Survey of Her2-neu Expression and its Correlation with Histology of Gastric Carcinoma and Gastroesophageal Junction Adenocarcinoma

Background: There is increasing evidence that HER2-neu is an important biomarker in gastric carcinomas (GC) and gastroesophageal junction (GEJ) adenocarcinomas. The aim of this study was to evaluate HER2-neu expression and also some clinicopathological features of these neoplasms. Materials and Methods: We selected 211 paraffin-embedded blocks, 193 GC and 18 GEJ. Then 4 micron sections were prepared for staining with hematoxylin and eosin and also for IHC (Her2-neu). The Chi-square test was used for significance between expression of HER2-neu and clinicopathological parameters. Results: In patients with advanced cancer of GC and GEJ, HER2-neu overexpression was more associated with the intestinal cancer subtype. Conclusions: This could be a guide to new complementary therapy for affected patients.     

HER2阳性胃癌临床病理特征分析

[目的]分析胃癌HER2阳性率,探讨HER2阳性胃癌临床病理特征。[方法]采用免疫组织化学法（IHC）检测HER2蛋白表达,采用荧光原位杂交（FISH）检测HER2基因扩增。[结果]110例胃癌组织HER2IHC阳性率为6．4％（7／110）,FISH阳性率为14．5％（16／110）。排除IHC2＋,IHC与FISH检测结果符合率为96％。HER2总体阳性率为10．9％。Lauren分型肠型胃癌HER2阳性率高于混合型和弥漫型（18．0％vs5．0％,P〈0．05）。WHO分型管状腺癌HER2阳性率高于其他类型（19.3％VS2．3％,P〈0．05）,中、高分化胃癌HER2阳性率高于低分化胃癌（20．0％vs5．7％,P〈0．05）。HER2阳性率在不同年龄、性别、肿瘤部位、肿瘤大小、淋巴结转移和TNM分期胃癌中无统计学差异（P〉0．05）。[结论]胃癌HER2阳性与Lauren分型及wHO分型、分级有关。     

Prevalence of HER2 Expression and Its Correlation with Clinicopathological Parameters in Gastric or Gastroesophageal Junction Adenocarcinoma in North-East Indian Population

Objective: Human epidermal growth factor receptor 2 (erbb2/HER2) overexpression, has now been implicatedin advanced gastric and gastroesophageal junction cancers. The study was conducted to determine the rate of HER2positivity in patients with locally advanced or metastatic gastric and gastroesophageal adenocarcinoma in North-EastIndia and to assess the impact of various demographic and clinical parameters on HER2 positivity. Methods: A total of68 patients of age >18 years of gastric and gastroesophageal adenocarcinoma diagnosed on histopathological examinationfrom September 2016 to February 2018 at Dr B Borooah Cancer Institute, Assam were enrolled for the observational(epidemiological) study. All patients were subjected to the HER2 immunohistochemistry test using a FDA-approved,standardized test kit. HER2 expression was correlated with various demographic and clinicopathological parameters.Results: The overall rate of HER2 positivity in the population studied was 56% (n=38). The rate was non-significantlyhigher in male, older age group (>60 years) and Hindu population. Similarly, HER2 positivity rate was higher in patientswith well differentiated histology and was more common in patients with stage II and III diseases, but neither of theassociations is statistically significant. HER2 positivity rate was significantly higher in proximal and in GEJ tumours(56% versus 44%, P=0.002). Conclusion: HER2 overexpression was evident in 56% of the North-East Indian patientswith locally advanced and metastatic gastric and gastroesophageal adenocarcinoma. The overexpression correlatedsignificantly with primary tumour site. Routine testing of gastric and gastroesophageal tumours for HER2 expressionis recommended to provide a therapeutic advantage in Indian patients.     

