dutasteride and Urinary-Bladder-Neoplasms

The ability of 5α-reductase inhibitors (5ARI) to reduce the risk of new onset bladder cancer (BC) has been studied with variable results. Our objective was to conduct a retrospective cohort population-based study to evaluate the association between 5ARI use, BC diagnosis, and BC mortality.. We used routinely collected health care data from Ontario, Canada. Men ≥66 years of age with a prescription for a 5ARI were matched to non-5ARI users. Matching was done using a propensity score of selected covariates to make 96 different covariates comparable. We measured 5 additional baseline variables which may have impacted the risk of future BC diagnosis: prior cystoscopy, urine cytology, urinalysis, gross hematuria episodes, and transurethral resection of a bladder lesion. Only the first period of continuous usage of 5ARIs was considered. The prespecified at-risk period for outcomes started 1 year after initiating therapy and ended at the last date of 5ARI exposure + 1 year.. We identified 93,197 men who initiated 5ARI therapy (52% dutasteride, and 48% finasteride) between 2003 and 2013 and matched them 1:1 to men who did not start a 5ARI. The median at-risk period for the 5ARI group was 1.68 years (interquartile range 1.00, 4.27). With adjustment for the variables related to prior BC investigations there was no significant difference in BC diagnosis (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.82-1.32) during the period of 0 to <2 years of 5ARI use; however, after ≥2 years of 5ARI use, the risk of BC diagnosis was significantly lower among the 5ARI group (HR 0.82, 95% CI 0.79-0.94). In a similarly adjusted model, BC mortality was lower among 5ARI users, but no longer statistically significant (HR 0.82, 95% CI 0.65, 1.02). When stratified by type of 5ARI, finasteride significantly reduced the risk of BC diagnosis after ≥2 years of continuous use (HR 0.86, 95% CI 0.76, 0.96); however, dutasteride did not (HR 0.92, 95% CI 0.83, 1.03).. In a large cohort of men, the use of a 5ARI was associated with a significantly decreased the risk of BC diagnosis after more than 2 years of continuous therapy.

Topics: 5-alpha Reductase Inhibitors; Dutasteride; Finasteride; Humans; Male; Ontario; Oxidoreductases; Prostatic Hyperplasia; Retrospective Studies; Urinary Bladder Neoplasms

The incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand the differences in the BCa control mechanisms based on gender. Our recent clinical study showed that androgen suppression therapy using 5α-reductase inhibitors and androgen deprivation therapy affects BCa progression, but the underlying mechanisms are still unknown.. mRNA expression levels of the androgen receptor (AR) and SLC39A9 (membrane AR) in T24 and J82 BCa cells were evaluated by reverse transcription-PCR (RT-PCR). The effect of dutasteride, a 5α-reductase inhibitor, in BCa progression was determined in cells transfected with control and AR-overexpressing plasmids. In addition, cell viability and migration assays, RT-PCR, and western blot analysis were performed to analyze the effect of dutasteride on BCa in the presence of testosterone. Finally, steroidal 5α-reductase 1 (SRD5A1), one of the dutasteride target genes, was silenced in T24 and J82 BCa cells using control and shRNA-containing plasmids, and the oncogenic role of SRD5A1 was evaluated.. Dutasteride treatment led to significant inhibition of the testosterone-induced increase dependent on AR and SLC39A9 in cell viability and migration of T24 and J82 BCa cells and induced alterations in the expression level of cancer progression proteins, such as metalloproteases, p21, BCL-2, NF-KB, and WNT in AR-negative BCa. Furthermore, the bioinformatic analysis showed that mRNA expression levels of SRD5A1 were significantly higher in BCa tissues than in normal paired tissues. A positive correlation between SRD5A1 expression and poor patient survival was observed in patients with BCa. Also, Dutasteride treatment reduced cell proliferation and migration via blocking the SRD5A1 in BCa.. Dutasteride inhibited testosterone-induced BCa progression dependent on SLC39A9 in AR-negative BCa and repressed oncogenic signaling pathways, including those of metalloproteases, p21, BCL-2, NF-KB, and WNT. Our results also suggest that SRD5A1 plays a pro-oncogenic role in BCa. This work provides potential therapeutic targets for the treatment of BCa.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Androgens; Azasteroids; Cell Line, Tumor; Dutasteride; Humans; Hyperplasia; NF-kappa B; Oxidoreductases; Prostate; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Testosterone; Urinary Bladder Neoplasms

