HER2 testing in gastric cancer: a practical approach

Rüschoff, Josef; Hanna, Wedad; Bilous, Michael; Hofmann, Manfred; Osamura, R. Yoshiyuki; Penault‐Llorca, Frédérique; Vijver, Marc J. van de; Viale, Giuseppe

doi:10.1038/modpathol.2011.198

Cited by 479 publications

(482 citation statements)

References 27 publications

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“…In other forms of cancer, including breast and gastric cancer, IHC determination of molecular markers, such as HER2 overexpression, is important for the treatment strategy (31,32). Patients with high HER2-expressing tumors derive the greatest benefit from trastuzumab therapy (31).…”

Section: Discussionmentioning

confidence: 99%

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Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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Abstract. Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

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Section: Discussionmentioning

confidence: 99%

“…Patients with high HER2-expressing tumors derive the greatest benefit from trastuzumab therapy (31). Additionally, it was previously determined that the interlaboratory reproducibility of HER2 expression in gastric cancer using two different antibodies was 48.3 vs. 75.9%, while the interobserver reproducibility was ~90% (32).…”

Section: Discussionmentioning

confidence: 99%

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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“…Tissue was processed using the PathVysion HER2 DNA Probe Kit (Abbott Molecular) according to the manufacturer's protocol. The HER2 gene was considered amplified if the HER2-tochomosome 17 centromere (CEP17) ratio was C2.0 and if the average HER2 gene copy number was at least 6 [21]. Regardless of HER2 status, TOP2A genomic alterations were measured in at least one whole tissue section per patient, next to the section where HER2 was investigated.…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

et al. 2016

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Background HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma. Methods HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri-or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC. Results Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P \ 0.018], independent of clinicalpathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared. Conclusions HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.

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“…MET amplification followed strict definitions as established for HER2 testing. 32 Briefly, we defined gene amplification as a MET/CEP7 ratio 42.0 in 20 tumor nuclei. Low or high polysomy were regarded as negative for gene amplification.…”

Section: Fluorescent and Bright-field Double In Situ Hybridizationmentioning

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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HER2 testing in gastric cancer: a practical approach

Cited by 479 publications

References 27 publications

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

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

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