Squamous Cell Carcinoma Of The Head And Neck Patients Research Articles

KDM5B promotes metastasis and epithelial-mesenchymal transition via Wnt/β-catenin pathway in squamous cell carcinoma of the head and neck.

Metastasis determines clinical management decision and restricts the therapeutic efficiency in patients with squamous cell carcinoma of the head and neck (SCCHN). Epigenetic factor KDM5B serves as an oncogene in multiple cancers. However, its role in SCCHN metastasis remains unclear. Our previous study showed that KDM5B is significantly elevated in SCCHN tissue and is positively correlated with metastasis and recurrence. KDM5B overexpression predicted a poor prognosis in both disease-free survival and overall survival, which served as an independent prognostic factor in SCCHN patients. This study further investigates the exact impact of KDM5B in metastasis of SCCHN. We found that KDM5B knockdown significantly inhibits the migration and invasion of SCCHN cells both in vitro and in vivo. On the contrary, forced expression of KDM5B leads to enhanced migration and invasion, accompanied by canonical alterations of epithelial-mesenchymal transition (EMT). Mechanism investigations demonstrated that KDM5B activates Wnt/β-catenin pathway, and inhibition of Wnt/β-catenin pathway via a small molecule inhibitor iCRT-14 partially reverses the enhanced migratory and invasive ability caused by KDM5B in SCCHN cells. Together, our data indicate that KDM5B promotes EMT and metastasis via Wnt/β-catenin pathway in SCCHN, suggesting that KDM5B may be a potential therapeutic target and prognosis biomarker in SCCHN.

Identification of an 8 HPV-related RNA signature as a novel prognostic biomarker for squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is a commonly detected cancer worldwide. Human papillomavirus (HPV) is emerging as an important risk factor affecting SCCHN prognosis. Therefore, identification of HPV status is essential for effective therapies in SCCHN. The aim of this study was to investigate the prognostic value of HPV-associated RNA biomarkers for SCCHN. The clinical data, survival data, and RNA-seq data of SCCHN were downloaded from The Cancer Genome Atlas database. Before the differential expression analysis, the heterogeneity between the 2 groups (HPV+ vs HPV-) of samples was analyzed using principal component analysis. The differentially expressed genes (DEGs) between HPV+ and HPV- SCCHN samples were analyzed using the R edgeR package. The Gene Ontology functional annotations, including biological process, molecular function and cellular component (CC), and Kyoto Encyclopedia of Genes And Genomes pathways enriched by the DEGs were analyzed using DAVID. The obtained matrix was analyzed by weighed gene coexpression network analysis. A total of 350 significant DEGs were identified through differential analysis, and these DEGs were significantly enriched in functions associated with keratinization, and the pathway of neuroactive ligand-receptor interaction. Moreover, 72 hub genes were identified through weighed gene coexpression network analysis. After the hub genes and DEGs were combined, we obtained 422 union genes, including 65 survival-associated genes. After regression analysis, a HPV-related prognostic model was established, which consisted of 8 genes, including Clorf105, CGA, CHRNA2, CRIP3, CTAG2, ENPP6, NEFH, and RNF212. The obtained regression model could be expressed by an equation as follows: risk score = 0.065 × Clorf105 + 0.012 × CGA + 0.01 × CHRNA2 + 0.047 × CRIP3 + 0.043 × CTAG2-0.034 × ENPP6 - 0.003 × NEFH - 0.068 × RNF212. CGA interacted with 3 drugs, and CHRNA2 interacted with 11 drugs. We have identified an 8 HPV-RNA signature associated with the prognosis of SCCHN patients. Such prognostic model might serve as possible candidate biomarker and therapeutic target for SCCHN.

Nivolumab in Squamous Cell Carcinomas of the Head and Neck (SCCHN): A Real-world Outcome Study in Ontario, Canada.

