Dataset Information

Conventional androgen deprivation therapy is associated with an increased risk of cardiovascular disease in advanced prostate cancer, a nationwide population-based study.

ABSTRACT:

Purpose

Androgen Deprivation Therapy (ADT) is the mainstay treatment in advanced prostate cancer. We conducted a nationwide population-based study to evaluate the association of ADT and cardiovascular diseases.

Methods

Between 2005 and 2009, patient data from the National Health Insurance database were obtained. We divided newly diagnosed prostate cancer patients into four groups, injection of gonadotropin-releasing hormone agonists and antagonists, oral antiandrogens, orchiectomy and radical prostatectomy only. Another matched non-cancerous control group was also assigned for comparison purposes. Study outcomes were newly onset Cardiovascular Diseases (CVD) and hospital admissions. Multi-variant Cox proportional regression analysis and the Kaplan-Meier method for cumulative incidence were performed.

Results

A total of 17,147 newly diagnosed prostate cancer patients were found. After exclusion criteria was considered, the 2,565 remaining patients were then divided into 1,088 subjects in the injection group, 286 in the orchiectomy group, 812 in the oral group and 379 in the radical prostatectomy only group. The mean age of all the patients was 71.2 years. Multi-variant analysis showed a significantly increased risk of CVD in the injection group, orchiectomy group, oral group and radical prostatectomy group (HR = 2.94, 95% CI 2.51 to 3.45, p<0.001, HR = 3.43, 95% CI 2.69 to 4.36, p<0.001, HR = 2.87, 95% CI 2.42 to 3.39, p<0.001, HR = 1.93, 95% CI 1.5 to 2.48, p<0.001, respectively). A time dependent increased risk of CVD was also observed amongst the study groups (p<0.001).

Conclusions

ADT is associated with an increased risk of CVD. For long-term prostate cancer castration therapy, doctors should be aware of this complication and arrange for proper management.

SUBMITTER: Li JR

PROVIDER: S-EPMC9239475 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAndrogen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.ObjectiveTo undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.Design, setting, and participantsRNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.Outcome measurements and statistical analysisWe searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.Results and limitationsWe identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.ConclusionsRNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.