Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma

Abstract

Background: Although heregulin and human epidermal growth factor receptor 3 (HER3) are frequently expressed at high levels in patients with head and neck cancer, their prognostic value remains unclear. The authors explored the prognostic significance of heregulin/HER3 expression in patients with oropharyngeal squamous cell carcinoma (OPSCC), taking into account other HER family members as well as p16 status.

Methods: Ninety-six primary tumor specimens from patients with OPSCC were retrospectively collected and analyzed for heregulin messenger RNA (mRNA) using in situ hybridization and for HER3, epidermal growth factor receptor, and human epidermal growth factor receptor 2 (HER2) using quantitative immunohistochemistry. Heregulin and HER3 mRNA levels were also examined among different tumor types using The Cancer Genome Atlas database.

Results: High heregulin mRNA (> the median) correlated significantly with poor overall survival (OS) (hazard ratio [HR], 8.48; 95% confidence interval [95% CI], 2.17-33.17 [P =.002]) but not disease-free survival (HR, 1.52; 95% CI, 0.64-3.65 [P =.341]) in patients with OPSCC. Heregulin mRNA correlated negatively with OS in both patients with p16-positive (P =.049) and p16-negative (P =.091) OPSCC on univariate analysis. High HER3 (> the median) also correlated with poor OS (HR, 4.68; 95% CI, 1.47-14.90 [P =.009]) on multivariate analysis. Epidermal growth factor receptor levels independently correlated with disease-free survival (P =.025) and inversely correlated with p16 status (P =.012). In addition, The Cancer Genome Atlas data demonstrated that head and neck squamous cell carcinoma exhibits higher heregulin expression compared with other solid tumor types examined.

Conclusions: High heregulin mRNA and high HER3 protein levels were found to independently correlate with poor OS in patients with OPSCC. These data support targeting HER3 in patients with heregulin-high OPSCC and warrant further clinical investigation.

Keywords: epidermal growth factor receptor (EGFR); head and neck cancer; heregulin; human epidermal growth factor receptor 3 (HER3); human papillomavirus.

Figure 1

Expression profile of heregulin and HER family members in OPSCC patients. Heregulin (A), HER2 (C) and HER3 (D) expression was not significantly different between p16-positive and p16-negative patients, whereas EGFR expression (B) was higher in p16-negative patients. A marginally significant correlation was found between expression of HER2 and HER3 (E).

Figure 2

Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) in the overall OPSCC patients based on heregulin expression. High heregulin expression (> median) correlated significantly with poor OS (A) but not DFS (B).

Figure 3

Kaplan-Meier estimates of OS in p16-positive and p16-negative OPSCC patients. High heregulin expression (> median) was marginally correlated with poor OS in p16-positive (A) and p16-negative (B) OPSCC patients.

Figure 4

Comparison of heregulin and HER3 mRNA expression among different tumor types using TCGA data. The normalized RNA-Seq V2, gene-specific RSEM-derived expression values from each cancer were downloaded and displayed as box plots. Heregulin mRNA expression was significantly higher in HNSCC compared to other tumor types. HER3 mRNA expression was lower in HNSCC than other tumor types except for lung squamous cell carcinoma. *, compared to HNSCC, P < 0.001. #, compared to HNSCC, P < 0.001.