HER2 neu Carbon
A kind of protein inside that
HER2/neu
HER2/neu is an oncogene whose protein product may function as a growth factor receptor. It can be detected by IHC demonstration of the protein product or by gene amplifications. Overexpression or amplification has been shown to correlate with a poor prognosis; however, the studies differ with regard to the method of detection used and the interpretation of results. HER2/neu overexpression has been used as a predictor of response to certain chemotherapeutic agents. Particularly, increased response to doxorubicin-based therapy has been reported in the treatment of patients with positive nodes and overexpression of HER2/neu.
B Models with HER2/neu Overexpression
HER2/neu (also known as ErbB-2) is a member of the epidermal growth factor receptor (EGFR) family, also known as the ErbB protein family that includes EGFR, HER2, HER3, and HER4. The HER2/neu is a transmembrane glycosylated tyrosine kinase that consists of an extracellular domain, which interacts with other EGFR family members and an intracellular tyrosine kinase domain. HER2 forms heterodimers with other EGFR family members, induced by binding of EGF to the EGFR. The interaction allows HER2/neu heterodimers to serve as a coreceptor of EGFR. The heterodimers are more stable and, therefore, elicit more potent signals than other EGFR dimers without HER-2/neu. HER2/neu and other members of the EGFR family have been implicated in human prostate cancer initiation and progression to castration-resistant stages.135 Transgenic mice that overexpress HER2/neu in prostate epithelial cells with the PB promoter develop PIN by the age of 5 months, which progresses to invasive carcinoma after
3.19.2.5.1.4 HER2
The HER2/neu gene is one of the family of genes encoding transmembrane receptors for four growth factors, including the epidermal growth factor receptor (EGFR), HER2/neu, HER3, and HER4. The intracellular domain of HER2/neu has tyrosine kinase activity, which regulates cell growth and proliferation (Brand et al., 2006; Burstein, 2005; Holbro et al., 2003; Menard et al., 2004; Rubin and Yarden, 2001; Yarden, 2001). HER2/neu is over-expressed in 20–25% of invasive breast cancers and is associated with an aggressive tumor, early relapse, and reduced survival (Nahta and Esteva, 2006; Stefano et al., 2004; Tokatli et al., 2005). In one study, a tumor cell line over-expressing HER2/neu had higher levels of choline-containing compounds measured by in vitro 1H-MRS, including phosphocholine, glycerophosphocholine, and choline (Aboagye and Bhujwalla, 1999). This finding led to the hypothesis that growth factor-mediated activation of the tyrosine kinase cascade can lead to an increase in tumor phosphocholine levels. Agrawal et al. (2007) found a correlation between HER2/neu status and the choline signal on 1H-MRS in a limited number of lesions. Baek et al. (2008a) compared choline levels in HER2/neu-negative and positive tumors. Of 66 cancers investigated, 45 (68%) were HER2/neu-negative, and 21 (32%) were HER2/neu-positive. 1H-MRS was positive for choline in 53/66 (80%) patients, with a higher detection rate in HER2/neu-positive (91%) versus HER2/neu-negative (76%) tumors, but the difference did not reach a significant level. It was therefore suggested that in vivo 1H-MRS may not play a major role in characterizing HER2/neu expression in carcinoma of the breast.
Salivary Duct Carcinoma
Salivary duct carcinoma (SDC) is a relatively uncommon, clinically aggressive adenocarcinoma of salivary origin that is histologically similar to carcinoma of the breast. In a review of 104 cases in 1994, Barnes and colleagues247 noted that the tumor was three times more common in men and occurred primarily in patients older than the age of 50 years (range 22 to 91 years). The tumor occurs mainly in the parotid gland (88% of all cases), infrequently in the submandibular gland (8% of all cases), and rarely in the minor salivary glands (4% of all cases). The tumor may arise de novo or from a pleomorphic adenoma (carcinoma ex pleomorphic adenoma).
