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      Her2/neu testing in gastric cancer: evaluating the risk of sampling errors

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          Abstract

          Background

          We evaluated the risk of sampling errors in specimens of biopsy size, which may be caused by heterogeneous overexpression of Her2/neu in gastric cancer (GC).

          Patients and methods

          The study cohort comprised 454 gastrectomy patients with adenocarcinoma of the stomach or esophago-gastric junction. Tissue micro-arrays (TMAs) served as ‘biopsy procedure’ and were generated from formalin-fixed and paraffin-embedded tissue: five tissue cylinders were collected randomly from each tumor, rendering 2230 core cylinders. These were compared with 454 whole tissue sections obtained from the same paraffin blocks. Her2/neu expression and gene amplification were analyzed by immunohistochemistry and in situ hybridization. The Her2/neu status was determined according to GC scoring system by two independent observers.

          Results

          In whole tissue sections, 37 (8.1%; observer 1) and 38 (8.4%; observer 2) of the GCs, and in the corresponding TMAs, 28 (6.3%; observer 1) and 28 (6.3%; observer 2) of the GCs were classified as Her2/neu-positive (kappa value 98.5% and 96.2%; P < 0001). Comparison of whole tissue sections with corresponding TMAs showed a false-negative rate of 24% and a false-positive rate of 3% for TMAs.

          Conclusion

          Assessment of the Her2/neu status in tissue biopsies carries a significant risk of sampling errors, thereby rendering patients unsuitable for treatment with trastuzumab.

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          HER2 testing in gastric cancer: a practical approach.

          Michael Bilous, Wedad Hanna, Robert Osamura … (2012)
          Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is approved by the European Medicines Agency for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry 3+ or immunohistochemistry 2+/fluorescence in situ hybridization-positive or immunohistochemistry 2+/silver in situ hybridization-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal junction. Approvals are underway in other countries, with recent approvals granted in the United States and Japan. Experience and data from trastuzumab use in breast cancer have highlighted the importance of quality HER2 testing and scoring to ensure accurate identification of patients eligible for treatment. HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity (focal staining) and incomplete membrane staining. Consequently, gastric cancer-specific HER2 testing protocols have been developed and standardized and it is imperative that these recommendations be adhered to. Given the predictive value of HER2 protein levels with response in the trastuzumab for GAstric cancer study (ToGA), immunohistochemistry should be the initial testing methodology and fluorescence in situ hybridization or silver in situ hybridization should be used to retest immunohistochemistry 2+ samples. Wherever possible, bright-field methodologies should be used as these are considered to be superior to fluorescent methodologies at identifying heterogeneous staining. Specific training is required before embarking on HER2 testing in gastric cancer, irrespective of the experience of HER2 testing in breast cancer. This paper provides the most up-to-date practical guidance on HER2 testing and scoring in patients with gastric and gastro-esophageal junction cancer, as agreed by a panel of expert pathologists with extensive experience of HER2 testing particularly reflecting the European Medicines Agency-approved indication. It is anticipated that these recommendations should ensure accurate and consistent HER2 testing, which will allow appropriate selection of patients eligible for treatment with trastuzumab.
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            Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis.

            Wilko Weichert, Annika Röske, Volker Gekeler … (2008)
            Although histone deacetylases (HDACs) are known to have an important regulatory role in cancer cells, and HDAC inhibitors (HDIs) have entered late-phase clinical trials for the treatment of several cancers, little is known about the expression patterns of HDAC isoforms in tumours. We aimed to clarify these expression patterns and identify potential diagnostic and prognostic uses of selected class I HDAC isoforms in gastric cancer. Tissue samples from a training cohort and a validation cohort of patients with gastric cancer from two German institutions were used for analyses. Tissue microarrays were generated from tumour tissue collected from patients in the training group, whereas tissue slides were used in the validation group. The tissues were scored for expression of class I HDAC isoforms 1, 2, and 3. Overall expression patterns (gHDAC) were grouped as being negative (all three isoforms negative), partially positive (one or two isoforms positive), or completely positive (all isoforms positive), and correlated with clinicopathological parameters and patient survival. The main endpoints were amount of expression of each of the three HDAC isoforms, patterns of expression of gHDAC, effect of metastasis on expression of HDAC and gHDAC, and overall survival according to HDAC expression patterns. 2617 tissue microarray spots from 143 patients in the training cohort and 606 tissue slides from 150 patients in the validation cohort were studied. 52 of the 143 (36%) gastric tumours in the training cohort and 32 of the 150 (21%) gastric tumours in the validation cohort showed nuclear expression of all three HDAC isoforms. 60 (42%) of tumours in the training cohort and 65 (43%) in the validation cohort expressed one or two isoforms in the nuclei, whereas 31 (22%) of tumours in the training cohort and 53 (35%) in the validation cohort were scored negative for all three proteins. gHDAC expression in both cohorts was higher when lymph-node metastases were present (p=0.0175 for the training group and p=0.0242 for the validation group). Survival data were available for 49 patients in the training group and 123 patients in the validation group. In the validation cohort, 3-year survival was 44% (95% CI 34-57) in the HDAC1-negative group, 50% (39-64) in the HDAC2-negative group, and 48% (34-67) in the gHDAC-negative group. 3-year survival decreased to 21% (11-37) when HDAC1 was positive, 16% (9-31) when HDAC2 was positive, and 5% (1-31) when gHDAC (all isoforms) were positive. Those patients highly expressing one or two isoforms (the gHDAC-intermediate group) had an estimated 3-year survival of 40% (29-56). In multivariate analyses, high gHDAC and HDAC2 expression were associated with shorter survival in the training cohort (gHDAC: hazard ratio [HR] 4.15 [1.23-13.99], p=0.0250; HDAC2: HR 3.58 [1.36-9.44], p=0.0100) and in the validation cohort (gHDAC: HR 2.18 [1.19-4.01], p=0.0433; HDAC2: HR 1.72 [1.08-2.73], p=0.0225), independent of standard clinical predictors. High HDAC expression is significantly associated with nodal spread and is an independent prognostic marker for gastric cancer. Additionally, we postulate that immunohistochemical detection of HDAC as a companion diagnostic method might predict treatment response to HDIs, thereby enabling selection of patients for this specific targeted treatment in gastric cancer.
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              HER2 diagnostics in gastric cancer—guideline validation and development of standardized immunohistochemical testing

