Central Nervous System Failure in Korean Breast Cancer Patients with HER2-Enriched Subtype: Korean Radiation Oncology Group 16-15 Multicenter Retrospective Study / 한국유방암학회지

PURPOSE: The purpose of this study was to evaluate the risk of central nervous system (CNS) failure in Korean patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer treated with surgery followed by postoperative radiotherapy (RT). METHODS: A total of 749 patients from eight institutions were enrolled in this study. All of them underwent surgery followed by postoperative RT from 2003 to 2011; 246 (32.8%) received neoadjuvant chemotherapy and 649 (81.7%) received adjuvant chemotherapy. Adjuvant trastuzumab was administered to 386 patients (48.6%). RESULTS: The median follow-up duration was 84 (range, 8–171) months. The 7-year disease-free and overall survival rates were 79.0% and 84.2%, respectively. On multivariate analysis, mastectomy, nodal involvement, and presence of lymphatic invasion were correlated with poor overall survival (p = 0.004, 0.022, and 0.011, respectively), whereas T stage and lymphatic invasion were associated with disease-free survival (p = 0.018 and 0.005, respectively). Regarding CNS failures, 30 brain metastases, 2 leptomeningeal metastases, and 8 brain and leptomeningeal metastases were noted. The 7-year CNS relapse-free survival rates in patients receiving and not receiving trastuzumab were 91.2% and 96.9%, respectively (p = 0.005). On multivariate analysis, the administration of adjuvant trastuzumab was the only prognostic factor in predicting a higher CNS failure rate (hazard ratio, 2.260; 95% confidence interval, 1.076–4.746; p = 0.031). CONCLUSION: Adjuvant trastuzumab was associated with higher CNS failure rate in Korean patients with HER2-enriched breast cancer. Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.

Expression of T-Lymphocyte Markers in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer / 한국유방암학회지

PURPOSE: The present study aimed to examine the clinical implications of CD4, CD8, and FOXP3 expression on the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer using a web-based database, and to compare the immunohistochemical expression of T-lymphocyte markers using primary and metastatic HER2-positive tumor tissues before and after HER2-targeted therapy. METHODS: Using the cBioPortal for Cancer Genomics and Kaplan-Meier plotter, the mRNA expression, association between T-lymphocyte markers, and survival in HER2-positive cancers were investigated according to various cutoff levels. Immunohistochemistry analysis was performed using paired primary and metastatic tissues of 29 HER2-positive tumors treated with systemic chemotherapy and HER2-directed therapy. RESULTS: HER2 mRNA was mutually exclusive of T-lymphocyte markers, and a significant correlation between T-cell markers was observed in the cBioPortal for Cancer Genomics. According to analysis of the Kaplan-Meier plotter, the impact of T-lymphocyte marker expression on survival was statistically insignificant in clinical HER2-positive tumors, irrespective of the cutoff levels. However, in the intrinsic HER2-positive subtype, the individual analyses of T-cell markers except for FOXP3 and combined analysis showed significantly favorable survival irrespective of cutoff points. Although the small clinical sample size made it difficult to show the statistical relevance of immunohistochemistry findings, good responses to neoadjuvant treatments might be associated with positive expression of combined T-lymphocyte markers, and approximately half of the samples showed discordance of combined markers between baseline and resistant tumors. CONCLUSION: T-lymphocyte markers could be favorable prognostic factors in HER2-positive breast cancers; however, a consensus on patient section criteria, detection methods, and cutoff value could not be reached. The resistance to HER2-directed therapy might involve different and personalized mechanisms, and further research is required to understand the association between immune function and HER2 expression and to overcome the resistance mechanisms to HER2-targeted therapies.

