HPV-unrelated Head And Neck Squamous Cell Carcinoma Research Articles

Abstract 7046: Proteogenomic and immunologic profiles of head and neck cancer patients of African ancestry

Abstract Blacks/African Americans (BAAs) with head and neck squamous cell carcinoma (HNSCC) have worse survival than Whites. However, the complex molecular biomarkers and signatures of HNSCC among BAAs and molecular distinction associated with HNSCC disparities are largely unknown. Here we show the results of a multi-omics analysis of 500 patients (48 BAAs and 452 Whites). Comparative analyses between the racial groups were performed at the level of genomics, pathways, molecular subtype, tumor immune infiltration, protein alterations and prognosis. We found that overall survival in BAAs with HPV-unrelated HNSCC is significantly shorter than in White patients. Ancestry-related differential mutation spectrum, DNA methylation, gene and protein expression pattern and immune infiltration landscape were identified. Particularly, FAT1 mutation is significantly associated with its gene expression in BAA HNSCC and poor overall survival in this group. In BAA HNSCC, SALL3 gene expression is positively associated with its gene CNVs, while RTP4 gene expression is inversely correlated with its methylation. High EGFR_pY1068 and RAD50 levels correlate with poor prognosis in BAAs with HNSCC. The immune infiltration enrichment scores of Th17 cells, activated dendritic cells, monocytes and neutrophils in BAA HNSCC were significantly lower than those in White HNSCC. By combining multi-omics analysis and data validation using in-house-made tumor tissue arrays, this study comprehensively elucidates the genetic landscape, immune response, and tumor biology in BAA and White HNSCC patients, providing a molecular basis for future research in identifying appropriate screening modalities and therapeutic interventions leading to improved outcomes in BAAs with HNSCC. Citation Format: Fan Yang, Fanghui Chen, Chloe Shay, Nabil F. Saba, Yong Teng. Proteogenomic and immunologic profiles of head and neck cancer patients of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7046.

Abstract 6646: Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is often marked by an immunosuppressive tumor microenvironment, which contributes to the dismal 10-20% response rate to immune checkpoint inhibitor (ICI) therapy in HNSCC patients. Radiotherapy (RT) is a currently standard of care and frontline therapy for HNSCC, yet resistance is common. We sought to examine the combination therapy of RT followed by ICI therapy to test if RT induces an in situ vaccination which enhances the efficacy of subsequent ICI. Methods: We utilized SCC cell lines derived from K15.KrasG12D/Smad4−/− SCCs, which mimic the progression of HPV-unrelated HNSCC, and transplanted SCC cells into immune-competent C57BL/6J mouse recipients. Mice were subjected to RT followed by anti-PD-L1/anti-TGFb therapy. CD8+ splenic T cells of responder or non-responder mice were examined by paired single-cell VDJ sequencing and single cell RNA sequencing (TCR/sc-RNAseq) to look for adaptations of the cytotoxic T cell compartment following combination therapy. Responder and non-responder tumor lines or tumors were treated with RT alone in vitro and in vivo, respectively, to examine major histocompatibility complex I (MHC-I) levels on tumor cells. Results: Responders to this combination therapy exhibited complete tumor eradication while non-responders displayed rapid tumor progression. When re-challenged with same HNSCCs cells, responders rejected implanted tumor cells while naïve recipients rapidly developed HNSCCs. Single-cell TCR sequencing of splenic CD8+ T cells revealed that responders, but not naïve recipients exhibited multiclonal CD8+ T cell expansion specifically of memory cell populations. Responder tumor cells exhibited greater levels of MHC-I protein level presentation than non-responders when stimulated with RT. Conclusions: Our data suggest that 1) elevated MHC-I by SCC tumor cells presentation driven by RT and ICI combination therapy facilitate a systemic expansion of memory CD8+ T cell clonotypes which drive anti-tumor immunity and 2) MHC-I expression at baseline or when induced by RT may serve as a predictive marker for therapeutic response to RT and ICI combination therapy in HNSCCs. Citation Format: Hanne Lind, Alexander Strait, Spencer Hall, Jack B. Goon, John D. Aleman, Samantha Chen, Philip Owens, Jing H. Wang, Christian Young, Xiao-Jing Wang. Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6646.

