High-risk Head And Neck Squamous Cell Carcinoma Research Articles

Deciphering a Prognostic Signature Based on Soluble Mediators Defines the Immune Landscape and Predicts Prognosis in HNSCC.

The study on Head and Neck Squamous Cell Carcinoma (HNSCC), a prevalent and aggressive form of head and neck cancer, focuses on the often-overlooked role of soluble mediators. The objective is to leverage a transcriptome-based risk analysis utilizing soluble mediator-related genes (SMRGs) to provide novel insights into prognosis and immunotherapy efficacy in HNSCC patients. We analyzed the expression and prognostic significance of 10,859 SMRGs using 502 HNSCC and 44 normal samples from the TCGA-HNSC cohort in The Cancer Genome Atlas (TCGA). The samples were divided into training and test sets in a 7:3 ratio, with an additional external validation using 40 tumor samples from the International Cancer Genome Consortium (ICGC). Key differentially expressed genes (DEGs) with prognostic significance were identified through univariate and Lasso-Cox regression analyses. A prognostic model based on 20 SMRGs was developed using Lasso and multivariate Cox regression. We assessed the clinical outcomes and immune status in high-risk (HR) and low-risk (LR) HNSCC patients utilizing the BEST databases and single-sample Gene Set Enrichment Analysis (ssGSEA). The 20 SMRGs were crucial in predicting the prognosis of HNSCC, with the SMRG signature emerging as an independent prognostic indicator. Patients classified in the HR group exhibited poorer outcomes compared to those in the LR group. A nomogram, integrating clinical characteristics and risk scores, demonstrated substantial prognostic value. Immunotherapy appeared to be more effective in the LR group, possibly attributed to enhanced immune infiltration and expression of immune checkpoints. The model based on soluble mediator-associated genes offers a fresh perspective for assessing the pre-immune efficacy and showcases robust predictive capabilities. This innovative approach holds significant promise in advancing the field of precision immuno-oncology research, providing valuable insights for personalized treatment strategies in HNSCC.

A novel immune-related prognostic model with surgical status to predict tumor immune cell infiltration and drug sensitivity in head and neck squamous cell carcinoma

Tumor-infiltrating immune cells (TICs) affect tumorigenesis and tumor development in head and neck squamous cell carcinoma (HNSCC). We constructed a novel predictive model for HNSCC based on immune-related genes (IRGs) from The Cancer Genome Atlas and the Immunology Database and Analysis Portal. After identifying the IRGs, a predictive model involving 13 IRGs with high stratification value of overall survival (OS) was constructed by multiple support vector machine recursive feature elimination and least absolute shrinkage and selection operator regression. We explored the relationship between the risk score (RS) and clinical characteristics. The nomogram showed high concordance and good agreement in OS. Four TICs affected the OS and were in agreement with the abundance analysis of the RS levels. Furthermore, the low-risk HNSCC group showed higher expression of PD-1, CTLA4, and TIGIT, while the high-risk group showed higher expression of EGFR. The high-risk HNSCC showed high sensitivity to eight drugs.

Circulating Cell-Free SEPT9 DNA Methylation in Blood Is a Biomarker for Minimal Residual Disease Detection in Head and Neck Squamous Cell Carcinoma Patients.

Tumorous SEPT9 (septin 9, SEPTIN9) circulating cell-free DNA (ccfDNA) methylation in blood plasma is a powerful biomarker for diagnosis, molecular staging, prognosis, and recurrence monitoring in head and neck squamous cell carcinoma (HNSCC) patients. The present study aimed to evaluate the clinical performance of SEPT9 ccfDNA methylation to detect post-surgical minimal residual disease (MRD) in patients with localized or locally advanced HNSCC treated with curative intent. We applied quasi-digital methylation-specific real-time PCR to quantify SEPT9 ccfDNA methylation levels 2 to 30 days post-surgically in plasma from n = 219 prospectively enrolled HNSCC patients. We tested the associations of SEPT9 ccfDNA methylation with clinicopathological parameters and used Kaplan-Meier and Cox proportional hazards analyses for univariate, pairwise bivariate, and multivariate analyses of disease-free survival. Of 219 patients, 26.5% (58/219) were post-surgically SEPT9 ccfDNA methylation positive. SEPT9 ccfDNA methylation positivity was significantly associated with tumor site, American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC; 8th edition) tumor stage, nodal category and extracapsular extension, lymphatic and vascular invasion, and surgical margin. Bivariate Cox proportional hazards analysis proved post-surgical SEPT9 ccfDNA methylation positivity to be an independent prognostic factor tested together with AJCC/UICC tumor stage (SEPT9: hazard ratio [HR] = 2.43, 95% CI, 1.37-4.30, P = 0.002; AJCC/UICC stage: HR = 1.48, 95% CI, 1.11-1.98, P = 0.008). Post-surgical SEPT9 ccfDNA methylation may aid to identify high-risk HNSCC patients who could benefit from an intensified adjuvant treatment and surveillance.

Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery will be eligible. Two hun-dred forty patients will be randomly assigned (1:1) to either standard aRCT with cisplatin (standard arm) or aRCT with cisplatin + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months) (interventional arm). Endpoints are event-free and overall survival. Recruitment started in August 2018 and is ongoing.

Identification of a Prognostic Pyroptostic-Related Model for Head and Neck Squamous Cell Carcinoma Based on LASSO-Cox Regression Analysis.

Pyroptosis is associated with the biological behavior of the tumor and with tumor immunity. We investigated the effect of pyroptosis on the tumor microenvironment and tumor immunity in head and neck squamous cell carcinoma (HNSCC). RNA sequencing data and clinical information of HNSCC were downloaded from TCGA. Differentially expressed pyroptosis-related genes in HNSCC were identified between HNSCC and normal tissue. Pyroptosis-related classification of HNSCC was conducted based on consensus clustering analysis. LASSO-Cox regression analysis was used to construct a prognostic risk model-based pyroptosis-related gene. Evaluation of the immune microenvironment was conducted in prognostic risk signature based on pyroptosis-related genes. Total 22 differentially expressed pyroptosis-related genes were identified in HNSCC. Six prognostic-related genes were included to construct a LASSO regression model with a prognostic risk score = (0.133 ∗ GSDME (DFNA5) + 0.084 ∗ NOD1 + 0.039 ∗ IL6 + 0.003 ∗ IL1B + 0.084 ∗ CASP3 + 0.028 ∗ NLRP2). Higher fraction of resting memory CD4+ T cells and macrophages M1 was infiltrated in the high-risk group compared with the low-risk group in HNSCC. Furthermore, the PI3K-Akt signaling pathway and the IL-17 signaling pathways were identified to be involved in the development of high-risk HNSCC. Our study constructed a prognostic risk signature based on pyroptosis-related genes, which emphasizes the critical importance of pyroptosis in HNSCC and provided a novel perspective of HNSCC therapy.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504

Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

707TiP Postoperative adjuvant radiochemotherapy (aRCH) with cisplatin versus aRCH with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma: The ADRISK trial

PD-1 immune checkpoint inhibitors have been approved for treatment of head and neck squamous cell carcinoma (HNSCC) in recurrent/metastatic settings as they significantly improve patients’ overall survival (OS). The next step is to explore the efficacy of immune checkpoint inhibitors in the curative setting, especially in patients with locoregional, pathologically intermediate and high-risk HNSCC which recur frequently despite adjuvant cisplatin-based radiochemotherapy (aRCH). Based on this rationale, we have developed the ADRISK trial to investigate the addition of pembrolizumab to standard aRCH in the treatment of patients with locally advanced intermediate- and high-risk HNSCC. Given the unmet need for reducing high rates of relapse in this patient group by improved adjuvant treatment, we expect that ADRISK will provide new insights into treatment and might demonstrate the ability of pembrolizumab to improve survival. ADRISK is a prospective, multicenter, randomized controlled phase II trial within the German Interdisciplinary Study Group of German Cancer Society. Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery who are eligible for cisplatin-based aRCH after surgery will receive either standard aRCH with cisplatin versus the same treatment + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months). The objectives are to show that addition of pembrolizumab to postoperative adjuvant cisplatin-based RCH improves event-free survival and OS compared with aRCH alone in locally advanced intermediate and high-risk HNSCC. To our knowledge, this is the only multicenter, randomized trial analyzing the addition of pembrolizumab to aRCH in this patient group without prior neoadjuvant treatment. Recruitment started in August 2018 and is ongoing. Until April 2022, 163 patients were registered for the trial and 157 patients were randomized. The planned sample size is 240 patients, the recruitment is estimated to be completed by July 2024 at the latest. NCT03480672. University of Leipzig.

