Research Papers:

Tumor biomarker conversion between primary and metastatic breast cancer: mRNA assessment and its concordance with immunohistochemistry

Stefan Stefanovic, Ralph Wirtz, Thomas M. Deutsch, Andreas Hartkopf, Peter Sinn, Zsuzsanna Varga, Bettina Sobottka, Lakis Sotiris, Florin-Andrei Taran, Christoph Domschke, Andre Hennigs, Sara Y. Brucker, Christof Sohn, Florian Schuetz, Andreas Schneeweiss and Markus Wallwiener _

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Oncotarget. 2017; 8:51416-51428. https://doi.org/10.18632/oncotarget.18006

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Stefan Stefanovic1,2,*, Ralph Wirtz3,*, Thomas M. Deutsch2, Andreas Hartkopf4, Peter Sinn5, Zsuzsanna Varga6, Bettina Sobottka6, Lakis Sotiris3, Florin-Andrei Taran4, Christoph Domschke1,2, Andre Hennigs1,2, Sara Y. Brucker7, Christof Sohn1,2, Florian Schuetz1,2, Andreas Schneeweiss1,2 and Markus Wallwiener1,2

1Department of Gynecology and Obstetrics, Heidelberg University Hospital, 69120 Heidelberg, Germany

2National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany

3Stratifyer Molecular Pathology GmbH, 50935 Cologne, Germany

4Department of Women’s Health, University Hospital Tübingen, 72076 Tübingen, Germany

5Department of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany

6Institute of Surgical Pathology, Zurich University Hospital, 8091 Zurich, Switzerland

7Research Institute for Women’s Health, Tübingen University Hospital, 72076 Tübingen, Germany

*These authors contributed equally to this work

Correspondence to:

Markus Wallwiener, email: [email protected]

Keywords: breast cancer, tumor biomarkers, receptor conversion, immunohistochemistry, real-time quantitative polymerase chain reaction

Received: February 15, 2017     Accepted: May 05, 2017     Published: May 19, 2017


Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests.

This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1, PGR, ERBB2, and MKI67 and the reference genes B2M and CALM2.

Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients (p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple-negative PTs (p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ESR1 (81%(κ 0.51) in PT and 84%(κ 0.34) in MT, PR/PGR (70%(κ 0.10) in PT and 78% (κ −0.32) in MT), and for HER2/ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor.

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