PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy.

Heidrun Gevensleben,Emily Eva Holmes,Diane Goltz,Jörg Ellinger,Glen Kristiansen,Jörn Dietrich,Dimo Dietrich,Verena Sailer

doi:10.18632/oncotarget.13161

Heidrun Gevensleben, Emily Eva Holmes + Show 6 more

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https://doi.org/10.18632/oncotarget.13161

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Journal: Oncotarget	Publication Date: Nov 7, 2016
Citations: 98	License type: cc-by

Affiliation: University Hospital Bonn, Weill Cornell Medicine

Abstract

BackgroundThe rapid development of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has generated an urgent need for biomarkers assisting the selection of patients eligible for therapy. The use of PD-L1 immunohistochemistry, which has been suggested as a predictive biomarker, however, is confounded by multiple unresolved issues. The aim of this study therefore was to quantify PD-L1 DNA methylation (mPD-L1) in prostate tissue samples and to evaluate its potential as a biomarker in prostate cancer (PCa).ResultsIn the training cohort, normal tissue showed significantly lower levels of mPD-L1 compared to tumor tissue. High mPD-L1 in PCa was associated with biochemical recurrence (BCR) in univariate Cox proportional hazards (hazard ratio (HR)=2.60 [95%CI: 1.50-4.51], p=0.001) and Kaplan-Meier analyses (p<0.001). These results were corroborated in an independent validation cohort in univariate Cox (HR=1.24 [95%CI: 1.08-1.43], p=0.002) and Kaplan-Meier analyses (p=0.029). Although mPD-L1 and PD-L1 protein expression did not correlate in the validation cohort, both parameters added significant prognostic information in bivariate Cox analysis (HR=1.22 [95%CI: 1.05-1.42], p=0.008 for mPD-L1 and HR=2.58 [95%CI: 1.43-4.63], p=0.002 for PD-L1 protein expression).MethodsmPD-L1 was analyzed in a training cohort from The Cancer Genome Atlas (n=498) and was subsequently measured in an independent validation cohort (n=299) by quantitative methylation-specific real-time PCR. All patients had undergone radical prostatectomy.ConclusionsmPD-L1 is a promising biomarker for the risk stratification of PCa patients and might offer additional relevant prognostic information to the implemented clinical parameters, particularly in the setting of immune checkpoint inhibition.

Highlights

The blockade of the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway, either with antibodies against the receptor PD-1 (Nivolumab, Pembrolizumab, Pidilizumab) or its ligand PD-L1 (BMS-936559, MPDL3280A, MEDI4736, MSB001718C), has shown promising results in several advanced cancers, e.g. malignant melanoma, non-small cell lung cancer, bladder cancer, head and neck cancer, and renal cell cancer [1,2]
Conclusions: PD-L1 promoter methylation (mPD-L1) is a promising biomarker for the risk stratification of prostate cancer (PCa) patients and might offer additional relevant prognostic information to the implemented clinical parameters, in the setting of immune checkpoint inhibition
We have very recently shown that promoter methylation of the immune checkpoint receptor PD-1 is an independent prognostic biomarker for biochemical recurrence (BCR)-free survival in PCa patients following radical prostatectomy [23]

Summary

Introduction

The blockade of the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway, either with antibodies against the receptor PD-1 (Nivolumab, Pembrolizumab, Pidilizumab) or its ligand PD-L1 (BMS-936559, MPDL3280A, MEDI4736, MSB001718C), has shown promising results in several advanced cancers, e.g. malignant melanoma, non-small cell lung cancer, bladder cancer, head and neck cancer, and renal cell cancer [1,2]. Detected PD-L1 expression has further been reported to be a predictive biomarker for the treatment with anti-PD-1/PD-L1 treatment [4]. We have previously shown that PD-L1 is highly expressed in aggressive primary prostate cancer (PCa) and is an independent predictor of biochemical disease progression [5]. Clinical trials for the treatment of PCa so far have yielded conflicting results [2, 6], our findings indicate that PD-1/PD-L1 targeted therapy might be a novel treatment option for hormone-naive tumors. For the successful implementation of reliable biomarkers into clinical practice, the robust and reproducible quantification of DNA methylation instead of immunohistochemistry might be highly beneficial. The aim of this study was to quantify PD-L1 DNA methylation (mPD-L1) in prostate tissue samples and to evaluate its potential as a biomarker in prostate cancer (PCa)

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