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The prognosis of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (SCC) is poor (median overall survival [OS] 10–13 mo), and effective treatments are needed. The cell-adhesion molecule Nectin-4 is expressed in a majority of HNCs. EV is a Nectin-4–directed antibody–drug conjugate approved as monotherapy in previously treated locally advanced or metastatic (la/m) urothelial carcinoma (UC) and, in the US, with pembrolizumab for previously untreated la/mUC ineligible for cisplatin. EV was evaluated in previously treated HNC in EV-202 (NCT04225117). In this open-label phase 2 study, pts with la/m solid tumors enrolled in tumor-specific cohorts. In this cohort, pts had HNC not amenable to curative-intent treatment, radiographic progression on/after the last regimen, progression/relapse/discontinuation for toxicity after 1 platinum-based therapy for la/m disease, and ≤2 lines of cytotoxic therapy in the la/m setting. Pts had received prior programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor unless contraindicated. Pts received intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-d cycle (C) until disease progression or discontinuation criteria were met. Primary endpoint was confirmed objective response rate (ORR) per investigator assessment. Secondary endpoints were duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per investigator assessment; OS; and safety/tolerability. Exploratory endpoints included immunogenicity, pharmacokinetic parameters, and pt-reported outcomes. As of April 11, 2022, 46 pts were enrolled; median follow-up was 9.3 mo. Median age was 65 y, 87.0% of pts were men, and 52.2% had ≥3 prior lines of systemic therapy in the metastatic setting. Forty-five pts had SCC; 1 had adenocarcinoma. Confirmed ORR was 23.9%; DCR was 56.5%. Median time to response was 1.7 mo. Median DOR was not estimable. Median PFS and OS were 3.9 and 6.0 mo, respectively. Common treatment-related adverse events (TRAEs) were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Grade ≥3 TRAEs occurring in >1 pt were anemia and decreased neutrophil count (both n=2). TRAEs of special interest were skin reactions (45.7%), peripheral neuropathy (32.6%), dry eye (6.5%), and hyperglycemia (4.3%). No antitherapeutic antibodies against EV were detected. Serum EV decreased substantially from end-of-infusion concentrations before subsequent doses in C1, while plasma concentration of free monomethyl auristatin E (drug component of EV) remained high between days 1 and 15 of C1. Median global pain assessment score was 4/10 at baseline, with numeric reduction in scores (indicating pain improvement) in C3 and beyond. EV demonstrated antitumor activity with manageable AEs in pts with heavily pretreated HNC post-platinum and PD-1/L1 inhibitor. [ABSTRACT FROM AUTHOR]

The immune microenvironment plays an essential role in the progression of head and neck squamous cell carcinoma (HNSCC). The association of the tumor microbiota and immune microenvironment is not well defined. The Cancer Genome Atlas Project (TCGA) analysis provided the diversity of microbiota in different cancer types. We analyzed the TCGA microbiome database to better understand the role of the tumor microbiome in HNSCC. Human papillomavirus (HPV) positive and HPV negative HNSCC samples in the TCGA database were analyzed. Data were accessed using cBioPortal. Spearman's test was used to correlate Lachnoclostridium microbiome signature with immune-related gene expressions. Microbiome signatures were compared in PDL1 low and PDL1 high HNSCC. Lachnoclostridium was among the top genus enriched in the PDL1 high expression group in both HPV+ and HPV- HNSCC. Lachnoclostridium was correlated with immune inflamed gene expression profile. To evaluate the differential gene expressions in Lachnoclostridium enriched HNSCC, the gene expression profile of Lachnoclostridium high and low HNSCC samples were compared. MHC class I genes; HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, TAP1, and TAP2 were among the top differentially expressed genes. Then we evaluated the correlation of MHC-I genes with Lachnoclostridium enrichment. Lachnoclostridium signature was significantly correlated with expression of these MHC I genes, with Spearman's correlation coefficient ranging between 0.51-0.59. Lachnoclostridium is a recently defined genus found in the human gut microbiome. Here we, for the first time, identify the enrichment of this genus in high PDL1 expressing HNSCC. The association of Lachnoclostridium signature with the immune inflamed gene expression profile and MHC-I gene signature suggests its potential role in modulating the immune microenvironment in HNSCC. [ABSTRACT FROM AUTHOR]