              Josef Rüschoff, Manfred Dietel, Gustavo Baretton … (2010)
              Trastuzumab-based therapy has been shown to confer overall survival benefit in HER2-positive patients with advanced gastric cancer in a large multicentric trial (ToGA study). Subgroup analysis identified adenocarcinomas of the stomach and gastroesophageal (GE) junction with overexpression of HER2 according to immunohistochemistry (IHC) as potential responders. Due to recent approval of trastuzumab for HER2 positive metastatic gastric and GE-junction cancer in Europe (EMEA) HER2 diagnostics is now mandatory with IHC being the primary test followed by fluorescence in situ hybridization (FISH) in IHC2+ cases. However, in order to not miss patients potentially responding to targeted therapy determination of a HER2-positive status for gastric cancer required modification of scoring as had been proposed in a pre-ToGA study. To validate this new HER2 status testing procedure in terms of inter-laboratory and inter-observer consensus for IHC scoring a series of 547 gastric cancer tissue samples on a tissue microarray (TMA) was used. In the first step, 30 representative cores were used to identify specific IHC HER2 scoring issues among eight French and German laboratories, while in the second step the full set of 547 cores was used to determine IHC HER2 intensity and area score concordance between six German pathologists. Specific issues relating to discordance were identified and recommendations formulated which proved to be effective to reliably determine HER2 status in a prospective test series of 447 diagnostic gastric cancer specimens.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Oncol
                Journal ID (iso-abbrev): Ann. Oncol
                Journal ID (publisher-id): annonc
                Journal ID (hwp): annonc
                Title: Annals of Oncology
                Publisher: Oxford University Press
                ISSN (Print): 0923-7534
                ISSN (Electronic): 1569-8041
                Publication date (Print): March 2013
                Publication date (Electronic): 8 November 2012
                Publication date PMC-release: 8 November 2012
                Volume: 24
                Issue: 3
                Pages: 725-733
                Affiliations
                [1 ]Department of Pathology, Christian-Albrechts University , Kiel
                [2 ]Department of Pathology, Charité University Hospital , Berlin
                [3 ]Department of General Surgery and Thoracic Surgery, Christian-Albrechts University , Kiel
                [4 ]University Cancer Centre Leipzig, University of Leipzig , Leipzig
                [5 ]Department of Medicine II, Faculty of Clinical Medicine Mannheim, University of Heidelberg , Mannheim, Germany
                Author notes
                [* ] Correspondence to: Dr C. Röcken, Department of Pathology, Christian-Albrechts University, Arnold-Heller-Str. 3, Haus 14, D-24105 Kiel, Germany. Tel: +49-431-597-3401; Fax: +49-431-597-3462; E-mail: christoph.roecken@ 123456uk-sh.de
                [†]

                VSW and H-MB contributed equally to this work.

                Article
                Publisher ID: mds528
                DOI: 10.1093/annonc/mds528
                PMC ID: 3574551
                PubMed ID: 23139264
                SO-VID: 5bf1200b-eff6-4998-876c-a71d0cb99e41
                Copyright © © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

                History
                Date received : 11 April 2012
                Date revision received : 2 September 2012
                Date accepted : 4 September 2012
                Categories
                Subject: Original Articles
                Subject: Gastrointestinal Tumors

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: biopsy,gastric cancer,her2/neu,sampling error
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: biopsy, gastric cancer, her2/neu, sampling error

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