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      Discordance Rate of HER2 Status in Primary Gastric Carcinomas and Synchronous Lymph Node Metastases: A Multicenter Retrospective Analysis

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          Abstract

          Background: The assessment of human epidermal growth factor receptor 2 (HER2) gene amplification is essential in order to identify those patients affected by advanced gastric cancer who may benefit from Trastuzumab targeted therapy. Materials and Methods: With the aim to investigate the concordance rate in HER2 status between primary gastric carcinoma (GC) and synchronous lymphnode metastases, we investigated HER2 status in a cohort of 108 surgical formalin-fixed paraffin-embedded specimens of GC and matched synchronous metastatic lymph nodes collected from three different units of Anatomic Pathology in southern of Italy. Fleiss-Cohen weighted k statistics were used to assess the concordance rate of HER2 status. Results: HER2 amplification was observed in 17% of primary GCs and the overall concordance rate with corresponding nodal metastases was 90.74%. Changes in HER2 status between primary GC and matched synchronous metastases were evidenced in 10 (9.26%) cases. Of these, 6 cases were HER2 amplified in the primary GC and not amplified in the metastases, while 4 were HER2 not amplified in the primary tumour and amplified in the lymph node metastases. Conclusions: Although at present the simultaneous determination of HER2 in advanced gastric cancer and corresponding metastatic lymph nodes is not mandatory, the possibility that the synchronous metastases of GC have a different HER2 status from that of the primary tumour is of remarkable significance; Indeed this may have influence on the therapeutic management and prognosis of the patients.

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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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            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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              A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases.

              Aron Goldhirsch, Giancarlo Pruneri, Giuseppe Curigliano … (2013)
              The discordance in oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status between primary and recurrent breast cancer is being intensively investigated and a large amount of data have been produced. However, results from different studies are heterogeneous and often conflicting. To highlight this issue, a meta-analysis of published data was performed. A literature search was performed using Medline, and all the studies published from 1983 to 2011 comparing changes in ER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumours were included. We used random-effects models to estimate pooled discordance proportions. We selected 48 articles, mostly reporting retrospective studies. Thirty-three, 24 and 31 articles were focused on ER, PgR and HER2 changes, respectively. A total of 4200, 2739 and 2987 tumours were evaluated for ER, PgR and HER2 discordance, respectively. The heterogeneity between study-specific discordance proportions was high for ER (I(2)=91%, p<0.0001), PgR (I(2)=79%, p<0.0001) and HER2 (I(2)=77%, p<0.0001). Pooled discordance proportions were 20% (95% confidence interval (CI): 16-35%) for ER, 33% (95% CI: 29-38%) for PgR and 8% (95% CI: 6-10%) for HER2. Pooled proportions of tumours shifting from positive to negative and from negative to positive were 24% and 14% for ER (p=0.0183), respectively. The same figures were 46% and 15% for PgR (p<0.0001), and 13% and 5% for HER2 (p=0.0004). Our findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer, suggesting clinical implications and a possible impact on treatment choice. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                William Chi-shing Cho: Role: External Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 03 December 2014
                Publication date Collection: December 2014
                Volume: 15
                Issue: 12
                Pages: 22331-22341
                Affiliations
                [1 ]Department of Human Pathology “Gaetano Barresi”, Section of Anatomic Pathology, University of Messina, Messina 98123, Italy; E-Mails: calaienco@ 123456hotmail.com (A.I.); vbarresi@ 123456unime.it (V.B.); rosariocaruso@ 123456tin.it (R.A.C.)
                [2 ]Department “G.F. Ingrassia”, Section of Anatomic Pathology, University of Catania, Catania 95123, Italy; E-Mails: rosario.caltabiano@ 123456unict.it (R.C.); lanzafas@ 123456unict.it (S.L.)
                [3 ]Department of Medicine and Surgery, University of Salerno, Salerno 84131, Italy; E-Mails: alessia.caleo@ 123456unisa.it (A.C.); pzeppa@ 123456unisa.it (P.Z.)
                [4 ]Department of Diagnostic Medicine, Clinics and Public Health, Section of Pathologic Anatomy, University of Modena, Modena 41121, Italy; E-Mail: reggiani.luca@ 123456policlinico.mo.it
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: tuccari@ 123456unime.it ; Tel.: +39-90-2212-539; Fax: +39-90-2928-150.
                Article
                Publisher ID: ijms-15-22331
                DOI: 10.3390/ijms151222331
                PMC ID: 4284711
                PubMed ID: 25479078
                SO-VID: 7d76413c-a783-450c-90f6-23cb06818902
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 November 2014
                Date revision received : 24 November 2014
                Date accepted : 27 November 2014
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: human epidermal growth factor receptor 2 (her2),gastric cancer,synchronous lymph nodes,metastases,prognosis
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: human epidermal growth factor receptor 2 (her2), gastric cancer, synchronous lymph nodes, metastases, prognosis

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