HER2-neu表达与胃癌预后关系的Meta分析

目的探讨肿瘤组织中HER2-neu表达与胃癌预后的相关性。方法计算机检索相关文献,运用Meta分析方法对纳入文献进行综合定量分析。计算合并相对危险比（HR）和95%可信区间（95% CI）。结果入选文献20篇,包括患者总数为4 398例。有单因素分析结果的文献16篇,一致性检验Q值为27.48（P=0.025）,合并HR为1.57（95%CI 1.30～1.90）;合并多因素分析结果的文献5篇,一致性检验Q值为4.03（P=0.401）,合并HR为1.30（95%CI 1.09～1.52）。结论HER2-neu是胃癌预后不良的一个生物标志物。     

DPPA2 Protein Expression is Associated with Gastric Cancer Metastasis

Gastric cancer (GC) as the fourth most common cause of malignancies shows high rate of morbidity appropriating the second leading cause of cancer-related death worldwide. Developmental pluripotency associated-2 (DPPA2), cancer-testis antigen (CT100), is commonly expressed only in the human germ line and pluripotent embryonic cells but it is also present in a significant subset of malignant tumors. To investigate whether or not DPPA2 expression is recalled in GC, our aim in this study was to elucidate DPPA2 protein expression in gastric cancer. Fifty five GC tumor and their related margin normal tissues were recruited to evaluate DPPA2 protein expression and its probable associations with different clinicopathological features of the patients. DPPA2 was overexpressed in GC cases compared with normal tissues (P < .005). While DPPA2 expression was detected in all GC samples, its high expression was found in 23 of 55 tumor tissues (41.8%). Interestingly, 50 of 55 normal samples (90.9%) were negative for DPPA2 protein expression and remained 5 samples showed very low expression of DPPA2. DPPA2 protein expression in GC was significantly correlated with lymph node metastasis (p = 0.012). The clinical relevance of DPPA2 in GC illustrated that high level expression of this protein was associated with lymph node metastasis supporting this hypothesis that alteration in DPPA2 was associated with aggressiveness of gastric cancer and may be an early event in progression of the disease. DPPA2 may be introduced as a new marker for invasive and metastatic GCs.     

HER2及VEGF在乳腺癌组织中的表达及其相关性研究(英文)

Objective:The aim of our study was to detect the correlation between the expressions of HER2 and VEGF in breast cancer, and their relations with some pathological factors. Methods:By immunohistochemistry technique, the expressions of HER2 and VEGF in the post-operation samples of 117 cases with breast cancer were assessed, and their relations with some pathological factors were analysed by statistical methods. Fifty samples of hyperplasia of mammary glands were observed as the control. Results: The positive...     

HER2 Expression in Ovarian Mucinous Carcinomas in Tunisia

Background: Ovarian mucinous carcinoma has a poor prognosis in advanced stages and a poor responseto conventional chemotherapy. An efficient treatment is not yet available. We heere investigated HER2expression and the potential for trastuzumab therapy in ovarian mucinous tumors. Materials and Methods:Immunohistochemistry was performed in formalin-fixed, paraffin-embedded tissue from 27 ovarian mucinoustumors including 14 carcinomas and 13 borderline tumors diagnosed in the Pathology Department, Farhet HachedHospital, Sousse, between 1993 and 2013. The HercepTest (DAKO) was used for immunohistochemistry. Results:HER2 expression was observed in only one borderline tumor (7.7%) and in 14.3% of mucinous carcinomasof the ovary. Conclusions: Our results suggest that trastuzumab therapy would be an option for patients withmucinous carcinoma when the tumor has HER2 overexpression.     

Correlation between HER2 Expression and Clinicopathological Features of Breast Cancer: A Cross- Sectional Study in Vietnam

Background: HER2 is the target of the therapeutic agents which are used to treat HER2-positive breast cancer. Reports have shown that the HER2 oncogene expression and its association with clinicopathological factors remain unclear in breast cancer (BC) patients.  This study aimed to determine the correlation between HER2 expression and clinicalpathological characteristics of breast cancer in Vietnamese women. Methods: Between June 2016 and August 2018, paraffin-embedded specimens from 237 patients with primary invasive breast carcinoma in Hue University Hospital and Hue Center Hospital, Hue city, Vietnam were examined for pathological features. The gene expression of HER2, ER, PR and Ki-67 were determined by immunohistochemistry (IHC). The gene amplification of Her2 was assessed by using Dual color in situ hybridization (DISH). Results: The most frequent histological type was invasive carcinoma of no special type (NST) with 77.35%, the highest percentage of patients with Grade II was detected (59.36%), tumor size > 2 cm accounted for 71.31% of cases, Lymph node metastases were available in 57.86% cases. Most patients were diagnosed at stage II (59.18%). The majority of patients were classified as moderate Nottingham prognostic index (54.9%). Estrogen receptor and Progesterone receptor were positive in 53.16% and 50.63%, respectively. 76.37% of cases were in high expression group of Ki-67 (≥14%). HER2 IHC 2+, 3+ were accounted for 28.69% and HER2 gene amplification was detected in 31% cases. HER2 gene amplification and/or overexpression was significantly associated with cell proliferation index Ki67. Furthermore, HER2 gene expression tended to be more frequently found in tumors with large tumor size, high grade, high stage and high Nottingham prognostic index and confirmed their prognostic independent role. Conclusions: Our data indicated that HER2 gene expression was significantly correlated with cell proliferation index Ki67, but not significantly associated with another clinicopathological factors in breast cancer of Vietnamese women.     

胃癌原发灶和淋巴结转移灶HER2表达的临床意义

目的 观察HER2在胃癌原发灶和淋巴结转移灶中的表达及其临床意义.方法 选取胃癌患者140例,其中淋巴结转移94例.采集胃癌患者的原发灶、淋巴结转移灶及癌旁组织,采用免疫组织化学法(Elivision)方法检测3种组织中HER2蛋白表达情况.结果 140例胃癌原发灶组织中HER2蛋白阳性表达与胃癌TNM分期、浸润深度及淋巴结转移有关(P<0.05),而与患者性别、年龄和分化程度无关(P>0.05),癌旁组织中HER2表达与性别、年龄、分化程度、TNM分期、浸润深度及淋巴结转移均无关(P>0.05);HER2蛋白在胃癌原发灶、淋巴结转移灶中表达水平均高于癌旁组织,差异有统计学意义,而94例淋巴结转移灶和对应的胃癌原发灶中HER2表达的差异无统计学意义;94例有淋巴结转移的患者淋巴结转移灶与原发灶HER2表达一致率为89.4%,两类标本HER2表达状态具有一致性(Z=6.386,P<0.001).结论 胃癌HER2蛋白的阳性表达与胃癌TNM分期、浸润深度及淋巴结转移有关,提示HER2的表达与胃癌的浸润转移有关;胃癌原发灶和淋巴结转移灶HER2的表达具有较好的一致性,患者在不能获取原发病灶的情况下,检测转移灶中HER-2可能为靶向治疗的选择提供依据,为晚期胃癌患者带来希望.     

Relationship of HER2 Alteration and Microsatellite Instability Status in Colorectal Adenocarcinoma

Background

The impact of HER2 somatic mutations in colorectal carcinoma (CRC) has not been well studied and its relationship with microsatellite instability-high (MSI-H) is yet to be fully elucidated.

Materials and Methods

From February 2017 to February 2020, the data of patients with CRC who underwent next-generation sequencing and had detailed record of clinicopathological information were investigated. HER2 alteration and its relationship with MSI-H were analyzed.

Results

Among 731 patients who underwent sequencing, 55 patients (7.5%) had HER2 alteration, including 29 (4.0%) with HER2 somatic mutations, 24 (3.3%) with HER2 gene amplification, and 2 patients (0.2%) with both HER2 mutations and amplification. R678Q was the most common mutated kinase domain, and no HER2 kinase domain in-frame insertions/deletions were found in HER2 mutated cases. MSI-H was found in 5.2% of our cohort and 36.8% of MSI-H patients had HER2 mutation. For HER2 mutated cases, 48.3% were MSI-H, whereas none of the HER2 amplification cases were MSI-H. MSI-H patients with HER2 mutation had significantly worse median progression-free survival for programmed death-1 (PD-1) antibody than those without HER2 alteration (p = .036).

