Human epidermal growth factor receptor 2 expression in head and neck squamous cell carcinoma: Variation within and across primary tumor sites, and implications for antigen-specific immunotherapy

Abstract

Background: The purpose of this study is to describe human epidermal growth factor 2 (HER2) overexpression in head and neck squamous cell carcinoma (HNSCC) and re-evaluate its potential as a target for HER2-directed immunotherapies.

Methods: A retrospective cohort of patients with HNSCC receiving curative treatment was identified, and HER2 expression evaluated in archival tissue by immunohistochemistry and correlated with clinicopathological characteristics. HER2 expression data were also determined for HNSCC patients in The Cancer Genome Atlas.

Results: Nineteen percent of HNSCC and 39% of oropharyngeal HNSCC (OPSCC) were HER2 positive. HER2 expression positively correlated with nodal metastasis (p = 0.035). Patients with HER2-positive tumors had decreased overall survival (p = 0.012), including within the human papilloma virus-positive OPSCC subgroup (p = 0.007).

Conclusions: A substantial fraction of HNSCC overexpresses HER2 protein, suggesting it may be a suitable target for antigen-directed immunotherapy. HER2 expression and its correlation with survival vary across HNSCC subsites, making it unsuitable as a prognostic marker.

Keywords: head and neck squamous cell carcinoma; human epidermal growth factor receptor 2 human papilloma virus immunotherapy oropharynx.

FIGURE 1

Representative immunohistochemical staining of human epidermal growth factor receptor 2 positive cells in head and neck squamous cell carcinoma. (A) Tumors with complete absence or nonspecific staining were scored as a 0. (B) Tumors with an H-score of 50 demonstrated at least weak staining in up to 50% of the cells present. (C) Tumors with an H-score of 100 demonstrated moderate staining in up to 50% of the cells present. (D) Tumors with H-scores of 225 demonstrated strong staining in up to 75% of the cells present. (E) The maximum H-score possible is 300, with strong staining in over 75% of cells. This image was taken at higher magnification (40X objective) to demonstrate membrane staining. All scale bars represent 100 μm [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Kaplan-Meier analysis of overall survival (OS), disease-free survival (DFS) according to clinicopathologic parameters for 115 patients with primary head and neck squamous cell carcinoma: (A,B) Primary tumor site (larynx, oral cavity, oropharynx); (C,D) T classification; (E,F) lymph node status; (G,H) human epidermal growth factor receptor 2 (HER2) expression. The OS correlated significantly with HER2 expression (p = 0.012); DFS showed a similar trend with HER2 expression but it was not significant (p = 0.066)

FIGURE 3

Kaplan-Meier survival curves of TCGA database patients with oropharyngeal or laryngeal SCC, according to: (A,B) human epidermal growth factor receptor 2 (HER2) RNA expression and (C,D) HER2 protein expression. Overall survival (OS) is significantly improved in the upper tertian of HER2 RNA expression (“HER2 RNA+”) (p < 0.001). There is no difference in OS based on HER2 protein expression. For laryngeal SCC, there is better OS for the upper tertian of both HER2 RNA expression and protein expression (p = 0.327 and 0.004). (E) Based on a linear regression, HER2 RNA expression (ERBB2 RNA seq) and HER2 protein expression are only loosely correlated in head and neck squamous cell carcinoma from all three sites, with an R squared of 0.24

FIGURE 4

Kaplan-Meier analysis of overall survival (OS), disease-free survival (DFS) in the TMA and TCGA subsets of OPSCC according to HPV status and human epidermal growth factor receptor 2 (HER2) expression. (A,B) HER2 expression. There is a significant improvement in OS and DFS in HPV positive patients (p < 0.001 and 0.001). (C,D) Conversely, HER2 positivity corresponds to a significant decrease in OS (p = 0.037). There is a non-significant trend toward improved DFS in patients with HER2 overexpression (p = 0.162). (E, F) Within the HPV+ subset of patients, those who were HER2+ had significantly worse OS and DFS (p = 0.007, 0.018). (G, H) In the TCGA group of OPSCC, HPV+ patients experienced improved OS (p < 0.0001); there was no effect of HER2 positivity on OS within the HPV+ subset (p = 0.539)