The Dermatology Digest • Innovations in Personalized Medicine November/December 2024 Supplement • Understanding and Utilizing DecisionDx-Melanoma®

A Q&A With J. Michael Guenther, MD, Surgical Oncologist, St. Elizabeth Physicians, Edgewood, KY

J. MICHAEL GUENTHER, MD: It is a test that provides prognostic information to guide management decisions for patients with cutaneous melanoma. The test is a second-generation prognostic tool that integrates the original 31-gene expression profile (31-GEP) test with clinicopathologic staging factors to give an individualized assessment of a patient’s risk of recurrence and/or metastasis and the likelihood of sentinel lymph node biopsy (SLNB) positivity. The 31-GEP test analyzes RNA in tissue from a primary melanoma for under- or overexpression of genes that provide information predictive of the tumor’s biological behavior. The clinicopathologic factors assessed include Breslow thickness, ulceration, mitotic rate, SLN status, age, and tumor location.

The test report includes a class result (1A, 1B, 2A, or 2B) determined from the 31-GEP score that informs the risk of recurrence and likelihood of SLN positivity. Integrating the 31-GEP score and the patient’s clinicopathologic factors (i31-GEP), the report also provides a personalized likelihood of SLN positivity and personalized risk of recurrence estimates for 5-year rate of melanoma-specific survival, distant metastasis-free survival, and recurrence-free survival.

DR. GUENTHER: The original 31-GEP test was evaluated in prospective studies and was shown to accurately classify patients into qualitative categories (low, intermediate, high) describing risk of SLNB positivity and recurrence. That is powerful information that no test before was able to provide successfully. Integration of the clinicopathologic factors allowed precise predictions of an individual’s risk for spread to the SLN and risk of recurrence at any point in time.

TDD: Why is the information provided by the DecisionDX-Melanoma test so important?

DR. GUENTHER: The biology and clinical behavior of cutaneous melanoma is highly variable. The tumor can regress spontaneously, grow, or spread at different rates, or recur after being dormant for years. Understanding a melanoma’s malignant potential is critical information for guiding patient care decisions. Before DecisionDX-Melanoma became available, we had no tools for predicting tumor behavior and patient outcomes.

Based on the information in the DecisionDx-Melanoma report, clinicians are better able to identify patients with high-risk disease and decide about treatment or appropriate careful surveillance to enable early detection of metastasis/recurrence and intervention that is more likely to be successful when metastatic disease burden is low. The DecisionDx-Melanoma report also identifies patients with low-risk disease who can safely forego SLNB.

The information from the DecisionDx-Melanoma test gives insight into the future. As an analogy, imagine having the ability to act on knowledge of when and where a hurricane will hit or how the stock market will perform. Similarly, guided by the DecisionDx-Melanoma test, clinicians can make good decisions for patients, knowing how the individual’s tumor will behave.

TDD: How does the DecisionDx-Melanoma test identify patients who can safely avoid SLNB?

DR. GUENTHER: As demonstrated by results of the DECIDE study, patients whose predicted risk for a positive SLN is <5% can safely avoid undergoing this costly and invasive procedure.1

DECIDE is a prospective study including patients with cutaneous melanoma being considered for SLNB. Within the study cohort, 35 patients with T1-T2 tumors and an i31-GEP predicted risk of SLN positivity of <5% underwent SLNB. None of those 35 patients had a positive SLN. In addition, the study found that all 68 patients in the lowest-risk 31-GEP Class category (Class 1A) were free from recurrence after three years of follow-up.

Studies show that the positivity rate for patients who undergo SLNB for cutaneous melanoma is only about 12%, which means that 88% of the time the SLNB is negative. Applying the result of the DecisionDx-Melanoma test to identify patients who can safely avoid SLNB spares a lot of patients from undergoing the procedure and saves a lot of money.

TDD: How should I manage patients identified as high-risk by DecisionDx-Melanoma but who are node negative?

