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NUT carcinoma is a fast-growing cancer of the midline of the body driven by a single fused gene, BRD4-NUTM1, that locks cells in an immature state. Chemotherapy and surgery rarely control it for long, but drugs that block the BET proteins the fusion depends on have produced responses and are the focus of trials.
NUT carcinoma is a poorly differentiated squamous carcinoma defined by rearrangement of NUTM1 (nuclear protein in testis), most often fused to BRD4 (about 70 percent), otherwise BRD3, NSD3 or ZNF532. The fusion protein tethers NUT's histone acetyltransferase-recruiting domain to BET bromodomains, creating megadomains of hyperacetylated chromatin that drive MYC and SOX2 expression and block squamous differentiation. It was first recognised in the mediastinum of children and young adults but occurs at any age and in the sinonasal tract, lung, and other sites; diagnosis requires NUT immunohistochemistry (highly specific) or fusion testing, and many cases were historically misdiagnosed as undifferentiated carcinoma or sarcoma.
The disease is among the most aggressive human cancers. Multimodality treatment (surgery, radiotherapy and ifosfamide- or platinum-based chemotherapy, Ewing-type regimens) achieves control in a minority, mostly those with localised disease amenable to complete resection and radiotherapy. The International NUT Carcinoma Registry (Brigham and Women's Hospital) has pooled outcomes and shown that initial resection or radiotherapy is associated with longer survival, and that non-BRD4 fusions have a somewhat better course.
Mechanistically the disease is an ideal test of BET inhibition: BRD4-NUTM1 requires bromodomain binding to chromatin. BET inhibitors (molibresib/GSK525762, birabresib/OTX015, ZEN-3694, NUV-868) have produced objective responses and disease stabilisation in NUT carcinoma cohorts of phase 1 and 2 trials, with thrombocytopenia as the dose-limiting toxicity; combination with chemotherapy, CDK9 or HDAC inhibitors, and next-generation BET degraders are the main directions. Rapid, accurate diagnosis is the first intervention that changes outcome.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
Very rare and under-recognised; arises at any age with a median in the twenties, most often in the head, neck and thorax.
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
Same organ: Acinic cell carcinoma of the salivary glands, Carcinoma ex pleomorphic adenoma, Multiple endocrine neoplasia type 1 (MEN1), Multiple endocrine neoplasia type 2 (MEN2A and MEN2B), Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma), Oropharyngeal cancer (tonsil and base of tongue), Laryngeal and hypopharyngeal cancer, Oral cavity cancer (mouth and tongue), Head and neck squamous cell carcinoma, Nasopharyngeal carcinoma, Salivary gland cancers, Papillary thyroid cancer, Follicular thyroid cancer, Medullary thyroid cancer, Anaplastic thyroid cancer, Thyroid cancer, Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), Parathyroid carcinoma, Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), HPV-positive oropharyngeal cancer, HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer), Recurrent or metastatic head and neck squamous cell carcinoma, Hypopharyngeal cancer, Adenoid cystic carcinoma, Salivary duct carcinoma, Mucoepidermoid carcinoma, Oral tongue and floor of mouth cancer, Buccal mucosa and gingivobuccal cancer (oral cancer in India), Lip cancer, Locoregionally advanced nasopharyngeal carcinoma (stage III to IVA), Recurrent and metastatic nasopharyngeal carcinoma, Esthesioneuroblastoma (olfactory neuroblastoma), Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma
Multimodality: complete resection where feasible, radiotherapy, and intensive chemotherapy (ifosfamide-based or platinum-based, often Ewing-type regimens); early referral to a centre with NUT carcinoma experience.
Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy.
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Query for this cancer: (TITLE:"NUT carcinoma" OR ABSTRACT:"NUT carcinoma" OR TITLE:"midline carcinoma with NUTM1 rearrangement" OR ABSTRACT:"midline carcinoma with NUTM1 rearrangement" OR TITLE:"NUT midline carcinoma" OR ABSTRACT:"NUT midline carcinoma" OR TITLE:"Midline tract carcinoma with NUT gene changes" OR ABSTRACT:"Midline tract carcinoma with NUT gene changes" OR TITLE:"NMC" OR ABSTRACT:"NMC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about NUT carcinoma (midline carcinoma with NUTM1 rearrangement), not a curated reading list.
French and colleagues identify the fusion gene.
Haack and colleagues: highly specific antibody enables diagnosis.
Filippakopoulos and colleagues, Nature: proof of concept for BET inhibition.
Birabresib (OTX015) and molibresib phase 1 cohorts.
Chau and colleagues, JCO: fusion partner and initial treatment predict survival.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
The leukaemia risk after chemotherapy was described in the era of mustards and etoposide, and it did not stay there. Platinum drugs carry it, PARP inhibitors raise it about two and a half times against placebo, and lenalidomide with oral melphalan raises it nearly fivefold against melphalan alone. The absolute numbers are small, but the choice of partner drug is sometimes a real decision.
See all on the product pages:CisplatinIfosfamide·Printable cards in the navigator
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