Analyses of clinical and biologic determinants of melanoma bone metastasis (Mel-Bone).

e21503 Background: Mel-Bone represents a clinical challenge due to its known association with pain and pathological fractures. While bone metastases occur as frequently as brain metastases in stage IV melanoma (40-50% of cases), their clinicopathological and molecular characteristics remain largely understudied. Methods: We studied Mel-Bone patients treated at NYU Langone Health (2002-2023) and enrolled in a prospective biospecimen clinicopathological database. We examined the association between Mel-Bone characteristics (site, number, and radiological patterns) and overall survival (OS) using Kaplan-Meier and Cox regression. We also analyzed radiological changes of Mel-Bone over time in response to treatment. To better understand the molecular alterations associated with Mel-Bone progression, we compared RNAseq profiling of metastatic lymph nodes tissues (LNs) among 3 groups (progressed to the bone, to other distant sites, or did not progress to distant sites). We also performed Digital Spatial Profiling (DSP) on matched pairs of primary and Mel-Bone tissues. Differentially expressed genes were identified using a threshold of logFC > 0.5 and Benjamini-hochberg adjusted p-value < 0.05. Immunohistochemical (IHC) analysis of tissue microarrays (TMAs) generated from Mel-Bone and non-melanoma bone metastases tissues were examined to validate transcriptomic findings and identify Mel-Bone-specific features. Results: We identified 233 patients who developed Mel-Bone during active follow-up. 79/233 (37%) were symptomatic at presentation and 168 (73%) had multiple Mel-Bone. Imaging studies revealed that the majority of patients (77%) had osteolytic lesions, while 8% had osteosclerotic, and 15% had mixed lesions. Patients with Mel-Bone confined to the peripheral skeleton had significantly lower mortality risk (HR = 0.41, 95% CI: 0.26-0.66, p < 0.001) and higher rate of complete resolution on imaging post-treatment compared to those with axial or combined lesions (p < 0.01). Patients with a solitary bone lesion (27%) or isolated Mel-Bone with no extraosseous metastases (6.4%) had significantly improved OS (p < 0.0001 or p < 0.001, respectively). DSP revealed significant upregulation of vascular endothelial growth factor A (VEGFA) in Mel-bone tissues compared to their matched primary tissues (p < 0.0001). VEGFA was upregulated in LNs that metastasized to bone versus LNs that metastasized to other organs (p = 0.02). VEGFA was also overexpressed in Mel-Bone compared to non-melanoma Bone metastases (p < 0.001). Conclusions: Our data reveal distinct clinical and radiological features associated with diverse clinical courses of Mel-Bone that can impact patient prognosis and inform treatment strategies. The data also support a role of VEGFA upregulation in the progression of melanoma to bone. Mechanistic investigations are underway to determine the impact of inhibiting VEGFA on the course of Mel-Bone.