The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic/advanced squamous cell carcinomas of the head and neck (SCCHN). We evaluated the outcomes of SCCHN patients in Ontario, Canada, treated with nivolumab through retrospective review of the provincial treatment registry. Kaplan-Meier method was used to estimate overall survival (OS) and Cox regression to evaluate the prognostic effect of selected factors. Nivolumab was used as second-line therapy after disease relapse for curative-intent platinum chemotherapy (PC) (indication 1-I1), as second-line therapy post-PC in noncurative intent (indication 2-I2), and as first-line therapy in noncurative intent due to contraindication for PC (indication 3-I3). The median OS for patients treated with nivolumab was 5.8 months (95% CI: 4.5-7.3), and the 1-year OS was 28.4% (CI: 2.10-36.1). When patients with I3 were excluded to match inclusion criteria for CheckMate-141, median OS was 4.8 months (CI: 3.6-6.7) with 1-year OS of 21.8% (14.4-30.1). Patients with lower body surface area (BSA) (<1.81) had a median OS of 3.9 months (CI: 3.1-6.7) versus 9.0 months (CI: 6.5-14.8) in those with higher BSA, hazard ratio (HR)=0.12 (CI: 0.04-0.39, P <0.001). Patients receiving nivolumab for I1 had a median OS of 7.2 months (CI 3.8-9.8) versus 11.9 months (CI: 6.2-not reached) for I3, HR=1.73 (CI: 0.94-3.16). Patients receiving nivolumab for I2 had a median OS of 3.9 months (CI: 2.9-5.4) as compared with I3, HR=3.27 (CI: 1.80-5.94). Real-world analysis of patients with advanced/metastatic SCCHN in Ontario, Canada, treated with nivolumab demonstrates poorer median OS compared with CheckMate-141 trial. Lower BSA was a predictor of poorer median OS.

Does Dual-Energy Computed Tomography Material Decomposition Improve Radiomics Capability to Predict Survival in Head and Neck Squamous Cell Carcinoma Patients? A Preliminary Investigation.

Our study objective was to explore the additional value of dual-energy CT (DECT) material decomposition for squamous cell carcinoma of the head and neck (SCCHN) survival prognostication. A group of 50 SCCHN patients (male, 37; female, 13; mean age, 63.6 ± 10.82 years) with baseline head and neck DECT between September 2014 and August 2020 were retrospectively included. Primary tumors were segmented, radiomics features were extracted, and DECT material decomposition was performed. We used independent train and validation datasets with cross-validation and 100 independent iterations to identify prognostic signatures applying elastic net (EN) and random survival forest (RSF). Features were ranked and intercorrelated according to their prognostic importance. We benchmarked the models against clinical parameters. Intraclass correlation coefficients were used to analyze the interreader variation. The exclusively radiomics-trained models achieved similar ( P = 0.947) prognostic performance of area under the curve (AUC) = 0.784 (95% confidence interval [CI], 0.775-0.812) (EN) and AUC = 0.785 (95% CI, 0.759-0.812) (RSF). The additional application of DECT material decomposition did not improve the model's performance (EN, P = 0.594; RSF, P = 0.198). In the clinical benchmark, the top averaged AUC value of 0.643 (95% CI, 0.611-0.675) was inferior to the quantitative imaging-biomarker models ( P < 0.001). A combined imaging and clinical model did not improve the imaging-based models ( P > 0.101). Shape features revealed high prognostic importance. Radiomics AI applications may be used for SCCHN survival prognostication, but the spectral information of DECT material decomposition did not improve the model's performance in our preliminary investigation.

Radiomics for therapy-specific head and neck squamous cell carcinoma survival prognostication (part I)

BackgroundTreatment plans for squamous cell carcinoma of the head and neck (SCCHN) are individually decided in tumor board meetings but some treatment decision-steps lack objective prognostic estimates. Our purpose was to explore the potential of radiomics for SCCHN therapy-specific survival prognostication and to increase the models’ interpretability by ranking the features based on their predictive importance.MethodsWe included 157 SCCHN patients (male, 119; female, 38; mean age, 64.39 ± 10.71 years) with baseline head and neck CT between 09/2014 and 08/2020 in this retrospective study. Patients were stratified according to their treatment. Using independent training and test datasets with cross-validation and 100 iterations, we identified, ranked and inter-correlated prognostic signatures using elastic net (EN) and random survival forest (RSF). We benchmarked the models against clinical parameters. Inter-reader variation was analyzed using intraclass-correlation coefficients (ICC).ResultsEN and RSF achieved top prognostication performances of AUC = 0.795 (95% CI 0.767–0.822) and AUC = 0.811 (95% CI 0.782–0.839). RSF prognostication slightly outperformed the EN for the complete (ΔAUC 0.035, p = 0.002) and radiochemotherapy (ΔAUC 0.092, p < 0.001) cohort. RSF was superior to most clinical benchmarking (p ≤ 0.006). The inter-reader correlation was moderate or high for all features classes (ICC ≥ 0.77 (± 0.19)). Shape features had the highest prognostic importance, followed by texture features.ConclusionsEN and RSF built on radiomics features may be used for survival prognostication. The prognostically leading features may vary between treatment subgroups. This warrants further validation to potentially aid clinical treatment decision making in the future.

206P Characterization of the immune microenvironment of recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) that progress on or after platinum and anti-PD(L)1 therapies: An EORTC IMMUcan sub-project

R/M SCCHN patients that progress after platinum therapy and PD-1 inhibitors represent an unmet medical need. A better characterization of the tumor molecular landscape and immune micro-environment is needed to guide the rational development of new therapeutic approaches.

Reiterative modeling of combined transcriptomic and proteomic features refines and improves the prediction of early recurrence in squamous cell carcinoma of head and neck

BackgroundPatients with squamous cell carcinoma of the head and neck (SCCHN) have a high-risk of recurrence. We aimed to develop machine learning methods to identify transcriptomic and proteomic features that provide accurate classification models for predicting risk of early recurrence in SCCHN patients. MethodsClinical, genomic, transcriptomic and proteomic features distinguishing recurrence risk were examined in SCCHN patients from The Cancer Genome Atlas (TCGA). Recurrence within one year after treatment was classified as high-risk and no recurrence as low-risk. ResultsNo significant differences in individual clinicopathological characteristics, mutation profiles or mRNA expression patterns were seen between the groups using conventional statistical analysis. Using the machine learning algorithm, extreme gradient boosting (XGBoost), ten proteins (RAD50, 4E-BP1, MYH11, MAP2K1, BECN1, NF2, RAB25, ERRFI1, KDR, SERPINE1) and five mRNAs (PLAUR, DKK1, AXIN2, ANG and VEGFA) made the greatest contribution to classification. These features were used to build improved models in XGBoost, achieving the best discrimination performance when combining transcriptomic and proteomic data, providing an accuracy of 0.939 and an Area Under the ROC Curve (AUC) of 0.951. ConclusionsThis study highlights machine learning to identify transcriptomic and proteomic factors that play important roles in predicting risk of recurrence in patients with SCCHN and to develop such models by iterative cycles to enhance their accuracy, thereby aiding the introduction of personalized treatment regimens.

Nivolumab in squamous cell carcinomas of the head and neck (SCCHN): A real-world outcome study in Ontario, Canada.

e18017 Background: The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic squamous cell carcinomas of the head and neck (SCCHN). We evaluated outcomes of SCCHN patients in Ontario, Canada treated with nivolumab since its funding through the New Drug Funding Program (NDFP) of Cancer Care Ontario (CCO). Methods: Retrospective review using the provincial treatment registry (CCO NDFP) was undertaken. Patient characteristics, reason for treatment, treatment length, and date of death were collected. Kaplan-Meier method was used to estimate overall survival and Cox regression to evaluate prognostic effect of selected factors. Results: 134 patients with SCCHN received nivolumab between March 2017 and March 2019. Median patient age was 63 years with 80.6% male. Nivolumab was used as second-line therapy after disease relapse within 6 months of curative-intent platinum chemotherapy (PC) in 39.6% of patients (Indication 1 – I1), used as second-line therapy post PC in non-curative intent in 42.6% of patients (Indication 2 – I2), and used as first-line therapy in non-curative intent due to contraindication for PC in 17.2% of patients (Indication 3 – I3). Median overall survival (mOS) was 5.8 months (95% confidence intervals (CI) 4.5-7.3), and one-year OS was 28.4% (CI 2.10-36.1). HPV status had no statistically significant impact on OS (p = 0.12). Patients with a lower BSA (&lt; 1.81) had median OS of 3.9 months (CI 3.1-6.7) versus 9.0 months (CI 6.5-14.8) in those with higher BSA, HR = 0.12 (CI 0.04-0.39, p &lt; 0.001). Differences between indications was statistically significant (p &lt; 0.001). Patients who received nivolumab for I1 had mOS 7.2 months (CI 3.8-9.8) versus 11.9 months (CI 6.2-not reached) for I3, HR = 1.73(CI 0.94-3.16). Patients who received nivolumab for I2 had mOS 3.9 months (CI 2.9-5.4) as compared to I3, HR = 3.27(CI 1.80-5.94). Patients who received nivolumab for I2 had poorer mOS as compared to I1 HR = 1.90(CI 1.23-2.92). Conclusions: Real world data in Ontario demonstrates poorer mOS, but similar 1-year survival compared to CheckMate-141 trial. HPV status had no significant impact on mOS. Patients who received nivolumab as first-line therapy in the non-curative setting appeared to have longer mOS than those who received initial PC for non-curative intent followed by nivolumab. Patients who received nivolumab as second-line therapy post PC in non-curative intent setting as compared to within 6 months of curative-intent therapy had poorer mOS.