Sensory nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs

Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth. We used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system. Calcitonin gene-related peptide (CGRP) directly inhibited CD8 Tcell activity invitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 Tcell activity invivo. Our data support sensory nerves playing a role in accelerating tumor growth by directly acting on the adaptive immune system to decrease Th1 CD4 Tcells and activated CD8 Tcells in the TME. These data support further investigation into the role of sensory nerves in the TME of HNSCC and points toward the possible treatment efficacy of blocking sensory nerve function or specifically inhibiting CGRP release or activity within the TME to improve outcomes. 1R01DE028282-01, 1R01DE028529-01, 1P50CA261605-01 (to S.D.K.), 1R01CA284651-01 (to S.D.K.), and F31 DE029997 (to L.B.D.).

Abstract 1834: Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs

Abstract Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). We investigate how nerves within the tumor microenvironment impact the adaptive immune system and tumor growth. RNA sequencing and proteomics data led us to identify cholinergic nerves as the potential drivers of tumor growth in human and mouse HNSCC. Using three syngeneic orthotopic murine models of HPV-unrelated HNSCC, experimental and pharmacologic manipulation of cholinergic output, and knockout mouse models, we discovered that activation of cholinergic nerves accelerate tumor growth by directly acting on the adaptive immune system. Cholinergic nerve release of calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking cholinergic nerves pharmacologically or genetically increased CD8 T cell activity in vivo. These data support therapeutic translation of cholinergic nerve targeting of CGRP release to enhance antitumor immune response within the HNSCC TME. Citation Format: Laurel B. Darragh, Tiffany T. Pham, Michael M. Knitz, Alexander Nguyen, Laith A. Mukdad, Yazeed Alhiyari, Maie St. John, Sana D. Karam. Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1834.

Analysis of Aldehyde Dehydrogenase 2 as a Prognostic Marker Associated with Immune Cell infiltration and Chemotherapy Efficacy in Head and Neck Squamous Cell Carcinoma.

Background: Previous investigations have demonstrated the role of Aldehyde Dehydrogenase 2 (ALDH2) levels in the cancer initiation and progression, prognosis, and treatment response in kinds of malignancies. However, its significance in the head and neck squamous cell carcinoma (HNSC) by different human papillomavirus (HPV) statuses remains unclear. Methods: We conducted an in-depth analysis of ALDH2 in HNSC using various bioinformatics tools, investigating its expression, alteration, differential levels, prognostic significance, molecular interactions, immune characteristics, and conducting experimental validation through immunohistochemistry (IHC) arrays and Western blot to compare expression levels between tumor and normal tissues, analyze the associations with clinicopathological features, and investigate its responses to chemotherapies. Results: ALDH2 levels are downregulated in HNSC tissues and associated with higher American Joint Committee on Cancer (AJCC) T classification and worse overall survival in HPV-unrelated HNSC, yet not in HPV-related HNSC. ALDH2 is positively regulated by copy-number variation and negatively regulated by DNA methylation. The association of ALDH2 with prognosis may be due to its interaction with ALDH6A1, and its co-expressed genes are predictive biomarkers of HNSC. We also found high ALDH2 levels in bulk tumors are associated with increased immune surveillance cells, such as naïve B cells and M1 macrophages in HPV-unrelated HNSC. IHC and western blot showed that ALDH2 is downregulated in the oral cavity, hypopharyngeal cancers, and well-differentiated carcinoma. In vitro, low ALDH2 levels showed reduced response to 5-fluorouracil in HNSC-derived cell lines. Conclusion: Our analyses revealed the genetic and cellular targets and drug response of ALDH2 in HNSC. We also found ALDH2 is involved in regulating the immune response of the tumor microenvironment, and high levels of ALDH2 in bulk HNSC may enhance antitumor immunity, which could improve prognosis. These findings suggest that ALDH2 could be a potential biomarker in improving risk stratification and tailoring treatment strategies in HNSC patients, especially in the HPV-unrelated subgroup.

