Purpose NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the NUT gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations. Experimental Design A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of NMC patients studied to date. Outcome data from 54 patients were available for survival analyses. Results The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (p<0.05). Geographic distribution of NMC patients has been concentrated in the United States (n=41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% CI of 1%–17% (1-year PFS 15% (5%–24%)) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27%–34%). Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome. Conclusions NMC portends a poor prognosis among all squamous cell neoplasms and appears to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival.

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.

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BackgroundPrecision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.MethodsWe utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.ResultsWES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.ConclusionsThis clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0366-0) contains supplementary material, which is available to authorized users.

<div>Abstract<p><b>Purpose:</b> NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the <i>NUT</i> gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations.</p><p><b>Experimental Design:</b> A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses.</p><p><b>Results:</b> The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (<i>P</i> < 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (<i>n</i> = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5–24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27–34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome.</p><p><b>Conclusions:</b> NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. <i>Clin Cancer Res; 18(20); 5773–9. ©2012 AACR</i>.</p></div>

<p>PDF file, 62K, Newly acquired unpublished clinical data for cases previously described by our group.</p>

<p>PDF file, 62K, Newly acquired unpublished clinical data for cases previously described by our group.</p>

<div>Abstract<p><b>Purpose:</b> NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the <i>NUT</i> gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations.</p><p><b>Experimental Design:</b> A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses.</p><p><b>Results:</b> The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (<i>P</i> < 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (<i>n</i> = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5–24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27–34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome.</p><p><b>Conclusions:</b> NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. <i>Clin Cancer Res; 18(20); 5773–9. ©2012 AACR</i>.</p></div>