Advancing Understanding and Therapeutic Strategies for NUT Sarcomas: Comprehensive Review of the Literature and Two Cases.

Soft tissue sarcomas (STSs) are a group of rare cancers, among which nuclear protein in testis (NUT) sarcomas represent an ultra-rare subset driven by gene fusions. This article presents two unique cases of NUT sarcomas and conducts a comprehensive review of the literature to include an additional 61 cases. Our review reveals that NUT sarcoma exhibits a slightly higher incidence among women (male-to-female ratio of 1:1.03) and tends to manifest at a relatively young age (median age of 40 years). The most prevalent partner genes were the family in 52% of patients (33 of 63 patients, including [ = 12], [ = 12], [ = 2], and [ = 7]), in 30% of patients ( = 19), and bromodomain (BRD) proteins in 8% of patients ( = 5 patients total, including [ = 4] and [ = 1]). Although 60% of NUT sarcomas (38 of 63 patients) are diagnosed in early stages, half of these patients (19 of 38 patients) experienced relapse despite curative-intent surgery. The median survival of the 21 patients evaluable for survival was 14 months. Finally, among 21 patients who received systemic therapy, only three patients receiving chemotherapy showed disease control, as defined by response or stability of the disease. This article emphasizes the importance of prompt diagnosis through immunohistochemistry and/or next-generation sequencing testing, advocates for the establishment of a NUT sarcoma registry, and emphasizes the need for clinical trials to advance drug development for this rare disease. Delving into a detailed analysis of pathogenesis of the distinct fusions, this article reviews innovative treatment approaches to NUT sarcoma. These strategies include BRD and extraterminal (BET) inhibitors, trabectedin, inhibitors of the EP300 histone acetyltransferase, and histone deacetylase inhibitors such as vorinostat. In the absence of clinical trials, the results from this review suggest that trabectedin-based or ifosfamide-based regimens, particularly in combination with doxorubicin, may offer a reasonable approach as frontline therapy for NUT sarcomas.