Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kB signalling, and we observed mutual exclusivity among tumours with somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

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.

IMPORTANCE Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. DESIGN, SETTING, AND PARTICIPANTSIn this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (ՆT2, or clinically node positive) were enrolled between 2016 to 2019.INTERVENTIONS Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2.MAIN OUTCOMES AND MEASURES Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers.RESULTS Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%.CONCLUSIONS AND RELEVANCE Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents.

PURPOSE To provide evidence-based recommendations for practicing physicians and other healthcare providers on the management of salivary gland malignancy. METHODS ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, neuroradiology, pathology, and patient advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2020. Outcomes of interest included survival, diagnostic accuracy, disease recurrence, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 293 relevant studies to inform the evidence base for this guideline. Six main clinical questions were addressed, which included subquestions on preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, and follow-up evaluations. RECOMMENDATIONS When possible, evidence-based recommendations were developed to address the diagnosis and appropriate preoperative evaluations for patients with a salivary gland malignancy, therapeutic procedures, and appropriate treatment options in various salivary gland histologies. Additional information is available at www.asco.org/head-neck-cancer-guidelines .

Background NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. Methods Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). Results For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. Conclusions We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.

Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.

BACKGROUND:The objective of this study was to examine the effects of marital status on stage at presentation, receipt of treatment, and survival in patients with head and neck cancer (HNC). METHODS: The Surveillance, Epidemiology, and End Results database was used to analyze 51,272 patients who were diagnosed with HNC from 2007 to 2010. The impact of marital status on cancer stage at presentation, receipt of definitive treatment, and HNC-specific mortality (HNCSM) was determined using multivariable logistic and Fine and Gray competing-risks regression models, as appropriate. RESULTS: Marriage had a protective effect against metastatic presentation of oral and laryngeal cancers (oral cancer: adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.60-0.87; P <.001; laryngeal cancer: AOR, 0.53; 95% CI, 0.42-0.67; P <.001) but not against oropharyngeal, hypopharyngeal, or nasopharyngeal cancers. Among patients with nonmetastatic disease, married patients were more likely to receive definitive treatment (overall AOR, 1.77; 95% CI, 1.60-1.95; P <.001) and had a lower risk of HNCSM (overall adjusted hazard ratio, 0.72; 95% CI, 0.68-0.77; P <.001); these associations remained significant across all HNC sites. CONCLUSIONS: Among patients with oral and laryngeal cancers, those who are married are less likely to present with metastatic disease. In addition, married patients are more likely to receive definitive treatment and less likely to die from HNC across all HNC sites. This suggests that spousal support may have a role in the surveillance of visual and symptomatic HNC types and leads to higher rates of treatment and better survival across all HNC sites.