DecisionDx®-SCC Informs Adjuvant Radiation Therapy Treatment Decisions for Patients with Cutaneous Squamous Cell Carcinoma

Sponsored by Castle Biosciences

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the United States, with almost 2 million cases diagnosed annually.¹ This number has steadily increased in recent years and shows no signs of slowing, a troubling trend as the number of deaths from cSCC has surpassed those from melanoma.²

While surgical treatment of cSCC is typically very effective, a significant number of patients experience local or distant recurrence and metastasis, requiring repeated interventions as well as invasive, costly treatments. With the increase in incidence of cSCC, these outcomes may affect more people as time goes on.

The DecisionDx-SCC (40-gene expression profile (GEP)) test measures the expression of 40 genes in a patient’s cSCC tumor to predict their individual risk of metastasis. The test is intended for use in patients with one or more risk factors and categorizes cSCC tumors into three increasing risk groups: Class 1 (low), Class 2A (higher), and Class 2B (highest), which reflect the patient’s individual predicted risk of metastasis based on the biology of their tumor. These results may help healthcare providers guide their clinical decisions regarding potential treatment pathways.

One such pathway, adjuvant radiation therapy (ART), uses ionizing radiation to irradiate the surgical site following the removal of the primary tumor, aiming to destroy any remaining cancer cells and potentially prevent recurrence or metastasis. Many different types of patients may be considered for ART, including patients with completely resected tumors that have other high-risk factors, even if cancer cells are not visible post-surgery.

Although ART has been shown to be effective at reducing the rates of cSCC metastasis, it can have side effects, including changes in skin color, hair loss, bruising, and blistering, among others. If the area being treated is on the head or neck (like many high-risk cSCC tumors), ART can permanently damage important structures like teeth and salivary glands. This can be especially difficult for patients with cSCC, since the disease is more common in the elderly population, who often have other existing health problems that may make the negative side effects of ART more difficult to manage.

Given these significant side effects, accurately identifying patients who truly need ART is crucial. The challenge lies in risk assessment; clinical and pathological features alone may be misleading. Some patients may appear low risk based on traditional clinical and pathological risk factors, but may actually have high biological risk of metastasis and may benefit from ART. Conversely, others may present with seemingly high-risk features but have low biological risk and could safely avoid unnecessary radiation therapy.

Recent clinical studies demonstrate that DecisionDx-SCC has the potential to effectively provide information for ART decisions when it comes to a patient’s predicted risk of metastasis. This newly indicated use of the test was first published by Arron et al.³ in the International Journal of Radiation Oncology, Biology, Physics (the Red Journal), then independently validated by Ruiz et al.⁴ in Future Oncology. Both studies matched patients based on their clinical and pathological features, and found that ART had no demonstrated benefit to patients who received Class 1 results from the DecisionDx-SCC test (the lowest risk level), since the risk of metastasis stayed the same in the majority of these patients regardless of whether they received ART.

As the studies highlighted, many of the patients who received ART did not demonstrably benefit from the treatment and could have been identified as low risk, and thus potentially safe to defer ART, if their treatment had been guided by DecisionDx-SCC test results. These patients were potentially exposed to ionizing radiation and negative side effects with no discernable benefit.

Conversely, patients with a DecisionDx-SCC Class 2B result (the highest risk result) who received ART had a 50% lower rate of metastasis than those who did not receive ART, meaning that the test predicted which patients would benefit most from the treatment. Compared to traditional clinical and pathological methods of risk assessment, a DecisionDx-SCC Class 2B result was the only variable in the study that demonstrated the ability to effectively predict benefit from ART for patients with cSCC.

In Arron et al.³ and Ruiz et al.⁴, patients with DecisionDx-SCC Class 2B results who received ART showed a significant decrease (~50%) in median risk of metastatic disease progression vs. patients who did not receive ART.

