dutasteride and Prostatic-Intraepithelial-Neoplasia

Our inability to distinguish between low-grade prostate cancers that pose no threat and those that can kill compels newly diagnosed early prostate cancer patients to make decisions that may negatively affect their lives needlessly for years afterward. To reliably stratify patients into different risk categories and apply appropriate treatment, we need a better molecular understanding of prostate cancer progression. Androgen ablation therapy and 5-alpha reductase inhibitors reduce dihydrotestosterone levels and increase apoptosis. Because of the differing biological potentials of tumor cells, however, these treatments may, in some cases, worsen outcome by selecting for or inducing adaptation of stronger androgen receptor signaling pathways. Reduced dihydrotestosterone also may be associated with altered survival pathways. Complicating treatment effects further, molecular adaptation may be accelerated by interactions between epithelial and stromal cells. The hypothesis that early prostate cancer cells with differing biological potential may respond differently to finasteride treatment is worth testing. Ongoing studies using a systems biology approach in a preoperative prostate cancer setting are testing this hypothesis toward developing more-rational clinical interventions.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Androgens; Animals; Anticarcinogenic Agents; Apoptosis; Apoptosis Regulatory Proteins; Azasteroids; Dihydrotestosterone; Disease Progression; Dutasteride; Epithelial Cells; Finasteride; Humans; Isoenzymes; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Patient Selection; Prostate; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Stromal Cells

High-grade prostatic intraepithelial neoplasia (HGPIN) is a potential precursor of prostate cancer (PCa), and patients with HGPIN are at high risk for PCa development. Objective of our study was to evaluate the efficacy of dutasteride 0.5 mg in PCa prevention among men with isolated HGPIN on biopsy.. This prospective, randomized, phase III, open-label 3-year trial assessed dutasteride versus active surveillance in patients with HGPIN. Patients were randomized to dutasteride 0.5 mg daily or active surveillance. Per-protocol prostate biopsies were performed at 6, 12, 24, and 36 months until cancer detection or study end. The primary end point was cancer-free survival (CFS). An intention-to-treat analysis was done for patients who underwent at least one per-protocol biopsy. An efficacy analysis was done for patients who completed the study. CFS was evaluated using Kaplan-Meier and log-rank analysis.. In total, 220 men were randomized (dutasteride, n = 107; surveillance, n = 113). PCa was detected in 47.6: 49.1 % in the surveillance group and 45.9 % in the treatment group (p = 0.66). The detected PCa differentiation by Gleason score (GS) was GS 6 in 76.9 %, GS 7 in 19.8 %, and GS ≥ 8 in 3.3 %, with no difference between groups. The 3-year PCa-free survival was 43.6 % in the surveillance and 49.6 % in the dutasteride group (log rank p = 0.57). Limitations include a relatively high non-adherence rate, open-label design, and baseline sextant biopsy scheme.. Dutasteride 0.5 mg for 3 years did not lower the PCa detection rate but did not worsen detected PCa characteristics in men with HGPIN.

Topics: 5-alpha Reductase Inhibitors; Aged; Biopsy; Carcinoma; Dutasteride; Humans; Male; Middle Aged; Neoplasm Grading; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms

A post hoc analysis of Asian men in the REDUCE study was conducted to investigate whether the outcomes were in line with those of the overall population.. REDUCE was a 4-year international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Inclusion criteria were men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/ml (50-60 years) or 3.0-10.0 ng/ml (>60 years), and a single, negative prostate biopsy (6-12 cores) within 6 months before enrollment. The primary endpoint was biopsy-detectable prostate cancer. This post hoc analysis included subjects who were recorded as Asian.. A total of 134 Asians, including 57 Japanese, were randomized to the study treatment. During the study period, the incidence of prostate cancer in the placebo and dutasteride groups was 19.6% (11/56) and 9.3% (5/54), respectively (relative risk reduction, 54%; 95% confidence intervals, -27 to 83%, P = 0.12), in the Asian subpopulation. Fewer tumors with the Gleason scores of 7-10 and 8-10 were detected among dutasteride-treated men. Although the incidences of drug-related sexual adverse events were higher in the dutasteride group, only in rare occasions did they lead to drug discontinuation.. The incidence of prostate cancer in the dutasteride group was lower than that in the placebo group, although the difference was not significant. These results paralleled those for the overall population and support the value of dutasteride for prostate cancer risk reduction in Asian men with an increased risk of prostate cancer.

