Simple SummaryOne of the great advantages of serum biomarkers is that they can be easily obtained in the form of a liquid biopsy of the patient’s blood, which is minimally invasive and allows for repeatable measurements. In particular, molecular biomarkers from signaling pathways provide information on tumor characteristics and heterogeneous molecular profiles and enable us to predict prognosis and develop a rationale for therapeutic strategies. The erythroblastic leukemia viral oncogene homolog (ERBB) family has been implicated in hepatocarcinogenesis and is associated with a worse prognosis in hepatocellular carcinoma (HCC). However, its role as a serum biomarker has not been fully evaluated. In the present study, we revealed that serum ERBB2 and neuregulin 4 (NGR4) are independent prognostic factors for survival and tumor recurrence and suggested a possible synergistic effect between these two prognostic factors. Our study could provide predictive biomarkers for evaluating HCC prognosis and monitoring treatment response in patients with HCC.AbstractAlthough the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719;p= 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338;p= 0.002) and NRG4 (HR, 431.763;p= 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC.