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Oncotarget. 2018 Feb 19;9(19):15001-15014. doi: 10.18632/oncotarget.24531. eCollection 2018 Mar 13.

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.

Author information

1
Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany.
2
STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
3
Institute of Pathology at The St. Elisabeth Hospital Köln-Hohenlind, Cologne, Germany.
4
Department of Urology, University of Erlangen-Nuremberg, Erlangen, Germany.
5
Department of Urology, University of Regensburg, Regensburg, Germany.
6
Institute of Pathology, Technical University Munich, Munich, Germany.
7
Department of Urology, University of Ulm, Ulm, Germany.
8
Department of Urology Mannheim, University of Heidelberg, Mannheim, Germany.

Abstract

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST RMW and SE are founders of STRATIFYER. RMW is an employee of STRATIFYER. All other authors declare that there is no conflicts of interest.

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