Gene Expression Profile Testing for Thin Melanoma

Abstract

Cutaneous melanoma incidence in the US is increasing, with an estimated 96 480 cases in 2019 compared with 47 700 in 2000 (https://seer.cancer.gov). Most cutaneous melanomas are limited to the skin (84%), defined as stage I or II disease by the American Joint Committee on Cancer. 1 For all stages combined, 5-year mortality rate is 7.8%, but mortality is more likely when cutaneous melanoma has metastasized to lymph nodes or organs (stage III or IV). 1 Thin melanomas, defined here as thickness of 1.0 mm or less (T1), include T1a (<0.8 mm thick, no ulceration) and T1b tumors (<0.8 mm thick with ulceration or 0.8-1.0 mm thick with or without ulceration); together they constitute approximately 70% of cutaneous melanomas. 1 Recommended treatment for both T1a and T1b tumors, according to National Comprehensive Cancer Network (NCCN) guidelines, is wide local excision. Sentinel lymph node (SLN) metastases at the time of melanoma diagnosis are more common in T1b disease (5%-10%) compared with T1a disease (<5%). 1,2 For that reason, NCCN guidelines recommend considering SLN biopsy (SLNB) only for T1b melanomas or for T1a melanomas with adverse features (high mitotic index, Ն2 mitoses/mm 2 [particularly in patients younger than 40 years old]; lymphovascular invasion;oracombinationofthesefactors). 1,3 Althoughstudies have provided guidance, the decision to proceed with SLNB in thin melanomas is not clear cut. If a noninvasive test could identify patients at high risk for metastasis, leading to a management plan that improved outcomes, then lives could be saved.A proprietary 31-gene expression profile (GEP) assay (Castle Biosciences) has been developed in an attempt to address this clinical dilemma. This assay uses quantitativereversetranscriptase-polymerasechainreactiontechniques on RNA extracted from formalin-fixed, paraffinembedded biopsy specimens to determine expression levels of reported genes associated with melanoma metastasis. Gene expression levels are used to stratify patients according to risk of future metastatic disease, with class 1A having lowest risk, class 1B/2A having intermediate risk, and class 2B having high risk. According to company-set parameters, patients with stage I/II disease have 5-year distant metastasis-free survival (DMFS) rates of 97% and 65% for class 1A and 2B, respectively. The ultimate goals are to help clinicians use risk categories to (1) determine whether to perform SLNB and (2) consider the intensityoffollow-up,referrals,andimaging.Assessingthe clinical utility of 31-GEP testing requires rigorous evaluation of whether the test accomplishes those goals, as well as consideration of disadvantages.The majority of published studies evaluating 31-GEP testing have been retrospective studies or prospective cohort studies without a comparator group. 4 In one study, VIEWPOINT

The Use of Gene Expression Profiling and Biomarkers in Melanoma Diagnosis and Predicting Recurrence: Implications for Surveillance and Treatment

“…There remains significant controversy in the role of GEP for melanoma prognostication, which have been articulated in numerous editorials [31,32,[61][62][63]. There is consensus that there is considerable opportunity to improve melanoma prognostication, especially among thin melanomas (<0.8 mm) and stage II/III melanomas with the aim of identifying patients in these cohorts with lower risk tumors that may not require invasive procedures or a strict surveillance schedule and conversely, identifying a high-risk cohort that will benefit from aggressive treatment or closer surveillance that would not receive either based on AJCC staging [31,32,61]. Ideally, randomized trials where patients are assigned to treatment groups based on the results of GEP tests are needed to truly understand how these test results should be interpreted.…”

Advances in melanoma: epidemiology, diagnosis, and prognosis

“…While clinicians believe that GEP testing may have clinical benefit for patients with stage II and IIIA disease, the controversy has been for testing patients with stage I disease, a group with a very low risk of recurrence and metastasis (128). As stage I disease make up over 70% of new cases melanoma each year in the US, the test has the potential for high utilization for this stage of the disease, which has raised concerns about the high cost of the test ($7,193 per test) with unknown clinical benefit at this time (132). Meta-analysis by Marchetti and coworkers have concluded the performance of GEP tests for stage I disease was poor and highlighted the potential harm for patients in this group (127,133).…”

“…Currently, the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) do not endorse the routine use of GEP. To settle the issue of validity and clinical applicability, authors have recommended prospective randomized clinical trial with predetermined end points free of industry sponsorship bias (128,132,133,136).…”

Overview of genetic signaling pathway interactions within cutaneous malignancies

“…A recent article believes that the testing should not be done on people with thin melanomas if there is no evidence on change of outcome and treatment plan. Once further studies on 31-GEP testing are done, the evidence of effectiveness in thin melanomas will be apparent [192] .…”