Given these results, DecisionDx-SCC has the potential to fill a much-needed clinical gap in helping guide physician and patient decisions regarding ART. If an apparent high-risk cSCC tumor, based on traditional methods of assessing cSCC risk, is tested with DecisionDx-SCC and receives a Class 1 (low risk) result, some much-needed clarity could be provided to reassure the patient and physician that ART is not necessary and the biological risk of disease progression is actually low. On the other hand, a Class 2B (highest risk) result may indicate that ART is the patient’s best option for an improved health outcome, as that patient is most likely to benefit from ART to divert disease progression.

In addition to the physical side effects, ART is also an expensive treatment. Somani et al. recently calculated that a course of radiation therapy for cSCC costs, on average, over $60,000 per patient.⁵ Within the Medicare system, this equates to nearly $1.4 billion in annual cost for use of ART in patients with cSCC. With the incidence of cSCC rising, this spending is expected to increase.

These costs may be greatly reduced with the use of the DecisionDx-SCC test to guide the ART decision-making process. If the test’s results were used to defer ART, up to $972 million could be saved every year by Medicare, freeing healthcare resources for those most likely to benefit from treatment.

Overall, existing guidelines for cSCC are inconsistent and too broadly defined for clinical guidance in everyday practice, leading clinicians to divergent recommendations for ART.⁶ These guidelines, which are based on clinical and pathological features of the patient’s tumor, may be better informed by incorporating DecisionDx-SCC test results. For patients and physicians confronting the difficult decision to initiate ART, having comprehensive information—particularly insights into tumor biology—is crucial before selecting a treatment pathway. This complete clinical picture is designed to enable more informed, personalized treatment decisions.

With this verified clinical utility of the DecisionDx-SCC test, clinicians have access to more tools to potentially help inform their ART decisions than ever before. A Class 1 test result may empower physicians to confidently de-escalate cSCC treatment when appropriate, potentially sparing low risk patients from the negative side effects of radiation therapy and potentially generating millions in annual healthcare savings. Simultaneously, this precision approach is designed to help ensure that intensive treatments are directed to high-risk patients who are most likely to benefit from treatment, as indicated by a DecisionDx-SCC Class 2B result, potentially improving both patient outcomes and healthcare resource allocation.

References:

1. Skin Cancer Foundation: Our New Approach to a Challenging Skin Cancer Statistic. The Skin Cancer Foundation, 2021. Accessed May 12, 2025. https://www.skincancer.org/blog/our-new-approach-to-a-challenging-skin-cancer-statistic/
2. Mansouri B, Housewright CD. The Treatment of Actinic Keratoses-The Rule Rather Than the Exception. JAMA Dermatol. 2017;153(11):1200. doi:10.1001/jamadermatol.2017.3395
3. Arron ST, Cañueto J, Siegel J, et al. Association of a 40-Gene Expression Profile With Risk of Metastatic Disease Progression of Cutaneous Squamous Cell Carcinoma and Specification of Benefit of Adjuvant Radiation Therapy. International Journal of Radiation Oncology, Biology, Physics. 2024;120(3):760-771. doi:10.1016/j.ijrobp.2024.05.022
4. Ruiz ES, Brito K, Karn EE, et al. Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the 40-gene expression profile. Future Oncol. 2024;20(35):2737. doi:10.1080/14796694.2024.2390820
5. Somani AK, Ibrahim SF, Tassavor M, Yoo J, Farberg AS. 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. J Clin Aesthet Dermatol. 2024;17(1):41-44.
6. Moody BR, Farberg AS, Somani AK, Taylor WA. Inconsistent Associations Between Risk Factor Profiles and Adjuvant Radiation Therapy (ART) Treatment in Patients with Cutaneous Squamous Cell Carcinoma and Utility of the 40-Gene Expression Profile to Refine ART Guidance. Dermatol Ther (Heidelb). 2024;14(4):861-873. doi:10.1007/s13555-024-01125-z