Assessment of a HER2 scoring system for gastric cancer: results from a validation study

Hofmann, Manfred; Stoß, Oliver; Shi, Daren; Büttner, Reinhard; Vijver, Marc J. van de; Kim, W; Ochiai, Atsushi; Rüschoff, Josef; Henkel, Thomas

doi:10.1111/j.1365-2559.2008.03028.x

Cited by 1,046 publications

(1,111 citation statements)

References 34 publications

(64 reference statements)

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“…Both membranous and cytoplasmic staining was scored as follows: 0, no reactivity or faint staining; 1 þ , faint or weak staining; 2 þ , moderate staining; 3 þ , strong staining in 410% of tumor cells. Membranous alone staining was scored by consensus recommendation on HER2 scoring for gastric carcinoma 30 : 0, no reactivity; 1 þ , faint/barely perceptible membranous reactivity; 2 þ , weak-to-moderate complete or basolateral membranous reactivity; 3 þ , moderate-to-strong complete or basolateral membranous reactivity in 410% of tumor cells. MET overexpression was defined as 2 þ or 3 þ by membranous and cytoplasmic interpretation and only 3 þ by membranous interpretation.…”

Section: Immunohistochemistry For Met Proteinmentioning

confidence: 99%

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

et al. 2013

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The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r ¼ 0.465, Po0.0001), increased copy number gain (r ¼ 0.393, P ¼ 0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; Po0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P ¼ 0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r ¼ 0.274, P ¼ 0.002), copy number gain or survival (P40.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors. Recently, the addition of trastuzumab to standard cytotoxic chemotherapy demonstrated significant survival benefit in HER2-positive gastric carcinomas. 2 Nevertheless, HER2 is positive in only a small portion of gastric cancer patients (7-20%); thus, more precise molecular segmentation is urgently needed. 3 One potential target in gastric cancer was identified as MET proto-oncogene (hepatocyte growth factor receptor) in preclinical studies. 1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its

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Section: Immunohistochemistry For Met Proteinmentioning

confidence: 99%

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

et al. 2013

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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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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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“…Most studies have been conducted in gastric cancer, which shows ErbB2-positivity rates that vary from 10 to 30%. [1][2][3][4][5] ErbB2 amplification or overexpression also seems to be associated with poorer prognosis, more aggressive disease and shorter survival in gastric cancer. [5][6][7] Preclinical and clinical studies of upper gastrointestinal adenocarcinomas, 2 and in particular, the large ToGA trial, which included adenocarcinomas of the stomach and gastro-oesophageal junction, have demonstrated that trastuzumab exerts antitumour activity on ErbB2-overexpressing tumours.…”

mentioning

confidence: 99%

“…Therefore, for gastric cancer, a modified ErbB2 scoring system for immunohistochemistry has been proposed. 3,10 Data on ErbB2 in oesophageal adenocarcinomas exist to a lesser extent than gastric cancer. The rate of ErbB2 overexpression/amplification in these cancers has been reported at approximately 20-25%, depending on the method of evaluation and the definition used.…”

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Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

et al. 2011

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Amplification and overexpression of ErbB2 (Her2) is a frequent event in oesophageal adenocarcinomas. Assessment of ErbB2 status is crucial for identifying patients who are likely to benefit from treatment with trastuzumab. In this study, we performed a comprehensive analysis of ErbB2 amplification and expression in 142 oesophageal adenocarcinomas by comparing the most commonly used methods for ErbB2 assessment: ErbB2 expression was determined by immunohistochemistry and was scored (0, 1 þ , 2 þ and 3 þ ) according to a recently described modified scoring system for gastric cancer. ErbB2 amplification was evaluated by bright field double in situ hybridisation. The results were compared with pathologic features, patients' survival and previously published data from fluorescence in situ hybridisation analysis. On the basis of immunohistochemistry, which was applicable in 110 cores of the cases, 83 tumours (75%) had a score of 0 or 1 þ (immunohistochemistry negative), 13 tumours (12%) were scored as 2 þ and 14 tumours (13%) were scored as 3 þ . In situ hybridisation data were obtained from 142 cases. There was a highly significant correlation of immunohistochemistry, bright field in situ hybridisation and fluorescent in situ hybridisation (Po0.001 each). In total, 41 tumours (29%) were categorised as ErbB2 positive, which was defined as immunohistochemistry 3 þ and/or an ErbB2/Chr17 quotient of Z2 as assessed by either bright field double in situ hybridisation or fluorescence in situ hybridisation. ErbB2 positivity was observed more frequently in tumours with lower differentiation grades (P ¼ 0.029). Patients with ErbB2-positive tumours had a significantly worse prognosis, both in univariate analysis (P ¼ 0.004) and in multivariate analysis (P ¼ 0.03).In conclusion, we demonstrate that a significant number of oesophageal adenocarcinomas are positive for ErbB2. Assessment of ErbB2 amplification can be equivalently performed by conventional fluorescence in situ hybridisation or other lightmicroscopy-based methods, such as the novel bright field double in situ hybridisation technique. Modern Pathology (2011) 24, 908-916;

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Assessment of a HER2 scoring system for gastric cancer: results from a validation study

Cited by 1,046 publications

References 34 publications

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

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

Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation

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