Microscopically, SDCs are characterized by both intraductal and infiltrating ductal carcinoma. The tumor grows in papillary, cribriform, and/or solid patterns, with central (comedo) necrosis (Fig. 9.25). In other instances the infiltrating tumor forms small ducts or cords of cells with a desmoplastic stromal resection such as seen in some forms of breast carcinoma. The tumor cells have amphophilic to pink cytoplasm and large, pleomorphic, vesicular nuclei with prominent nucleoli. Some have an apocrine appearance and can even demonstrate apical snouts. Mitoses, lymphatic, vascular, and perineural invasion are common. Dystrophic calcification may also be seen, sometimes even on radiographs, and may masquerade as calculi.
The presence of a uniform layer of cells around tumor islands that are positive for myoepithelial markers such as p63 is useful in identifying an in situ (intraductal) component of the tumor. Lewis and colleagues248 studied 25 cases and observed that 100% were positive for EMA, 88% for AE 1/3, 76% for GCDFP, and 72% for CEA. In contrast to breast carcinomas, which are frequently positive for estrogen and progesterone receptors, SDCs, with rare exceptions, are negative for these receptors. More than 90% of SDCs, however, are positive for androgen receptor (Fig 9.26).249 Rare cases may also stain with prostate-specific antigen (PSA) and/or prostatic acid phosphatase (PA), which together with a positive androgen receptor may result in confusion with a metastatic prostatic carcinoma.250
HER2/neu (C-erb B-2) overexpression has been found in 25% to 88% of SDCs (Fig. 9.27).251 Whether it has prognostic significance, however, is controversial. In one study of HER 2-neu and SDC, Skalova and colleagues252 observed that 8 of 11 cases showed strong distinct membrane staining for this marker (score 3+) with immunohistochemistry, while the remaining three cases were inconclusive with scores of 1+ to 2+. Using FISH, they observed that 4 of the 10 cases that were analyzed showed HER2/neu gene amplification. They, however, observed no differences in prognosis between amplified and nonamplified tumors. p53 positivity was found in 58% of SDCs studied by Felix and colleagues251 but did not correlate with the clinical course.
KEY DIAGNOSTIC POINTS
Salivary Duct Carcinoma
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Salivary duct carcinoma (SDC) resembles some breast carcinomas histologically.
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SDC is positive for androgen receptor and HER2/neu; HER2/neu is often amplified by FISH.
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ONCOGENES AND PROTO-ONCOGENES | Overview
R. Salgia, O. Abidoye, in Encyclopedia of Respiratory Medicine, 2006
HER2/neu
The HER2/neu gene is localized on the long arm (q21) of chromosome 17. This gene codes for a 185 kDa receptor-type tyrosine protein kinase (p185 neu or c-erbB-2) similar to EGFR. This 1255 amino acid transmembrane glycoprotein is composed of three domains: an extracellular factor-binding domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. In NSCLC, 25–30% of tumors overexpress HER2/neu, while a smaller percentage of patients with SCLC overexpress HER2/neu. This gene is involved in regulation of normal cell growth and differentiation, and can be associated with multiple signal transduction pathways. Overexpression of HER2/neu in lung cancer has shown a correlation with poor prognosis, and recently in some adenocarcinomas, HER2/neu mutations in the tyrosine kinase domain have been detected.
Trastuzumab (Herceptin, Genentech) is a humanized monoclonal antibody that targets the HER2/neu receptor. It has recently been FDA approved and is currently in several nonrandomized phase II trials in combination with cytotoxic chemotherapy.
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Ductal Carcinoma in Situ of the Breast
Melinda S. Epstein, ... Melvin J. Silverstein, in The Breast (Fifth Edition), 2018
Determination of HER2/neu Status and Potential Benefit of Neoadjuvant Trastuzumab
The HER2/neu gene is amplified or overexpressed in approximately 25% to 30% of invasive breast carcinomas.153 It is now standard of care to treat HER2/neu-positive invasive breast cancers greater than 10 mm with the monoclonal antibody trastuzumab (Herceptin). Indeed, this therapy has had a major impact on relapse in patients with HER2/neu-positive invasive breast cancers. Although approximately 40% of DCIS lesions also exhibit amplification and/or overexpression of HER2/neu,50,52,154,155 there is a lack of evidence that HER2/neu-positive DCIS will respond to trastuzumab therapy in a manner equivalent to invasive disease.