Abstract 321: Identification of proteins associated with FAT1 mutations which potentially contribute to oncogenesis and progression of head and neck cancers

Abstract Objectives: The Cancer Genome Atlas (TCGA) reported a FAT1 mutation rate of 23% in head and neck squamous cell carcinoma (HNSCC), which was higher in human papilloma virus (HPV)-negative cancer. Wild-type FAT1 exhibits a tumor suppressor activity, and the majority of mutated FAT1 genes are inactivated by missense or truncation, leading to altered or terminated gene products. However, the roles of FAT1 mutants in HNSCC oncogenesis and progression remain poorly understood. Methods: We investigated the landscape of altered protein and gene expression associated with FAT1 mutation, which predicted clinical outcomes of 329 HNSCC patients. The relationships of FAT1 mutation with clinical information from HNSCC datasets of TCGA were tested using Chi-Square or Fisher's exact test. The association of FAT1 mutation with more than 200 proteins or phosphorylated sites detected by Reverse Phase Protein Arrays (RPPA) was revealed using Student's T-test. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan Meier method, Log-rank tests, and COX model. Hierarchical clustering classified HNSCC subgroups, and the underlying signaling pathways and regulatory networks were revealed by Ingenuity Pathway Analysis (IPA). Results: Clinically, the prevalence of FAT1 mutation was significantly associated with HPV(-), female, or older patients, and enriched in the oral cavity and larynx/hypopharynx primary tumor sites. FAT1 mutation was significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, CAVEOLIN1 and VEGFR2, while twelve proteins were upregulated in patients with wild type FAT1, including immune check point molecule PD1. Poorer OS or PFS was observed in patients with FAT1 mutation and/or altered HER3_pY1289, IRS1, CYCLINE2, RET_pY905, P16INK4A, CMYC, MTORpS2448, or CAVEOLIN. IPA revealed dominant ERBB/neuregulin pathways, and protein signature panels divulged the heterogeneity of patient subgroups and predicted PFS. Alteration of FAT1 appears to involve mostly HPV-unrelated HNSCC and may contribute to the resistance to EGFR-targeted therapy and immunotherapy. Summary: We revealed dozens of actionable proteins associated with FAT1 mutation, which provide important insight into possible prospective clinical investigation with therapeutic relevance. (Supported by grants from a pilot Winship Invests Grant of Emory University Winship Cancer Institute to GZC and NFS; and NIDCD/NIH intramural projects Z01-DC-00016, 73, 74 to ZC, and partially by the University of Illinois Cancer Center Biostatistics Shared Resource Core). Citation Format: Zhuo Georgia Chen, Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, Nabil F. Saba, Zhong Chen. Identification of proteins associated with FAT1 mutations which potentially contribute to oncogenesis and progression of head and neck cancers [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 321.

The emergence of oral cavity cancer and the stabilization of oropharyngeal cancer: Recent contrasting epidemics in the South Korean population.

By analyzing the recent epidemiologic trajectory of head and neck squamous cell carcinoma (HNSCC) in South Korea, we tracked 2 findings that have been reported recently in other countries: the stabilization of human papillomavirus (HPV)-related HNSCC incidence and the acceleration of oral cavity cancer incidence. We analyzed data from the comprehensive population-based Korean Central Cancer Registry for the period 1999 to 2017. The age-standardized incidence rate (ASR), annual percent change (APC), and relative survival were calculated. The ASR of total HNSCC decreased from 1999 to 2017 (APC, -0.2 [95% CI, -0.3 to -0.0]), as did the ASR of HPV-unrelated HNSCC (APC, -0.6 [95% CI, -0.8 to -0.5]); however, the ASR of HPV-related HNSCC increased (APC, 2.9 [95% CI, 2.5 to 3.2]). The rapidly increasing incidence of tonsil squamous cell carcinoma, which was the main subsite of HPV-related HNSCC, stabilized after 2011 (APC pre-2011, 6.8 [95% CI, 5.0 to 8.3]; APC post-2011, 1.6 [95% CI, -2.1 to 5.5]), and the difference was significant (P = .017). In contrast, oral cavity cancer incidence demonstrated the only increase among HPV-unrelated subsites, with the increase occurring after 2006 (APC pre-2006, 1.6 [95% CI, 0.3 to 2.8]; APC post-2006, 2.8 [95% CI, 2.2 to 3.5]); the main cause of this change was an increase in the ASR of tongue cancer. This study demonstrates the recent stabilization of tonsil cancer incidence and the contrasting increase in oral cavity cancer incidence, unlike other HPV-unrelated cancers. These trends require further surveillance and understanding in terms of tumor biology and prevention.