Expression and significance of WWOX、ErbB2 and Ki67 in non-small cell lung cancer / 中国综合临床

Objective To study the expression of WWOX, ErbB2 and Ki67 protein in non-small cell lung cancer(NSCLC) and the relationships with cell proliferation. Methods WWOX and ErbB2 protein expressions were evaluated by immunohistochemistry in 81 NSCLC patients (50 squamous cell carcinomas,31 adenocarcinomas and 20 adjacent normal lung tissues) and the correlations with histopathologic cell proliferation were analyzed. Results WWOX expression was absent/reduced in 72.8% of NSCLC, while it was normal in 80.0% of adjacent normal lung tissues. WWOX expression was strongly associated with tumor histology, histologic grade and lymph node metastasis ( X2 = 5.44, P = 0.019 ; X2 = 4.740, P = 0.029, X2 = 4.51, P = 0.034 ), reduced WWOX expression was higher in squamous cell carcinomas and in poorly differentiated tumors. The overexpression of ErbB2 was associated with TNM stage and lymph node metastasis ( X2 = 6.90, P = 0.009 ; X2= 5.68, P=0.017). WWOX expression was negatively related to the overexpression of ErbB2 (r=-0.239, P <0.05 ). WWOX expression intensity was nega-tively related to the high index of cell proliferation (r=-0.252, P<0.05 ). Conclusion The loss of WWOX ex-pression plays different roles in tumorigenesis of NSCLC and is related to high aggressiveness of tumors. The loss of WWOX expression and the overexpression of ErbB2 can estimate the prognosis of NSCLC.

Expression of c-erbB-2 and Cyclooxygenase-2 in Pancreatic Ductal Adenocarcinoma

Background : Carcinoma of the pancreas is a fatal malignant disease with limited therapeutic options. Cyclooxygenase-2 (COX-2) and c-erbB-2 are known to be involved in the carcinogenesis, differentiation and invasiveness of various neoplasms. We studied the immunohistochemical expressions of c-erbB-2 and COX-2 and the correlation between these expressions and the clinicopathologic parameters and the relation between the expressions. Methods : Immunohistochemical staining for c-erbB-2 and COX-2 were performed on the paraffin embedded sections of 36 cases of surgically resected ductal adenocarcinoma of the pancreas and 10 cases of non-neoplastic pancreas tissue. Results : The non-neoplastic control group showed a c-erbB-2 expression in the acini (8/10) and ducts (2/10), and a COX-2 expression in the acini (6/10) and ducts (3/10). The overexpression of c-erbB-2 was observed in 58% (21/36) of the carcinoma specimens. No significant correlation was found between c-erbB-2 and age, gender, tumor size, gross type, histologic grade, vascular invasion, perineural invasion, lymph node metastasis, and the TNM stage. The overexpression of COX-2 was observed in 41.7% (15/36) of the carcinoma specimens. The COX-2 expression was significantly high in the lymph node metastasis group (p<0.05), but it was not correlated with the other clinicopathologic parameters. Also there was no significant correlation between the c-erbB-2 and COX-2 expressions. Conclusions : In pancreatic ductal adenocarcinomas, c-erbB-2 and COX-2 were frequently overexpressed, and COX-2 overexpression was correlated with lymph node metastasis.

Genetic Expression Pattern of Gastric Carcinomas According to Cellular Mucin Phenotypes

BACKGROUND: Gastric carcinomas (GCs) have recently been reclassified according to the mucin phenotypes. We aimed to characterize the relationship between the mucin phenotypes and the genetic alterations or the clinicopathologic parameters of GCs. METHODS: Immunohistochemistry was performed for MUC1, MUC5AC, MUC6, MUC2, CD10, p53, hMLH1, CerbB2 and E-cadherin in 150 GCs. The mucin phenotypes of the GCs were classified as 4 phenotypes: gastric, intestinal, mixed and unclassified. RESULTS: MUC1, MUC5AC, MUC6, MUC2 and CD10 were expressed in 63.3%, 42.7%, 14.0%, 24.7% and 14.0% of the GCs, respectively. The mucin phenotypes of the GCs corresponded to the gastric type in 31.3%, the intestinal type in 20.0%, the mixed type in 15.3% and the unclassified type in 33.3%. The incidence of a p53 overexpression was higher in the gastric or mixed phenotype than in the intestinal or unclassified phenotype. MUC5AC expression, p53 overexpression and the gastric or mixed phenotype were associated with poor patient survival by multivariate analysis. CONCLUSION: This study suggests the gastric or mixed mucin phenotype may more likely go through the p53 pathway in carcinogenesis and the mucin phenotype may be considered as a prognostic indicator.

