Use of the 40-gene Expression Profile (40-GEP) Test in Medicare-eligible Patients Diagnosed with Cutaneous Squamous Cell Carcinoma (cSCC) to Guide Adjuvant Radiation Therapy (ART) Decisions Leads to a Significant Reduction in Healthcare Costs.

Objective: Adjuvant radiation therapy (ART) is often recommended for high-risk cSCC patients but carries significant costs and risks. This study aims to determine if utilizing the 40-GEP test to guide ART can reduce healthcare costs in cSCC management. Methods: Medical claims data with new diagnoses of cSCC for the 12 months ending June 2022 in the Medicare (≥65 years) population (source: IQVIA claims database) were obtained and normalized to the general population for missingness. CPT codes associated with radiation therapy within one-year post diagnosis were used to establish adjuvant RT use (defined as 'ART'). Average weighted direct costs for four major ART modalities were calculated from published studies and (IQVIA). Sensitivity analysis was used to assess the financial impact of ART treatment using varying distributions of 40-GEP Class results. Results: Normalized medical claims data identified 22,917 Medicare-eligible cSCC patients who received ART within the United States. The weighted average direct cost for ART, which includes the four most used CPT code-defined modalities (IGRT, IMRT, IMPT, and XRT), was $60,693 per patient, amounting to an annual projected ART cost of $1.4 billion. Using the distribution of 40-GEP results from published studies, utilization of a 40-GEP test result to avoid ART in these patients could save up to $972 million in Medicare-eligible population. Sensitivity analysis shows, depending upon the distribution of the 40-GEP results, that for every 10% of Class 2A test results omitting ART, an extra $38-66 million in annual savings is expected. Limitations: Potential limitations include a need for more comprehensive patient information and the cost of ART-related complications. Conclusion: Utilizing the 40-GEP test results to guide ART decision-making would result in material savings to Medicare.

Current Methods and Caveats to Risk Factor Assessment in Cutaneous Squamous Cell Carcinoma (cSCC): A Narrative Review.

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.

Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test.

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.

Plain language summary Cutaneous squamous cell carcinoma is a common skin cancer, with approximately 2 million cases diagnosed each year in the USA. Because substantial numbers of patients experience metastasis, which can result in death, accurate metastatic risk assessment is important. Clinicians use clinicopathologic factors to determine risk for disease progression. However, traditional methods miss pinpointing many patients who experience metastasis and sometimes categorize patients as at risk who do not develop metastasis, indicating that additional tools are needed. A molecular test, the 40-gene expression profile (40-GEP), was developed to predict metastatic risk based on the biology of the tumor. This study demonstrates that the 40-GEP, either as an independent tool or together with traditional methods, accurately identifies patients' risk of metastasis. Using the 40-GEP could improve patient management to improve patient outcomes.

Dose-response effect of human equivalent radiation in the murine mandible: Part II. A biomechanical assessment.

BACKGROUND: Despite the widespread use of adjuvant irradiation for head and neck cancer, the extent of damage to the underlying bone is not well understood. However, patients can suffer serious clinical consequences, including pathologic fractures, nonunion, and osteoradionecrosis. The authors' specific aim was to objectively quantify the human equivalent radiation dose-response effect of radiation on the biomechanical properties of the murine mandible. METHODS: Twelve Sprague-Dawley rats were randomized into three radiation dosage groups--low (5.91 Gy), middle (7 Gy), and high (8.89 Gy)--delivered in five daily fractions. The fractionation regimen was used to approximate 75, 100, and 150 percent, respectively, of the bioequivalent dose humans receive in conventional head and neck cancer treatment. Fifty-six days after irradiation, hemimandibles were loaded to failure in a uniaxial tension at 0.5 mm/second. Load displacement curves were analyzed for yield and breaking load, and values were considered statistically significant at p<0.05. RESULTS: The authors' data demonstrated a statistically significant decrease in the yield and breaking load metrics. The authors' reported averages for low, middle, and high radiation dosages were 162, 136, and 69 N, respectively, for yield; and 215, 211, and 141 N, respectively, for breaking load. Both of these quantitative biomechanical properties were diminished in a dose-response pattern. CONCLUSIONS: In this article, the authors report a dose-response effect in the degradation of the biomechanical properties of the mandible after fractionated human equivalent radiation. The authors' findings and model can now be used to formulate therapies aimed at remediating those effects and augmenting bone regeneration and healing after adjuvant radiotherapy in head and neck cancer patients.

Dose-response effect of human equivalent radiation in the murine mandible: part I. A histomorphometric assessment.

BACKGROUND: The authors' laboratory previously demonstrated that radiation significantly alters new bone formation in the murine mandible, impeding the use of distraction osteogenesis as a viable reconstructive option after radiotherapy in head and neck cancer. The authors hypothesize that the deleterious effects of radiation on regenerate formation results from a dose-response depletion of essential osteogenic cells. The authors' specific aim was to use quantitative histomorphometry to objectively measure the human equivalent dose-response effects of radiation on the integrity of the mandible's cellular and tissue composition. METHODS: Twenty Sprague-Dawley rats were randomized into three radiation dosage groups: low (5.91 Gy), middle (7 Gy), and high (8.89 Gy), delivered in five daily fractions. These dosages approximated 75, 100, and 150 percent, respectively, of the biological equivalent dose the mandible experiences in the clinical regimen of head and neck cancer patients. Hemimandibles were harvested 56 days after radiation and stained with Gomori trichrome. Quantitative histomorphometry was performed using Bioquant software and analysis with a one-way analysis of variance Kruskal-Wallis test. RESULTS: The authors' data revealed a statistically significant diminution in the mean number of osteocytes. The authors also demonstrated a corresponding significant increase in the mean values of empty lacunae. Both of these quantitative histomorphometric changes demonstrated a dose-response relationship. CONCLUSIONS: The authors' study supports their hypothesis that radiation induces a dose-response depletion in osteocytes and an increase in empty lacunae. These reliable and reproducible metrics can now be used to determine the efficacy of therapies aimed at safeguarding the cells essential for optimal bone regeneration and potentially enhance the use of distraction osteogenesis in head and neck cancer patients.