• Radiation Oncology Journal
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• v.25 no.4
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• pp.233-241
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• 2007

Purpose: We examined the effect of the dual EGFR/HER2 tyrosine kinase inhibitor, GW572016, on EGFR/HER2 receptor phosphorylation, inhibition of downstream signaling and radiosensitization in either an EGFR or HER2 overexpressing human breast cancer xenograft. Materials and Methods: We established SCID mice xenografts from 4 human breast cancer cell line that overexpressed EGFR or HER 2 (SUM 102, SUM 149, SUM 185, SUM 225). Two series of xenografts were established. One series was established for determining inhibition of the EGFR/HER2 receptor and downstream signaling activities by GW572016. The other series was established for determining the radiosensitization effect of GW572016. Inhibition of the receptor and downstream signaling proteins were measured by the use of immunoprecipitation and Western blotting. For determining the in vivo radiosensitization effect of GW572016, we compared tumor growth delay curves in the following four treatment arms: a) control; b) GW572016 alone; c) radiotherapy (RT) alone; d) GW572016 and RT. Results: GW572016 inhibited EGFR, HER2 receptor phosphorylation in SUM 149 and SUM 185 xenografts. In addition, the p44/42 MAPK (ERK 1/2) downstream signaling pathway was inactivated by GW572016 in the SUM 185 xenograft. In the SUM 225 xenograft, we could not observe inhibition of HER2 receptor phosphorylation by GW572016; both p44/42 MAPK (Erk1/2) and Akt downstream signal protein phosphorylation were inhibited by GW572016. GW572016 inhibited growth of the tumor xenograft of SUM 149 and SUM 185. The combination of GW572016 and RT enhanced growth inhibition greater than that with GW572016 alone or with RT alone in the SUM 149 xenograft. GW572016 appears to act as an in vivo radiosensitizer. Conclusion: GW572016 inhibited EGFR/HER2 receptor phosphorylation and downstream signaling pathway proteins. GW572016 modestly inhibited the growth of tumor in the SUM 185 xenograft and showed radiosensitization in the SUM 149 xenograft. Our results suggest that a better predictor of radiation response would be inhibition of a crucial signaling pathway than inhibition of a receptor.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2555-2558
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• 2016

Background: Gastric cancer is the second most common gastrointestinal cancer and is still associated with significant morbidity and mortality due to late presentation and diagnosis at advanced stages. Studies have reported that a variable proportion of gastric cancer is positive for the human epidermal growth factor receptor 2 (HER2) and patients with HER2 positive (HER2 +ve) lesions can benefit from targeted therapy. This study was conducted to assess the prevalence of HER2 +ve gastric cancers in Brunei Darussalam, a developing Southeast Asian nation. Materials and Methods: Patients were identified from the Department of Pathology registry and retrospectively reviewed. HER2 expression was assessed by immunohistochemistry and only those staining 3+were considered positive. Results: Our study included 103 cases (66 males and 37 females) with a mean age of $65.1{\pm}14.8$ years old. There were 14 cases positive for HER2 (10 males and 4 females) giving a prevalence of 13.6%. The HER2 +ve cases were significantly older ($70.6{\pm}19.3$ years old) than the negative cases ($64.2{\pm}13.8$, p=0.041) and had significantly more advanced disease (stages 3 and 4, p=0.026). There were no significant differences in gender distribution, presence of intestinal metaplasia, EBV status, Helicobacter pylori status, tumor location (proximal vs. distal) and degree of tumor differentiation (all p values >0.05). Conclusions: Our study showed that 13.6% of our gastric cancers are positive for HER2, the affected patients being older and having more advanced disease at diagnosis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7597-7602
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• 2014

