Identification of TargetableERBB2Aberrations in Head and Neck Squamous Cell Carcinoma

Abstract

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.

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…In a recent study only 2/42 (5%) laryngeal SCCs and 2/94 (2%) oral cavity SCCs were positive for ErbB2 (HER2) overexpression on immunohistochemistry. (206) Earlier studies have reported an inverse relationship between EGFR and HER2 expression although this was not observed by Maubec et al (2005) in metastatic cSCC and the absence of HER 2 positivity in our cohort precluded this assessment. (189) The lack of HER2 expression in these tumours mechanistically is likely to lead to higher EGFR activation as EGFR will homodimerize in the absence of its preferred heterodimeric partner.…”

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

“…Around 3% of SCCHN patient tumours express HER2, whereas activation of Src has been commonly involved in epithelial–mesenchymal transition or erlotinib resistance of SCCHN. 31–33 Moreover, one-fifth of breast cancer patient tumours have excessive HER2 expression, which means 80% of breast cancers do not possess dysregulated HER2. This suggests that in HER2 negative breast cancer and most cases of head and neck cancer, LDHA is not tyrosine phosphorylated by oncogenic receptor tyrosine kinases but that tyrosine phosphorylation of LDHA by kinase cascades involving cytoplasmic tyrosine kinases such as Src may mediate LDHA activation.…”

Genomic sequencing and precision medicine in head and neck cancers

“…Indeed, there have been reports of remarkable response of agents used in precision medicine paradigms that have not been traditionally used in a specific cancer type [77]. Early investigations into genetic aberrations in HNSCC suggest that multiple agents FDA-approved in other cancers may have potential in HNSCCs, such as using trastuzumab (currently approved for breast and gastrointestinal cancer) in ERBB2 positive HNSCCS [78]. …”