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  • Much evidence has demonstrated that the differential

    2021-10-13

    Much evidence has demonstrated that the differential HER2 level between normal tissue and a tumor helps to define HER2 as an ideal diagnostic and treatment target. Thus, HER2 status can be incorporated into a clinical decision, along with other prognostic factors, such as the N-Methyl-D-aspartic acid receptor (ER) and progesterone receptor (PR), regarding whether to give any adjuvant therapy. In clinical practice, HER2-positive breast cancer is normally treated with the monoclonal antibody, trastuzumab. Trastuzumab, marketed by Roche as Herceptin®, the first drug that targets HER2, is a recombinant humanized murine monoclonal antibody that targets the extracellular domain of HER2, resulting in inhibition of tyrosine kinase activity and cellular proliferation in tumors caused by HER2 overexpression [17]. The addition of trastuzumab to the chemotherapy regimen has been associated with a longer time to disease progression, a longer duration of response, a higher 1 year survival rate, and longer overall survival [17]. First released in 2007, updated in 2013 and newly focused updated in 2018, the N-Methyl-D-aspartic acid recommendations by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human HER2 testing Expert Panel are aimed at improving the analytic validity of HER2 testing and the clinical utility of HER2 as a predictive biomarker for potential responsiveness to therapies targeting the HER2 protein [18], [19], [20]. These guidelines pointed out that all newly diagnosed patients with breast cancer must have a HER2 test performed. Patients who then develop metastatic disease must have a HER2 test performed in a metastatic site, if tissue sample is available [20]. The set of recommendations from 2007, 2013 and 2018, highlighting changes, is listed in Table 1. Upon the request of guidance, a few methods have been developed for the detection of HER2 status in breast cancer specimens in clinical practice at the levels of protein and DNA (Table 2). Those assays have been approved by the FDA, such as immunohistochemical (IHC) detection of HER2 protein expression, in situ hybridization (ISH) assessment of HER2 gene amplification like fluorescent ISH (FISH). Currently, these two assays are most commonly used. Both IHC and FISH have the advantage of being morphologically driven, allowing for correlations between HER2 expression and morphologic features in tissue sections [39]. However, inconsistent results of IHC or FISH may be obtained, which are partially due to the variation in procedures made by different labs and partially stems from the inherent heterogeneity in distribution of HER2-positive tumor cells within the tumor [40]. Regarding these issues, several novel methods have been developed for HER2 testing in recent years. For example, mass spectrometry has emerged as a tool for HER2 testing because of its powerful quantification capability [41]. This chapter provides an overview of HER2 detection techniques with emphasis on those new methods. Notably, each method has its own advantages and disadvantages. There is still no consensus on which method is superior for assessing the HER2 status in breast cancer samples. These methods are discussed separately below.
    Commercial assays
    Methods in development and not yet approved by FDA
    Detection of the HER2 protein in serum samples Both the IHC and ISH methods lack “real-time” follow-up [107]. In clinics, these methods are mainly applied to tumor biopsies. As patients who were diagnosed with HER2-positive breast cancer and are undertaking treatment return for follow-up testing, the HER2 status is not routinely retested. However, the clinician may need to know whether the HER2 status of the tumor has changed and subsequently alter the treatment at times. Within this context, neither IHC nor ISH is a practical assay [31]. In contrast, patient serum may be a good option for real-time testing. Currently, it is well known that the extracellular domain (ECD) of the HER2 protein is cleaved and released into the circulation. Serum concentrations of HER2 are elevated in 20%–50% of patients with primary breast cancer and in 50%–62% of those with metastatic disease [108]. Normal individuals usually have a HER2 concentration between 2 and 15ng/mL in serum, whereas breast cancer patients have serum HER2 levels in the range of 15–75ng/mL [109]. Moreover, serum collection is noninvasive, which may reduce patient suffering from biopsy.