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 evaluate the frequency, overexpression pattern, clinical significance, and concordance between the results for protein expression 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 were immunohistochemically 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 clinicopathological parameters was also assessed. In addition, concordance between CISH and IHC was detected. Results: This study demonstrated a significant difference in the overexpression of HER2/neu in gastric tumors. The overexpression of HER2/neu was significantly higher in intestinal type, poorly differentiated grade, large size ($5cm{\leq}$) and positive nodal involvement tumors (p-value=0.041, 0.015, 0.038 and 0.071, respectively). Also, amplification of HER2/neu according to CISH test, had a significant positive correlation with tumor size and tumor type (p-value=0.018 and 0.058, 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 resulting in incomplete membranous reactivity and/or a higher rate of tumor heterogeneity in gastric cancers compared to breast cancers. Therefore, this can be a potential marker for targeted therapy of malignant gastric tumors.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10607-10611
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• 2015

Background: HER2 expression in the primary tumor and its lymph node metastases vary in gastric cancer, reflecting intratumoral heterogeneity. This finding also suggests that proliferation of a different clone in metastatic nodes is possible. In the current study, we aimed to determine the cause of discordance in HER-2 expression in the primary tumor and lymph node metastases for patients with gastric cancer. Materials and Methods: Eighty-one patients with gastric cancer who had undergone radical gastrectomy and were found to have lymph node metastasis upon pathological examination were included. Histopathological samples were obtained from biopsies obtained during patient gastrectomies and lymph node dissection. HER2 status was evaluated by both immunohistochemistry (IHC) and silver in situ hybridization (SISH). Results: Sixty-four (79%) patients were SISH (-), while 17 (21%) were SISH (+) in the primary tumor. However, in metastatic lymph nodes, HER2 status was SISH positive in 5 (28.3%) of the 64 SISH (-) primary tumor specimens. One of the 17 SISH (+) primary tumors was SISH (-) in the metastatic lymph nodes. Thus, SISH results for HER2 in both primary tumors and lymph node metastases were comparable, showing a concordance of 92.5%. In total, six patients demonstrated discordance between the primary tumor and lymph node metastases. The prevalence of HER2 discordance was significantly higher for patients in the pN2 and N3 stages (p=0.007). Although discordant patients had worse survival rates than concordant patients, the differences were not significant (p>0.05).Conclusions: Our study indicates that the frequency of concordance in HER2 status, as determined by IHC or SISH, is high in primary tumors and their corresponding lymph node metastases for patients with gastric cancer. If there is a discrepancy in HER2 status, its evaluation by both IHC and SISH may be useful for detecting patients who would benefit from trastuzumab, and it would therefore help guide decision-making processes in administering treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3733-3736
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• 2016

HER2/neu is a well-established prognostic and predictive factor for invasive breast cancer. However, the role of HER2/neu in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that it is mainly linked to in situ local recurrence. Although molecular data suggest that atypical ductal hyperplasia (ADH) and duct carcinoma in situ (DCIS) are related lesions, albeit with vastly different clinical implications, the role of HER2/neu expression in atypical ductal hyperplasia is not well defined either. The aim of this study was to evaluate over expression of HER2/neu in DCIS and cases of ADH in comparison with invasive breast carcinoma. Archival primary breast carcinoma paraffin blocks (n=15), DCIS only (n=10) and ductal epithelial hyperplasia and other breast benign lesions (n=25) were analyzed for HER2/neu immunoexpression. Follow up was available for 40% of the patients. HER2/neu was positive in 80%of both DCIS and invasive carcinoma, and 67% of atypical ductal hyperplasia (ADH) cases. Thus at least a subset of patients with preinvasive breast lesions were positive, which strongly suggests a role for Her2/neu in identifying high-risk patients for malignant transformation. Although these are preliminary data, which need further studies of gene amplification within these patients as well as a larger patient cohort with longer periods of follow up, they support the implementation of routine Her2/neu testing in patients diagnosed as pure DCIS and in florid ADH.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6415-6421
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• 2012

