Abstract
BackgroundThe CXCR4/CXCL12 axis plays a central role in systemic metastasis of prostate carcinoma (PCa), thereby representing a promising target for future therapies. Recent data suggest that the CXCR4/CXCL12 axis is functionally linked to the PD-1/PD-L1 immune checkpoint. We evaluated the prognostic value of aberrant CXCL12 DNA methylation with respect to PD-L1 expression in primary PCa.ResultsCXCL12 methylation showed a consistent significant correlation with Gleason grading groups in both cohorts (p < 0.001 for training and p = 0.034 for testing cohort). Short BCR-free survival was significantly associated with aberrant CXCL12 methylation in both cohorts and served as an independent prognostic factor in the testing cohort (hazard ratio = 1.92 [95%CI: 1.12–3.27], p = 0.049). Concomitant aberrant CXCL12 methylation and high PD-L1 expression was significantly associated with shorter BCR-free survival (p = 0.005). In comparative analysis, the CXCL12 methylation assay was able to provide approximately equivalent results in biopsy and prostatectomy specimens.Materials and MethodsCXCL12 methylation was determined by means of a methylation specific quantitative PCR analysis in a radical prostatectomy patient cohort (n = 247, training cohort). Data published by The Cancer Genome Atlas served as a testing cohort (n = 498). CXCL12 methylation results were correlated to clinicopathological parameters including biochemical recurrence (BCR)-free survival.ConclusionsCXCL12 methylation is a powerful prognostic biomarker for BCR in PCa patients after radical prostatectomy. Further studies need to ascertain if CXCL12 methylation may aid in planning active surveillance strategies.
Highlights
Prostate cancer (PCa) is a highly prevalent disease that remains clinically silent in the majority of cases and is mostly curable when localized
Short biochemical recurrence (BCR)-free survival was significantly associated with aberrant CXCL12 methylation in both cohorts and served as an independent prognostic factor in the testing cohort
Concomitant aberrant CXCL12 methylation and high programmed deathligand 1 (PD-L1) expression was significantly associated with shorter BCR-free survival (p = 0.005)
Summary
Prostate cancer (PCa) is a highly prevalent disease that remains clinically silent in the majority of cases and is mostly curable when localized. Advanced stages of PCa initially respond well to anti-androgen therapy but will usually progress to castration resistance with poor prognosis. New prognostic tools are needed to allow for an early recognition of aggressive versus indolent forms of PCa. the development of novel targeted therapies for advanced PCa, e.g. immunotherapies, necessitates the development of future predictive biomarkers as companion diagnostics. Recent data suggest a chief position of the CXCR4/ CXCL12 axis initializing androgen dependent proliferation, tumor cell motility, and metastatic growth in PCa [9]. The CXCR4/CXCL12 axis plays a central role in systemic metastasis of prostate carcinoma (PCa), thereby representing a promising target for future therapies. Recent data suggest that the CXCR4/CXCL12 axis is functionally linked to the PD-1/PD-L1 immune checkpoint. We evaluated the prognostic value of aberrant CXCL12 DNA methylation with respect to PD-L1 expression in primary PCa
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