The Dermatology Digest • Innovations in Personalized Medicine November/December 2024 Supplement • Decisions, Decisions

Case-based insights on the use of the integrated 31-Gene Expression Profile (i31-GEP) test, also known as DecisionDx-Melanoma, in clinical practice.

A 40-year-old mother with a history of health-related anxiety is diagnosed with her first melanoma. The tumor has a Breslow depth measuring 0.5mm without ulceration or mitotic figures appreciated. Based on the American Joint Committee on Cancer (AJCC) staging alone her tumor would be predicted to have a less than 5% risk of sentinel lymph node (SLN) positivity and would therefore not typically be considered for SLN biopsy; however, there is significant uncertainty in the adequacy of the histologic features to accurately predict her risk of SLN positivity. It is now possible to more accurately prognosticate her risk using additional methods. The current guidelines call for removing the melanoma with 1cm surgical margins with no additional procedures and annual follow-up. The patient, however, was far too anxious to leave anything to chance.

The psychological impact of a melanoma diagnosis is substantial. For this “worried well” patient, more assurances were needed. We ordered the DecisionDx-Melanoma i31-GEP test to classify her risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B).

The test results came back as class 1A, which was fantastic news for this patient and provided her with significant reassurance. Further, the i31-GEP test result provided precise risk scores for the patient’s likelihood of SLN positivity and risk of recurrence. These results confirmed that there was no need for SLN biopsy as the patient was predicted to have a 4% risk of SLN positivity (below the 5% risk threshold for the procedure). The risk of recurrence information reported a 99% chance of recurrence-free survival at five years, confirming the patient’s excellent prognosis without additional surveillance imaging. With the addition of the i31-GEP result, we can tell the patient more than just a generic statement such as “you have a ‘favorable’ prognosis.” We can use this well-validated molecular diagnostic test to reinforce the histopathology with the personalized result of a 99% chance of recurrence-free survival. Every mother would want this type of assurance. In this case, the DecisionDx- Melanoma results gave the patient an added layer of security and peace of mind.

A 65-year-old man received a biopsy report showing that his melanoma tumor was 0.4 mm thick but had a transected base (i.e., the base of a tumor is not fully visible in a single pathology specimen). The exact depth is, therefore, unknown, leading to uncertainty in the adequacy of the histologic features of his tumor to accurately define the patient’s risk of SLN positivity and subsequent risk of recurrence. A surgical oncologist may recommend an SLN biopsy without additional knowledge about the tumor’s characteristics. Alternatively, another surgical oncologist may forego the procedure, assuming that the provisional Breslow depth accurately reflects the depth of invasion. This variation in clinical practice patterns based on clinical and pathologic features alone can lead to potential overtreatment and unnecessary complications or even undertreatment.

In this challenging clinical scenario, we ordered the i31-GEP test, which provides the GEP Class result and the precise integrated risk of SLN positivity and risk of recurrence information to inform our next management decisions. Importantly, the i31-GEP test is performed on the formalin-fixed, paraffin-embedded (FFPE) biopsy specimen used to diagnose invasive melanoma and does not require additional tissue or surgical procedures. We ordered the test because the results will inform our next management decisions. If the test comes back as low-risk GEP result (<5% i31-GEP) for SLN positivity, the patient can safely avoid an unnecessary SLN biopsy, but if the tumor returns a high-risk GEP result (>5% i31-GEP) for SLN positivity, we can discuss and consider the SLN biopsy procedure. If the SLN is performed and is negative, the GEP Class score and i31-GEP for risk of recurrence provide additional prognostic clarity to inform decisions for follow-up frequency, imaging as part of surveillance, and referrals to multidisciplinary care. If the SLN is performed and is positive, then the GEP score continues to add prognostic value and can help refine risk prediction in the context of multidisciplinary conversations for appropriate treatment and follow-up care for a patient with Stage III melanoma. In this case, the test showed the tumor was low-risk Class 1A with a 3.2% SLN positivity. After a conversation with the patient, we decided to avoid the SLNB, and now, four years later, the patient is doing well without any evidence of melanoma recurrence.

A 68-year-old woman undergoes an SLN biopsy for a diagnosis of a non-ulcerated cutaneous melanoma with a Breslow depth of 1.0 mm. More than 80% of SLN biopsy reports come back negative. Still, we know that many of these patients have a greater risk of developing another primary melanoma than they do of having any sort of recurrence or metastasis of the initial melanoma. The guidelines suggest that such patients see their dermatologist for a full-body exam every three to six months in hopes of catching any new melanoma early. This approach, however, leaves a lot to chance as the risk of recurrence may be significantly underestimated for patients with pathologically Stage I-II melanoma (meaning with SLN-negative melanoma).

We ordered the i31-GEP test to learn more about the tumor and to improve the prognostic accuracy for this patient with a pathological Stage IA tumor that is considered “low risk” by AJCC staging. The patient’s i31-GEP test returned a high-risk result (Class 2B). Based on recently published evidence demonstrating the utility of using high-risk i31-GEP test results to inform surveillance imaging for SLN-negative Stage I-II patients, we opted to add surveillance imaging to our prior plan of close clinical follow- up alone. Following the evidence from Dhillon et al,1 we elected to proceed with a computed tomography (CT) scan every six months to look for metastasis for the first three years after diagnosis. On her six-month scan after diagnosis, radiology identified a small nodule in her lung that was subsequently biopsied and found to be a lung metastasis of her melanoma. The identification of this small metastasis was clearly due to the impact of the patient’s GEP test result. The patient was immediately referred to medical oncology and is now receiving immunotherapy. There is clear evidence in other cancers, as well as in melanoma, that cancer recurrences/metastases found at earlier time points with smaller tumor burden have more favorable outcomes. Currently, when clinical management decisions are based only on the risk described by clinical and pathologic factors, the recommendation is only to perform imaging when symptoms are present for patients with Stage I-IIA melanoma. However, the advent of the i31-GEP test gives us the ability to improve the risk stratification of our patients with these early-stage tumors and identify those that may benefit from the addition of surveillance imaging.

Fifteen years ago, this earlier identification of smaller tumors may not have mattered because we didn’t have therapies that could help treat early metastasis. But today we can offer adjuvant and neoadjuvant immunotherapy approaches. The i31-GEP test does not just provide SLN biopsy guidance; it also can help predict a patient’s chances of recurrence and, therefore, guide treatment and management decisions with greater accuracy.

AARON S. FARBERG, MD, Chief Medical Officer and Founder at Bare Dermatology in Dallas, TX, and an Assistant Professor at the University of North Texas Health Science Center, has been working with Castle Biosciences since 2015 and has contributed to the development and validation of their growing suite of gene expression profile tests.

Dr. Farberg shared three cases where the i31-GEP test results helped guide melanoma management and treatment decisions.