To assess whether receipt of 5-alpha reductase inhibitors (5-ARIs) influences the findings on surgical pathology at the time of radical cystectomy (RC) and subsequent clinical outcomes. 5-ARIs may slow the progression of non-muscle-invasive bladder cancer.. We retrospectively reviewed all patients who underwent RC at our institution between 2009 and 2017. Men were included who had urothelial cancer in the RC specimen. Patients with nonurothelial pathology or who had no cancer in the specimen were excluded. Odds ratios for pathologic features and hazard ratios for survival were adjusted for baseline patient characteristics and disease stage.. Our study cohort included 338 men; 48 patients (14%) were receiving dutasteride or finasteride at time of RC, 58 (17%) metformin, and 195 (58%) statins. Among patients receiving 5-ARIs, there was a lower proportion of positive margins (P = .08) and lymphovascular invasion (P = .05). This was statistically significant when patients with urothelial carcinoma variants were excluded. Multivariable logistic regression analysis demonstrated that 5-ARI receipt was associated with a lower odds ratio (OR) for the presence of lymphovascular invasion (OR = 0.49; 95% confidence interval, 0.24-1.00; P = .049) and positive surgical margins (OR = 0.30; 95% confidence interval, 0.09-1.07; P = .063). Further, 5-ARI receipt was associated with better overall survival, with an adjusted hazard ratio of 0.40 (95% confidence interval, 0.19-0.83; P = .015). No similar tendencies were observed with metformin or statins.. 5-ARIs may exert a protective biologic effect on the invasive properties of high-grade urothelial carcinoma. Further research is needed to understand the therapeutic implications.

Topics: 5-alpha Reductase Inhibitors; Aged; Carcinoma, Transitional Cell; Cystectomy; Dutasteride; Finasteride; Humans; Logistic Models; Male; Margins of Excision; Neoadjuvant Therapy; Neoplasm Invasiveness; Retrospective Studies; Survival Analysis; Treatment Outcome; Urinary Bladder Neoplasms

Androgens may have a role in bladder carcinogenesis. We studied whether 5α-reductase inhibitors were associated with bladder cancer specific mortality in a population based cohort of men with bladder cancer.. The study cohort consisted of 10,720 Finnish men with bladder cancer newly diagnosed in 1997 to 2012 who were identified in a national cancer registry. Median followup was 4.17 years after bladder cancer diagnosis. We analyzed the HR and 95% CI of the risk of bladder cancer death by 5α-reductase inhibitor administration using Cox regression adjusted for age, gender, comorbidities, primary bladder cancer treatment and tumor extent at diagnosis. Lag time analyses were performed to assess the long-term risk association. Simultaneous administration α-blockers was considered to estimate possible confounding by indication.. Administering 5α-reductase inhibitors before bladder cancer diagnosis was associated with a lower risk of bladder cancer death (HR 0.84, 95% CI 0.73-0.97). The risk decrease became stronger with years of use. Conversely prediagnostic administration of α-blockers was not associated with bladder cancer survival (HR 1.02, 95% CI 0.91-1.13). Similarly 5α-reductase inhibitor administration after diagnosis was associated with a decreased risk of bladder cancer death (HR 0.77, 95% CI 0.68-0.88). Bladder cancer survival was not associated with α-blockers (HR 0.98, 95% CI 0.90-1.07). The risk decrease due to 5α-reductase inhibitors persisted up to 5 years.. Patients who receive 5α-reductase inhibitors have improved disease specific survival after bladder cancer diagnosis compared to those who do not receive them while α-blockers were not associated with survival. This supports the benefits of 5α-reductase inhibitors in bladder cancer.

Topics: 5-alpha Reductase Inhibitors; Aged; Cohort Studies; Dutasteride; Finasteride; Humans; Male; Retrospective Studies; Survival Rate; Urinary Bladder Neoplasms