Topics: 5-alpha Reductase Inhibitors; Aged; Asian People; Azasteroids; Double-Blind Method; Dutasteride; Humans; International Agencies; Male; Maximum Tolerated Dose; Middle Aged; Placebos; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Risk Reduction Behavior; Survival Rate; Treatment Outcome

To perform the first evaluation of the effects of the 5-alpha-reductase inhibitor class of drugs on cancer histopathologic features at radical prostatectomy in a placebo-controlled multicenter trial.. We analyzed prostatectomy slides in a blinded manner from 17 men treated with dutasteride, an inhibitor of types 1 and 2 isoenzymes of 5-alpha-reductase, and 18 men treated with placebo for 5 to 11 weeks before radical prostatectomy. The histopathologic features of benign epithelium, high-grade prostatic intraepithelial neoplasia, and cancer were recorded, and the treatment effect was scored. Digital imaging analysis was used to measure the stroma/epithelium ratio and epithelial height, as well as the nuclear area in cancer.. In benign epithelium, treatment caused distinctive cytoarchitectural changes of atrophy and a decrease in the epithelial height (P = 0.053). The peripheral zone showed the most marked response to treatment. In cancer tissue, the tumor volume was significantly lower in the dutasteride-treated men than in the placebo-treated men (mean 15% versus 24%, respectively, P = 0.025), the percentage of atrophic epithelium was increased (P = 0.041), and the stroma/gland ratio was doubled (P = 0.046). The treatment alteration effect score was doubled (P = 0.055) and did not correlate with any Gleason score changes.. After short-term dutasteride treatment, benign epithelium showed involution and epithelial shrinkage, and prostate cancer tissue demonstrated a decrease in epithelium relative to stroma. These findings indicate that dutasteride induces significant phenotypic alterations in both the benign and the neoplastic prostate, supportive of a chemopreventive or chemoactive role.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Atrophy; Azasteroids; Combined Modality Therapy; Double-Blind Method; Dutasteride; Epithelial Cells; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Proteins; Pilot Projects; Prostate; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Stromal Cells

Although men on active surveillance for prostate cancer (PCa) may benefit from intervention with 5α-reductase inhibitors (5-ARIs), it has not been resolved whether 5-ARIs are effective for delaying disease progression and, if so, whether specific patients are more likely to benefit.. To identify molecular features predictive of patient response to 5-ARIs.. Nkx3.1 mutant mice, a model of early-stage PCa, were treated with the 5-ARI finasteride, and histopathological and molecular analyses were performed. Cross-species computational analyses were used to compare expression profiles for treated mice with those of patients who had received 5-ARIs before prostatectomy.. Finasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively.. Endpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses.. Finasteride treatment of Nkx3.1 mutant mice resulted in a significant reduction in prostatic intraepithelial neoplasia (PIN), as evident from histopathological and expression profiling analyses. Cross-species computational analysis comparing finasteride-treated mice with two independent 5-ARI-treated patient cohorts showed that reduced NKX3.1 expression is predictive of response to 5-ARI. A limitation of the study is that these retrospective human cohorts have relatively few patients with limited clinical outcome data. Future prospective clinical trials are needed to validate whether stratifying patients on the basis of NKX3.1 expression improves the benefit of 5-ARIs during active surveillance.. This co-clinical study implicates NKX3.1 status as a predictor of response to 5-ARIs, and suggests that molecular features, including NKX3.1 expression, may help to identify PCa patients most likely to benefit from 5-ARIs during active surveillance.. The aim of precision cancer prevention is to tailor interventions on the basis of individualized patient characteristics. We propose that patients with low NKX3.1 expression are optimal candidates for intervention with 5α-reductase inhibitors as an adjunct to active surveillance.

Topics: 5-alpha Reductase Inhibitors; Aged; Animals; Biomarkers, Tumor; Chemotherapy, Adjuvant; Clinical Decision-Making; DNA Mutational Analysis; Dutasteride; Finasteride; Homeodomain Proteins; Humans; Male; Mice, Knockout; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Patient Selection; Precision Medicine; Predictive Value of Tests; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Retrospective Studies; Time Factors; Transcription Factors; Treatment Outcome