of patients with cSCC, accurate identification of patients at high risk for poor outcomes is critical, potentially allowing for early and appropriate adjuvant therapy. This review summarizes the current cSCC literature with a focus on how differing clinical assessments within each of the five selected risk factors (perineural invasion, differentiation, depth of invasion, size, and location) can influence the evaluation of patient outcomes, along with summarizing the utility of staging and guidelines, and highlighting the potential for molecular tools to improve upon cSCC risk assessment.

Ibrahim, S.F., Kasprzak, J.M., Hall, M.A., Fitzgerald, A.L., Siegel, J.J., Kurley, S.J., Covington, K.R., Goldberg, M.S., Farberg, A.S., Trotter, S.C., Reed, K., Brodland, D.G., Koyfman, S.A., Somani, A.K., Arron, S.T. and Wysong, A. (2021). “Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test.” Future Oncol Nov 25. [Epub ahead of print].

Full text of this article.

Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan-Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for Class 1 and ≥50% for Class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies.

Lewis, K., R. Dummer, A. S. Farberg, A. Guminski, N. Squittieri and M. Migden (2021). “Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial.” Dermatol Ther (Heidelb) Oct 20. [Epub ahead of print].

Full text of this article.

INTRODUCTION: Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. METHODS: BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. RESULTS: The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). CONCLUSION: Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01327053.

Newman, J.G., Hall, M.A., Kurley, S.J., Cook, R.W., Farberg, A.S., Geiger, J.L. and Koyfman, S.A. (2021). “Adjuvant therapy for high-risk cutaneous squamous cell carcinoma: A 10-year review.” Head Neck Jun 7. [Epub ahead of print].

Full text of this article.

Standard of care for high-risk cutaneous squamous cell carcinoma (cSCC) is surgical excision of the primary lesion with clear margins when possible, and additional resection of positive margins when feasible. Even with negative margins, certain high-risk factors warrant consideration of adjuvant therapy. However, which patients might benefit from adjuvant therapy is unclear, and supporting evidence is conflicting and limited to mostly small retrospective cohorts. Here, we review literature from the last decade regarding adjuvant radiation therapy and systemic therapy in high-risk cSCC, including recent and current trials and the role of immune checkpoint inhibitors. We demonstrate evidence gaps in adjuvant therapy for high-risk cSCC and the need for prognostic tools, such as gene expression profiling, to guide patient selection. More large-cohort clinical studies are needed for collecting high-quality, evidence-based data for determining which patients with high-risk cSCC may benefit from adjuvant therapy and which therapy is most appropriate for patient management.