Elevated serum HER-2 predicts poor prognosis in breast cancer and is correlated to ADAM10 expression

Human epidermal growth factor receptor-2 (HER-2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER-2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER-2 ECD can be a marker of HER-2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER-2 ECD shedding and tissue HER-2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER-2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER-2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER-2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER-2 ECD concentration was related to tissue HER-2 status. Nevertheless, 36.9% of patients with tissue HER-2 overexpression had low levels of HER-2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER-2 ECD shedding was also associated with protein expression and alpha-secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression-free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER-2 IHC 3+ were analyzed using Kaplan-Meier plotter. The patients with serum HER-2 ECD above 15 ng/mL had lower progression-free survival than those with serum HER-2 ECD <15 ng/mL. Thus, serum HER-2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER-2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.