A Novel 2-Metagene Signature to Identify High-Risk HNSCC Patients amongst Those Who Are Clinically at Intermediate Risk and Are Treated with PORT.

Simple SummaryThe aim of this matched-pair study including patients with locally advanced head and neck squamous cell carcinoma (HNSCC) was to identify patients who are biologically at high risk for the development of loco–regional recurrences after surgery and postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors, with the help of a novel predictive gene signature. These patients may benefit from treatment with postoperative radiochemotherapy (PORT-C). Based on 108 matched patient pairs treated with PORT and PORT-C, we identified a gene signature consisting of two metagenes. A significant association of the interaction between the risk classification by this signature and the type of treatment was observed for the endpoint loco–regional control (LRC), i.e., the 2-metagene signature was indicative for the type of treatment. The developed signature may thus help to identify high-risk patients currently treated with PORT, who may benefit from additional concurrent chemotherapy.(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.

Abstract CT182: Phase I trials of personalized cancer vaccine TG4050 in surgically treated high-risk head and neck squamous cell carcinoma (HNSCC) and relapsing ovarian cancer (OvC) patients

Abstract Background: Cancer mutations acquired during carcinogenesis are not subject to central tolerance and thus, are cornerstone in cancer immunosurveillance. The use of mutation-derived neoepitopes to design cancer vaccines is an unprecedented opportunity to target efficient antigens, but the stochastic occurrence of mutations implies that a tailored vaccine needs to be designed and manufactured for each patient. We used next generation sequencing, machine learning based genomic data analysis and advances in genome editing to systematically identify private neoepitopes in high-risk HPV negative HNSCC and relapsing OvC patients. Methods: Mutations were identified by DNA and RNA sequencing and putative epitopes were selected for vaccine design on their likelihood to elicit a class I or II response based on HLA binding, allelic frequency, prediction of processing and expression at RNA level. The vaccine was a recombinant virus of the modified Vaccinia Ankara (MVA) strain encoding for up to 30 sequences of 29 amino acids centred on the predicted epitope and flanked with the normal germline sequence in case of missense mutations, and of the mutated protein sequence in case of frameshift mutations. The viral vaccine was amplified under GMP conditions and administered to patients after curative intent treatment in two phase I trials. Treatment was started for OvC patients at relapse defined as elevation of CA-125 or onset of suspicious radiological findings and, after first line therapy for HNSCC patients with locally advanced disease with either extracapsular extension or positive resection margins following upfront surgery. The vaccine was administered for 6 weeks and a booster dose every three weeks over a year, in absence of other cancer therapy. Results: Six patients (4 OvC and 2 HNSCC) were treated and experienced only mild related adverse events. After 6 doses of vaccine, we measured immunoreactive T cells in PBMCs against each of the targeted epitopes using an ex vivo IFNγ ELISPOT showed robust responses in all evaluable patients. Positive responses to vaccination were observed for a total of 46 epitopes over 115 tested with a median of 11 epitopes (6 to 18) per patient. Responses were directed against both class I and II epitopes and were either de novo responses (64%) or amplification of pre-existing responses (36%). In parallel, phenotyping of patient PBMCs showed, in all treated patients, a decline in naïve CD4 and CD8 cells and the onset of effector CD27- CD4 and CD27-/CD57+ CD8; similarly, CD56dim NK cells increased suggesting a stimulation of antitumor innate immunity. In one ovarian cancer patient, these immune changes correlated with a normalization of CA-125 that lasted 7 months. Conclusions: These data show that the personalized approach with TG4050 is feasible, safe and immunogenic. The two phase I trials are ongoing. Citation Format: Matthew S. Block, Jean-Pierre Delord, Christian H. Ottensmeier, Christophe Le Tourneau, Ana Lalanne, Olivier Lantz, Keith L. Knutson, Gisèle Lacoste, Annette Tavernaro, Maud Brandely, Nathalie Silvestre, Benoit Grellier, Yoshiko Yamashita, Onoue Kousuke, Naoko Yamagata, Eric Quemeneur, Kaidre Bendjama. Phase I trials of personalized cancer vaccine TG4050 in surgically treated high-risk head and neck squamous cell carcinoma (HNSCC) and relapsing ovarian cancer (OvC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT182.

