Research Papers:

A multicenter round robin test of PD-L1 expression assessment in urothelial bladder cancer by immunohistochemistry and RT-qPCR with emphasis on prognosis prediction after radical cystectomy

Markus Eckstein _, Ralph M. Wirtz, Carolin Pfannstil, Sven Wach, Robert Stoehr, Johannes Breyer, Franziska Erlmeier, Cagatay Günes, Katja Nitschke, Wilko Weichert, Wolfgang Otto, Bastian Keck, Sebastian Eidt, Maximilian Burger, Helge Taubert, Bernd Wullich, Christian Bolenz, Arndt Hartmann and Philipp Erben

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Oncotarget. 2018; 9:15001-15014. https://doi.org/10.18632/oncotarget.24531

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Markus Eckstein1,*, Ralph M. Wirtz2,3,*, Carolin Pfannstil1,*, Sven Wach4,*, Robert Stoehr1,*, Johannes Breyer6,*, Franziska Erlmeier7,*, Cagatay Günes8,*, Katja Nitschke5,*, Wilko Weichert7,*, Wolfgang Otto6,*, Bastian Keck4,*, Sebastian Eidt3,*, Maximilian Burger6,*, Helge Taubert4,*, Bernd Wullich4,*, Christian Bolenz8,*, Arndt Hartmann1,* and Philipp Erben5,*

1Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany

2STRATIFYER Molecular Pathology GmbH, Cologne, Germany

3Institute of Pathology at The St. Elisabeth Hospital Köln-Hohenlind, Cologne, Germany

4Department of Urology, University of Erlangen-Nuremberg, Erlangen, Germany

5Department of Urology Mannheim, University of Heidelberg, Mannheim, Germany

6Department of Urology, University of Regensburg, Regensburg, Germany

7Institute of Pathology, Technical University Munich, Munich, Germany

8Department of Urology, University of Ulm, Ulm, Germany

*On behalf of the BRIDGE-Consortium Germany

Correspondence to:

Markus Eckstein, email: [email protected]

Keywords: bladder cancer; PD-L1; checkpoint inhibitors; molecular therapy stratification; immunohistochemistry

Received: October 26, 2017     Accepted: February 10, 2018     Epub: February 19, 2018     Published: March 13, 2018


Background: Immunohistochemical PD-L1 assessment is currently used to identify responders towards checkpoint inhibitors although it is limited by inter-observer effects. Here, we conducted a multi-center round robin test to prove the possibility of assessing the PD-L1 status by gene expression to avoid inter-observer effects.

Patients and methods: Gene expression of PD-L1 was analyzed in a total of 294 samples (14 cases non-muscle invasive and muscle-invasive bladder cancer; MIBC) in seven centers by a RT-qPCR kit and compared with immunohistochemical scoring of three pathologists (DAKO, 22c3). Both assays were compared towards prognosis prediction in a cohort of 88 patients with MIBC.

Results: PD-L1 gene expression revealed very high inter center correlation (centrally extracted RNA: r = 0.68–0.98, p ≤ 0.0076; locally extracted RNA: r = 0.81–0.98, p ≤ 0.0014). IHC Inter-observer concordance was moderate to substantial for immune cells (IC), fair for combined IC/ tumor cell (TC) (IC: κ = 0.50–0.61; IC + TC: κ = 0.50), and fair for TC scoring (κ = 0.26–0.35). Gene expression assessment resulted in more positive cases (9/14 cases positive vs. 6/14 cases [IHC]) which could be validated in the independent cohort. Positive mRNA status was associated with significantly better overall and disease-specific survival (5-year OS: 50% vs. 26%, p = 0.0042, HR = 0.48; 5 year DSS: 65% vs. 40%, p = 0.012, HR = 0.49). The 1% IHC IC cut-off also revealed significant better OS (5 year OS: 58% vs. 31%, p = 0.036, HR = 0.62).

Conclusion: Gene expression showed very high inter-center agreement. Gene expression assessment also resulted in more positive cases and revealed better prognosis prediction. PD-L1 mRNA expression seems to be a reproducible and robust tool for PD-L1 assessment.

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