Relation of p16 and C-erbB-2 Protein Expression to Theclinical Pathology Characteristics of Gastri c Cancer / 医学研究杂志

0.05). Conclusions The expression of p16、 C-erbB-2 protein is correlated with gastric cancer and p16、C-erbB-2 protein can be used to evaluate the biological behavior and prognosis of gastric cancer.

Overexpression of hTERT and c-erbB-2 are correlated in ovarian epithelial cancer / 부인종양

OBJECTIVE: It is still unclear how the abnormal hTERT expression is involved in the process of ovarian carcinogenesis. A recent report demonstrated that the introduction of c-erbB-2 could efficiently induce tumorigenicity of cells with the transfection of SV40 large T antigen and hTERT. It is designed to find correlation between overexpression of hTERT and c-erbB-2 in ovarian carcinogenesis. METHODS: Using immunohistochemistry, we tested whether overexpression of hTERT and c-erbB-2 were associated in ovarian cancer. Immunohistochemical staining of hTERT and c-erbB-2 was done in 63 cases of ovarian cancer. Overexpression of hTERT and c-erbB-2 were correlated to clinicopathological variables. RESULTS: Overexpression of hTERT was found in 7 (11.1%) of cases, whereas overexpression of c-erbB2 was founded in 3 (4.8%) of cases. It was found that overexpression of hTERT and c-erbB-2 were significantly correlated (p=0.03). Neither overexpression of hTERT nor that of c-erbB-2 was associated with any of clinicopathological variables, such as stage, grade, and histology. CONCLUSION: Although the significant correlation between hTERT and c-erbB-2 was found, the low frequency of overexpression of hTERT and c-erbB-2 suggests that cooperation of hTERT and c-erbB-2 may be minor mechanism of ovarian carcinogenesis.

Overexpression of hTERT and c-erbB-2 are correlated in ovarian epithelial cancer / 부인종양

OBJECTIVE: It is still unclear how the abnormal hTERT expression is involved in the process of ovarian carcinogenesis. A recent report demonstrated that the introduction of c-erbB-2 could efficiently induce tumorigenicity of cells with the transfection of SV40 large T antigen and hTERT. It is designed to find correlation between overexpression of hTERT and c-erbB-2 in ovarian carcinogenesis. METHODS: Using immunohistochemistry, we tested whether overexpression of hTERT and c-erbB-2 were associated in ovarian cancer. Immunohistochemical staining of hTERT and c-erbB-2 was done in 63 cases of ovarian cancer. Overexpression of hTERT and c-erbB-2 were correlated to clinicopathological variables. RESULTS: Overexpression of hTERT was found in 7 (11.1%) of cases, whereas overexpression of c-erbB2 was founded in 3 (4.8%) of cases. It was found that overexpression of hTERT and c-erbB-2 were significantly correlated (p=0.03). Neither overexpression of hTERT nor that of c-erbB-2 was associated with any of clinicopathological variables, such as stage, grade, and histology. CONCLUSION: Although the significant correlation between hTERT and c-erbB-2 was found, the low frequency of overexpression of hTERT and c-erbB-2 suggests that cooperation of hTERT and c-erbB-2 may be minor mechanism of ovarian carcinogenesis.

Epidermal Growth Factor Receptor and c-erbB-2 Expressions in Biliary Tract Cancers

PURPOSE: The expressions of epidermal growth factor receptor (EGFR) and c-erbB-2 have been considered to be implicated in the genesis and progression of cholangiocarcinomas. However, their clinical roles and pathological characteristics remain uninvestigated. The purpose of this study was to assess the expressions of EGFR and c-erbB-2, and to identify their clinical and pathological significances in biliary tract cancers. METHODS: One hundred and fourteen samples were obtained from surgically resected biliary tract cancers (72 extrahepatic bile duct cancers, 33 gallbladder cancers, and 9 intrahepatic bile duct cancers). Expressions of EGFR and c-erbB-2 were examined by immunohistochemical staining. Expression rates were analyzed according to the location of the tumor, histologic differentiation, depth of invasion, lymph node metastasis, lymphovascular invasion, recurrence, and survival rate. RESULTS: The expression rate of EGFR was 10.7% in biliary tract cancers. EGFR expression was more often observed in moderately- or poorly-differentiated carcinomas than in well-differentiated carcinomas (p=0.0252). No correlations were observed with age, gender, location of tumor, depth of invasion, lymph node metastasis, lymphovascular invasion, recurrence rate, or survival rate. c-erbB-2 was expressed in 4.5% of biliary tract cancers. c-erbB-2 expression had no significant relationships with clinical and pathological prognostic factors. CONCLUSION: EGFR expression can be used restrictively as a prognostic indicator of biliary tract cancers. c-erbB-2 expression in biliary tract cancers is very low, and does not show any prognostic significance.