Positive impact of oncology nurse navigation based on health insurance in head and neck cancer patients.

e18545 Background: Health disparity in squamous cell carcinoma of the head and neck (SCCHN) is well-recognized. Privately insured SCCHN patients are observed to have better outcomes, but underlying factors are poorly understood. Oncology nurse navigators (ONN) are a well-established role focused on optimizing cancer care and patient experience. The effects of ONN on bridging health disparities have not been demonstrated. We sought to characterize health and outcome disparities in patients diagnosed with oropharyngeal cancers and to assess if the implementation of ONN bridges gaps in health disparities. Methods: Patients aged &gt;18 diagnosed with node positive, non-metastatic oropharyngeal cancers at a large hybrid academic-community cancer center between June 2018 and September 2021 were analyzed retrospectively. Baseline demographic, socioeconomic and clinicopathologic factors including the frequency and percentage of patients receiving ONN were summarized. Clinical outcomes were assessed as a function of baseline factors and ONN. Overall survival (OS) and progression free survival (PFS) were evaluated with Kaplan Meier methods. Results: 184 patients were evaluated. Median age at diagnosis 62 (range 33-91). Median follow-up 24 months. The majority were HPV+ (73%). Navigation received in 64%. More males presented with cN1+ disease than females (57% v. 37%; p = 0.053). More Black patients presented with cN1+ disease than White patients (76% v. 50%; p = 0.017). More privately insured patients (92%) went to imaging after definitive treatment versus those with Medicaid (MD)/Self-pay (SP) (78%) or Medicare (MC)/Veteran’s affairs (VA) (78%) (p = 0.043), while more navigated patients went to imaging after definitive treatment than non-navigated patients (70% v. 40%; p = 0.003). Univariate modeling indicated clinical nodal stage, HPV status, race, and insurance status were associated with OS and PFS. In multivariable modeling adjusted for age, nodal stage, and HPV status, there was a disparity in OS associated with insurance type (MD/SP v. Private: HR 9.24, 95% CI = 2.34 to 36.41 and MC/VA; p = 0.004). There was a significant interaction of navigation and insurance type (p = 0.0157). In those not navigated, a difference in hazards exists between MD/SP or MC/VA compared with private insurance. This difference was not detected in those navigated. Similar interaction of navigation and insurance was noted in the analysis of PFS. Conclusions: We observed a disparity in patients with non-private insurance having an inferior PFS, OS and reduced rates of imaging after definitive treatment. An improved rate of post-treatment imaging was significantly associated with ONN. There was a trend towards benefit in outcomes for those receiving ONN but without private insurance suggesting that ONN may help mitigate disparities in the non-private insurance groups.

Concordance, Correlation, and Clinical Impact of Standardized PD-L1 and TIL Scoring in SCCHN.

Simple SummaryIn patients with relapsed or metastasized squamous cell cancer of the head and neck (R/M SCCHN), the PD-L1 Combined Positive Score (CPS) is currently the only predictive biomarker for treatment with anti-PD-1 agents. However, ambiguous results have been determined regarding the overall response rates of immunotherapeutic agents based on PD-L1 status, which may be partially attributed to spatiotemporal heterogeneity. Furthermore, tumor-infiltrating lymphocytes (TILs) have proven to be of significant prognostic value, yet lack of a standardized method for quantification impedes their integration into the current armamentarium of biomarkers in SCCHN. In this paper, concordance of PD-L1 CPS and stromal TILs was investigated in different paired samples of SCCHN subtypes. The results were then linked to well-known clinicopathological variables and prognosis.Background: The clinical significance of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression has been thoroughly researched in squamous cell carcinoma of the head and neck (SCCHN). To address the impact of intra- and intertumoral heterogeneity in these biomarkers, we explored the concordance of PD-L1 combined positive score (CPS) and stromal TILs in different paired tissue sample types, while evaluating their internal relationship and prognostic impact. Methods: A total of 165 tissue blocks from 80 SCCHN patients were reviewed for TILs and PD-L1 CPS. Concordance between paired tissue samples was evaluated, and their association with several clinicopathological variables, overall survival (OS), and disease-free survival (DFS) was determined. Results: Biopsies and paired resection material were severely discordant in 39% and 34% of samples for CPS and TIL count, respectively, of which CPS was underscored in 27% of biopsies. In paired primary tumor–metastatic lesions, the disagreement was lower for CPS (19%) but not for TIL count (44%). PD-L1 CPS was correlated with prolonged OS when calculated from tissue acquirement, while extended OS and DFS were observed for high TIL density. Conclusion: Intertumoral and, especially, intratumoral heterogeneity were confounding factors when determining PD-L1 CPS and TIL count on paired tissue samples, indicating the increasing necessity of assessing both biomarkers on representative tissue material. Although TILs hold valuable prognostic information in SCCHN, the robustness of PD-L1 as a biomarker in SCCHN remains ambiguous.

Efficacy and Safety of Tisotumab Vedotin in Patients with Head and Neck Squamous Cell Carcinoma: Results From a Phase II Cohort

<h3>Purpose/Objective(s)</h3> Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. <h3>Materials/Methods</h3> In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. <h3>Results</h3> Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. <h3>Conclusion</h3> TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209).

Institutional Comparison between Radiation with Concurrent Cisplatin Versus Carboplatin/paclitaxel for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

<h3>Purpose/Objective(s)</h3> For SCCHN patients receiving definitive chemoradiation or adjuvant chemoradiation, cisplatin is the standard systemic agent. Carboplatin/paclitaxel has been considered as an alternative in cisplatin-ineligible patients. No head-to-head trials have been conducted comparing the two regimens. We present a retrospective single institution data comparing the two regimens in the definitive and post-operative setting. <h3>Materials/Methods</h3> Patients with SCCHN who received at least one dose of cisplatin or carboplatin/paclitaxel were included. We assessed locoregional control (LRC), overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and safety. Descriptive statistics, Kaplan Meier method, Cox proportional hazards model through both univariate and multivariable analysis (MVA) were used. <h3>Results</h3> Among 308 patients, 157 received carboplatin/paclitaxel and 151 received cisplatin. IMRT (90.6%) was primarily utilized and the median total dose of radiation was 70 Gy. Majority were male (78.6%) and Caucasian (76.3%) with a median age of 63. Oropharynx was the most common primary tumor site (53.2%) with 84.7% being HPV positive. Ninety-seven patients (31.5%) underwent surgery; more carboplatin/paclitaxel (34.0%) patients had positive margins versus cisplatin (16%) patients (p = 0.04). Most of the cisplatin patients received weekly 40 mg/m² (78.8%) and the median cumulative cisplatin dose was 240 mg/m². A majority of patients received carboplatin AUC 2 and paclitaxel 45 mg/m² with a median cumulative paclitaxel dose of 270 mg/m². More patients in the carboplatin/paclitaxel (68.2%) group had T3/T4 disease versus cisplatin (55.6%) patients (p = 0.024). By MVA, no statistically significant differences were observed for LRC or OS. However, carboplatin/paclitaxel significantly improved DMFS [HR 0.49 (0.24-0.99) p=0.048] with a 5 year DMFS of 86.5% versus 77.2% in the cisplatin group. A trend favoring carboplatin/paclitaxel was seen for PFS [HR 0.62 (0.36-1.08) p = 0.09]. In the subgroup of surgical patients, DMFS [HR 0.39 (0.14-1.08) p = 0.071] and PFS [HR 0.41 (0.17-0.94) p=0.036] favored carboplatin/paclitaxel. Carboplatin/paclitaxel had higher grade 3/4 toxicities for leukopenia, anemia, and dermatitis and more feeding tube placements and hospitalizations. <h3>Conclusion</h3> Carboplatin/paclitaxel is comparable to cisplatin and may be more beneficial in the post-operative setting. A prospective, randomized trial is needed to determine whether carboplatin/paclitaxel is non-inferior or even superior to cisplatin and to better characterize its safety profile.

Microenvironment-driven intratumoral heterogeneity in head and neck cancers: clinical challenges and opportunities for precision medicine.