In 2012, Von Minckwitz and colleagues156 examined the effect of chemotherapy plus trastuzumab on HER2/neu-positive DCIS adjacent to HER2/neu-positive invasive breast cancer. Treatment reduced the volume of adjacent DCIS suggesting the possibility of a therapeutic impact of chemotherapy plus trastuzumab on the HER2/neu-positive in situ component.
In contrast, in 2011 Kuerer and colleagues157 described the results of a pilot study in which patients with large areas of HER-2/neu-positive DCIS (mean 5.2 cm) received a single dose of trastuzumab with follow-up surgical excision and reevaluation 14 to 28 days post therapy. No overt histologic response to the biological therapy was recorded; there was no alteration in ki67 or cleaved caspase.157 However, pretreatment increased antibody-dependent cell-mediated cytotoxicity.157
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Breast Cancer
Catherine Van Poznak, Andrew D. Seidman, in Encyclopedia of Cancer (Second Edition), 2002
VII.B.3 Monoclonal Antibody Therapy
The HER2/neu gene product is a transmembrane tyrosine kinase receptor belonging to a family of epidermal growth factor receptors structurally related to the human epidermal growth factor receptor. HER2/neu is overexpressed or amplified in approximately 30% of human breast cancers and is a poor prognostic feature. However, it predicts for a positive response to a monoclonal antibody, trastuzumab, targeted against the HER2/neu receptor. Trastuzumab has activity as a single agent and has been shown to improve response rate and overall survival when used in combination chemotherapy regimens. Trastuzumab demonstrated a significantly increased incidence of symptomatic cardiac toxicity when used simultaneously with anthracycline-based chemotherapy and therefore this combination is contraindicated outside of a clinical trial until further safety data are available.
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Brain Metastases from Breast Cancer in Patients Receiving Trastuzumab
Renata Duchnowska, Jacek Jassem, in Brain Metastases from Primary Tumors, Volume 3, 2016
HER2 Receptor
The HER2/neu proto-oncogene is located in chromosome 17q11-q21 (Popescu et al., 1989). In physiological conditions, this gene encodes a glycoprotein with molecular mass of 185 kDa (p185), named HER2 receptor or HER2 protein. HER2 and three structurally related tyrosine kinase receptors—HER1 (epidermal growth factor receptor (EGFR)), HER3 (ErbB3) and HER4 (ErbB4)—constitute the ErbB family. HER2/neu gene amplification and/or overexpression, which occur in 15–20% of invasive breast cancers and in up to 60% of intraductal breast carcinomas, play(s) an important role in signal transduction during cell growth (Slamon et al., 1987). Tumors with HER2/neu gene aberrations, compared to HER2/neu negative tumors, have a more aggressive clinical behavior, characterized by more frequent recurrences and shorter survival (Hynes and Stern, 1994). Upon activation, HER2 forms homodimers and/or heterodimers with EGFR, HER3, and HER4. This triggers a network of signaling cascades mediated mainly by AKT and MAPK, which regulate cell proliferation, angiogenesis, migration, and survival (Arteaga, 2003). Some studies suggest a dominant role for EGFR and HER3 as key coreceptors driving HER2-amplified breast cancers (Lee-Hoeflich et al., 2008).
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Invasive Breast Carcinoma
A. Sahin, H. Zhang, in Pathobiology of Human Disease, 2014
HER2/neu
HER2/neu holds the greatest promise as a single biomarker that has both prognostic and predictive value. The human HER2 gene is located on chromosome 17 and encodes the transmembrane protein p185 with structural homology to the epidermal growth factor receptor. The receptors bind to extracellular growth factors and ligands (except the orphan receptor ERBB2), may become activated via phosphorylation, and are internalized for signaling or degradation. All normal cells and the majority of breast cancer cells bear two copies of the ERBB2 gene and produce low levels of the encoded protein p185. ERBB2's activation of important downstream signal transduction systems influences cell motility, invasion, apoptosis, and proliferation and affects other procarcinogenic pathways, thereby having diverse effects on cancer cell biology.