Expression of c-erbB-2 and ki67 proteins in simple intestinal metaplasia,atypical intestinal metaplasia and gastric adenocarcinoma / 中国现代普通外科进展

Objective:To study the expressions of c-erbB-2 and ki67 proteins in simple intestinal metaplasia(SIM),atypical intestinal metaplasia(AIM) and gastric adenocarcinoma,and the relationships among them.Methods:The immunohistochemical EnVision method was used to determine the expressions of c-erbB-2 and ki67 in 27 cases of SIM,26 cases of AIM and 37 cases of gastric adenocarcinoma.Results:The positive rates of c-erbB-2 and ki67 in gastric adenocarcinoma were significantly higher than that in SIM(P0.05).Conclusion:The high expression of c-erbB-2 and ki67 in AIM and gastric adenocarcinoma suggested that AIM may play an important role in gastric adenocarcinoma.The AIM is one kind of precancerosis of gastric adenocarcinoma.

Relationship between the expression of EGFR,C-erbB-2 proteins and the lung metastatic potential of salivary adenoid cystic carcinoma cell lines / 实用口腔医学杂志

Objective:To investigate the expressions of epidermal growth factor receptor(EGFR) and C-erbB-2 in two salivary adenoid cystic carcinoma cell lines with different metastatic potential. Methods:Salivary adenoid cystic carcinoma SACC-83 cell line and its lung metastatic cell line SACC-LM were cultured in vitro, their cytoplasm and membrane samples were extracted, and the expressions of EGFR and C-erbB-2 were detected by Western blot, the results were quantitatively analyzed by FluorChem V2.0 software.Results:EGFR expression level in cell membrane was higher than that in cytoplasm(P0.05) in both cell lines.Conclusion:Higher EGFR expression in cytoplasm and higher C-erbB-2 expression may be related to the metastatic potential of SACC-LM cells.

Expression of ER, PR and C-erbB-2 in breast cancer and their clinical significance / 肿瘤研究与临床

Objective To investigate the expression and clinical significance of ER, PR and C-erbB-2 in breast cancer. Methods 82 cases of primary breast cancer were examined for ER, PR and C-erbB-2 by immunohistochemical S-P methods. Results The expressions of ER, PR and C-erbB-2 were 54.9 %, 40.2 %, 47.6 % respectively. There was a negative correlation between ER and C-erbB-2(P

Clinicopathologic Characteristics and p53, c-erbB2, nm23 Protein Expression in Gastric Remnant Cancer / 대한암학회지

