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HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma

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Abstract

Gallbladder carcinoma (GBC) is an aggressive type of cancer with a dismal prognosis. Recent case reports have highlighted the human epidermal growth factor receptor 2 (HER2) as a promising target for individualized therapy in biliary tract cancer; however, current data on HER2 positivity in GBC is contradictory. This study aimed to assess the proportion of HER2 positivity and its clinical implications in a large and well-characterized European GBC cohort. HER2 status was determined in 186 cases of surgically resected gallbladder adenocarcinoma and a subset of coexistent high-grade biliary intraepithelial neoplasia (BilIN, n = 74) in accordance with the up-to-date consensus for HER2 testing in gastric cancer by immunohistochemistry and dual-color chromogenic in situ hybridization. Positivity for HER2 was observed in 5.4% of all cases (n = 10). In those patients with concomitant high-grade BilIN, two of four positive samples also showed amplification in the precursor lesion, while in the two remaining cases, positivity was either confined to invasive tumor or high-grade BilIN, exclusively. Equivocal staining found in eleven cases was not accompanied by gene amplification. Staging of the HER2-positive group was significantly different from the HER2-negative group with most cases presenting at stage IV, paralleled by a trend towards decreased survival. One patient who received dual HER2 inhibition almost went into full clinical remission despite treatment initiation in a metastasized state. Our results reveal a low prevalence of HER2 positivity and highlight HER2 gene amplification as an early, potentially driving event in gallbladder carcinogenesis. Prospective standardized HER2 testing and randomized control studies are needed to prove clinical efficacy of targeted HER2 inhibition in GBC.

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Acknowledgments

The authors would like to thank John Moyers (Institute of Pathology, University of Heidelberg) for his excellent technical assistance and the NCT tissue bank Heidelberg for its support (tissue banking, tissue microarray manufacturing, and technical assistance).

Contribution statement

TA and BG conceived the study design and drafted the manuscript. BG, MR, VG, and AT collected, revised, and analyzed the GBC cohort and clinicopathological data. CH, CS, and CR collected clinical data and established the patient cohort from Kiel. SR, SS, and MA were involved in data interpretation, analysis, and presentation. AM, MNV, AP, EB, BK, CR, KHW, and CS provided clinical data. MR, MNV, and PS provided important intellectual content and critically revised the manuscript. All authors reviewed the manuscript and approved the final version.

Funding

The German Research Foundation (DFG) CRC SFB/TR 209 (Liver Cancer) to T.A. (GEROK Stipend), P.S. (project Z01), and S.R. (project B01). The European Union’s Horizon 2020 research and innovation program under grant agreement no. 667273 (HEP-CAR) to P.S. and S.R. Research grant from the Wilhelm Sander-Stiftung (Nr. 2015.111.1) to S.R. and B.G. All funding parties had no impact on the content of this research project.

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Authors and Affiliations

  1. Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Thomas Albrecht, Melina Rausch, Stephanie Roessler, Marcus Renner, Stephan Singer, Peter Schirmacher & Benjamin Goeppert

  2. Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany

    Thomas Albrecht, Stephanie Roessler, Arianeb Mehrabi, Elena Busch, Bruno Köhler, Christian Rupp, Karl Heinz Weiss, Christoph Springfeld, Peter Schirmacher & Benjamin Goeppert

  3. Tissue Bank of the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Veronika Geissler

  4. European Center for Angioscience (ECAS), Medical Faculty of Mannheim, Heidelberg University, Heidelberg, Germany

    Michael Albrecht

  5. Institute of Pathology, Schleswig-Holstein University Hospital, Kiel, Germany

    Christine Halske, Carolin Seifert & Christoph Röcken

  6. Department of General Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

    Arianeb Mehrabi

  7. Diagnostic and Interventional Radiology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany

    Monika Nadja Vogel

  8. Department of Internal Medicine IV, Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany

    Anita Pathil-Warth, Christian Rupp & Karl Heinz Weiss

  9. Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Elena Busch, Bruno Köhler & Christoph Springfeld

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  1. Thomas Albrecht
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Correspondence to Benjamin Goeppert.

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Tissues were used in accordance with the ethical regulations of the NCT tissue bank established by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg University, approval code S-207/2015).

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PS received funding for grants, boards, and presentations from Novartis. The other authors declare that they have no conflict of interest.

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Albrecht, T., Rausch, M., Roessler, S. et al. HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma. Virchows Arch 476, 871–880 (2020). https://doi.org/10.1007/s00428-019-02706-6

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