Nanoparticle albumin-bound paclitaxel with cetuximab and carboplatin as first-line therapy for recurrent or metastatic head and neck cancer: A single-arm, multicenter, phase 2 trial

ObjectivesMacropinocytosis promotes internalization of albumin into cells to serve as a nutrient supply and is constitutively driven by signaling pathways frequently hyperactivated in head and neck squamous-cell carcinoma (HNSCC). In this way, drugs bound to albumin may selectively target HNSCC. nab-paclitaxel is a nanoparticle albumin-bound formulation of paclitaxel that improves drug delivery into tumor compared to paclitaxel. The primary aim of this single-arm, multicenter, phase 2 trial was to determine if nab-paclitaxel, cetuximab, and carboplatin (CACTUX regimen) would result in longer progression-free survival (PFS) than the historical regimen (EXTREME: 5-fluorouracil, cetuximab, and a platinum). Materials and methodsPatients with untreated recurrent or metastatic HNSCC received six, three-week cycles of nab-paclitaxel, cetuximab, and carboplatin, followed by maintenance nab-paclitaxel and cetuximab until progression. We hypothesized the median PFS with CACTUX would be 35% longer than with EXTREME (corresponding to 7.6 vs 5.6 months; power 0.80, α = 0.05, one-sided test, n = 70). Secondary outcomes included objective response rate (ORR) and overall survival (OS). ResultsSeventy-four patients enrolled into the trial; seventy were evaluable. The median PFS was 6.1 months (95% CI, 4.1–7.4). The ORR was 60%. Median follow-up was 18 months (IQR: 4.7–23). The median OS was 17.8 months (95% CI, 8.5–21.7) for all patients, and 19.8 months (95% CI, 10.9–22.0) for human papillomavirus (HPV)-related oropharynx SCC and 14.0 months (95% CI, 4.6–23.3) for HPV-unrelated HNSCC. ConclusionAmong patients with recurrent or metastatic HNSCC, CACTUX did not result in a longer PFS than historical EXTREME. However, CACTUX did result in a more favorable ORR and OS.

Abstract B01: Surgical outcomes following neoadjuvant hypofractionated radiation in combination with nivolumab: High rate of pathologic complete response in patients with p16+ head and neck squamous cell carcinoma

Abstract Hypothesis: Hypofractionated radiation therapy (HFRT) in combination with checkpoint blockade may modulate the tumor microenvironment to induce favorable antitumor immune responses and enhance surgical resection. Purpose: The purpose of this first-in-human phase Ib clinical trial was to test the safety and immunologic effects of neoadjuvant immunoradiotherapy prior to surgery in patients with head and neck squamous cell carcinoma (HNSCC) (NCT03247712). Methods: Patients with previously untreated stage I-III (AJCC 8th Ed) p16 positive squamous cell carcinoma of the oropharynx (OPSCC) or cervical lymph nodes from an unknown primary (SCCUP) were eligible to enroll. Neoadjuvant treatment consisted of sandwich nivolumab in combination with HFRT to gross tumor volume in one of two dose-finding cohorts of 8Gy x5 (Monday-Friday) or 8Gy x3 (Monday-Wednesday-Friday), followed five weeks later by definitive surgical resection. The primary endpoint was < 33% unplanned surgical delay; secondary endpoint was pathologic response. Surgical complications were assessed using the Clavien-Dindo scale, a validated scoring tool for surgical complications, applied for 90 days postoperatively. Serial blood and tissue specimens were obtained longitudinally for immunogenomic changes over time. Results: 10 patients (stage: T0N1M0, N=3; T1N1M0, N=1; T2N1M0, N=6) enrolled and underwent neoadjuvant immunoradiotherapy prior to surgery with curative intent, which consisted of selective neck dissection (level II-IV) and transoral robotic assisted oropharyngectomy for patients with mucosal disease. Surgery was safely performed in all patients without delay, thus meeting the primary endpoint. 7 patients demonstrated a partial radiologic response (PR) by RECIST criteria prior to surgery and 3 patients had stable disease (SD). The pathologic complete response rate (pCR) was 90% (8GyX5 cohort=5/5; 8GyX3 cohort=4/5) with the remaining patient achieving a major pathologic response (MPR; <10% viable tumor cells). All patients were successfully downstaged prior to surgery (ypT0N0M0=9; ypT0N1M0=1) and no patient required adjuvant radiation or chemoradiation. Grade 3 surgical complications as assessed by Clavien-Dindo occurred in 3/5 patients in the 8Gy X5 cohort, but there were no grade 3 or 4 complications in in the 8Gy X3 cohort. All patients are alive without evidence of disease (median follow-up <1 year). Conclusions: Neoadjuvant HFRT in combination with nivolumab is safe, does not delay definitive surgical resection, and results in significant downstaging with major pathologic response. A lower toxicity profile favors a radiation dose of 8Gy x3 for future development in both human papilloma virus (HPV)-related and HPV-unrelated HNSCC. Citation Format: R. Bryan Bell, Rom Leidner, Marcus Couey, Ashish Patel, Amber Watters, Hong Ziao, Carlo Bifulco, Brian Piening, George Morris, Lessli Rushforth, Dawn Brucker, Shoren Nemeth, Kristina Young, Michael Gough, Marka Crittenden. Surgical outcomes following neoadjuvant hypofractionated radiation in combination with nivolumab: High rate of pathologic complete response in patients with p16+ head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B01.