Carotid artery stenosis (CAS) is a known potential late effect of neck radiation. There are varying estimates of its incidence and mixed consensus on whether screening for this late effect standard practice should be. As treatment techniques have evolved and the presence of HPV has increased, the impact on the future trajectory of this problem is unclear. A sample of head and neck cancer (HNC) patients treated from 1997 through 2022 who underwent carotid ultrasound (US) at any time after receiving radiation therapy to the neck were identified from an IRB-approved, single institution database. Patient treatment characteristics including radiation laterality, co-morbidities at consult, and smoking history were coded in addition to carotid US dates and results. CAS was defined as >40% stenosis of either side of the vessel, which prompted a vascular surgery consult. A total of 308 patients were included in this study with an average follow up of 70 months (range: 3.3-255.9 months). All included patients received bilateral neck radiation and had no evidence of disease at their last follow up. Most patients received definitive, concurrent chemoradiation (96.4%), were male (85.1%) and had a primary oropharyngeal tumor (64%). The most common co-morbidity at time of consult was hypertension (HTN, 45.8%). Median time to CAS was 10.7 years. The five- and ten-year rates of CAS were 15.4% and 39.6%, respectively. On Cox regression univariate analysis age at consult (HR=1.054, 95% CI= 0.649-1.941, p<0.001), having known HTN (HR=2.551, 95% CI=1.610-4.032, p<0.0001), hyperlipidemia (HR=1.658, 95% CI= 1.066-2.584, p=0.0248), diabetes (HR=2.398, 95% CI=1.397-4.115, p=0.0015), or cardiac disease (HR=2.283, 95% CI=1.333-3.922, p=0.0026) at time of consult, and being an ever smoker (HR=2.336, 95% CI=1.403-3.891, p=0.0011) were statistically predictive of CAS. On multivariate analysis, patients who were older (HR=1.037, 95% CI=1.008-1.068, p=0.0122), were an ever smoker (HR=2.375, 95% CI=1.425-3.968, p=0.0009), and having known hypertension (HR=2.037, 95% CI=1.235-3.356, 0.0053) at consult were at highest risk for CAS. CAS was frequently detected five and ten years after head and neck radiation. Carotid artery US screening should be strongly considered in these patients, especially older patients with a history of smoking and/or HTN. Future prospective studies are warranted to verify this finding. [ABSTRACT FROM AUTHOR]

The purpose of the study was to define whether circulating tumor DNA (ctDNA) can be used as a measure to detect minimal residual disease (MRD) following surgical intervention in high-risk positive patients for head and neck squamous cell carcinoma (HNSCC). IRB approval was obtained through our institution. Patients with HNSCC with surgical resection of their tumor were enrolled. Of these, 28 patients had ctDNA levels determined post-operatively (n = 28) using the Signatera test. Data were extracted from electronic medical records by trained abstractors. The patient cohort (20 male and 8 female) had an average age of 67.0 ± 9.82 years at the time of surgery. Patients were assessed using The Eastern Cooperative Oncology Group (ECOG) functional scores, with 17.9% scoring 0, 75.0% scoring ECOG 1, and 7.14% of patients with ECOG 2 or 3. All patients had primary laryngeal or oral cavity cancer, including gingival, tongue, and mandibular. The study had two patients with pathologic Stage I cancer, three with Stage II, five with Stage III, eleven with Stage IVA, and seven with Stage IVB. One patient received neoadjuvant chemotherapy prior to surgery. There were 19 high-risk positive cancers, defined as positive extranodal extension or positive margins during surgery. 15 of these 19 patients patients received adjuvant chemotherapy and radiation, with or without a platinum agent, depending on their chemotherapy eligibility. In these high-risk patients, 18 had data in the post-operative period, prior to adjuvant therapy, for which 61.1% had positive ctDNA. Conversely, there were 9 patients without high-risk features, of whom only two had positive MRD post-operatively, and two with disease recurrence. There was a significantly lower tumor recurrence in the patients without high-risk features compared to those with high-risk features (22.9% vs. 54.5%, respectively) which correlated with ctDNA. At the time of data collection, 7 patients had disease recurrence for which 5 were post-operative ctDNA positive. Two patients were ongoing adjuvant treatment and follow-up without recurrence data. ctDNA was detected frequently in the HNSCC patients with high-risk features post-operatively. Although we have a small number of the patients, the patients with recurrence following adjuvant treatment had high rates of positive ctDNA after the surgery. Therefore post-operative ctDNA for high-risk patients may be prognostic and considered in clinical trials designed for treatment intensification. [ABSTRACT FROM AUTHOR]

