Abstract 3931: BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort

Abstract Background: NUT rearrangements drive NUT carcinomas (NCs), which are rare, poorly differentiated tumors with a survival from diagnosis of ~6-7 months. Common NUT fusion partners (NCFPs) include BRD4, BRD3, NSD3, and ZNF532, which are associated with epigenetic changes leading to tumor growth. Recent clinical trials have aimed to address NCs, but little is known about fusions involving NCFPs in other histologies. We characterized NCFPs in a large, pan-cancer cohort. Methods: The MSK-IMPACT (DNA sequencing; n=71,423) and MSK-Fusion (RNA sequencing; n=10,897) clinical cohorts were mined to identify patients (pts) with all forms of structural variants (SVs) involving NCFPs, detected between April, 2015 and June, 2022. The targeted NGS panels included BRD4 and NSD3 only; detection of BRD3 and ZNF532 SVs was possible for fusions with a partner present on either panel. SVs were manually reviewed to identify in-frame fusions with oncogenic potential if critical domains present in NC fusions were conserved. Pts were followed through July 2022 and manual chart review enabled assessment of treatment history and clinical outcomes. Results: SVs involving NCFP genes were detected in 182 (BRD4=110, NSD3=61, BRD3=8 and ZNF532=3) pts (0.002%). Putative NCFP fusions not involving any of the NUT gene family members comprised a total of 20 fusions with likely oncogenic potential including 11 with BRD4 (55%), 5 with NSD3 (25%), 3 with ZNF532 (15%), and 1 with BRD3 (5%). BRD4::NOTCH3 and ZNF532::MALT1 were the most enriched fusions, present in 3 samples each. The most common histologies were breast (3 ductal; 1 lobular), lung (2 squamous cell carcinoma, 1 adenocarcinoma and 1 mixed histology), and colon and esophageal adenocarcinoma (2 samples each). Median age at diagnosis was 62. 11 (55%) pts were female and 9 (45%) were male. 13 (65%) pts ultimately were diagnosed with stage IV disease and had a median overall survival from stage IV diagnosis of 2.5 years (95% CI: 1.41, NR). DNA sequencing in 19/20 tumors revealed a mean tumor mutational burden (TMB) of 5.0 mut/Mb including 15 with low TMB (<10) and 3 with high TMB (>10). No tumor showed microsatellite instability (MSI-high). TP53 mutations were the most common co-alteration, found in 11 (58%) cases. 18/20 pts received systemic therapy; 18 (90%) received cytotoxic chemotherapy and/or mAb therapy, including 13 (65%) who received a platinum. 8 pts (40%) received immunotherapy (IO), and 4 (20%) received small molecule inhibitors. No pts received BET inhibitors. Among pts who received IO, median time to treatment discontinuation was 64 days (95% CI: 20, NR). Conclusion: Tumor sequencing from a large cohort reveals potential oncogenic fusions involving BRD4, BRD3, NSD3, and ZNF532 across multiple histologies. Further biological characterization of their oncogenicity and potential targetability is warranted. Citation Format: Ian R. Nykaza, Christopher A. Febres-Aldana, Sabrina T. Lin, Ryma Benayed, Kerry Mullaney, Emiliano Cocco, Alexia Iasonos, Marc Ladanyi, Alexander E. Drilon, Yonina R. Murciano-Goroff. BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3931.