Conclusion

High MSI-H rate was found in HER2 mutated cases, but no MSI-H was found in HER2 amplification cases. MSI-H patients with HER2 mutated had worse progression-free survival for PD-1 antibody than those without.

Implications for Practice

This study highlights the high microsatellite instability-high (MSI-H) rate in HER2 mutated cases but no MSI-H in HER2 amplification cases. Moreover MSI-H patients with HER2 mutated had worse progression-free survival for programmed death-1 antibody than those without. Further research to explore the internal relationship between HER2 alteration and MSI-H is needed.

     

Evaluation of HER-2/neu Overexpression in Gastric Carcinoma using a Tissue Microarray

Background: Amplification and overexpression of human epidermal growth factor receptor 2 (HER2 /neu) oncogene has considerable prognostic value in breast and gastric cancers. This study aimed to evaluatethe frequency, overexpression pattern, clinical significance, and concordance between the results for proteinexpression and gene amplification of HER-2/neu in gastric and gastro-esophageal junction carcinomas.Materials and Methods: In this study, 101 gastric tissue samples which were included in tissue microarray wereimmunohistochemically examined for overexpression of HER2/neu. Chromogenic in situ hybridization (CISH)was used for HER-2/neu amplification. The correlation of HER2/neu amplification with clinicopathologicalparameters was also assessed. In addition, concordance between CISH and IHC was detected. Results: This studydemonstrated a significant difference in the overexpression of HER2/neu in gastric tumors. The overexpression ofHER2/neu was significantly higher in intestinal type, poorly differentiated grade, large size (5 cm≤) and positivenodal involvement tumors (p-value=0.041, 0.015, 0.038 and 0.071, respectively). Also, amplification of HER2/neuaccording to CISH test, had a significant positive correlation with tumor size and tumor type (p-value=0.018 and0.058, respectively).Concordance between CISH and IHC was 76.9% in 101 evaluable samples. Conclusions:IHC/CISH differences were attributed to basolateral membranous immunoreactivity of glandular cells resultingin incomplete membranous reactivity and/or a higher rate of tumor heterogeneity in gastric cancers comparedto breast cancers. Therefore, this can be a potential marker for targeted therapy of malignant gastric tumors.     

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma

Background:

Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma.

Methods:

The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours.

Results:

Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis.

Conclusion:

The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.     

Differential Expression of HER2 and SKP2 in Benign and Malignant Colorectal Lesions

Background: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Both HER2 and SKP2 have a carcinogenic role in CRC making them attractive targets for tailored treatment. This work aims to correlate HER2 and SKP2 protein expression as well as HER2 gene amplification with clinicopathological parameters aiming at identifying potential candidates for targeted therapy. Methods: This Study was conducted on 127 paraffin-embedded tissue samples of different colorectal lesions [controls, chronic colitis, ulcerative colitis (UC), hyperplastic polyps (HPs), adenomas and CRCs] to investigate HER2 and SKP2 expression by immunohistochemistry (IHC), Selected CRC cases [equivocal (2+) and positive (3+) by IHC] were further evaluated by ISH (CISH and SISH ) to assess HER2 gene amplification. Results: Chronic colitis, UC, HPs and adenomas were HER2-negative. HER2 positivity (scores 2+ and 3+) was found only in15% of CRCs. Both SISH and CISH showed the same results with high concordance as 66.7% of equivocal and 100% of positive cases showed amplification of HER2 gene. SKP2 positivity was detected in 26.7% and 45% of adenomas and CRCs respectively, while other studied groups were negative. A significant correlation was noted between HER2 and SKP2 expression. Conclusion: A small percent of CRCs exhibited HER2 gene amplification, which would be potential candidates for anti HER2 therapy whereas IHC could be a primary screening test for patient selection. A potential carcinogenic role of SKP2 was suggested by the findings that SKP2 expression was undetectable in normal colonic mucosa but significantly increases from adenoma to carcinoma, hoping adenoma patients to get benefit from targeted therapy.     

Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Purpose

The purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.