PURPOSE: The goal of this study was to evaluate the clinicopathologic characteristics and to investigate the expression of p53, c-erbB2, and nm23 protein in gastric remnant cancer. MATERIALS AND METHODS: We evaluated the clinicopathologic characteristics and expression of p53, c-erbB2, and nm23 protein in 37 cases gastric remnant cancer (GRC) that detected at least 5 years after initial surgery, and compare them with adenocarcinoma from intact stomach. Twenty-seven patients among the 37 patients of GRC and 271 patients of primary gastric cancer (PGC) were chosen for immunohistochemical staining against p53, c-erbB2, and nm23. RESULTS: The median age was 59 years, male was predominant and median time interval between operations were 15 years. GRC initially operated for benign disease were detected later after initial gastrectomy and had a tendency toward lymph node metastasis than those initially operated for malignant disease. Resection was performed in 31 patients (81.0%) in whom 28 patient (71.0%) with curative intent. The overall 5-year survival rate was 44.8%. Multivariate analysis had revealed that depth of invasion was the most significant prognostic factor. p53, c-erbB2, and nm23 protein expression rates of GRC were 44.4%, 14.8%, and 66.7%, respectively and those of PGC were 45.4%, 16.2%, and 85.1%, respectively. p53 protein was more frequently expressed in well differentiated, Laurens intestinal carcinoma in both GRC and PGC. p53 protein expression and depth of invasion had an inverse relationship only in GRC. c-erbB2 protein was more frequently expressed in well differentiated, Laurens intestinal carcinoma in PGC. nm23 protein expression was more frequently expressed in the group of positive lymph node metastasis in GRC. CONCLUSION: Early detection by periodic endoscopic follow-up and radical resection is a reasonable treatment policy for GRC. The results of p53, c-erbB2, and nm23 expression suggest that they might have somewhat different roles in the pathogenesis and progression in GRC and PGC, so further study may be of benefit hereafter.

Type of Intestinal Metaplasia in the Surrounding Mucosa of Gastric Carcinoma and Expression of bcl-2, p53 and c-erbB-2 Prtein in Gastric Carcinoma / 대한암학회지

PURPOSE: This study was carried out to clarify significance of types of intestinal metaplasia and roles of bcl-2, p53 and c-erbB-2 protein in the development of gastric carcinoma. MATERIALS AND METHODS: Total one hundred fifty nine cases of surgically resected stomachs with benign ulcer (n=21), dysplasia (n=18) and gastric carcinoma (n=120) were studied histologically, histochemically and immunohistochemically. RESULTS: Type III intestinal metaplasia was significantly more common in the carcinoma patients in older age group. Bcl-2 expression was found in 94.4% cases of dysplasia and 75.0% cases of carcinoma. Positivity for bcl-2 protein was significantly higher in intestinal type carcinomas than in diffuse type carcinomas (p=0.000). The expression of p53 protein showed 50.0% cases of dysplasia and 49.2% cases of carcinoma. The expression of p53 protein was significantly correlated with depth of invasion (p=0.000), regional lymph node metastasis (p=0.001), and tumor size (p=0.001). C-erbB-2 protein was only expressed in 15.0% cases of carcinoma. The expression of c-erbB-2 protein was found more often in advanced carcinomas (p=0.001) and carcinomas with regional lymph node metastasis (p=0.003). CONCLUSION: Type III intestinal metaplasia was associated with age, but not with types of gastric carcinoma. Bcl-2 protein is probably involved in dysplastic lesion of gastric carcinogenic sequence and associated with intestinal type carcinoma, and p53 protein is also involved in dysplasia. p53 protein and c-erbB-2 protein may have a role of tumor invasion and nodal metastasis as poor prognostic factors.

The clinical significance and detection of p53、c-erbB-2、p21、nm23 oncoprotein expression with immunohistochemical method in gastric cancer tissue / 中国免疫学杂志

Objective:To evaluate p53,c erbB 2,p21 and nm23 oncoprotein expression in diagnosis and treatment of gastric cancer.Methods:The expression of p53,c erbB 2,p21 and nm23 oncoproteins was detected with immunohistochemical method in 63 surgically resected specimens and its endoscopic biopsy specimens of gastric cancer.Results:The positive rates of p53,c erbB 2,p21 and nm23 oncoprotein expression were 37 6%～46 2%,34 6%～56 8%,37 8%～61 5%,70 3%～30 8% respectively.Oncoprotein expression was not observed in non tumor endoscopic biopsy specimens.The expression of c erbB 2,p21 was correlated with grade of tumor differentiation and the expression of p21,nm23 oncoproteins was correlated with the depth of tumor invasion and clinical different stage,namely tumor metastasis.Positive rates of p53,c erbB 2,p21 and nm23 oncoproteins between biopsy and resected specimens was of coincidence.Conclusion:Determination of p53,c erbB 2,p21 and nm23 oncoprotein expression was might be useful in diagnosis and treatment of gastric cancer,differentiating benign and malignant tumor and clinical stages,of gastric cancer. [