Background: Canine mammary gland tumors (CMGTs) are the most common tumor found in bitches. Changes in HER-2/neu genes in human breast cancer (HBC) lead to decrease in disease-free survival (DFS) and overall survival rate (OSR). Previous studies have demonstrated that the biological behavior of malignant mammary gland tumors (MMGTs) is similar to that of HBC. The present study aimed at evaluating the relationship between overexpression of HER-2/neu and clinicopathological features in MMGTs to represent a model of prognostic factors for HBC. Materials and Method: The clinicopathological data of 35 MMGTs were obtained. Immunohistochemical staining with HER-2, Ki-67 and CD34 markers was conducted with sections from paraffin-embedded blocks. According to standard protocols, histological type, grade, margin status, lymphovascular invasion (LVI), HER-2/neu score, proliferation rate and microvessel density (MVD) of tumors were determined and the association of HER-2/neu overexpression with these parameters was assessed statistically. Results: The IHC results showed that 12 (34.3%) cases were HER-2/neu positive. Statistical analyses indicated a significant relationship between HER-2 positivity and tumor grade (p=0.043), which also was demonstrated with cancer stage (p=0.035), tumor margin involvement (p=0.016), proliferation index (p=0.001) and MVD (p=0.001); however, there was no statistical relationship between LVI and tumor size. Overexpression of the HER-2/neu gene in MMGTs results in similar biological behavior as that of HBC; as a result, these tumors have can be considered to have important similarities in clinicopathological characteristics. Conclusions: MMGTs can be regarded as an HBC animal model. Further studies in this field would result in new treatments that could be beneficial for both dogs and humans.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.295-298
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• 2016

Background: Breast cancer is a very common health problem in Iranian women. The HER2-neu gene is a transmembrane receptor tyrosine kinase with homology to members of the EGF receptor family. The aim of this study was to investigate the association between HER2-neu oncogene status with prognostic factors of breast cancer in Kermanshah province, Iran. Materials and Methods: Relationship between HER2-neu and prognostic factors of 130 cases of breast cancer were evaluated during two years in Imam Reza hospital in Kermanshah, Iran. Data were analyzed using descriptive statistics and the T-test and Mann-Whitney U non-parametric test using SPSS 19. Results: The mean age for the patients was $46.0{\pm}8.0years$, all being female. Among the predictive factors for breast cancer were family history, stage of disease, involvement of the lymphovascular system, number of involved lymph nodes in axillaries, grading and hormone receptor status with HER2-neu oncogene had direct correlation and between factors, tumor location, patient age and histological characteristics and HER2-neu oncogene had no significant relationship. We found significant correlation between HER2 with ER and PR and also HER2 with ER, PR negative. Conclusions: HER2-neu is risk factor that can be a good prognostic and also predictive factor. For these reasons, we recommend that it be evaluated for all types of BC.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4119-4123
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• 2012

Background: Neoadjuvant systemic chemotherapy is the accepted approach for women with locally advanced breast cancer. Anthracycline- and taxane-based regimens have been extensively studied in clinical trials and consequently are widely used. In this study aimed to research the complete response (pCR) rates in different regimens for neoadjuvant setting and determine associated clinical and biological factors. Methods: This study included 63 patients diagnosed with breast carcinoma among 95 patients that had been treated with neoadjuvant chemotherapy between 2007 and 2010. TNM staging system was used for staging. The histologic response to neoadjuvant chemotherapy was characterized as a pCR when there was no evidence of residual invasive tumor in the breast or axillary lymph nodes. Biologic subclassification using estrogen receptor (ER), progesterone receptor (PR), HER2 were performed. Luminal A was defined as ER+, PR+, HER2-; Luminal B tumor was defined as ER+, PR-, HER2-; ER+, PR-, HER2+; ER-, PR+, HER2-; ER+, PR+, HER2+; HER2 like tumor ER-, PR+, HER2+; and triple negative tumor ER, PR, HER2 negative. Results: Patients median age was 54.14 (min-max: 30-75). Thirty-two patients (50.8%) were premenapousal and 31 (49.2%) were postmenapousal. Staging was performed postoperatively based on the pathology report and appropriated imaging modalities The TNM (tumor, lymph node, metastasis) system was used for clinical and pathological staging. Fifty-seven (90.5%) were invasive ductal carcinomas, 6 (9.5%) were other subtypes. Thirty nine (61.9%) were grade II and 24 (38.1%) were grade III. Seven (11.1%) patients were stage II and 56 (88.9) patients were stage III. The patients were classified for ER, PR receptor and HER2 positivity. Seventeen patients had complete response to chemotherapy. Forty patients (63.5%) were treated with dose dense regimen (cyclophosphamide 600 mg/m2 and doxorubicine 60 mg/m every two weeks than paclitaxel 175 mg/m2 every two weeks with filgrastim support) 40 patients (48%) were treated anthracycline and taxane containing regimens. Thirteen patients (76%) from 17 patients with pCR were treated with the dose dense regimen but without statistical significance (p=0.06). pCR was higher in HER2(-), ER(-), grade III, premenopausal patients. Conclusion: pCR rate was higher in the group that treated with dose dense regimen, which should thus be the selected regimen in neoadjuvant setting. Some other factors can predict pCR in Turkish patients, like grade, menopausal status, triple negativity, percentage of ER positivity, and HER2 expression.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5773-5777
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• 2015

