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“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like, , or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”
Developed by and commercially available from Castle Biosciences,classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.
One validityand three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see ; , and ). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.
The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.
Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.
The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”
The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”
Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”
On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”
DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”
For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”
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Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.