Challenges in the clinical utility of the serum test for HER2 ECD.

The extracellular domain of Her2 in serum as a biomarker of breast cancer.

Determination of the human epidermal growth factor receptor 2 (HER2; also known as ERBB2) status of breast tumours is emphasised in various national guidelines as a necessary step for the diagnosis of breast cancer. As an alternative to tissue-based diagnostic methods, there has been substantial interest in the establishment of an easily accessible serum-based alternative that could be used for prognosis and diagnosis. Detection of serum-soluble-HER2 extracellular domain (ECD) and establishment of its potential clinical usefulness has created much debate. We assessed whether identification of circulating concentrations of HER2 ECD have clinical usefulness for management of patients with HER2-positive breast cancer. We examined data from 63 studies of patients with breast cancer. Prevalence of increased concentrations varied greatly between studies. Some studies showed significant associations between raised concentrations and poor prognosis, poor response to treatments including trastuzumab, or tumour characteristics associated with aggressive disease, whereas others did not. Examination of existing data showed that concentrations of HER2 ECD are not consistently related to patient outcomes; therefore, there is insufficient evidence to support the clinical use of serum HER2 ECD testing. Design and execution of future large-scale trials to investigate the clinical use of HER2 ECD testing, in view of the progressive non-supportive evidence, is not recommended. Oncologists should continue to adhere to national guidelines for determining HER2 status. Furthermore, oncologists should continue to use clinical parameters when making decisions about initiation, continuation, and discontinuation of HER2-targeted treatments.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(10)70297-7.pdf

Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls

Circulating Biomarkers in Breast Cancer.

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FceRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FceRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FceRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.

Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells

PURPOSE: The extracellular domain (ECD) of the HER2 receptor is proposed as a real-time marker of HER2-positive breast cancer (BC). In this study, ECD-HER2 levels were compared with standard clinical and pathological prognostic factors. PATIENTS AND METHODS: In 247 consecutive patients (116 with early or localized BC, 116 with advanced or metastatic BC, and 16 with benign mastopathies), serum ECD-HER2 levels were measured. In 116 advanced-disease patients ECD-HER2 status was also studied by immunohistochemistry (IHC) and compared with established clinical and pathological variables. RESULTS: Mean serum ECD-HER2 value was 19.62 ng/ml (median 10.35, range 3-->250). Mean value in benign mastopathies was 9.04 ng/ml, 9.4 ng/ml in early disease and 34.5 ng/ml in advanced disease. No difference between benign mastopathies and early BC was observed, while significant difference between early and advanced BC (p<0.001) was noted. However, in advanced-disease patients a positive correlation of ECD-HER2 with IHC (p=0.002), disease grade (p=0.034) and level II axillary node involvement (p=0.011) was noted, as well as a significant negative correlation with estrogen receptor (ER) and progesterone receptor (PR) (p=0.035 and p=0.011, respectively). CONCLUSION: ECD-HER2 is a reliable marker for breast cancer, as suggested from the existing literature; therefore, its integration in the initial workup and follow-up routine of breast cancer, particularly the HER2-positive, is proposed.

Extracellular domain of HER2: a useful marker for the initial workup and follow-up of HER2-positive breast cancer.

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Extracellular domain of HER2: a useful marker for the initial workup and follow-up of HER2-positive breast cancer.