Novel agents that downregulate EGFR,HER2, and HER3 in parallel

EGFR, HER2, and HER3 contribute to the initiation and progression of human cancers, and are therapeutic targets for monoclonal antibodies and tyrosine kinase inhibitors. An important source of resistance to these agents arises from functional redundancy among EGFR, HER2, and HER3. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR, HER2, and HER3 in unison. Here we describe the identification of compounds that kill breast cancer cells that overexpress EGFR or HER2. Cell death parallels downregulation of EGFR, HER2, and HER3. These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs). DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity. DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.     

HER2基因表达与骨肉瘤预后

目的:研究骨肉瘤中HER2基因的表达与临床预后的关系。方法:对82例骨肉瘤患者的临床病理资料进行回顾性研究,应用HER2单克隆抗体对组织切片进行免疫组织化学染色,并将上述资料与患者的预后进行分析。结果:骨肉瘤患者HER2表达与患者预后相关(P<0.05),HER2高表达的骨肉瘤患者预后较差。结论:HER2检测是骨肉瘤预后判断的一项有价值的指标;同时,HER2为骨肉瘤的治疗提供一种可能的生物靶点。     

曲妥珠单抗用于HER2阳性晚期胃癌治疗的近远期疗效及对患者肿瘤标志物的影响

目的 探讨曲妥珠单抗用于人表皮生长因子受体(HER2)阳性胃癌治疗的疗效及对患者血清肿瘤标志物的影响.方法 前瞻性入组HER2阳性胃癌患者80例,随机分为观察组(40例)和对照组(40例).对照组给予顺铂+卡培他滨化疗;在此治疗方案基础上,观察组于化疗第1天加用曲妥珠单抗静脉滴注,8 mg/kg.21 d为1个周期,2组均治疗6个周期.比较2组患者的临床疗效、血清肿瘤标志物水平和不良反应发生情况.结果 治疗6个周期后,观察组总有效率为55.0%,对照组总有效率为32.5%,2组差异有统计学意义(P<0.05);观察组患者的血清癌胚抗原(CEA)、单核细胞趋化因子(MCP-1)等水平均显著低于对照组,差异均有统计学意义(P<0.05).2组患者的恶心呕吐、肝功能损害等不良反应发生率均无统计学差异(P>0.05).结论 曲妥珠单抗具有较好的抗肿瘤效果,可改善HER2阳性胃癌患者的临床疗效,其机制可能与抑制IL-1β、上调MCP-1的表达有关.     

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.     

The Role of Human Epidermal Growth Factor Receptor (HER2/neu) in the Prognosis of Patients with Gastric Cancer

Objective: Gastric cancer is one of the oncological challenges, and tendency toward target therapy in this cancerhas been increased. Controversy still exists on prognostic value of HER2/neu expression and its relationship withclinicopathological characteristics and survival of gastric cancer patients. In this regard, the present study examinedthe status of HER2/neu in patients with gastric cancer and its prognostic effects. Methods: Pathological samples of 97gastric cancer patients diagnosed over the last 8 or 9 years (from 2008 to the end of 2017) and treated with 5-fluorouracil,Docetaxel, and Cisplatin (TCF) were studied in this investigation. Patients were assigned to two groups according totheir HER2/neu status. First group included patients with positive HER2/neu (Score 3) and second group involvedpatients with negative HER2/neu (Score 0 and 1). Patients were compared in terms of disease stage, survival rate,and mortality. Results: The mean age of patients was 58 years old. There were 75 men and 22 women in this study.In terms of disease stage, 4, 21, 41, and 31 patients were in stage I, II, III, and IV, respectively. Using IHC method,it was found that 27, 23, 25, and 22 patients had HER2/neu expression with score 0, score +1, score 2+ and score+3,respectively. We discovered that expression of positive HER2/neu was associated with male sex. We also observedthat survival and mortality rates following treatment initiation were significantly different between HER2/neu positiveand negative gastric cancer patients (P<0.01). Conclusion: Evaluation of HER2/neu status in gastric cancer patientsshowed that HER2/neu 3+ expression could reduce the patients’ survival. Therefore, it is recommended that patientswho may benefit from trastuzumab, be treated. A clinical multi-center trial should be also considered for use of thisdrug in adjuvant cases.