title: 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.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Ning
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Merrimack Pharmaceuticals Inc, Cambridge, Massachusetts.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Merrimack Pharmaceuticals Inc, Cambridge, Massachusetts.
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D020890:Neuregulin-1 / Q000235:genetics*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors; D005819:Genetic Markers; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C000614131:CDKN2A protein, human; C094131:NRG1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: epidermal growth factor receptor (EGFR); head and neck cancer; heregulin; human epidermal growth factor receptor 3 (HER3); human papillomavirus