Background: Oral squamous cell carcinoma (OSCC) is thought to develop from precancerous dysplastic lesions through multistep processes of carcinogenesis involving activation of oncogenes and loss of tumor suppressor genes. The human epidermal growth factor receptor 2 (Her-2/neu [erbB-2]), a cell membrane glycoprotein, is a growth factor receptor that has receptor tyrosine kinase activity. Her2/neu activation plays a central role in cell proliferation and survival. It has been shown that overexpression of Her2/neu increases the rate of cell division and growth, leading to precancerous changes. The aim of the present study was to compare the serum and salivary Her2/neu levels between cases with premalignant and malignant oral lesions. Materials and Methods: Fasting blood samples and unstimulated saliva by passive drooling were collected from three groups of healthy control (n=20), premalignant disorder (PMD) (n=20) and OSCC (n=25) subjects. The HER2 extracellular domain (HER2 ECD) levels were measured using ELISA. Results: The levels of serum Her2/neu showed no significant differences between any of the groups but on the other hand salivary Her2/neu levels were found to be significantly (p<0.05) higher when compared between control (median 68.7 pg/ml, range: 21.5 - 75.8) and OSCC (median 145.6 pg/ml, range: 45.1-191.1). A similar trend was observed when comparing between PMD (median 43.3, range: 22.1 -94.7) and OSCC with a statistical significance of p<0.05. Conclusions: Our study provided evidence of increased salivary Her2/neu in OSCC when compared to PMD and control which was not the case for serum levels. This suggests that probably Her2/neu is not highly amplified as in breast cancer so as to be reflected in serum. Since saliva is in local vicinity of the OSCC, even a mild increase might be mirrored. On the whole, this study proposes Her2/neu as marker for distinguishing premalignant and malignant conditions.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.329-337
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• 2012

Considerable attention has been given to the accuracy of HER-2 testing and the correlation between the results of different testing methods. This interest reflects the growing importance of HER-2 status in the management of patients with breast cancer. In this study the detection of HER-2 gene and centromere 17 status was evaluated using dual-colour primed in situ labelling (PRINS) in comparison with fluorescence in situ hybridization (FISH). These two methods were evaluated on a series of 27 formalin fixed paraffin embedded breast carcinoma tumours, previously tested for protein overexpression by HercepTest (grouped into Hercep 1+/0, 2+ and 3+). HER-2 gene amplification (ratio${\geq}2.2$) by PRINS was found in 3:3, 6:21 and 0:3 in IHC 3+, 2+ and 1+/0 cases, respectively. Comparing FISH and IHC (immunohistochemistry), showed the same results as for PRINS and IHC. Chromosome 17 aneusomy was found in 10 of 21 IHC 2+ cases (47.6%), of which 1 (10%) showed hypodisomy (chromosome 17 copy number per cell${\leq}1.75$), 7 (70%) showed low polysomy (chromosome 17 copy number per cell=2.26 - 3.75) and 2 (20%) showed high polysomy (chromosome 17 copy number per cell ${\geq}3.76$). The overall concordance of detection of HER-2 gene amplification by FISH and PRINS was 100% (27:27). Furthermore, both the level of HER-2 amplification and copy number of CEN17 analysis results correlated well between the two methods. In conclusion, PRINS is a reliable, reproducible technique and in our opinion can be used as an additional test to determine HER-2 status in breast tumours.