Extensive studies have demonstrated that HER2 amplification and its associated protein overexpression are present in 15–30% of breast cancers. Comparing to HER2-negative tumors, breast carcinomas with HER2 overexpression have higher proliferation rates, higher motility, and invasive potential; thus, they tend to have more opportunity for regional and distant metastases and more aggressive clinical course. HER2 abnormality detected by either fluorescence in situ hybridization (FISH) or IHC is usually associated with other markers of poor outcome, including nodal metastases, high histological grade, hormone receptor negativity, and younger age, which limits its prognostic value. However, HER2 abnormality predicts response to anti-HER2 treatments such as trastuzumab or other generic chemotoxic agents.
Trastuzumab (Herceptin) is a humanized monoclonal antibody that interferes with the HER2/neu receptor. Since its approval by the US Food and Drug Administration (FDA) for patients with invasive breast cancers with HER2 overexpression, trastuzumab has made a major impact on the treatment of HER2-positive breast cancers, initially in only patients with metastatic disease, but later as an adjuvant treatment for patients with localized breast cancers. Many clinical trials have found that the combination of trastuzumab and cytotoxic chemotherapy increases disease-free survival and overall survival despite its efficacy in the treatment of HER2-positive breast cancers.
Trastuzumab is a very expensive drug with certain adverse effects. Therefore, correctly assessing a patient's HER2 status before making treatment decision is essential.
The two most commonly used methods to evaluate HER2 in breast cancer are IHC and in situ hybridization with FISH or chromogenic ISH (CISH). Using a HER2-specific antibody, IHC detects HER2 protein at the cell membrane in a semiquantitative manner. IHC is a slide-based assay that can be performed on fixed, paraffin-embedded primary tumor tissue. It facilitates the microscopic visualization of the primary tumor and the semiquantitative analysis of HER2 protein levels in the tumor cells. FDA-approved IHC assay kits, as well as other commercial and self-made reagents, are available for IHC testing for HER2. Two-colored FISH analysis for HER2 involves fluorescent probes, and CISH analysis involves chromogenic probes, to quantify the HER2 gene copy numbers in the tumor cells. IHC testing may be less reliable, less sensitive, and less accurate than in situ hybridization testing. Many laboratories use IHC as an initial screening test to identify more than 50% of patients whose disease is clearly HER2-negative. Indeterminate or weak positive cases are then retested using FISH or CISH. To minimize the subjectivity and variation of HER2 testing, the American Society of Clinical Oncology and College of American Pathologists (CAP) collaborate to provide HER2/neu testing guidelines, which are updated and refined as additional clinical data become available, to standardize the preanalytic and analytic issues in performing HER2 testing and interpreting the results.
An additional variable for HER2 assessment is intra- and intertumoral heterogeneity, which has become a critical issue in the decision-making process in the treatment of patients with metastatic breast cancers. Pathologists typically examine only one section or fragment of tumor tissue, which is believed to be representative of the primary tumors and/or metastases. The HER2 expression or gene copy number of recurrent or metastatic lesions may vary from that of the primary tumor in up to 10% of patients. In addition, scoring systems that use a cutoff value do not reflect the heterogeneity noted in the representative samples. In 2009, CAP expert panel published supplemental HER2 testing recommendations suggesting that tumors in which FISH detects HER2 amplification in 5–50% of the cells to be reported as 'heterogeneous for HER2 gene amplification.' CAP also strongly suggests the test methodology and dichotomous reporting scale to be included in the final pathology report. However, the optimal criteria for reporting HER2 heterogeneity in routine pathology practice have not yet been identified.