BCA101 is a first-in-class bifunctional EGFR/TGFβ inhibitor with a manageable safety profile and preliminary efficacy in advanced solid tumors (ESMO 2022 731MO). Pembrolizumab is approved for recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the CPS≥1 population. Here we report updated results from the fully enrolled expansion cohort combining BCA101 + pembrolizumab as first line therapy in R/M HNSCC. This ongoing single-arm, multicenter dose expansion cohort enrolled patients (pts) with R/M HNSCC as part of a phase 1/1b trial. Pts with tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1) were eligible. Pts received BCA101 (1500 mg IV on days 1, 8, 15) with pembrolizumab (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response, progression-free survival (PFS), overall survival. Exploratory: molecular and immunologic predictors of response. Forty-two pts received at least one dose of study drug and 39 pts were evaluable for efficacy. Pts were more often men (30, 71%); median age: 63 (range: 31-84). Twenty pts (48%) had baseline PD-L1 CPS scores of 1-19 and 22 (52%) were ≥20. Oropharynx (20, 48%) [12/20 (60%) HPV/p16-positive] and oral cavity (13, 31%) were the most common subsites. Thirty-three pts (79%) had distant metastases. The ORR was 46% (5 CR, 13 PRs) with 57% (16/28) of HPV/p16-negative pts achieving response. Similar response rates were observed for HPV-negative pts with CPS scores 1-19 (54%, 7/13) and CPS≥20 (60%, 9/15), as well as in pts with distant metastasis (55%, 12/22) and locoregional disease (67%, 4/6). Median PFS (mPFS) continues to mature and currently has not been reached among HPV-negative pts with 13/28 responses ongoing (>30% for more than 6 months), with updates expected to be available at the time of the meeting. Grade 3+ treatment-related adverse events (TRAEs) were observed in 17/42 pts (40%). There were no treatment-related deaths. Acneiform rash was the most common TRAE of any grade (31/42, 74%). Permanent discontinuation of study treatment due to TRAEs was required in 6/42 pts (14%). BCA101 + pembrolizumab exhibits encouraging safety and anti-tumor activity in first line R/M HNSCC, particularly among HPV-negative pts in both CPS 1-19 and ≥20. Further investigation in HPV-negative pts is planned in a larger randomized study. Study funded by Bicara Therapeutics Inc. and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (NCT04429542). [ABSTRACT FROM AUTHOR]

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, with only ∼20% of patients responding to anti-PD-1 checkpoint immunotherapy. CD47 is another targetable immune checkpoint. By interacting with SIRPα, CD47 triggers a "don't eat me" signal to inhibit macrophage phagocytosis which is upregulated in the HNSCC tumor microenvironment. The aim of our study was to examine the effect of anti-CD47 as monotherapy and in combination with anti-PD-L1/PD-1 checkpoint blockade, on tumor growth response and survival in syngeneic orthotopic models of HNSCC. Syngeneic murine HNSCC cell lines were injected orthotopically (tongue) into C57/B6 mice: MOC1, ROC1, and ROC3 (n=5-10 per group). The MOC1 mice were then subjected to immunotherapy intraperitoneally with either control (IgG), anti-CD47, anti-PD-L1 or the combination. ROC1 and ROC3 mice were injected intratumorally with anti-CD-47 and anti-PD-1 was administered intraperitoneally to ROC3 mice in combination with anti-PD-1. Tumor rechallenge (via inoculation of cancer cells was performed in mice exhibiting complete responses to therapy). Tumor volumes were recorded, and survival curves were generated. RNA was isolated from treated tumors and mRNA expression data was collected. Statistical analysis was performed. In MOC1 implanted mice, anti-CD47 monotherapy resulted in no significant difference in tumor volume or survival compared to control (IgG). However, when used in combination with anti-PD-L1, anti-CD47 treatment resulted in a statistically significant decrease in tumor volume and significantly increased overall survival (p<0.05). There were 6/10 complete responders in the combination group (and no mice grew tumors after re-challenge at 100 days). ROC3 implanted mice treated with anti-CD47 treatment showed a significant decrease in tumor volume with monotherapy, compared to control, and maintained complete responses after tumor cell re-challenge (p<0.05). Conversely, the more aggressive ROC1 mouse model showed no significant difference in treatment arms which included anti-CD47, anti-PD-1 and the combination. RNA expression analysis of MOC1 tumors treated with anti-PD-L1 demonstrated significantly increased CD47 expression. We have demonstrated that anti-CD47 and anti-PD-L1 have a synergistic effect in MOC1 tumor models while monotherapy with anti-CD47 works effectively in the ROC3 model. Combination therapy showed no response in the ROC1 model. PD-L1 treatment of MOC1 tumors caused increased expression of CD47 in tumors, indicating that increased CD47 may be an immunosuppressive mechanism that may contribute to PD-L1 immune checkpoint inhibitor resistance. Combining anti-CD47 with anti-PD-L1 immunotherapy may be effective in HNSCC patients with higher baseline immune cell infiltration. [ABSTRACT FROM AUTHOR]

