International guidelines on the diagnosis and treatment of NUT carcinoma

Public summary

* BRD4:NUTM1 is the fusion oncogene driver in ∼70% of NUT carcinomas.

* NUT IHC is recommended as an initial screening for malignant tumors exhibiting poorly differentiated phenotype.

* Existing chemotherapy regimens and BET inhibitors have limited efficacy in NUT carcinoma.

* For patients with advanced NUT carcinoma, rational clinical trial combinations should be considered.

Abstract

Nuclear protein in testis (NUT) carcinoma (NC) represents a rare, clinically aggressive cancer defined by pathognomonic NUT Midline Carcinoma Family Member 1 (NUTM1) gene fusions, with bromodomain and extraterminal domain (BET) protein 4 (BRD4)-NUTM1 being the predominant oncogenic driver. Since its description in 1991, gradual advances have clarified the pathologic mechanisms of NC and its diagnostic methods; however, NC treatment remains a significant challenge. Moreover, diagnostic and treatment approaches for this cancer require further validation and standardization. These guidelines were developed by the Chinese Alliance of Research for NC (ChARN) based on current evidence in the literature and incorporate consensus-based input from multiple international experts. They provide comprehensive guidance on NC diagnosis and treatment, covering epidemiology, pathogenesis, diagnostic methods, therapeutic strategies, BET-inhibitor toxicity, palliative care, and prognostic assessment during follow-up. They also emphasize the importance of multidisciplinary team collaboration in NC treatment and recommend prioritizing enrollment in prospective clinical trials for patients. Current mainstays of treatment include surgical resection, radiotherapy, and medical treatment (chemotherapy, targeted therapy, and immunotherapy), although no standard treatment protocol exists. Future research directions include improving diagnostic efficiency, exploring new therapeutic strategies (such as highly selective BET inhibitors, BET-inhibitor combinations, and PROTAC technologies), and recommending basket trials as a research approach for patients with NUTM1 gene fusions.