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive biomarkers and new therapeutic strategies for personalized clinical management of SCCHN patients. Targeting the SCCHN-associated microenvironment or the interaction of the latter with cancer cells may represent such paradigm shift in the development of new strategies to treat SCCHN patients, as exemplified by the recent implementation of immune checkpoint inhibitors to improve clinical outcomes by increasing anti-tumor immune responses in SCCHN patients. Several clinical trials are in progress in SCCHN patients to evaluate the activity of monoclonal antibodies and small-molecule inhibitors targeting the tumor microenvironment (TME) at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. This review describes the current knowledge about the influence of the TME on intratumoral heterogeneity and clinical relapse in human SCCHN patients. More precisely, the role of hypoxia as well as the presence of non-cancer cells (e.g. cancer-associated fibroblasts and immune cells) on therapy response of SCCHN cells is highlighted. We also discuss relevant (pre)clinical models that may help integrate the microenvironment-tumor cell interplay in translational research studies for SCCHN. Finally, this review explores potential therapeutic strategies that may exploit the crosstalk between TME and SCCHN cells in order to implement fundamental changes in the tumor treatment paradigm of patients with locally advanced or R/M SCCHN.

Photodynamic therapy for squamous cell carcinoma of the head and neck: narrative review focusing on photosensitizers.

This narrative review aimed to evaluate the effectiveness of PDT in early or advanced squamous cell carcinoma of the head and neck (SCCHN). Scopus, MEDLINE/PubMed, and Embase were searched electronically following the PRISMA protocol. Quality assessment was performed according to JBI, NIH, and AMSTAR protocols. The main outcomes evaluated were treatment response, recurrence, survival, and adverse effects. A total of 49 articles met the search criteria: 43 case series, two cohort studies, two prospective before-after clinical trials, one systematic review, and one meta-analysis. Data from 2121 SCCHN patients were included. The response to PDT was variable according to the type of photosensitizer, tumor location, and tumor stage. In general, higher complete responses rated were observed in T1/T2 SCCHN, mainly with mTHPC-mediated PDT. With regard to T3/T4 or advanced SCCHN tumors, there is no compelling evidence suggesting the effectiveness of PDT. Any adverse effects reported were well tolerated by patients. The present review suggests that PDT is a promising treatment modality for early-stage SCCHN. Although there are limitations due to the low level of evidence of the included studies, we believe that the present review could help to design robust clinical trials to determine the efficacy of PDT in SCCHN.

Prognostic Matrisomal Gene Panel and Its Association with Immune Cell Infiltration in Head and Neck Carcinomas.

Simple SummarySquamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous group of tumors arising from squamous cells lining different anatomic sites. This type of malignancy has been mainly investigated by focusing primarily on tumor cells, but recent evidence highlighted the importance of the tumor microenvironment (TME) in cancer growth, progression and metastasis. Hence, we hypothesized that dysregulated matrisomal components could have a common association with patient survival, irrespective of the subsite of origin of the SCCHN. Using bioinformatic methods and public datasets, we successfully identified a gene panel with prognostic value in HPV-negative and non-metastatic node-negative tumors and demonstrated its association with immune cell infiltration.Squamous cell carcinoma of the head and neck (SCCHN) is common worldwide and related to several risk factors including smoking, alcohol consumption, poor dentition and human papillomavirus (HPV) infection. Different etiological factors may influence the tumor microenvironment and play a role in dictating response to therapeutics. Here, we sought to investigate whether an early-stage SCCHN-specific prognostic matrisome-derived gene signature could be identified for HPV-negative SCCHN patients (n = 168), by applying a bioinformatics pipeline to the publicly available SCCHN-TCGA dataset. We identified six matrisome-derived genes with high association with prognostic outcomes in SCCHN. A six-gene risk score, the SCCHN TMI (SCCHN-tumor matrisome index: composed of MASP1, EGFL6, SFRP5, SPP1, MMP8 and P4HA1) was constructed and used to stratify patients into risk groups. Using machine learning-based deconvolution methods, we found that the risk groups were characterized by a differing abundance of infiltrating immune cells. This work highlights the key role of immune infiltration cells in the overall survival of patients affected by HPV-negative SCCHN. The identified SCCHN TMI represents a genomic tool that could potentially aid patient stratification and selection for therapy in these patients.