Treatment of oropharyngeal cancer with definitive radiation/chemoradiation (RT/CRT) is an effective treatment and rapid regression of tumor can occur. Following treatment some patients will develop a pharyngeal ulcer which may or may not be associated with disease persistence. Data for the management of ulcers could improve post radiation care. From an IRB approved database of head and neck cancer cases at a tertiary care center, we reviewed patients with non-metastatic squamous cell carcinoma of the oropharynx treated curatively in non-operative fashion with RT/CRT between 1/1/2011 and 1/1/2022. Patients were reviewed for clinical, radiographic and laryngoscopic evidence of pharyngeal ulcer development following completion of radiation. Pharyngeal ulcer patients were evaluated for management strategy of the ulcer and associated complications and association with recurrence. A total of 45 patients with a pharyngeal ulceration following RT/CRT with a median follow up of 30.8 months were identified. The median age of patients was 60 (range 35-82) years, 80% of patients were caucasian, 82% were male, and 42% of patients were active smokers at the time of RT/CRT. 75% of patients had p16/HPV+ disease with T stages of T1/2, T3 and T4 of 44, 20 and 36% respectively. 93% of patients were treated with concurrent chemotherapy (74% cisplatin) to a median dose of 70 Gy (range 60-74 Gy). The median time to development of ulcer was 3.1 months (range 0.2-31.4 months). 19 patients (42%) underwent biopsy of their ulcer of whom 9 (47%) where found to have disease persistence. Ultimately thirteen patients (29%) had associated tumor persistence. Among the 32 patients with ulcer not associated with recurrence, 28 (87.5%) were p16/HPV+ and 90.6% has received chemotherapy. 3 ulcers (9.4%) were associated with exposed bone. Treatment of ulcers revealed 15 (46%) received antibiotics, 23 (72%) needed narcotics and 5 (16%) required feeding tube placement for pharyngeal rest. Three patients (9.4%) required surgical reconstruction to facilitate resolution. Overall, at time of last follow up 28 (88%) of ulcers not associated cancer had resolved with a median time to resolution of 3.6 months (range 1.3-75.2) months. The overall survival of the non-malignant ulcer group was 83% at 3 years compared to 28% in the patients with ulcers associated with persistent cancer. Pharyngeal ulceration is a significant potential complication of RT/CRT in oropharyngeal cancer. Ulceration is frequently identified around 3 months post treatment and when not associated with disease persistence has a high rate of resolution with conservative measures including antibiotics and pain control. Severe case may necessitate feeding tube and rarely surgical reconstruction. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is an emerging biomarker utilized in some cancers as a predictive tool to determine benefit to immune checkpoint inhibitor therapy and high TMB alone is an indication for pembrolizumab monotherapy, tumor agnostic. For head and neck squamous cell carcinoma (HNSCC), there is limited data utilizing TMB as a biomarker to predict response to PD-L1 inhibitors. This study assesses TMB score and progression of disease in HNSCC patients treated with immunotherapy. From an IRB-approved database, we retrospectively analyzed 51 patients treated between 2016 and 2023 with HNSCC who had at least one dose of pembrolizumab and known next generation sequencing (NGS). Patients were stratified between high TMB (≥10 mutations/Mb) and low (<10 mutations/Mb). Of the 51 patients, 40 (78%) had progression of disease while on pembrolizumab. The median TMB of those who progressed was 6.9 mutations/Mb. The median time to disease progression was 5.8 months. There were 37 patients who were classified as low TMB with a median 5.0 mutations/Mb. Of these 37, 29 (78%) had progression while on pembrolizumab with a median time to progression of 3.5 months. For the 14 patients with high TMB scores, the median was 12.0 mutations/Mb. Of these 14, 11 (79%) had progression while on pembrolizumab with a median time to progression of 5.8 months. There was no statistical difference in time to progression between high and low TMB cohorts (p=0.3483). Of the 11 (22%) without progression, all patients started pembrolizumab in the setting of recurrent HNSCC (7 metastatic, 4 locoregionally recurrent). The majority in this cohort are classified as having low TMB (n=8/11) with a median TMB of 5.0 mutations/Mb. Of the 10 patients who actively remain on pembrolizumab, they have been on pembrolizumab for a median of 14.7 months. A multivariable analysis revealed that TMB as a continuous variable (i.e., increase in TMB mutations), the risk of progression decreased (p=0.0238, HR 0.940). Although there was no statistical difference in time to progression between our high TMB and low TMB cohorts, a higher TMB score correlated with decreased risk of progression in our cohort of HNSCC patients. Further research is needed to better understand the utility of TMB as a biomarker in HNSCC. [ABSTRACT FROM AUTHOR]

While surgery (with or without radioactive iodine (RAI)) is the mainstay of locoregional control in differentiated thyroid cancer (DTC), patients with unresectable disease present a clinical challenge. Uncontrolled disease in the neck can lead to substantial morbidity and mortality in DTC and obtaining locoregional control is vital to preserving quality of life and longevity. High dose definitive radiotherapy (RT) for gross disease in DTC is understudied. This study examines the efficacy of definitive RT in this setting. From an IRB-approved registry of head and neck cancer cases treated at a tertiary care center over a period of 8 years (2014-2022), patients with incompletely resected or unresectable DTC including papillary, follicular, mixed, medullary, and poorly differentiated types were identified. All patients were treated to the neck and/or thyroid regions with visible gross disease to a definitive dose of radiation. The primary endpoint was local control within the radiated portal with a secondary endpoint of locoregional control within the neck. A total of 31 patients were identified, of whom 74.2% were Caucasian. Fourteen were female (45.2%), and 17 (54.8%) were male. The median age was 68 years (range 26-90) and the median follow-up was 31 months. Histologically, 19 (61.3%) cases were papillary, 4 (12.9%) were follicular, 2 (6.5%) were mixed, 3 (9.7%) were medullary, and 3 (9.7%) were poorly differentiated. Among patients with non-medullary DTC 18 (69.2%) received prior RAI. Twelve patients were treated with radiation at initial diagnosis, while 19 patients were treated at the time of recurrence; two patients received concurrent chemotherapy. Twenty-eight patients (90.3%) were treated with IMRT and 3 (9.7%) were treated with SBRT. The median dose to the gross disease was 66 Gy (range 30-70.4) in 32 fractions (range 5-35). Overall, 5 patients (16.1%) experienced a locoregional failure after RT and all experienced failure in the RT portal. The actuarial infield control/locoregional control of radiation therapy at 3 and 5 years was 84.8% and 74.2%, respectively. Overall survival at 3 and 5 years was 68.5% and 47.4%, respectively. Among patients who had a locoregional failure after RT, 2 patients were salvaged with systemic therapy, 2 patients with surgery, and 1 patient with SBRT re-irradiation (40 Gy/5 fractions). The patient salvaged with SBRT remains without disease 8 months post-RT. Definitive radiotherapy is a highly effective strategy to obtain durable control of unresected DTC. It should be standard for unresected disease and considered as a viable alternative for patients with borderline resectable disease for whom resection would be highly morbid. [ABSTRACT FROM AUTHOR]

Most head and neck cancers (HNC) overexpress EGFR, a feature associated with poor clinical outcome. Preclinical and clinical data suggest that peritumoral myofibroblasts (MF) express EGFR ligands and the presence of a high MF density in the tumor stroma is associated with statistically worse survival in patients with locally advanced HNC. We evaluated whether peritumoral MF density was prognostic of outcome in patients treated on RTOG 0522, a negative phase III trial evaluating the addition of C225 to cisplatin-based chemoradiation (CRT). We also evaluated whether MF density was predictive of benefit to C225. Specimens from HPV-negative patients treated on RTOG 0522 were obtained from the NRG Oncology Biospecimen Repository and evaluated by a blinded pathologist (JW). MF density was determined as a percentage and the skewed data were normalized using Box-Cox transformation, from which the mean was calculated and used to stratify patients into low- and high-density groups. Overall survival (OS), progression-free survival (PFS), and distant metastasis (DM) rates were estimated using the Kaplan-Meier method and a multivariable analysis (MVA) by Cox proportional hazards model was used to test for the prognostic effect of this biomarker for patients with low vs. high MF density. To test for predictive effect of MF density on clinical outcomes in patients treated with CRT vs. CRT+C225, a Cox model with a treatment-by-biomarker interaction term was used. A total of 186 patients were evaluated, 94 were treated with CRT and 92 were treated with CRT+C225. On MVA, including primary site, age, PS, smoking history, T-stage, N-stage, and EGFR level, there was no significant difference in OS (Hazard ratio [HR], 0.65; 95% CI, 0.41-1.02; P=0.06), PFS (HR, 0.75; 95% CI, 0.50-1.12; P=0.16), or DM (HR, 0.76; 95% CI, 0.38-1.54; P=0.44) based on MF density. However, MVA Cox model including biomarker, treatment arm and biomarker-treatment interaction demonstrated that this interaction was significant (P=0.01). Within the low MF density subgroup, patients treated with CRT+C225 had significantly higher PFS (HR, 0.42; 95% CI, 0.21 to 0.82; P=0.01) and lower incidence of DM (HR, 0.18; 95% CI, 0.04 to 0.82; P=0.01), as well as numerically higher OS (HR, 0.48; 95% CI, 0.22 to 1.05; P=0.06) compared to patients treated with CRT. Patients with high MF density demonstrated no difference in OS, PFS, or DM based on treatment arm. Peritumoral MF density was not prognostic of OS, PFS, or DM among patients treated on RTOG 0522. However, patients with low peritumoral MF density who received CRT+C225 had significantly higher PFS and lower incidence of DM compared to patients who received CRT alone. These results suggest that MF density is not a prognostic biomarker but may be predictive of benefit to C225. Further investigations are needed to validate these exploratory findings. [ABSTRACT FROM AUTHOR]

Carotid artery stenosis (CAS) is a known potential late effect of neck radiation. There are varying estimates of its incidence and mixed consensus on whether screening for this late effect should be standard practice. As patients are being treated at younger ages and living longer, especially in the HPV era, this question is becoming increasingly important. Head and neck cancer (HNC) patients treated from 1997 through 2020 who underwent carotid ultrasound (US) at any time after receiving radiation therapy to the neck were identified from an IRB-approved, single institution database. The primary outcome for this study was clinically significant CAS, defined as >50% stenosis in any carotid artery in the radiation field. Framingham risk score (FRS) was also calculated for each patient based on risk factors present at the time of consultation to determine 10-year risk of developing cardiovascular disease (CVD). The FRS takes gender, smoking, blood pressure control, and cholesterol into consideration to determine cardiovascular risk. Patient treatment characteristics including radiation laterality, co-morbidities, and smoking history were also coded. Kaplan Meier analysis was used to estimate the rates of CAS. Logistic regression analysis was used to identify factors associated with CAS. A total 79 patients were included in this initial analysis with the median follow up of 5.1 years. Most patients had definitive, concurrent chemoradiation (96.2%), were male (79.7%), and received bilateral neck radiation (89.9%). A FRS was able to be calculated for 53 patients at time of consult with a majority of patients having either an intermediate (41.5%) or high (49.1%) risk of developing CVD disease in 10 years. The most common co-morbidity at time of treatment was hypertension (50.6%). Overall, 28 patients (35.4%) were found to have CAS based on US results. The two- and five-year rates of CAS were 7% and 20%, respectively. On Cox regression univariate analysis, only the presence of having a co-morbidity of hypertension was statistically predictive of CAS (HR=2.51, 95% CI= 1.12-5.62, p=0.0251). Age, FRS, smoking status at time of treatment, and bilateral vs unilateral radiation were not associated with an increased risk of CAS. Clinically significant CAS increases with time with increasing duration of follow up. Patients with baseline hypertension appear to be at higher risk and should be more strongly considered for screening. Longer follow up is needed to correlate CAS with adverse outcomes and quantify longer term risks (e.g. 10-20 years post treatment) in this highly curable population. [ABSTRACT FROM AUTHOR]

Immunotherapy (IO) with cemiplimab or pembrolizumab is approved for treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC). There is evidence of objective response to these anti-PD-1 agents in locally advanced cSCC. Cranial nerve (CN) involvement is seen in less than 5% of cSCC and is a poor prognostic factor. Radiotherapy (RT) can be used for locally advanced cSCC, however comprehensive delineation and eradication of perineural invasion can be challenging. To our knowledge, there are no published studies indicating how patients with CN involvement respond to IO. Patients were identified and retrospectively reviewed under an Institutional Review Board approved protocol at a tertiary care center. Selection criteria included histologically proven locally advanced cSCC of the head and neck cancer with CN involvement treated with IO. A total of 8 patients met inclusion criteria; demographic, disease, and treatment characteristics are summarized in Table 1. Most patients were men, with a median age at diagnosis of 74 years and had a median follow-up of 8.4 months. All received cemiplimab 350 mg intravenously every 3 weeks; 1 patient was initially treated with pembrolizumab, then transitioned to cemiplimab. 2 patients received IO for recurrence of previously diagnosed locally advanced cSCC, 1 of which had prior treatment with cetuximab and RT. 6 patients presented with CN involvement at diagnosis, and the additional 2 at time of recurrence after previous non-IO therapy. 1 patient treated with IO was immunosuppressed due to CLL and also had nodal involvement. 4 patients received RT prior to IO, and 1 patient received stereotactic radiosurgery (SRS) concurrent with IO. 3 patients never received RT and all had clinical benefit with IO: 2 having stable disease (SD) and 1 partial response (PR). Overall, 4 patients had PR, 2 SD and 2 progressive disease (PD) as best response. 5 patients are alive at last follow up, 1 completed a full year of IO and is currently off treatment, and 4 remain on IO treatment. In this limited cohort of patients with locally advanced cSCC with CN involvement, IO has shown clinical benefit in 75% of the cases. All patients treated with IO alone demonstrated a clinical response, indicating IO can be an effective monotherapy. Given the challenges of RT with extensive perineural invasion, RT can be reserved in the event of local failure after IO. [ABSTRACT FROM AUTHOR]

Loco-regional Failure (LRF) can be an important cause of morbidity and mortality in patients with advanced medullary thyroid cancer (MTC), especially in the era of more effective systemic therapies. We sought to identify risk factors predictive of LRF and the role of radiation therapy in modifying this outcome. Patients with MTC treated with definitive surgical resection between 2004 and 2020 were identified in an IRB approved database. Patients who did not undergo definitive surgery, with or without metastatic disease, or those treated with radiation alone were excluded. Patients who underwent postoperative radiation (PORT) to a dose of >45Gy were included. LRF was defined as any failure in the thyroid bed, neck or mediastinum. Kaplan Meier analysis was performed to calculate rates of LRF and log rank analysis was used to identify associations of specific high-risk features with LRF. High-risk pathologic factors included in this analysis were positive surgical margins, multifocal disease, angiolymphatic and/or lymphovascular space invasion (LVI), extrathyroidal extension, nodal extracapsular extension, and rising CEA or calcitonin postoperatively. Of 68 patients who were included in this study, 36 (53%) were stage I/II and 32 (47%) were stage III/IV. MTC was co-incidental with a papillary thyroid cancer in 34 patients (50%). LRF occurred in 1 (3%) stage I/II and 12 (38%) stage III/IV patients. Among stage III/IV patients with known mutational analysis, 14/25 (56%) harbored RET mutations, 11 of whom received targeted therapies. Patients with these mutations had numerically lower rates of LRF compared to non-mutated tumors (18% vs. 43%; p=0.23). Patients with positive margin, LVI, or multifocal disease trended towards an increased risk of 3-yr LRF (36.2% vs 0%; p=0.22). No other pathologic risk factors were associated with LRF. PORT was used in 14 stage III/IV patients (44%), and was associated with a lower 3-yr LRF rate (7% vs. 38%; p=0.17). This was independent of known risk factors. Patients with stage III/IV MTC treated with definitive resection with either a positive margin, LVI and/or multifocal disease have high rates of LRF and may benefit from PORT. Further studies are needed to corroborate this finding, especially in RET mutated tumors in the era of targeted therapies. [ABSTRACT FROM AUTHOR]

Adenosquamous carcinoma of the head and neck (ASC-HN) is a rare and aggressive variant of squamous cell carcinoma (SCC). Limited data suggests inferior outcomes compared to conventional SCC. We report one of the largest single institutional experiences of this disease in patients treated definitively to further elucidate oncologic outcomes. Patients with non-metastatic ASC-HN treated definitively between 2003 and 2021 were identified retrospectively from an IRB approved database with histology verified by head and neck pathologists. All tumors of the oropharynx were tested for p16 and/or HPV to document HPV associated disease. For non-oropharyngeal lesions, a designation of HPV positivity required the presence of HPV DNA/RNA per CISH. Actuarial analyses were performed for PFS and OS. 29 patients with ASC-HN (72.4% male, 93.1% Caucasian) with median age of 66 (range 34-91) and a median follow up of 33 months (range 6.6-126.7) were identified. The most common primary tumor sites were: oropharynx (27.6%), oral cavity (20.7%), nasal cavity (17.2%), and larynx (17.2%). 3 patients had primaries in the hypopharynx, nasopharynx and parotid gland respectively. 11 patients (37.9%) were HPV positive of whom 8 had oropharyngeal primaries. The majority (n=23, 79.3%) were treated with primary surgery of whom 19 (82.6%) received adjuvant radiation (RT) to a median dose of 60 Gy (range 36-70 Gy) with 7 receiving concurrent chemotherapy. 6 patients were treated with definitive RT to a median dose of 70 Gy with two receiving concurrent chemotherapy. There were 10 recurrences (34.5%) which occurred at a median of 14.3 months (range 5.4-28) after diagnosis including 8 loco-regional and 2 distant recurrences. Recurrences were documented in patients with primary salivary gland, oral cavity, laryngeal, hypo-pharyngeal, and oropharyngeal tumors. 3 of the 10 recurrences were in patients with HPV positive disease. Among the 6 patients treated with definitive radiation or chemo-radiation no failures were observed. 9 patients (31%) were deceased at the time of analysis. Overall, 3-year PFS and OS were 54.2% and 72.9%, respectively. 3-year PFS and OS were 45.6% and 69.6% for primary surgery and 83.3% and 83.3% in the definitive RT group. 3-year PFS was 50% and 75% for HPV negative and positive patients respectively. In our single institutional experience of 29 patients with adenosquamous carcinoma of the head and neck there was a 34.5% recurrence rate. Loco-regional recurrence was the primary mode of failure. [ABSTRACT FROM AUTHOR]

Pembrolizumab and nivolumab are approved in the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, real-world effectiveness may vary from clinical trial efficacy, partly due to strict exclusion criteria. We reviewed the effectiveness of immunotherapy (IO) in recurrent/metastatic HNSCC at a single tertiary referral center. All HNSCC patients who received single-agent palliative IO for recurrent/metastatic disease were identified from the electronic medical record via ICD codes under an IRB approved protocol. Wilcoxon rank sums test and chi squared test of independence were used to compare characteristics between IO responders (any response) and non-responders (stable or progressive disease) respectively. Kaplan-Meier method was used to estimate overall (OS) and progression free survival (PFS). Multivariable cox proportional hazards method was used to identify predictors of OS. A total of 138 patients were identified with the following primary tumor sites: p16+ oropharynx (n=45), p16- oropharynx (21), oral cavity (29), larynx (21), hypopharynx (7), nasal/sinus (7), or unknown primary (8). Concurrent chemoradiation was given to 68.8% (95) of patients and palliative chemotherapy was given prior to IO in 26.1% (36). IO was given for unresectable recurrent or metastatic disease in 23.2% (32) and 76.8% (106) of patients respectively, with 95.7% (132) receiving pembrolizumab and 4.3% (6) receiving nivolumab. Median age was 64 years (IQR 58-71), with ECOG status of 0, 1, and 2 in 23.9% (33), 60.9% (84), and 15.2% (21) of patients respectively. Combined positive scores (CPS) were available in 45.7% (63) of patients, with 33.3% (46) having CPS≥1 and 23.9% (33) having CPS≥20. The median number of IO cycles received was 4 (IQR 2-7). Of the 96 patients who survived to undergo imaging after ≥3 cycles, 43.8% (42) of patients had progression, 15.6% (15) had stable disease, 36.5% (35) had partial responses, and 4.2% (4) had complete responses. There were no significant differences in age, time from definitive radiation to IO, or absolute lymphocyte count (ALC) at IO initiation between responders and non-responders. Median PFS from IO initiation was 3.2 months (95%CI 2.8-4.4) months while median OS from IO initiation was 6.6 months (4.7-10.3). In a multivariable model, ECOG status of 1 (HR=2.00, 1.16-3.45) or 2 (HR=3.03, 1.51-6.09) vs ECOG 0 and decreased ALC at IO initiation (100 cells/µL, HR=1.06, 1.01-1.12) were significant predictors of worse OS. In this real-world cohort, survival with palliative IO in HNSCC was similar to that in randomized control trials. Though ECOG status and ALC were significant predictors of OS, further work into predictors of OS mediated through evidence of tumor response is needed. [ABSTRACT FROM AUTHOR]

Adenosquamous carcinoma of the head and neck (ASC-HN) is a rare and aggressive variant of squamous cell carcinoma (SCC). Limited data suggests inferior outcomes compared to conventional SCC. We report one of the largest single institutional experiences of this disease in patients treated definitively to further elucidate oncologic outcomes. Patients with non-metastatic ASC-HN treated definitively between 2003 and 2021 were identified retrospectively from an IRB approved database with histology verified by head and neck pathologists. All tumors of the oropharynx were tested for p16 and/or HPV to document HPV associated disease. For non-oropharyngeal lesions, a designation of HPV positivity required the presence of HPV DNA/RNA per FISH. Actuarial analyses were performed for PFS and OS. 29 patients with ASC-HN (72.4% male, 93.1% Caucasian) with median age of 66 (range 34-91) and a median follow up of 33 months (range 6.6-126.7) were identified. The most common primary tumor sites were: oropharynx (27.6%), oral cavity (20.7%), nasal cavity (17.2%), and larynx (17.2%). 3 patients had primaries in the hypopharynx, nasopharynx and parotid gland respectively. 11 patients (37.9%) were HPV positive of whom 8 had oropharyngeal primaries. The majority (n=23, 79.3%) were treated with primary surgery of whom 19 (82.6%) received adjuvant radiation (RT) to a median dose of 60 Gy (range 36-70 Gy) with 7 receiving concurrent chemotherapy. 6 patients were treated with definitive RT to a median dose of 70 Gy with two receiving concurrent chemotherapy. There were 10 recurrences (34.5%) which occurred at a median of 14.3 months (range 5.4-28) after diagnosis including 8 loco-regional and 2 distant recurrences. Recurrences were documented in patients with primary salivary gland, oral cavity, laryngeal, hypo-pharyngeal, and oropharyngeal tumors. 3 of the 10 recurrences were in patients with HPV positive disease. Among the 6 patients treated with definitive radiation or chemo-radiation no failures were observed. 9 patients (31%) were deceased at the time of analysis. Overall 3 year PFS and OS were 54.2% and 72.9% respectively. 3 year PFS and OS were 45.6% and 69.6% for primary surgery and 83.3% and 83.3% in the definitive RT group. 3 year PFS was 50% and 75% for HPV negative and positive patients respectively. In our single institutional experience of 29 patients with adenosquamous carcinoma of the head and neck there was a 34.5% recurrence rate. Loco-regional recurrence was the primary mode of failure. [ABSTRACT FROM AUTHOR]