Abstract 3785: Clinical and genomic characterization of melanoma brain metastases
Authors: Mazzeo Michel Padilla , Walch Henry S. , Kumar Rahul , Eichholz Jordan , Cooper Claire , Nandakumar Nishta , Shen Junchao , Khatri Ishaani , Balzo Luke Del , Skakodub Anna , Miao Emily , Kelly Daniel W. , Yu Kenny Kwok Hei , Wilcox Jessica , Imber Brandon S. , Yu Yao , Yamada Yoshiya , Vasudevan Harish , Ilica Ahmet , Schultz Nikolaus , Pike Luke R. 
Published: March 2024

Abstract
Introduction: Melanoma has a high propensity for brain metastasis (BM). Although advancements in brain-penetrant treatments have resulted in improved central nervous system (CNS) disease control, BMs remain a significant cause of morbidity and mortality. The molecular features of melanoma BM are poorly defined, and there is an unmet need to identify biomarkers associated with CNS-specific outcomes.
Methods: We retrospectively identified 109 patients with melanoma BM who underwent craniotomy at Memorial Sloan Kettering Cancer Center (MSK) between 01/2014 and 04/2023. BM specimens were sequenced using MSK-IMPACT, an FDA-approved next-generation sequencing assay covering 341-505 genes with 700X coverage. Clinical characteristics and CNS-specific outcomes were available from 107 patients; CNS-specific radiographic endpoints were verified through direct inspection of contrast-enhanced MRI imaging by a board-certified neuroradiologist. Clinical data included baseline characteristics, prior systemic or radiotherapy (RT), and CNS-directed follow up including recording local progression of disease (POD), regional POD, and development of leptomeningeal disease (LMD).
Results: Majority (68%,73/107) patients were male with a median age at the time of primary diagnosis of 56 (range 3-88). Forty-eight patients (45%) had advanced disease (stages III and IV) at the time of initial diagnosis. At the time of BM development, half of the patients had 2-5 intracranial tumors present (50%) with a median diameter of largest BM of 33.4mm (range .9mm-64mm). The median KPS was 80 at the time of BM diagnosis, and 79% had neurologic symptoms prior to resection. 81 patients (76%) were treatment naïve at the time of resection and 56 patients (53%) developed CNS recurrence with the majority of those having local POD (29%,16/56) followed closely by regional POD of 1 lesion (25%,14/56). The most frequent genomic alterations in the cohort were TERT (87%), CDKN2A (50%), BRAF (43%), NRAS (28%), and PTEN (25%). The median fraction genome altered was 0.3047 and the median tumor mutational burden was 13.2 muts/Mb. We compared the genomic profiles of BM tumors of patients that had no progression, local POD, regional POD, and LMD. Compared to patients with no progression, patients with local POD were more likely to have RB1 alterations (18.1% vs 2.1%, p = 0.04, q = 0.83) and patients with LMD were less likely to have TERT alterations (62.5% vs 93.8%, p = 0.03, q = 0.75).
Conclusions: Our analysis between genomic markers and clinical outcomes in melanoma BM reveals genomic features which may improve prediction and treatment strategies.
Citation Format: Michel Padilla Mazzeo, Henry S. Walch, Rahul Kumar, Jordan Eichholz, Claire Cooper, Nishta Nandakumar, Junchao Shen, Ishaani Khatri, Luke Del Balzo, Anna Skakodub, Emily Miao, Daniel W. Kelly, Kenny Kwok Hei Yu, Jessica Wilcox, Brandon S. Imber, Yao Yu, Yoshiya Yamada, Harish Vasudevan, Ahmet Ilica, Nikolaus Schultz, Luke R. Pike. Clinical and genomic characterization of melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3785.