title: Human epidermal growth factor receptor 4 (HER4) is a favorable prognostic marker of breast cancer: a systematic review and meta-analysis.
abstract: Based on a large cohort of clinical studies involving a total of 8024 patients and reporting the effects of HER4 on breast cancer prognosis, we conducted the first meta-analysis and review of this type. We identified 26 studies published between 1985 and 2016 and assessed the prognostic value of HER4 in breast cancer by either real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR, for mRNA levels) or immunohistochemistry (IHC, for protein levels). Elevated expression of HER4 was significantly associated with longer relapse-free survival (RFS) (HR = 0.63; CI: 0.48-0.83; P = 0.001, random effects). Further subgroup analysis showed that our results were stable irrespective of subtype [Luminal: HR = 0.40, CI: 0.30-0.53, P < 0.001, fixed effects; triple negative breast cancer (TNBC): HR = 0.49, CI: 0.26-0.90, P = 0.02, fixed effects; and HER2-positive: HR = 0.53, CI: 0.40-0.71, P < 0.001, fixed effects]. Cytoplasmic HER4 was more effective than nuclear HER4 (HR = 0.74, CI: 0.60-0.92, P = 0.007, fixed effects) for predicting RFS. HER4 was also found to be a favorable prognostic marker for overall survival (OS) among patients with non-TNBC in the subgroup analysis (Luminal: HR = 0.71, CI: 0.52-0.95, P = 0.023, fixed effects; HER2-positive: HR = 0.48, CI: 0.26-0.89, P = 0.020, fixed effects).
authors.affiliation: Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China, Department of General Surgery, Jinan Hospital, Jinan, Shandong, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Epidemiology, School of Public Health, the University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Xingsong
authors.initials: X
authors.lastname: Tian
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D005260:Female; D015870:Gene Expression; D006801:Humans; D011379:Prognosis; D021381:Protein Transport; D017594:Publication Bias; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4
keywords: HER4/ErbB-4; breast cancer; marker; meta-analysis; prognosis