Nodal Metastasis Count and Oncologic Outcomes in Head and Neck Cancer: A Secondary Analysis of NRG/RTOG 9501, NRG/RTOG 0234, and EORTC 22931

A better understanding of the relationship between the spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LNs) and the frequency and manner of treatment failure should help design better treatment intensification strategies. In this study, we evaluated the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LNs in HNSCC in 3 prospective randomized controlled trials. We performed a secondary analysis of 947 patients with HNSCC enrolled in RTOG 9501 (n = 410), RTOG 0234 (n = 203), and EORTC 22931 (n = 334) undergoing surgery and postoperative radiation ± systemic therapy. Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), locoregional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN number and outcomes. In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 +LNs (OS: hazard ratio [HR], 1.21 per +LN; 95% confidence interval [CI], 1.10-1.34; P < .001; DFS: HR per +LN, 1.19; 95% CI, 1.08-1.30; P < .001) and more gradually beyond this (OS: HR per +LN, 1.02; 95% CI, 1.01-1.06; P < .001; DFS: HR per +LN, 1.04; 95% CI, 1.02-1.06; P < .001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.28; 95% CI, 1.10-1.50; P < .001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.96-1.04; P = .98), DM risk increased continuously with increasing +LNs (≤5 +LNs: HR per +LN, 1.10; 95% CI, 1.01-1.20; P = .04; >5 +LNs: HR per +LN, 1.05; 95% CI, 1.02-1.08; P = .003). In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LNs, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments.

OShnscc: a novel user-friendly online survival analysis tool for head and neck squamous cell carcinoma based on RNA expression profiles and long-term survival information.

Head and neck squamous cell carcinoma (HNSCC), as the most common type (>90%) of head and neck cancer, includes various epithelial malignancies that arise in the nasal cavity, oral cavity, pharynx, and larynx. In 2020, approximately 878 ‍ 000 new cases and 444 000 deaths linked to HNSCC occurred worldwide (Sung et al., 2021). Due to the associated frequent recurrence and metastasis, HNSCC patients have poor prognosis with a five-year survival rate of 40%-50% (Jou and Hess, 2017). Therefore, novel prognostic biomarkers need to be developed to identify high-risk HNSCC patients and improve their disease outcomes.

A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma

Background: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis and immune escape of cancers. This study aimed to investigate NET-related genes, their clinical prognostic value and their correlation with immunotherapy and anticancer drugs in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Differentially expressed NET-related genes in HNSCC were identified based on multiple public databases. To improve the clinical practicability and avoid overfitting, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were used to construct a prognostic risk model. A nomogram was further used to explore the clinical value of the model. Internal and external validation were conducted to test the model. Furthermore, the immune microenvironment, immunophenoscore (IPS) and sensitivity to anticancer drugs in HNSCC patients with different prognostic risks were explored. Results: Six NET-related genes were screened to construct the risk model. In the training cohort, Kaplan–Meier (K-M) analysis showed that the overall survival (OS) of low-risk HNSCC patients was significantly better than that of high-risk HNSCC patients (p < 0.001). The nomogram also showed a promising prognostic value with a better C-index (0.726 vs 0.640) and area under the curve (AUC) (0.743 vs 0.706 at 3 years, 0.743 vs 0.645 at 5 years) than those in previous studies. Calibration plots and decision curve analysis (DCA) also showed the satisfactory predictive capacity of the nomogram. Internal and external validation further strengthened the credibility of the clinical prognostic model. The level of tumor mutational burden (TMB) in the high-risk group was significantly higher than that in the low-risk group (p = 0.017), and the TMB was positively correlated with the risk score (R = 0.11; p = 0.019). Moreover, the difference in immune infiltration was significant in HNSCC patients with different risks (p < 0.05). Furthermore, the IPS analysis indicated that anti-PD-1 (p < 0.001), anti-CTLA4 (p < 0.001) or combining immunotherapies (p < 0.001) were more beneficial for low-risk HNSCC patients. The response to anticancer drugs was also closely correlated with the expression of NET-related genes (p < 0.001). Conclusion: This study identified a novel prognostic model that might be beneficial to develop personalized treatment for HNSCC patients.

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity.

Simple SummarySquamous cell carcinoma (SCC) is the most prevalent type of human cancer worldwide and represents the majority of head and neck tumors. As SCC from aerodigestive or genitourinary tracts share not only common etiology and histological features but also molecular patterns, the major objectives of this study were the establishment of a pan-SCC-related prognostic gene signature by an integrative analysis of multi-omics data and the elucidation of underlying oncogenic pathway activities as potential vulnerabilities for a more efficient and less toxic therapy. Our approach delivers a reliable molecular classifier to identify HNSCC and other SCC patients at higher risk for treatment failure with tumors characterized by a more prominent MAPK activity, who might benefit from a targeted treatment with MEK inhibitors.Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer, including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified 37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort (n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups. The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection Operator Cox regression model and were used to identify subgroups with high or low risks for unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2, FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib) as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion, our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who might benefit from treatment with MEK inhibitors.

Lymphatic drainage map of the head and neck skin squamous cell carcinoma detected by sentinel lymph node biopsy.

Squamous cell carcinoma of the skin often affects the scalp and neck region and has a potential for complex lymphatic metastases. The aim of this study was to examine the pattern of lymphatic drainage that would enable better insight and prediction of lymphatic metastasis of head and neck squamous cell carcinoma (HNSCC) in relation to the anatomical localization of the primary process. A prospective analysis included 64 patients who underwent sentinel lymph node (SLN) biopsy. The biopsy was performed in patients with high-risk cutaneous head and neck squamous cell carcinoma between 2006 and 2010. SLNs in tumors of the forehead, temporal region, lateral cheek, and auricle were found in the cervical region at level II and parotid lymph nodes (p<0.001). In tumors of the nose, periorbital region, and postauricular tumors, SLNs were found in parotid lymph nodes (p<0.001), in tumors of the medial cheek in level I cervical lymph nodes and parotid lymph nodes (p=0.003). In tumors of the neck, SLNs were detected in the cervical region at level IV, whereas in tumors of the posterior scalp they were found in the occipital region (p<0.001). The results of SLN biopsy in high-risk cutaneous HNSCCs show the regularity of metastasis based on which a lymphatic drainage map can be constructed and thus potential metastatic sites depending on the primary tumor localization predicted.

NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

Simple SummaryThe anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma. Patients with locoregional, pathologically high-risk disease recur frequently despite adjuvant cisplatin–radiation therapy. Targeting PD1 may reverse immunosuppression induced by cancer, chemotherapy, or radiation therapy. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule for adding fixed-dose pembrolizumab to standard adjuvant cisplatin–radiation therapy. Eligible patients had resected, human papillomavirus-negative, stage III–IV oral cavity, pharynx, or larynx cancer with extracapsular nodal extension or positive margin. A total of four dose-limiting toxicities were observed in 34 patients (fever, wound infection, diverticulitis, nausea). Three of four were successfully rechallenged with pembrolizumab. The recommended phase II schedule was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before adjuvant CRT. The regimen was safe and feasible in the cooperative group setting. Further development is warranted.The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

Current landscape of immunotherapy trials in locally advanced and high-risk head and neck cancer.

