Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck

Abstract

Background NUT midline carcinoma (NMC) is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck (HN). HNNMC characteristics and optimal management are unclear. Methods We performed a retrospective review of all known cases of HNNMC in the International NMC Registry, data as of December 31, 2014. Of 48 consecutive patients treated from 1993–2014, clinicopathologic variables and outcomes from 40 patients were available for analyses, the largest cohort of HN NMC studied to date. Overall survival (OS) and progression-free survival (PFS) according to patient characteristics and treatment were analyzed. Results We identified a five-fold increase in diagnosis of HNNMC from 2011 to 2014. Median age was 21.9 years (range 0.1–81.7), male:female was 40%:60%, and 86% had BRD4-NUT fusion. Initial treatment was initial surgery (S) +/− adjuvant chemoradiation (CRT) or adjuvant radiation (RT) (56%), initial RT +/− chemotherapy (C) (15%), or initial C +/− S or RT (28%). Median PFS was 6.6 months (range 4.7–8.4). Median OS was 9.7 months (range 6.6–15.6). Two-year PFS was 26% (95% CI, 13%–40%). Two-year OS was 30% (95% CI, 16%–46%). Initial S +/− post-operative CRT or RT (p=0.04), and complete resection with negative margins (p=0.01) were significant predictors of improved OS even after adjustment for age, tumor size and neck lymphadenopathy. Initial RT or C, and NUT translocation type were not associated with outcome. Conclusions HNNMC portends a poor prognosis. Aggressive initial surgical resection +/− post-operative CRT or RT was associated with significantly enhanced survival. C or RT alone is often inadequate.

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study

“…The head and neck and thorax regions were predilected sites for NUT carcinoma in our study, as in other studies (Table ) . The median age of patients was 48.0 years, which was older than that reported previously (Table ) . Because of its rarity and undifferentiated histology, NUT carcinoma is often misdiagnosed in 61.5% of cases in our series and 50%‐66% of other cases as other tumors, including undifferentiated and poorly differentiated carcinoma, sinonasal undifferentiated carcinoma, and Ewing sarcoma/primary neuroectodermal tumor .…”

“…Similarly, our six patients who underwent upfront surgery survived significantly longer than the others, and two of them with stage IV disease (NC2 and 3) survived for approximately 2 years. Although long‐term remission in response to chemoradiotherapy without surgery was reported in two patients previously , the benefit of chemotherapy or radiotherapy without surgery was unclear . In our patients, the long‐term survivor, NC3 underwent aggressive gross total resection, including metastasectomy plus chemoradiotherapy, which suggests the important role of local modalities in the treatment of advanced NUT carcinoma.…”

“…The median age of patients was 48.0 years, which was older than that reported previously (Table ) . Because of its rarity and undifferentiated histology, NUT carcinoma is often misdiagnosed in 61.5% of cases in our series and 50%‐66% of other cases as other tumors, including undifferentiated and poorly differentiated carcinoma, sinonasal undifferentiated carcinoma, and Ewing sarcoma/primary neuroectodermal tumor . In our archived head and/or neck carcinoma data set, 40% of tumors initially diagnosed as sinonasal undifferentiated carcinoma were subsequently diagnosed as NUT carcinoma .…”

“…Although NUT carcinoma has a dismal outcome (median OS, 4.7‐9.7 months), upfront and intensive local approaches, such as gross total resection and radiotherapy, may provide survival benefits (Table ) . Similarly, our six patients who underwent upfront surgery survived significantly longer than the others, and two of them with stage IV disease (NC2 and 3) survived for approximately 2 years.…”

Plasticity in binding confers selectivity in ligand-induced protein degradation

“…The notion that pharmacological selectivity can be achieved through induced protein-protein interactions distal from the immediate binding site of the small molecule affords new opportunities for the development of target-specific degrader molecules. The ability to selectively degrade BRD4 has potential implications for future drug development efforts since efficacy of BRD4 downregulation has been established for a variety of malignancies 37,38 . While pan BET inhibitors show toxicity, as observed in pre-clinical and clinical studies 39 , it is conceivable that selective degradation of BRD4 will retain efficacy, while significantly reducing pan-BET dependent toxicity for example in NUT midline carcinomas, which uniquely depend on the BRD4-NUT fusion protein.…”