Optimizing brief, focused assessment of priority symptoms and concerns in recurrent and/or metastatic squamous cell carcinoma of the head and neck: Content validation of the Functional Assessment of Cancer Therapy/National Comprehensive Cancer Network Head and Neck Symptom Index-10 (FHNSI-10).

Background and AimsPatients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) experience vast disease and treatment burdens. Brief, focused instruments are needed to assess patient‐reported priority symptoms and concerns as targeted outcome assessments for use in clinical research. Although the instrument was developed based on expert and patient input and is psychometrically valid, the Functional Assessment of Cancer Therapy (FACT)/National Comprehensive Cancer Network (NCCN) Head and Neck Symptom Index‐10 (FHNSI‐10) has yet to undergo content validation from the perspective of R/M SCCHN patients to evaluate its use as a brief symptom‐focused targeted endpoint assessment for use in clinical research.MethodsInterviews conducted with R/M SCCHN patients explored priority symptoms and concerns, followed by cognitive debriefing of the FHNSI‐10 to evaluate face validity. Transcripts were analyzed, and results were mapped to the FHNSI‐10. In accordance with published recommendations, expert input from the original development and published literature was considered for content validity assessment.ResultsA total of 18 patients participated in a concept elicitation interview; saturation was obtained at interview 17. Most (83%) were undergoing active treatment, male (94%), white (72%), and did not have a college degree (67%). The most commonly mentioned symptoms were lumps/swelling, pain, sore throat, difficulty swallowing, and voice changes. For all items, ≥75% reported each question was relevant to their R/M SCCHN experience and 94% reported the instrument captured their experiences with R/M SCCHN.ConclusionResults provide support for the content validity of the FHNSI‐10, inasmuch as all 10 items were spontaneously reported and considered relevant to R/M SCCHN. Content validity might be enhanced by adding cough and hearing impairment items; however, the existing FHNSI‐10 covers the majority of symptoms uncovered in interviews with a small sample of R/M SCCHN patients.

CETUXIMAB: A POTENTIALLY UNDER RECOGNIZED ETIOLOGY OF SUDDEN CARDIAC DEATH

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Certain medications have been linked to an increased risk of sudden cardiac death through varying mechanisms. Herein, we describe a case of a cardiac arrest where cetuximab was presumed the culprit. CASE PRESENTATION: A 58-year-old female with a history relevant for TxN3bM0 squamous cell carcinoma of the neck on chemoradiation therapy was transferred to the hospital after having a cardiac arrest while receiving cetuximab. She presented earlier to the cancer center with no complaints. During cetuximab infusion, she had a cardiac arrest (pulseless electrical activity). She was resuscitated per ACLS guidelines and had a return of spontaneous circulation (ROSC) within eight minutes. Post ROSC, she was hemodynamically stable, with appropriate oxygenation and ventilation. An electrocardiogram showed normal sinus rhythm with no signs of ischemia. Point of care ultrasonography (POCUS) showed a normal left ventricular ejection fraction, with no evidence of wall motion abnormalities, right ventricular strain, or pericardial effusion. POCUS also ruled out deep vein thrombosis and pneumothorax. Cardiac enzymes, brain natriuretic peptide, potassium, calcium, and magnesium, were normal. Post-cardiac arrest care was provided, including targeted temperature management. The next day, she was following commands and meeting extubation criteria. She was extubated and transferred to the floor one day after. Formal echocardiography confirmed POCUS findings. In the absence of another explanation for her cardiac arrest, cetuximab was to blame. DISCUSSION: Cetuximab is a monoclonal antibody that binds the epidermal growth factor receptor (EGFR), competitively inhibiting the binding of EGF and resulting in inhibition of cell growth and induction of apoptosis. Cetuximab is indicated for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) in combination with radiation therapy. The addition of cetuximab in this population increased median overall survival by 20 months1. In patients with SCCHN treated with cetuximab and radiation therapy, 2% had sudden death1. Cardiac arrest also occurred in 3% of SCCHN patients treated with cetuximab in combination with platinum-based therapy and fluorouracil2. As a result, cetuximab's package has "sudden death" as a black box warning. Of note, 50% of patients treated with cetuximab may develop hypomagnesemia, and weekly monitoring of electrolytes is recommended. In our patient, electrolytes were normal, and the exact mechanism of cetuximab-induced cardiac arrest remains unclear. CONCLUSIONS: Cetuximab-induced cardiac arrest occurs in 2%-3% of treated patients in controlled studies. Real-world incidence may be higher. We report this case to add to the literature what we believe is a case of cetuximab-related cardiac arrest. REFERENCE #1: 1. Bonner JA, et. al. New England Journal of Medicine. 2006 Feb 9;354(6):567-78. REFERENCE #2: 2. Vermorken JB, et al. New England Journal of Medicine. 2008 Sep 11;359(11):1116-27. DISCLOSURES: No relevant relationships by Tony Abdo, source=Web Response No relevant relationships by Ammaar Azeem, source=Web Response No relevant relationships by SYED HUSSAIN, source=Web Response

