Predicting Tissue HER2 Status Using Serum HER2 Levels in Patients with Metastatic Breast Cancer

Abstract

Background: Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are reliable ways to identify amplification of the HER-2/neu (HER2, symbol ERBB2) gene, but each technique requires a high-quality tissue sample, which may not be available. We investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to tissue HER2 status in metastatic breast cancer, and we defined an optimal decision level of serum HER2 for prediction of tissue HER2 status. Methods: We determined HER2 expression in 195 metastatic breast cancer patients by IHC and performed FISH analysis on tumors for which IHC staining was graded as 2؉. We measured serum HER2 by immunoassay and used receiver operating characteristics (ROC) curve analysis to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status. Results: IHC results were 0/1؉ for 30 (15%) of the patients, 2؉ for 89 (46%), and 3؉ for 76 (39%). FISH revealed HER2 amplification in 19 (21%) of the IHC 2؉ tumors. Mean (SE) serum HER2 ECD was 22.2 (5.1) g/L in the tissue HER2-negative group, significantly lower than the concentration of 363 (96) g/L in the tissue HER2-positive group (P <0.0001). ROC curve analysis showed 95% specificity and 62% sensitivity for tissue HER2 positivity at 37 g/L of serum HER2. Conclusion: To use serum HER2 concentration as an alternative to direct determination of tissue HER2 status, we suggest 37 g/L as a cutoff for predicting positive tissue HER2 with 95% specificity. Sensitivity, however, is low.

Serum HER2 levels and HER2 status in tumor cells in advanced gastric cancer patients

“…First, using the cutoff value, 15 ng/ml, which is most widely used in breast cancer (7,9,10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), the evaluable 100 patients were stratified into serum HER2-positive (≥15 ng/ml) or -negative (<15 ng/ml) groups, as well as. Sensitivity and specificity were defined as the proportion of the true-positive (TP)/true-negative (TN) patients among tissue HER2-positive/negative patients.…”

CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients

“…Although serum HER-ECD levels represent a promising surrogate marker, various technical variables limit its wide application. The most important issues that have to be clarified are the optimal serum HER-ECD concentration threshold for differentiation between positive and negative HER status and the relatively low sensitivity and specificity of the method currently applied (42). Recently, a pooled analysis of seven clinical trials of first-line trastuzumab therapy (with or without chemotherapy) with serial measurements of serum HER-ECD indicated that patients with <20% decrease in serum HER-ECD levels have lower clinical benefit (31).…”

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

“…Attempts to use this serum-based test as the sole classifier of HER-2 status for newly diagnosed cases have not been widely accepted, although fairly good correlation exists between serum HER-2 ECD levels and the results of IHC and FISH assessments on primary tumor tissues [228]. It has been recommended that a 37 g/l serum HER-2 ECD cutoff be used, which can achieve 95% specificity but low sensitivity for HER-2-positive status determined on primary tumors [229]. Studies of breast cancer prognosis based on the serum ECD test have been conflicting, with some finding significant correlation [116] and others finding weak or no correlation [230].…”