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HER2 testing in gastric cancer diagnosis: insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany

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Abstract

HER2 testing in metastatic gastric or gastroesophageal junction cancer (mGC/mGEJC) is standard practice. Variations in HER2-positivity rates suggest factors affecting test quality; however, the influence of patient-, tumor-, and laboratory-related factors on HER2-positivity rates remains unknown. This observational, prospective study collected routine HER2 testing data from 50 pathology centers in Germany (January 2013–December 2015). For each sample, HER2 status, primary tumor location, method of sample retrieval, and other patient- and tumor-related parameters were recorded. A model for predicting the probability of HER2-positivity was developed using stepwise multiple logistic regression to identify influencing factors. Documented positivity rates and corresponding predicted HER2-positivity probabilities were compared to identify institutes with deviations in HER2-positivity. Data from 2761 mGC/mGEJC routine diagnostic specimens included 2033 with HER2 test results (1554 mGC, 479 mGEJC); overall HER2-positivity rates across centers were 19.8% and 30.5%, respectively. HER2-positivity correlated most with Lauren classification, then HER2 testing rate, primary tumor location, sample type, and testing method (all p < 0.05). Three institutes had model-predicted HER2-positivity rates outside the 95% confidence interval of their documented rate, which could not be explained by sample and center characteristics. Results demonstrated the high quality of routine HER2 testing in the mGC/mGEJC cohort analyzed. This is the first study investigating parameters impacting on HER2-positivity rates in mGC/mGEJC in routine practice and suggests that assessment of HER2 testing quality should consider primary tumor location, testing method and rate, and tumor characteristics. Accurate identification of patients with HER2-positive mGC/mGEJC is essential for appropriate use of HER2-targeted therapies.

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Acknowledgments

We would like to thank the patients, their families, the nurses, and the investigators who participated in this study. We would like to thank the centers of the Nicht-interventionelle Untersuchung (NIU) HER2 Study Group who provided information on samples, along with clinical and diagnostic data for the analyses (listed in Online Resource 1). In addition, we would like to thank Johannes Ammann for operative and scientific support. Support for third-party writing assistance for this manuscript, furnished by Helen Keyworth, PhD, of Health Interactions, was provided by Roche Pharma AG, Grenzach-Wyhlen, Germany.

Funding

This study was funded by Roche Pharma AG, Grenzach-Wyhlen, Germany.

Author information

Author notes

  1. Karl-Heinz Berghäuser

    Present address: Zentrum für ambulante Medizin, Uniklinikum Jena gGmbH, Carl-Zeiss-Platz 8, 07743, Jena, Germany

Authors and Affiliations

  1. Institut für Pathologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Fetscherstraße 74, 01307, Dresden, Germany

    Gustavo Baretton

  2. Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Hans H. Kreipe

  3. Pathologische Institut, Universitätsklinik Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Peter Schirmacher

  4. Pathologisches Institut Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167, Mannheim, Germany

    Timo Gaiser

  5. Interdisziplinären Tumorzentrum, Universitätsmedizin Mannheim, Theodor-Kutzer Ufer 1–3, 68167, Mannheim, Germany

    Ralf Hofheinz

  6. Thüringen-Kliniken “Georgius Agricola” GmbH, Rainweg 68, 07318, Saalfeld/Saale, Germany

    Karl-Heinz Berghäuser

  7. BDS Koch, Bibienastraße 5, 68723, Schwetzingen, Germany

    Winfried Koch

  8. Roche Pharma AG, Emil-Barell-Straße 1, 79639, Grenzach-Wyhlen, Germany

    Claudia Künzel & Stefanie Morris

  9. Institut für Pathologie Nordhessen and Targos Molecular Pathology GmbH, Germaniastr 7, 34119, Kassel, Germany

    Josef Rüschoff

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  1. Gustavo Baretton
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On behalf of the Nicht-interventionelle Untersuchung (NIU) HER2 Study Group

Contributions

RH, SM, and JR contributed to the conception and study design. HHK, TG, RH, KB, and JR contributed to the collection and assembly of data. GB, PS, TG, RH, WK, CK, and JR contributed to the analysis and interpretation of the data. WK performed the statistical analysis. All the authors contributed to the drafting of the article, provided critical revision for important intellectual content, and approved the final version. CK provided administrative, technical, or logistic support for this article.

Corresponding author

Correspondence to Gustavo Baretton.

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Ethical approval

Experimental protocols were reviewed and approved by the local ethical committee of the principal investigator and were available for submission to the local ethical committees of the participating centers.

Conflict of interest

GB and PS have received reimbursement and honoraria for attending symposia and advisory boards, and supplies for research from Roche Pharma AG. HK has received honoraria and reimbursement from, and acted in an advisory and/or consulting role for, Roche Pharma, Genomic Health, and AstraZeneca. TG has received honoraria for lectures and/or consultant activities from Roche. RH has received honoraria and research funding from, and acted in an advisory role for, Roche. WK is employed by BDS Koch, which receives payment from Roche for statistical services. CK is an employee of Roche Pharma AG, Germany. SM is an employee of Roche. JR has acted in an advisory and/or consulting role for Roche, MSD, and BMS, and received research funding from Roche. KB has declared no conflicts of interest.

Data sharing statement

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche’s criteria for eligible studies are available here: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For further detail on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

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The investigators in the NIU HER2 study group are listed in Online Resource 1.

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Baretton, G., Kreipe, H.H., Schirmacher, P. et al. HER2 testing in gastric cancer diagnosis: insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany. Virchows Arch 474, 551–560 (2019). https://doi.org/10.1007/s00428-019-02541-9

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