The relationship between expression of Her-2 and human papillomavirus and clinicopathological features in esophageal and stomach multiple primary cancers / 肿瘤研究与临床

Objective To analyze the relationship between expression of Her-2 protein and the infection of human papillomavirus (HPV) and clinicopathological features in upper gastrointestinal multiple primary cancers, and to explore the relationship between the different histological malignancies in a single-system. Methods 39 patients were primary esophageal squamous cell carcinoma and gastric/cardia adenocarcinoma. By using immunohistochemistry (IHC) methods, the expression of Her-2 protein in 39 cases of multiple primary cancers specimens were examined, and by using insitu hybridization (ISH) technology, the infection of HPV in the same ones were detected. Results The over-expression of Her-2 protein in esophageal squamous cell carcinoma was not significantly relative to the degree of differentiation, the depth of penetration, the lymph node metastasis and the patientsˊage and gender (P> 0.05). The over-expression of Her-2 protein in gastric adenocarcinoma was closely correlated to the invasion depth and lymph node metastasis (P 0.05). The infection of HPV in esophageal squamous cell carcinoma and gastric adenocarcinoma was not significantly relative to the degree of differentiation, the depth of penetration,the lymph node metastasis, and the age and gender of the patients (P> 0.05). In the upper gastrointestinal multiple primary cancers, the Her-2 protein over-expression had the consistency (κ= 0.56, P< 0.05). Meanwhile, the HPV-DNA expression also had the consistency (κ=0.80, P<0.05). Conclusion Both Her-2 protein and HPV expression show the consistency in upper gastrointestinal multiple primary cancers,which suggests that Her-2 protein and HPV may be the common oncogenic factors for both esophageal squamous cell carcinoma and gastric adenocarcinoma.

Comparison of hormonal receptor and HER2 status between ultrasound-guided 14-gauge core needle biopsy and surgery in breast cancer patients

PURPOSE: To evaluate the concordance of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) statuses between ultrasound (US)-guided 14-gauge core needle biopsy (CNB) and surgery and to analyze whether the clinicopathological and imaging features including those from mammography and ultrasonography can predict the concordance in breast cancer patients. METHODS: The concordance of receptor status between CNB and surgery was assessed for 55 breast cancers in 55 women who underwent CNB before treatment. The clinicopathological and imaging features and the concordance rates were compared between the non-neoadjuvant chemotherapy (non-NAC) group and the NAC group according to the initial treatment. The concordance rates were analyzed according to the clinicopathological and imaging features, by using the chi-square or Fisher exact test and McNemar test for the categorical and the independent t-test for continuous variables. RESULTS: Among 55 women, 22 women (40%) were part of the non-NAC group and 33 women (60%) were part of the NAC group. The concordance rates were 0.86-1.00 in the non-NAC group and 0.76-0.88 in the NAC group. In all three receptors, the difference in the concordance rate between the two groups was not significant. In the NAC group, the absence of axillary lymph node metastasis (1.00, P=0.02) and visibility of cancer on mammography (0.93, P=0.04) showed the higher concordance of the HER2 status. CONCLUSION: Concordance of the receptor status between surgery and US-guided 14-gauge CNB was feasible in breast cancer patients. The absence of axillary lymph node metastasis after NAC and the visibility of cancer on mammography prior to NAC may be helpful for predicting the concordance of HER2 in breast cancer patients.

Expresión y amplificación del gen HER2 en el cáncer gástrico avanzado / HER2 gene amplification and overexpression in advanced gastric cancer

Background:Overexpression/amplification of the HER2 gene in advanced gastric cancer is a predictor of response to adjuvant therapy with monoclonal antibodies.Aim: To determine the frequency of HER2 gene overexpression and amplificationin advanced gastric cancer. Material and Methods: One hundred nine advancedgastric cancer biopsy specimens, from 76 men and 33 women aged 67 ± 14 and 62± 12 years respectively, were selected. Three histological patterns (diffuse, intestinaland mixed) were recognized. Automated immunohistochemistry was performedwith monoclonal c-erbB-2 (NCL-356) Novocastra. Fluorescent in situ hybridization (FISH) for HER2 was performed in positive cases. Results: In 39% of cases,immunohistochemical staining was negative. It was 1+, 2+ and 3+ positive in 15,36 and 11% of cases, respectively. It was positive in 16% and 3% of intestinal typeand mixed carcinomas, respectively. It was negative in all diffuse carcinomas. FISHwas performed in 39 (2 +) cases and in 11 (3 +) cases. The gene amplification waspositive in two (2 +) and 11 (3 +) cases (11.9%). The overall concordance betweenimmunohistochemical staining and in situ hybridization was 85%. Conclusions: Inadvanced gastric cancer, HER2 gene overexpression or amplification was observed in11% and 12% of cases, respectively.

A functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on heregulin-beta1-induced MMP-1 and MMP-9 expression in breast cancer cells

Overexpression of HER2 correlates with more aggressive tumors and increased resistance to cancer chemotherapy. However, a functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on tumor metastasis has not been conducted. Herein we examined the regulation mechanism of heregulin-beta1 (HRG)-induced MMP-1 and -9 expression in breast cancer cell lines. Our results showed that the basal levels of MMP-1 and -9 mRNA and protein expression were increased by HRG treatment. In addition, HRG-induced MMP-1 and -9 expression was significantly decreased by MEK1/2 inhibitor, U0126 but not by phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002. To confirm the role of MEK/ERK pathway on HRG-induced MMP-1 and -9 expression, MCF7 cells were transfected with constitutively active adenoviral-MEK (CA-MEK). The level of MMP-1 and -9 expressions was increased by CA-MEK. MMP-1 and -9 mRNA and protein expressions in response to HRG were higher in HER2 overexpressed cells than in vector alone. The phosphorylation of HER2, HER3, ERK, Akt, and JNK were also significantly increased in HER2 overexpressed MCF7 cells compared with vector alone. HRG-induced MMP-1 and -9 expressions were significantly decreased by lapatinib, which inhibits HER1 and HER2 activity, in both vector alone and HER2 overexpressed MCF7 cells. Finally, HRG-induced MMP-1 and MMP-9 expression was decreased by HER3 siRNA overexpression. Taken together, we suggested that HRG-induced MMP-1 and MMP-9 expression is mediated through HER3 dependent pathway and highly expressed HER2 may be associated with more aggressive metastasis than the low expressed HER2 in breast cancer cells.

Pilot Study of the Clinical Significance of Serum and Urinary HER-2/neu Protein in Bladder Cancer Patients

PURPOSE: HER-2/neu overexpression is documented in some bladder cancers. To our knowledge, there are no current studies evaluating urine HER-2/neu levels. Therefore, we examined the clinical significance of serum and urine HER-2/neu protein in bladder cancer. MATERIALS AND METHODS: Urothelial bladder carcinoma patients (n=38, including 31 men and 7 women) and healthy controls (n=25, including 20 men and 5 women) were included in the study. Urine cytology and serum and urine HER-2/neu levels were measured before the transurethral resection of bladder tumor procedure. Prognostic factors including tumor stage, histologic grade, tumor size, multiplicity, and preoperative urine cytology and their association with urinary HER-2/neu were analyzed by simple and multiple regression analyses. RESULTS: There was no significant difference in serum HER-2/neu between the two groups (p=0.489). The mean urinary HER-2/neu was 7,586.82 relative luminescence unit (RLU) in bladder cancer patients and 4,245.84 RLU in healthy controls. The mean RLU values of urinary HER-2/neu in the bladder cancer patient group were significantly higher than in healthy controls (p=0.012). An receiver operating characteristic curve was generated, and using the cutoff value of > or =4,800 RLU of urinary HER-2/neu, 71.1% sensitivity and 84.0% specificity were obtained. Among the clinical factors, only positive preoperative urine cytology samples were associated with urinary HER-2/neu levels by both simple and multiple regression analyses. CONCLUSIONS: Bladder cancer patients demonstrated significantly higher urinary HER-2/neu than did healthy controls. These findings suggest that urinary HER-2/neu may be valuable as a new urinary marker. The application of urinary HER-2/neu needs additional investigation.

Automated Silver-enhanced In Situ Hybridization for Evaluation of HER2 Gene Status in Breast Carcinoma: Comparison with Fluorescence In Situ Hybridization and Immunohistochemistry

BACKGROUND: The human epidermal growth factor receptor 2 (HER2) is amplified in 20-25% of breast cancers. HER2 overexpression or amplification is associated with a worse clinical outcome and it can predict the benefit from anthracycline and anti-HER2 therapies. The HER2 status has usually been assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) in clinical samples. A new silver-enhanced in situ hybridization (SISH) technique was recently introduced. Therefore we evaluated the usefulness of SISH for detecting HER2 amplification. METHODS: Tissue microarrays (TMAs) were constructed with 144 invasive breast cancer tissue samples. We performed IHC, FISH and SISH for HER2 on the tissue sections from the TMAs and we interpreted the results according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. The concordant rates between the two different tests were calculated. RESULTS: HER2 was overexpressed and amplified in 16.9%, 16.9%, and 18% of the cases by IHC, FISH and SISH, respectively. The concordant rates between IHC and FISH, IHC and SISH, and FISH and SISH were 95.1%, 95.7%, and 97.8%, respectively. CONCLUSIONS: SISH can be an alternative test for evaluating HER2 amplification because the 97.8% concordance with FISH satisfies the ASCO/CAP requirement of > 95% concordance with an alternative validated method.