Nab-Paclitaxel-based induction chemotherapy followed by cisplatin and radiation therapy for human papillomavirus-unrelated head and neck squamous-cell carcinoma.

In patients with locally advanced human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC), cisplatin and radiation therapy (CisRT) resulted in a local-regional recurrence (LRR) rate of 35%, progression-free survival (PFS) of 49%, and overall survival (OS) of 60%. We, and others, showed that nab-paclitaxel is an active agent in metastatic and locally advanced HNSCC. The aim of this report was to assess the efficacy of nab-paclitaxel-based induction chemotherapy and CisRT in HPV-unrelated HNSCC. We performed a retrospective single-institution analysis of patients treated with nab-paclitaxel-based chemotherapy and CisRT. Key inclusion criteria included stage III-IV HPV-unrelated HNSCC. Induction chemotherapy included nab-paclitaxel and cisplatin (AP), AP + 5-fluorouracil (APF), or APF + Cetuximab (APF-C). Endpoints included LRR, overall relapse, PFS, and OS. Thirty-eight patients were the subject of this analysis. Patient characteristics included median age 59years (IQR: 54-64) and smoking history in 36 patients (95%). Primary tumor sites included larynx/hypopharynx (27), p16 negative oropharynx (10), and oral cavity (1). Most patients had bulky disease: 82% T3-4 (n = 31) and 74% N2b-3 (n = 28). Median follow-up was 44months (IQR: 23-59). The three-year LRR rate was 16% (95% confidence interval [CI] 7-34) and the overall relapse rate was 22% (95% CI 11-41). The three-year PFS was 64% (95% CI 46-77) and OS was 72% (95% CI 54-84). Among patients with HPV-unrelated HNSCC, nab-paclitaxel-based induction chemotherapy and CisRT resulted in a lower-than-expected rate of LRR and more favorable PFS and OS compared to historical results with CisRT.

Palbociclib plus cetuximab versus placebo plus cetuximab in platinum-resistant, cetuximab-naive, HPV-unrelated head and neck cancer: A double-blind randomized phase II trial (PALATINUS).

6013 Background: Cetuximab monotherapy results in a median overall survival (OS) of approximately 6 months (mo) in platinum-resistant recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). HNSCC unrelated to human papillomavirus (HPV) is driven by hyperactivation of the CDK4/6 and cyclin D1 (CD1) regulatory complex, resulting in cell cycle progression and tumor growth, suggesting that CDK4/6 inhibition can be a rational therapeutic strategy in this setting. Palbociclib (PAL) is a selective CDK4/6 inhibitor that may reverse cetuximab resistance by countering the actions of deregulated CD1. PAL plus an epidermal growth factor receptor inhibitor synergistically reduced cell viability of HPV-unrelated HNSCC cell lines. In a single-arm, multicenter trial of platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC, PAL in combination with cetuximab resulted in a median OS of 9.5 mo. Methods: In a double-blind randomized phase II trial, patients (pts) with platinum-resistant, cetuximab-naïve, HPV-unrelated HNSCC were treated with cetuximab plus either PAL (arm A) or placebo (arm B). Pts were stratified by performance status (PS) and prior immunotherapy (IT). 120 pts were required for 1:1 randomization to have ≥ 80% power to detect a hazard ratio (HR) of 0.6 (corresponding to a median OS of 10 mo in arm A and 6 mo in arm B) using a 1-sided log-rank test P=0.10). Key secondary endpoints included progression-free survival (PFS), adverse events (AEs), and p16 status. Results: Pts (n=125) were randomized (arm A, 65; arm B, 60). PS and prior IT were balanced between the arms. Median (95% CI) follow-up for OS was 15.9 (15.0–19.4) mo. Median OS was 9.7 (7.3–13.9) mo in arm A and 7.8 (6.7–10.6) mo in Arm B (stratified by PS: HR=0.82 [95% CI, 0.54–1.25], P=0.18). Median PFS was 3.9 mo in arm A and 4.6 mo in arm B (stratified by PS: HR=1.00 [0.7–1.5], P=0.5). Hematologic AEs were more common in arm A. Only 11 pts (9%) received IT after being treated on the trial. Conclusions: Among pts with platinum-resistant, HPV-unrelated HNSCC, PAL plus cetuximab resulted in a trend of prolongation of median OS compared with cetuximab. Clinical trial information: NCT02499120.

Nab-Paclitaxel-based induction chemotherapy with or without cetuximab for locally advanced head and neck squamous cell carcinoma

ObjectivesTo explore the effect of incorporating cetuximab into induction chemotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC). Materials and methodsRetrospective comparative analysis of two consecutive prospective phase II trials was performed: trial 1 with nab-paclitaxel/cisplatin/5-FU and cetuximab (APF-C; n=30) and trial 2 with APF (n=30). Patients were scheduled to receive chemoradiation therapy (CRT) with cisplatin. T2-4 classification oropharynx (OP)/larynx/hypopharynx SCC were included. Cumulative incidence of death of disease (CIDD), overall survival (OS), and cumulative incidence of relapse were compared between APF-C and APF. ResultsNo significant differences in patient or tumor characteristics were noted between the groups. Median follow-up of surviving patients was 52 (25–95) months. Relapse occurred in 5 (17%) patients treated with APF-C and in 2 (7%) treated with APF (p=0.37). In human papillomavirus (HPV)-related OPSCC (n=34), the CIDD at 52months was 3.4% with APF-C and 2.6% with APF and the two-year OSs were 94%. In HPV-unrelated HNSCC (n=25), the CIDD at 52months was 4.4% with APF-C and 3.3% with APF and two-year OSs were 83% and 92%, respectively. CIDD or OS did not differ when stratified by treatment group and HPV status (CIDD: p=0.80; OS: p=0.30). ConclusionThis exploratory retrospective comparative analysis demonstrated no significant difference in CIDD, OS, or cumulative incidence of relapse between patients treated with APF-C or APF.

Nab-Paclitaxel, cisplatin, and 5-fluorouracil followed by concurrent cisplatin and radiation for head and neck squamous cell carcinoma

ObjectivesWe previously reported the efficacy of nab-paclitaxel added to cisplatin, 5-FU, and cetuximab (APF-C) followed by concurrent high dose bolus cisplatin and radiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In this phase II trial, we determined the efficacy of APF (without cetuximab) followed by CRT in similar patients. Materials and methodsEligible patients had stage III–IV oropharynx (OP), larynx, or hypopharynx SCC and adequate organ function and performance status. T1 tumors were excluded. Patients were treated with three cycles of APF followed by CRT. Efficacy endpoints included two-year disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS), and relapse rate. ResultsThirty patients were enrolled. Most patients were smokers (77%) with bulky T3/4 (73%) and N2/3 (83%) tumors. Analyses were stratified for human papilloma virus (HPV) status: HPV-related OPSCC (n=17; 57%) and HPV-unrelated HNSCC (n=13; 43%). With a minimum follow-up of 21months, relapse occurred in 1 (3%) patient. Two-year DSS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year PFS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year OS was 94% in HPV-related OPSCC and 92% in HPV-unrelated HNSCC. Causes of death were relapse (1), treatment-related mortality (1), and co-morbidity (1). Two patients with HPV-unrelated HNSCC treated with APF declined CRT and remained free of relapse at 36 and 28months of follow-up. ConclusionThis phase II trial demonstrated favorable two-year DSS, PFS, and OS and a low relapse rate in HPV-unrelated HNSCC and HPV-related OPSCC treated with APF followed by CRT.

