Human epidermal growth factor receptor 4 (HER4) is a favorable prognostic marker of breast cancer: a systematic review and meta-analysis.

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).