The current standard of therapy for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) is limited by toxicity and suboptimal control. The role of immunotherapy (IO) is being evaluated in the LA setting. This review aims to summarize the recent advances and the direction of clinical trials in IO in LA or high-riskHNSCC. Despite negative results in some studies, several early phase trials suggest the feasibility and efficacy of IO-based strategies in LA or high-risk HNSCC. Further refining of patient selection and biomarker development is warranted for successful incorporation of IO in this patient population.

Combined Inhibition of Rad51 and Wee1 Enhances Cell Killing in HNSCC Through Induction of Apoptosis Associated With Excessive DNA Damage and Replication Stress.

Despite advances in surgery, chemotherapy, and radiation, there are limited treatment options for advanced head and neck squamous cell carcinoma (HNSCC) and survival remains very poor. Therefore, effective therapies are desperately needed. Recently, selective exploitation of DNA damage and replication stress responses has become a novel approach for cancer treatment. Wee1 kinase and Rad51 recombinase are two proteins involved in regulating replication stress and homologous recombination repair in cancer cells. In this study, we investigated the combined effect of Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) in vitro and in vivo in various HNSCC cell lines. Clonogenic survival assays demonstrated that B02 synergized with AZD1775 in vitro in all HNSCC cell lines tested. The synergy between these drugs was associated with forced CDK1 activation and reduced Chk1 phosphorylation leading to induction of excessive DNA damage and replication stress, culminating in aberrant mitosis and apoptosis. Our results showed that elevated Rad51 mRNA expression correlated with worse survival in HNSCC patients with HPV-positive tumors. The combination of B02 and AZD1775 significantly inhibited tumor growth in vivo in mice bearing HPV-positive HNSCC tumors as compared to HPV-negative HNSCC. This differential sensitivity appears to be linked to HPV-positive tumors having more in vivo endogenous replication stress owing to transformation by E6 and E7 oncogenes. Furthermore, addition of B02 radiosensitized the HPV-negative HNSCC tumors in vitro and in vivo In conclusion, our data implicate that a novel rational combination with Rad51 and Wee1 inhibitors holds promise as synthetic lethal therapy, particularly in high-risk HPV-positive HNSCC.

High Dose-Rate Brachytherapy in Recurrent High-Risk Head and Neck Cancer

Background: Thirty to fifty percent of HNSCC patients treated with chemoradiation therapy present with recurrence and can be treated with maximum debulking surgery combined with re-irradiation. Re-irradiation can be done using external beam radiation therapy (EBRT) or brachytherapy. The advantage of brachytherapy over EBRT is that owing to rapid dose falls off, a higher dose can be delivered to the target area sparing normal tissue. Hence, we evaluated toxicity and outcomes [overall survival (OS) and disease-free survival (DFS)] in high-risk (HR) recurrent HNSCC patients undergoing re-irradiation using interstitial brachytherapy following surgery. Objectives: To evaluate toxicity and outcomes of re-irradiation using Interstitial High Dose-Rate Brachytherapy (HDR-BRT) in high-risk Head and Neck Squamous Cell Carcinoma (HNSCC) patients. Methods: Ten biopsy-proven recurrent HNSCC patients treated with primary chemoradiation therapy who had the HR of the second recurrence at nodal disease were evaluated. All patients underwent surgery followed by the intraoperative placement of catheters in a single plane, at 10 - 12 mm apart and fixed with stay sutures. The CT simulation was done on the 5th - 7th postoperative day. Volumetric optimization was done with a 5-mm dwell position. The dose of 30 Gy/10 Fractions, 3 Gy/Fraction, two fractions per day, 6 hours apart after 5 days was planned. Results: The DFS and OS for the entire cohort in 1 and 2 years were 60% and 40%, respectively. One patient had carotid blowout where the disease was stuck to the carotid vessel. No other significant acute or late toxicity was noted. Conclusions: The HDR-interstitial brachytherapy in the recurrent HR, HNSCC with the intraoperative placement of catheters at tumor bed provides reasonably good local control without significant acute or late toxicity.

MiR-125a-5p Functions as Tumor Suppressor microRNA And Is a Marker of Locoregional Recurrence And Poor prognosis in Head And Neck Cancer

MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer. However, the role of miR-125a-5p has not been fully investigated in head and neck squamous cell carcinoma (HNSCC). We performed microRNA microarray profiling of HNSCC tumor samples obtained from a prospective clinical trial evaluating the role of postoperative radiotherapy in head and neck cancer. We also mined through The Cancer Genome Atlas to evaluate expression and survival data. Biological experiments, including cell proliferation, flow cytometry, cell migration and invasion, clonogenic survival, and fluorescent microscopy, were conducted using HN5 and UM-SCC-22B cell lines. miR-125a-5p downregulation was associated with recurrent disease in a panel of high-risk HNSCC and then confirmed poor survival associated with low expression in HNSCC via the Cancer Genome Atlas, suggesting that miR-125a-5p acts as a tumor suppressor miRNA. We then demonstrated that miR-125a-5p regulates cell proliferation through cell cycle regulation at the G1/S transition. We also show that miR-125a-5p can alter cell migration and modulate sensitivity to ionizing radiation. Finally, we identified putative mRNA targets of miR-125a-5p, including ERBB2, EIF4EBP1, and TXNRD1, which support the tumor suppressive mechanism of miR-125a-5p. Functional validation of ERBB2 suggests that miR-125a-5p affects cell proliferation and sensitivity to ionizing radiation, in part, through ERBB2. Our data suggests that miR-125a-5p acts as a tumor suppressor miRNA, has potential as a diagnostic tool and may be a potential therapeutic target for the management and treatment of squamous cell carcinoma of the head and neck.

NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (Pembrolizumab) in high-risk head and neck squamous cell carcinoma (HNSCC).

6023 Background: Pembrolizumab, an anti-PD1 monoclonal antibody, improves survival in advanced HNSCC. Patients with pathologic high risk, HPV-negative HNSCC have a high recurrence rate despite adjuvant cisplatin-IMRT (CRT), the current standard. Immunosuppression is induced by HNSCC and CRT, and may be reversible by targeting PD1. Methods: We conducted a phase I trial with expansion cohort to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to adjuvant CRT (NCT02775812). Eligibility: oral cavity, pharynx, or larynx primary; HPV-negative; pathologic high risk (positive margin or extranodal extension [ENE]); Zubrod 0-1. During phase I, patients enrolled in descending cohorts of 12 (Table). RP2S was declared if ≤ 3 dose-limiting toxicities (DLT) occurred. DLT was defined as ≥ Grade 3 non-hematologic adverse event (AE) related to pembrolizumab, immune-related (ir)AE requiring &gt; 2 weeks of systemic steroids, or unacceptable delay in IMRT. The expansion cohort enrolled 20. Results: From Nov 2016-Oct 2018, 34 eligible patients enrolled at 22 NRG institutions. During the first cohort, 1 DLT was observed (Grade 3 fever). RP2S was declared as Schedule 3 and the expansion cohort triggered. Among all 34 patients, median age was 60 years (26-83); 68% were male; 74% had Zubrod 1; 85% had oral cavity; 88% had ENE; 21% had positive margin. During expansion, 3 additional patients with DLT were observed: wound infection; diverticulitis; nausea. No DLT unacceptably delayed IMRT. Twenty-eight of 34 (82%) received ≥ 5 doses of pembrolizumab; 17 (50%) got all 8 doses. Thirty-one of 32 (97%) DLT-evaluable patients received all adjuvant RT; 1 withdrew consent after starting protocol. Conclusions: The RP2S is pembrolizumab 200 mg IV q 3 weeks for 8 doses, starting the week before adjuvant CRT. This regimen was safe and feasible in a cooperative group setting. irAE were rare in this population. Clinical trial information: NCT02775812. [Table: see text]