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Article

Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment

1
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
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Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Cepheid, Department of Medical and Scientific Affairs and Strategy, Oncology, 904 Caribbean Drive, Sunnyvale, CA 94089, USA
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Qualitätssicherungs-Initiative Pathologie QuIP GmbH, 10117 Berlin, Germany
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Department of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
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Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
7
Centre Jean Perrin, Department of Pathology and Clermont Auvergne University, INSERM, U1240, “Imagerie Moléculaire et Stratégies Théranostiques”, F-63011 Clermont Ferrand, France
8
Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain
9
CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
10
Department of Pathology, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
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Facultad de Medicina, Universidad de Alcalá de Henares, 28871 Madrid, Spain
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Institute of Pathology, UKGM—University Hospital Marburg, Philipps-University Marburg, 35043 Marburg, Germany
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MVZ Helios Hospital Emil von Behring GmbH, 14165 Berlin, Germany
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Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: David Wong
Cancers 2021, 13(18), 4718; https://doi.org/10.3390/cancers13184718
Received: 10 August 2021 / Accepted: 8 September 2021 / Published: 21 September 2021
Four biomarkers [estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2], are used to stratify breast cancer (BC) into subtypes predictive of therapy response. In a Europe-wide external quality assessment, we compared performance of an mRNA-based method [Xpert® Breast Cancer STRAT4 (CE-IVD)] for determining ESR1, PGR, ERBB2, and MKI67 expression against the gold standard [immunohistochemistry (IHC)/HER2 in situ hybridization (ISH)]. The coordinating center (CC) and five European laboratories tested ten breast cancer samples. STRAT4 binary (positive or negative) results of each marker were compared with the gold standard. ESR1 and ERBB2 mRNA results were concordant with IHC/ISH in all single analyses. In contrast, PGR and MKI67 results were discordant in a few cases, which had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. STRAT4 assay may be a reproducible method. However, cases with expression values close to cut-offs should be carefully reviewed.
Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed. View Full-Text
Keywords: breast cancer; ESR1; PGR; ERBB2; MKI67; mRNA expression testing; STRAT4; GeneXpert; Xpert breast cancer; ESR1; PGR; ERBB2; MKI67; mRNA expression testing; STRAT4; GeneXpert; Xpert
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Figure 1

MDPI and ACS Style

Erber, R.; Hartmann, A.; Fasching, P.A.; Ruebner, M.; Stöhr, R.; Beckmann, M.W.; Zentgraf, M.; Popp, V.; Weidler, J.; Simon, I.; Becker, S.; Huebner, H.; Fischer, J.; Guerini Rocco, E.; Viale, G.; Cayre, A.; Penault-Llorca, F.; Caniego Casas, T.; Pérez-Miés, B.; Palacios, J.; Jank, P.; Denkert, C.; Khoury, L.; Mairinger, T.; Ferrazzi, F. Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment. Cancers 2021, 13, 4718. https://doi.org/10.3390/cancers13184718

AMA Style

Erber R, Hartmann A, Fasching PA, Ruebner M, Stöhr R, Beckmann MW, Zentgraf M, Popp V, Weidler J, Simon I, Becker S, Huebner H, Fischer J, Guerini Rocco E, Viale G, Cayre A, Penault-Llorca F, Caniego Casas T, Pérez-Miés B, Palacios J, Jank P, Denkert C, Khoury L, Mairinger T, Ferrazzi F. Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment. Cancers. 2021; 13(18):4718. https://doi.org/10.3390/cancers13184718

Chicago/Turabian Style

Erber, Ramona, Arndt Hartmann, Peter A. Fasching, Matthias Ruebner, Robert Stöhr, Matthias W. Beckmann, Miriam Zentgraf, Verena Popp, Jodi Weidler, Iris Simon, Steffi Becker, Hanna Huebner, Josephine Fischer, Elena Guerini Rocco, Giuseppe Viale, Anne Cayre, Frederique Penault-Llorca, Tamara Caniego Casas, Belén Pérez-Miés, José Palacios, Paul Jank, Carsten Denkert, Lina Khoury, Thomas Mairinger, and Fulvia Ferrazzi. 2021. "Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment" Cancers 13, no. 18: 4718. https://doi.org/10.3390/cancers13184718

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