Abstract
BackgroundDespite the preclinical outcomes and biologic significance of the presence of the human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD), there is little evidence supporting the measurement of ECD levels in any clinical setting. The aim of this study was to determine the prevalence of elevated serum HER2 ECD levels, the association between these levels and tissue HER2 overexpression, and the potential clinical prognostic value of HER2 ECD in primary invasive breast cancer.MethodsSerum HER2 ECD levels were examined preoperatively in 2,862 consecutive stage I–III primary breast cancer patients between 2007 and 2009. Serum HER2 ECD levels were measured by chemiluminescence immunoassay (ADVIA Centaur), and the tissue HER2 status was assessed by immunohistochemistry and fluorescence in situ hybridization. The cutoff value for the serum level of HER2 ECD was set at 15.2 ng/ml.ResultsAmong the 2,862 patients, 126 (4.4%) had elevated serum HER2 ECD levels, and HER2 was overexpressed in the tumor tissue of 692 patients (24.2%), with a concordance of 78.7%. Multivariate analysis revealed that elevated serum HER2 ECD was a significant independent prognostic factor for worse distant-metastasis-free survival [DMFS; hazard ratio (HR) = 2.50, 95% confidence interval (CI) = 1.5–4.3, P = 0.001] and breast-cancer-specific survival (BCSS; HR = 2.0, 95% CI = 1.1–3.8, P = 0.036), which were much stronger in patients with tissue HER2-positive tumors (DMFS: HR = 3.8, 95% CI = 2.0–7.0, P < 0.001; BCSS: HR = 2.6, 95% CI = 1.2-5.3, P = 0.012).ConclusionsGiven the prevalence of HER2 expression, its measurement as an independent prognostic factor can be clinically useful, particularly in patients with tissue HER2-positive tumors.
Highlights
Despite the preclinical outcomes and biologic significance of the presence of the human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD), there is little evidence supporting the measurement of ECD levels in any clinical setting
The quantification of serum HER2 ECD in primary breast cancer could theoretically enhance the sensitivity of tissue HER2 testing in the minority population in which HER2 expression is significant, but is not sufficiently high to be considered as HER2-positive by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guidelines, possibly due to tumor heterogeneity [11,20,21,22]
The aims of the present study were to establish the prevalence of elevated HER2 ECD levels, and determine whether there is an association between serum HER2 ECD levels and tissue HER2 overexpression in a large number of patients with primary breast cancer, using a single assay approved by the US Food and Drug Administration (FDA)
Summary
Despite the preclinical outcomes and biologic significance of the presence of the human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD), there is little evidence supporting the measurement of ECD levels in any clinical setting. Human epidermal growth factor receptor-2 (HER2) overexpression or amplification in tumor tissue is reportedly observed in 20–30% of primary breast cancers. The current consensus is that preoperative HER2 ECD appears to be correlated with tumor size and nodal involvement, it may not be related to tissue HER2 status, especially in primary breast cancer, and there is insufficient evidence to support incorporating measurement of this parameter into the routine clinical management of women with breast cancer as an independent prognostic factor [14,34]
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