Importance HER2 is an important drug target in breast cancer, where anti-HER2 therapy has been shown to lead to improvements in disease recurrence and overall survival. HER2 status in head and neck squamous cell carcinoma (HNSCC) has not been well studied. Identification of HER2 positive tumors and characterization of response to HER2 therapy could lead to targeted treatment options in HNSCC. Objective To identify HER2 aberrations in HNSCCs and investigate potential for HER2 targeted therapy in HNSCCs. Design, Setting, and Participants Retrospective case series of patients with laryngeal and oral cavity SCC enrolled in the University of MichiganSPORE. Publically available sequencing data(TCGA) was reviewed to identify additional mutations and overexpression in HER2 in HNSCC. Established HNSCC cell lines were used for follow-up in vitro analysis. Interventions Using targeted, amplicon-based sequencing with the Oncomine Cancer Panel, we assessed the copy number and mutation status of commonly altered genes in HNSCCs. Immunohistochemical staining was performed on tissue microarrays of HNSCCs to assess expression of HER2. Western blotting for HNSCC cell line HER2 expression, and cell survival assays after treatment with HER2 inhibitors were performed. Main Outcomes and Measures Prevalence of HER2 genetic aberrations and HER2 overexpression in laryngeal and oral cavity squamous cell carcinomas (SCCs). Prevalence of HER2 aberrations in HNSCC in TCGA. HER2 protein expression in HNSCC cell lines. Response of HNSCC cell lines to targeted HER2 inhibitors. Results Forty-two laryngeal SCC samples were screened by targeted sequencing, of which 4 were positive for HER2 amplification. Two samples identified with sequencing showed HER2 overexpression on immunohistochemistry. Two of 94 oral cavity SCC samples were positive for HER2 on immunohistochemistry. Analysis of 288 patients from publicly available HNSCC sequencing data revealed 9 amplifications in HER2. Protein expression was variable across HNSCC cell lines, and a subset of these cell lines show responsiveness to anti-HER2 therapy. Conclusions and Relevance HER2 aberrations are identified in a subset of HNSCCs. These tumors may be responsive to targeted therapy against HER2. Screening for HER2 aberrations and applying targeted therapy in HER2 positive patients may provide a useful tool for personalized therapy trials, particularly in patients that are refractory to current treatment paradigms.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with poor overall survival. New therapeutic strategies that target specific molecular lesions driving advanced disease are needed. Herein we demonstrate the utility of the chicken chorioallantoic membrane (CAM) assay for in vivo human HNSCC tumor growth and metastasis and the tumor suppressive effects of a new chemotherapeutic agent.MethodsWe tested anti-metastatic effects of a WNT pathway inhibitor, WNT974 (also known as LGK974), which targets porcupine (PORCN) the palmityl-transferase that is essential for secretion of Wnt proteins. CAM assays were performed with 8 HNSCC cell lines: UM-SCC-1, UM-SCC-10A, UM-SCC-10B, UM-SCC-11A, UM-SCC-14A UM-SCC-17A, UM-SCC-17B, UM-SCC-25, and UM-SCC-34.ResultsUM-SCC-1 (University of Michigan Squamous Cell Carcinoma cell line) CAM xenografts contain CD44+ and ALDH+ cancer stem cell (CSC) proportions similar to UM-SCC-1 mouse xenografts supporting the applicability of the CAM assay for study of CSCs. Inhibition of WNT signaling by the PORCN inhibitor WNT974 reduced metastatic spread of UM-SCC cells, especially in UM-SCCs with Notch1 deficiency.ConclusionsOur data demonstrate decreased tumor growth and metastases in tumors from cell lines that showed in vitro responses to WNT974, providing evidence that this agent may have a role in future HNSCC therapy.

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