SMYD2 overexpression is associated with tumor cell proliferation and a worse outcome in human papillomavirus–unrelated nonmultiple head and neck carcinomas

Human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease, and there are no suitable prognostic or predictive markers. The SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase for histone H3K36 and p53K370, that regulates transcription was previously found to be a cancer-promoting gene in esophageal squamous cell carcinoma. In this study, we investigated whether SMYD2 is a possible oncogene and a prognostic indicator in HPV-unrelated, multiple and nonmultiple HNSCC. Among 197 HPV-unrelated HNSCC cases, overexpression of SMYD2 protein was detected in 75 (60%) of 126 nonmultiple cases and 51 (70%) of 71 multiple cases. In nonmultiple cases, patients with SMYD2-overexpressing tumors had a worse overall survival rate than did those with nonexpressing tumors (P = .017, log-rank test), and SMYD2 positivity was independently associated with overall survival in the multivariate analysis (P = .003). In both nonmultiple and multiple groups, the combination of SMYD2 and p53 immunopositivity was a significant prognostic indicator (P = .027 and .015). In 5 HNSCC cell lines, overexpression of SMYD2 messenger RNA and protein was observed, but there was no notable amplification at 1q32-41.1. The proliferation of UM-SCC-17B HPV-unrelated HNSCC cell line was inhibited by knockdown of SMYD2 gene expression. These findings suggest that SMYD2 plays a role in tumor progression and might be a useful prognosticator in HPV-unrelated, nonmultiple HNSCC.

A phase I trial of the addition of the CDK 4/6 inhibitor palbociclib to cetuximab in patients with incurable head and neck squamous cell carcinoma (HNSCC).

6043 Background: Overexpression of cyclin D1 and inactivation of p16 occur in the majority ( > 90%) of HPV-unrelated HNSCC. Resistance to cetuximab and cisplatin, the two most effective systemic ag...

Incidence and risk factors of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma in HIV-infected individuals

To examine the risk and trends of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma (HNSCC) in HIV-infected individuals and assess whether immunosuppression (measured through CD4 cell count) and other risk factors impact HNSCC risk. Incident HNSCCs at HPV-related and HPV-unrelated anatomic sites were detected in HIV-infected participants from pooled data from 17 prospective studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 1996 and 2009. HNSCC cases were validated using chart review or cancer registry matching. Risk factors for incident HPV-related and HPV-unrelated HNSCC were explored using mixed effects Poisson regression in a full prospective analysis, and the effect of CD4 prior to cancer diagnosis was examined in a nested case control analysis. 66 HPV-related and 182 HPV-unrelated incident HNSCCs were detected among 82,375 HIV-infected participants. Standardized incidence ratios (SIRs) for both HPV-related (SIR=3.2, 95%CI=2.5-3.4) and HPV-unrelated (SIR=3.0, 95%CI=2.5-4.1) HNSCC were significantly elevated in HIV-infected individuals compared with the US general population. Between 1996 and 2009, the age-standardized HPV-related HNSCC incidence increased non-significantly from 6.8 to 11.4per 100,000 person-years (p-trend=0.31) while the age-standardized incidence of HPV-unrelated HNSCC decreased non-significantly from 41.9 to 29.3 per 100,000 person-years (p-trend=0.16). Lower CD4 cell count prior to cancer diagnosis was significantly associated with increased HPV-related and HPV-unrelated HNSCC risk. The standardized incidence of HPV-related and HPV-unrelated HNSCC are both elevated in HIV-infected individuals. Immunosuppression may have a role in the development of both HPV-related and HPV-unrelated HNSCC.

Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair.