HER-2 amplification is highly homogenous in gastric cancer

Marx, Andreas; Tharun, Lars; Muth, Johanna; Dancau, Ana-Maria; Simon, Ronald; Yekebas, Emre F.; Kaifi, Jussuf T.; Mirlacher, Martina; Brümmendorf, Tim H.; Bokemeyer, Carsten; Izbicki, Jakob R.; Sauter, Guido

doi:10.1016/j.humpath.2008.11.014

Cited by 193 publications

(196 citation statements)

References 36 publications

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“…These findings clearly show that CD90 potentially has a value as a target for immunotherapy. ERBB2 amplification is found in 20-30% of gastric carcinomas and is reported to be significantly associated with shorter survival of cancer patients (Tanner et al, 2005;Yano et al, 2006;Marx et al, 2009). How ERBB2 signaling affects tumor growth, invasion and metastasis is still not clear.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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Section: Discussionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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“…Wang et al, 10 Marx et al, 15 Song et al, 30 Garcia et al, 31 Ghaderi et al, 36 Oshima et al, 38 Allgayer et al 39 Wang et al, 10 Marx et al, 15 Zhang et al, 18 Potrc et al, 23 Garcia et al, 31 Ghaderi et al, 36 Wang et al, 37 Allgayer et al 39 Zhang et al, 18 Yu et al, 19 Potrc et al, 23 Park et al, 24 Lee et al, 32 Pinto-de-Sousa et al, 34 Ghaderi et al, 36 Allgayer et al 39 [11 Studies (3 studies between 1990 and 1999 not displayed)]…”

Section: Tumor Gradementioning

confidence: 99%

“…Early Grabsch et al, 11 Marx et al, 15 Yu et al, 19 Hayashi et al, 22 Potrc et al, 23 Song et al, 30 Pinto-de-Sousa et al, 34 Ghaderi et al 36 [15 Studies (7 studies between 1990 and 1999 not displayed)]…”

Section: /4mentioning

confidence: 99%

Clinicopathologic factors associated with HER2‐positive gastric cancer and its impact on survival outcomes—A systematic review

Chua

Merrett

2011

Intl Journal of Cancer

163

111

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With the availability of a therapeutic target and an effective agent in trastuzumab, a systematic examination of the literature to investigate the role of human epidermal growth factor 2 (HER2) as a prognostic factor for survival and its association with clinicopathologic markers may improve treatment. An electronic search of the MEDLINE and PubMed databases (January 1990 to January 2011) was undertaken to identify translational studies that correlated HER2 with clinicopathologic markers and/or survival outcome. This review included 49 studies totaling 11,337 patients. Forty-four percent of patients had Stage I/II, and 56% had Stage III/IV disease. Immunohistochemistry was most commonly used to assess HER2 expression, identifying a median rate of 18% (range, 4-53%) of gastric cancer demonstrating HER2 overexpression. In patients with and without HER2 overexpression, the median 3-year disease-free survival rate was 58% (range, 50-88%) and 86% (range, 62-97%), respectively. Of the 35 studies reporting the impact of HER2 overexpression on survival, 20 studies (57%) reported no difference in overall survival, two studies (6%) reported significantly longer overall survival in patients with HER2 overexpression and 13 studies (37%) reported significantly poorer overall survival in patients with HER2 overexpression. The median overall survival and 5-year survival rate was 21 (range, 10-57) months and 42%, and 33 (range, 13-80) months and 52% in patients with and without HER2 overexpression, respectively. HER2 overexpression appears to be associated with poorer survival and with intestinal-type gastric cancer in this group of patients for whom majority undergone curative gastrectomy.On a global scale, gastric cancer remains the second most common cause of cancer-related death with an estimated 930,000 new cases diagnosed each year albeit an overall decline in incidence. 1 Noncardia gastric cancers have steadily declined. However, it has been observed that proximal gastric cancers (cardia and oesophago-gastric tumors) are increasing at a rate of up to 10% per year, far exceeding that of any other type of cancer. Metastatic or advanced unresectable gastric cancer is an aggressive malignancy with a poor prognosis despite chemotherapy treatment with median survival of 7.5 to 12 months and a median survival of 3 to 5 months if managed by best supportive care. 2 Gastric cancer is a chemosensitive disease where a range of chemotherapy agents may achieve response rates of 30 to 40%; however, in the advanced setting, the disease is limited by a low complete response rate and the response duration is protracted often leading to disease progression and treatment related toxicities. 3 Combination chemotherapy with a Japanese standard doublet of fluoropyrimidine and platinum or western triplet regimens has shown better response rates and outcomes over single agent chemotherapy. However, there remains no established global standard for treatment.The human epidermal growth factor 2 (HER2) gene is a proto-oncogene where high amplifica...

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“…21,22 Conflicting results are published on heterogeneity of ERBB2 amplification in gastric cancer. [23][24][25] In lung cancer, heterogeneity of HER2 positivity has not been systematically analyzed. This study had the purpose to thoroughly evaluate the possible extent of HER2 heterogeneity in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung.…”

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confidence: 99%

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

et al. 2012

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The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogeneity of the HER2 status in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung, 590 tumors were analyzed for HER2 overexpression and ERBB2 amplification using FDA-approved reagents for immunohistochemistry and fluorescence in-situ hybridization (FISH). Moderate and strong immunostaining (2 þ , 3 þ ) was seen in 10% of the tumors. ERBB2 amplification was found in 17 (3%) lung cancer patients including 10 cases (2%) with high-level amplification forming gene clusters. ERBB2 amplification was significantly related to histologic subtype and tumor grade, resulting in 12% ERBB2 amplified tumors in the subgroup of high-grade adenocarcinomas. Heterogeneity was analyzed in all highly amplified tumors. For this purpose, all available tumor tissue blocks from these patients were evaluated. Heterogeneity of ERBB2 amplification was found in 4 of 10 tumors as assessed by FISH. These included two tumors with a mixture of low-level and high-level amplification and two tumors with non-amplified tumor areas next to regions with high-level ERBB2 amplification. High-level ERBB2 amplification occurs in a small fraction of lung cancers with a strong propensity to high-grade adenocarcinomas. Heterogeneity of amplification may limit the utility of anti-HER2 therapy in some of these tumors. Further attempts to assess the utility of HER2-targeting therapy in homogeneously amplified lung cancers appear to be justified. Keywords: adenocarcinoma of the lung; ERBB2 gene amplification; fluorescence in-situ hybridization; HER2 expression; heterogeneity; large cell undifferentiated carcinoma of the lung; squamous cell carcinoma of the lungThe human epidermal growth factor receptor 2 gene (ERBB2, HER2/neu) is involved in the development of numerous types of human cancers and has been linked to poor prognosis in many of them. 1-3 The ERBB2 gene product HER2 is the target of an antibody-based therapy (trastuzumab), which has been shown to be remarkably effective in both the metastatic and adjuvant setting for HER2-positive breast cancer 4-6 and in advanced HER2-positive gastric cancer. 7 Moreover, with the tyrosine kinase inhibitor lapatinib which targets both EGFR and HER2 an alternative option for HER2-positive breast cancers has been introduced 8 and is under analysis for other tumor types.

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HER-2 amplification is highly homogenous in gastric cancer

Cited by 193 publications

References 36 publications

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Clinicopathologic factors associated with HER2‐positive gastric cancer and its impact on survival outcomes—A systematic review

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung

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