Comparison of the composition of lymphocyte subpopulations in non-relapse and relapse patients with squamous cell carcinoma of the head and neck before, during radiochemotherapy and in the follow-up period: a multicenter prospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)

BackgroundRadiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT.MethodsEDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry.ResultsPatients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5).ConclusionMonitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed.Trial registrationObservational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668.

Abstract LB018: Cloud-based biological domain knowledge derived gene expression classifier to predict the cancer clinical outcome

Abstract We report the advances of a cloud-based software utilizing advanced algorithms to identify the molecular cancer drivers and its signal transduction. To test, a classifier based on the NFκB signaling pathway gene expression profiles that predicts the clinical therapeutic response to chemo-radiation therapy of Squamous Cell Carcinomas of the Head and Neck (SCCHN) patients are described here. Expression of HPV16, p16 and 84 NFκB signaling pathway genes were determined using real time RT PCR in SCCHN patient samples and SCCHN cell lines. Gene expression was correlated to chemo-radiation response in cell lines and the model was blindly tested in SCCHN patients to predict their clinical outcome to chemo-radiation. This tool intends to fuse biological domain knowledge by way of integrating disease targets, cell line experiments towards creating a gene expression classifier for clinical outcome. The gene expression-based predicted clinical outcome compared with patients actual observed clinical outcome correctly identified the clinical response in 73% of the cases. Such work will allow design of tailored individualized clinical treatment strategies to target NFκB inhibition using biological modifying agents with or without chemo/radiation therapy. This will help to develop several targets to directly inhibit the NFκB activity or inhibit the downstream pivotal targets. The significance of the classifier would be the ability to use the biologic attributes of a tumor to tailor specific treatment protocols for each individual patient. This would not only spare the chemo-radiation resistant patients the ill effects of the therapy but will also decrease the delay in effective treatment among the resistant patients. The long-term objective is to use such pro-survival driver genes in other cancers; SMAD, TGFβ in pancreatic cancer, and AR in prostate cancer. This tool (MeghaOncomine) intends to fuse biological domain knowledge by way of integrating cancer targets, cell line experiments towards creating a gene expression classifier for clinical outcome. Citation Format: Rao V. Papineni, Seema Gupta, Aravindan Natarajan, Ram Papineni, Chandra Kasinathan. Cloud-based biological domain knowledge derived gene expression classifier to predict the cancer clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB018.

Prognostic Value of the Overexpression of Fatty Acid Metabolism-Related Enzymes in Squamous Cell Carcinoma of the Head and Neck.

Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related enzyme expression and determine its correlation with clinicopathological variables in SCCHN patients. Immunohistochemical analysis (IHC) of FAO-related protein expression, including carnitine palmitoyltransferase 1 (CPT1), the acyl-CoA dehydrogenase family, and fatty acid synthase (FAS), was performed using tissue microarrays from 102 resected SCCHN tumors. Expressions were categorized according to IHC scores, and the statistical association with clinicopathological factors was determined. Moderate-to-high expression of long-chain acyl-CoA dehydrogenase (LCAD) had a protective role against cancer-related death (adjusted hazard ratio (HR), 0.2; 95% confidence interval (CI), 0.05–0.87) after covariate adjustment. Age and clinical stage remained independent predictors of survival (adjusted HR, 1.75; 95% CI, 1.22–2.49 for age; adjusted HR, 14.33; 95% CI, 1.89–108.60 for stage III/IV disease). Overexpression of medium-chain acyl-CoA dehydrogenase and FAS correlated with advanced tumor stage (T3/T4); however, none of these factors were independent predictors of survival. Several FAO-related enzymes were upregulated and LCAD overexpression had a protective effect on overall survival in advanced SCCHN patients. FAO-related-enzyme expression might have a prognostic impact on survival outcomes in SCCHN.