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High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients

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Abstract

Introduction and objectives

Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification.

Materials and methods

We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS).

Results

We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72 years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (ρ: 0.6024, p < 0.0001), CD3/PDL1 (ρ: 0.5728, p < 0.0001) and CD3/PD1 (ρ: 0.7005, p < 0.0001). Kaplan–Meier analysis revealed that high PDL1 mRNA expression (≥ 33.83) is a favorable prognostic factor with regard to better RFS (p = 0.0018), PFS (p = 0.021) and CSS (p = 0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS [HR 0.48 (0.31–0.72), p = 0.0005], PFS [HR 0.45 (0.24–0.80), p = 0.0059] and CSS [HR 0.31 (0.13–0.67), p = 0.0021].

Conclusion

High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy.

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Abbreviations

BCG:

Bacillus-Calmette-Guerin

CALM2:

Calmodulin 2

CD3:

Cluster of differentiation 3

cDNA:

Complementary deoxyribonucleic acid

CSS:

Cancer-specific survival

FDA:

Food and Drug Administration

FFPE:

Formaline fixed paraffin embedded

GOI:

Gene of interest

HPF:

High-power field

HR:

Hazard ratio

IHC:

Immunohistochemistry

IVD:

In vitro diagnostic

MIBC:

Muscle-invasive bladder cancer

MMC:

Mitomycin C

mRNA:

Messenger ribonucleic acid

NMIBC:

Non-muscle-invasive bladder cancer

NSCLC:

Non-small-cell lung cancer

OS:

Overall survival

PD1:

Programmed death 1

PDL1:

Programmed death ligand 1

PFS:

Progression-free survival

REF:

Reference gene

RFS:

Recurrence-free survival

RNA:

Ribonucleic acid

RT-qPCR:

Reverse transcription quantitative real time polymerase chain reaction

TIMC:

Tumor-infiltrating mononuclear cell

TURB:

Transurethral resection of the bladder

WHO:

World Health Organization

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Acknowledgements

We would like to thank Stefanie Herlein, Elke Veltrup and Silke Claas for excellent technical support.

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Authors and Affiliations

  1. Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Landshuter Str. 65, 93053, Regensburg, Germany

    Johannes Breyer, Wolfgang Otto, Stefan Denzinger & Maximilian Burger

  2. STRATIFYER Molecular Pathology GmbH, Cologne, Germany

    Ralph M. Wirtz

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

    Ralph M. Wirtz

  4. Department of Urology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Philipp Erben & Thomas S. Worst

  5. Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany

    Robert Stoehr, Markus Eckstein & Arndt Hartmann

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  1. Johannes Breyer
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Corresponding author

Correspondence to Johannes Breyer.

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Funding

This study was funded by the German Cancer Aid (Deutsche Krebshilfe (DKH)), grant number 110541.

Conflict of interest

Ralph Markus Wirtz is founder and employee of STRATIFYER Molecular Pathology GmbH. All other authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Johannes Breyer, Ralph M. Wirtz, Wolfgang Otto, Philipp Erben, Thomas S. Worst, Robert Stoehr, Markus Eckstein, Maximilian Burger, Arndt Hartmann: on behalf of the BRIDGE (Bladder Cancer Research Initiative for Drug Targets Germany) Consortium e.V.Mannheim, Germany.

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Breyer, J., Wirtz, R.M., Otto, W. et al. High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients. Cancer Immunol Immunother 67, 403–412 (2018). https://doi.org/10.1007/s00262-017-2093-9

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