DR. GUENTHER: The emphasis on management for such patients is on maximizing survivorship, and so they should be followed closely for recurrence because there is clear evidence early detection of recurrence at a time when tumor burden is less leads to better outcomes. I and other leaders in this field recommend in-person examination every three months and radiological surveillance for metastatic disease every six months for four years. The imaging for all patients should consist of a CT scan of the draining nodal basins, chest, and abdomen and also include the pelvis if the primary tumor is in a lower extremity. In addition, I am ordering brain magnetic resonance imaging once a year for high-risk patients, considering data that these individuals have a 14% risk of brain metastasis.2

TDD: What do studies tell us about the utility of the DecisionDx-Melanoma test?

DR. GUENTHER: Studies have all shown that it is highly accurate for predicting outcomes for patients with cutaneous melanoma and that the information it provides has a positive impact on survival for patients with high-risk disease. Plainly said, having information from the DecisionDx-Melanoma test gives high-risk patients the best chance to live.

One of the largest studies assessing the effect of the 31-GEP test on survival of patients with cutaneous melanoma was undertaken as a collaboration between the SEER Program of the National Cancer Institute and Castle Biosciences.3 The results showed that the 3-year overall survival rate was 1.5% higher among patients who had the 31-GEP test compared to a matched group of untested patients (92.4% vs. 90.9%). At face value, the 1.5% difference in overall survival rate does not sound like much, but it is a threefold greater difference than the benefit found for the Oncotype DX breast cancer gene expression assay that led to its inclusion as recommended testing in National Comprehensive Cancer Network Breast Cancer Guidelines.

TDD: How is the DecisionDx-Melanoma test done? Is there a learning curve for interpreting the report?

DR. GUENTHER: The testing process is simple. The order for the test, the patient’s insurance information, and a preprinted letter explaining what the test is for, are transmitted to Castle Biosciences, and the company takes care of the rest. Castle reaches out to the pathology lab to obtain a tumor sample and then performs the testing. The report is generally sent out within three to five days after tissue receipt (within two weeks from the date the order is submitted). The cost is covered by Medicare and most private insurers, and the company offers an industry-leading patient assistance program.

There is a short learning curve for interpreting the information in the test report and applying it to patient care decisions. However, the latter step is straightforward and almost algorithmic so that it is very different from learning a new surgical technique where one needs time to develop new skills. I believe that any physician who does melanoma surgery should be very comfortable using the DecisionDx-Melanoma test almost immediately upon hearing the concept explained and will become more facile integrating it into patient care the more it is used.

DR. GUENTHER: I am not aware of any published data, but it is self-evident that DecisionDx-Melanoma is cost-effective considering its impact for reducing the number of unnecessary SLNBs and improving patient survival. The cost of an SLNB is about $30,000, and so every SLNB avoided would pay for six or seven DecisionDx-Melanoma tests. The cost-effectiveness of the test, however, depends on its effect on reducing the number of unnecessary SLNBs, and the available data for DecisionDx-Melanoma show that when used to inform management decisions, it reduces the number of patients with T1-T2 melanoma who undergo SLNB by 30% to 40%.1

Additional monetary savings come from avoiding unnecessary intensive follow-up with physician visits and costly diagnostic tests for patients identified as having a low risk of metastasis/ recurrence and improving survival of high-risk patients. Furthermore, I believe there is unmeasurable value for accurately identifying low-risk patients by being able to tell them that they have a 99+% likelihood of being cured after surgical removal of the primary tumor. Imagine the psychological and emotional burden that is lifted from these patients and their families by hearing this information.

TDD: What role will GEP testing play in the future for patients with a cutaneous malignancy?

DR. GUENTHER: Physicians need to get comfortable using GEP tests to understand tumor biology, predict outcomes, and guide personalized management decisions because they represent the present and the future for patient care. A test for predicting the risk of squamous cell cancer (SCC) metastasis (DecisionDx-SCC) in patients with one or more risk factors is already available, and others will be coming. SCC is responsible for more deaths annually than melanoma, and there is clear evidence that DecisionDx-SCC has value for informing decisions on need for adjuvant radiation therapy.