1067 - Evaluation of Genomic and Pathologic Features Associated with Outcomes among Patients with Sentinel Lymph Node-Positive Melanoma in the Contemporary Era

S. O. Dudzinski¹, A. Farooqi², S. Roy², A. J. Bishop², D. Swanson², P. Nagarajan³, R. Amaria², J. McQuade², R. Weiser², S. Fisher², M. I. Ross², B. A. Guadagnolo², and D. Mitra²; ¹Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ²The University of Texas MD Anderson Cancer Center, Houston, TX, ³Department of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX

Purpose/Objective(s): Outcomes for melanoma patients with nodal disease have improved with advances in systemic therapy. Previous genomic studies have shown melanoma patients with mutations in TERT and/or ATRX that enable replicative immortality through telomere maintenance have poor outcomes. However, these studies predate the contemporary era and focus on patients with advanced disease. Therefore, we sought to evaluate whether mutations activating telomere maintenance or other cell growth pathways (i.e NRAS and BRAF) were prognostic for outcome among patients with sentinel lymph node (SLN) positive disease. Materials/

Methods: We identified patients with primary cutaneous melanoma at our institution who had SLN biopsy (SLNB) between 3/2016 and 3/2023 and genomic testing within 60 days, prior to relapse. Testing was performed using a PCR-based next-generation sequencing platform focused on an institutional gene panel. Mutational status of TERT/ATRX was compared using 2-tail Fischer’s exact test for single variables and Pearson’s test for grouped variables. Time-to-event analyses were calculated from SLNB date by the Kaplan Meier method with Log-Rank testing for univariate predictors of outcome.
Results: We identified 438 patients with SLN+ disease; 198 of these had upfront genomic testing. 84 patients (42%) had TERT/ATRX mutations, 93 (47%) had BRAF mutations, and 25 (13%) had NRAS mutations. There were no significant differences in patient, disease or treatment characteristics between the wild type and TERT/ATRX mutant cohorts except patients with TERT/ATRX mutations had more frequent primary tumors in the head and neck (31% vs. 12%, p=0.003) and lentigo maligna histology (14% vs. 1%, p=0.0001). There were no significant differences in nodal control (NC), distant-metastasis free survival (DMFS), and disease-free survival (DFS) by TERT/ATRX, BRAF, or NRAS mutational status. However, pathologic risk factors for poor prognosis were validated with worse DFS in the context of Breslow thickness >4 mm (2yr DFS 50% vs. 72%, p=0.003), microsatellitosis (2yr DFS 41% vs. 73%, p=0.0006), lymphovascular invasion (2yr DFS 55% vs. 72%, p=0.009), >1 mm nodal deposit size (2yr DFS 59% vs. 73%, p=0.004), and extracapsular extension (ECE, 2yr DFS 52% vs. 68%, p=0.0007). Similar factors were predictive of NC and DMFS.
Conclusion: Among melanoma patients with SLN+ disease, we did not find an association between disease outcomes and the presence of TERT/ATRX, BRAF, or NRAS mutations. However, pathologic features such as larger nodal disease burden and ECE continue to predict for worse outcomes and can be used to guide adjuvant treatment decisions. Whether treatment intensification with adjuvant nodal RT for high-risk SLN+ patients may improve outcomes is currently being tested on the NCT04594187 “MelPORT” randomized prospective clinical trial.