Prostate Cancer Incidence and Mortality in Men Exposed to α1-Adrenoceptor Antagonists.

BACKGROUND: α1-antagonists are commonly used to treat benign prostatic hyperplasia. Preclinical studies suggest they induce cell death and inhibit tumor growth. This study evaluates the risk of prostate cancer death in men using α1-antagonists. METHODS: A population-based cohort study in Stockholm, Sweden (January 1, 2007 to December 31, 2019) including 451,779 men with a prostate-specific antigen (PSA) test. Study entry was one year after the first PSA test. Men were considered exposed at their second filled prescription. Primary outcome: prostate cancer mortality. Secondary outcomes: all-cause mortality and prostate cancer incidence. Cox proportional hazard regression models were used to calculate adjusted hazard ratios (HRs) and 95% CIs for all outcomes. Inverse probability weighting with marginal structural models accounted for time-dependent confounders. RESULTS: Of 351,297 men in the cohort, 39,856 (11.3%) were exposed to α1-antagonists. Median follow-up for prostate cancer mortality was 8.9 years and median exposure time to α1-antagonists was 4.4 years. There was no evidence of an association between α1-antagonist use and prostate cancer mortality, all-cause mortality, or high-grade prostate cancer. α1-antagonist-use was associated with an increased risk of prostate cancer (HR: 1.11, 95% CI: 1.06-1.17) and low-grade prostate cancer (HR: 1.22, 95% CI: 1.11-1.33). Men treated with α1-antagonists had more frequent PSA testing. CONCLUSIONS: Our findings show no significant association between α1-adrenoceptor antagonist exposure and prostate cancer mortality or high-grade prostate cancer. Although the preclinical evidence indicates a potential chemopreventive effect, this study's findings do not support it.

Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial.

Importance: Prostate cancer guidelines often recommend obtaining magnetic resonance imaging (MRI) before a biopsy, yet MRI access is limited. To date, no randomized clinical trial has compared the use of novel biomarkers for risk estimation vs MRI-based diagnostic approaches for prostate cancer screening. Objective: To evaluate biomarker-based risk estimation (Stockholm3 risk scores or prostate-specific antigen [PSA] levels) with systematic biopsies vs an MRI-enhanced strategy (PSA levels and MRI with systematic and targeted biopsy) for the detection of clinically significant prostate cancer in a screening setting. Design, Setting, and Participants: This open-label randomized clinical trial conducted in Stockholm, Sweden, between April 4, 2018, and December 10, 2020, recruited men aged 50 to 74 years with no history of prostate cancer. Participants underwent blood sampling for PSA and Stockholm3 tests to estimate their risk of clinically significant prostate cancer (Gleason score ≥3 + 4). After the blood tests were performed, participants were randomly assigned in a 2:3 ratio to receive a Stockholm3 test with systematic biopsy (biomarker group) or a PSA test followed by MRI with systematic and targeted biopsy (MRI-enhanced group). Data were analyzed from September 1 to November 5, 2023. Interventions: In the biomarker group, men with a Stockholm3 risk score of 0.15 or higher underwent systematic biopsies. In the MRI-enhanced group, men with a PSA level of 3 ng/mL or higher had an MRI and those with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or higher (range: 1-5, with higher scores indicating a higher likelihood of clinically significant prostate cancer) underwent targeted and systematic biopsies. Main Outcomes and Measures: Primary outcome was detection of clinically significant prostate cancer (Gleason score ≥3 + 4). Secondary outcomes included detection of clinically insignificant cancer (Gleason score ≤6) and the number of biopsy procedures performed. Results: Of 12 743 male participants (median [IQR] age, 61 [55-67] years), 5134 were assigned to the biomarker group and 7609 to the MRI-enhanced group. In the biomarker group, 8.0% of men (413) had Stockholm3 risk scores of 0.15 or higher and were referred for systematic biopsies. In the MRI-enhanced group, 12.2% of men (929) had a PSA level of 3 ng/mL or higher and were referred for MRI with biopsies if they had a PI-RADS score of 3 or higher. Detection rates of clinically significant prostate cancer were comparable between the 2 groups: 2.3% in the biomarker group and 2.5% in the MRI-enhanced group (relative proportion, 0.92; 95% CI, 0.73-1.15). More biopsies were performed in the biomarker group than in the MRI-enhanced group (326 of 5134 [6.3%] vs 338 of 7609 [4.4%]; relative proportion, 1.43 [95% CI, 1.23-1.66]), and more indolent prostate cancers were detected (61 [1.2%] vs 41 [0.5%]; relative proportion, 2.21 [95% CI, 1.49-3.27]). Conclusions and Relevance: Findings of this randomized clinical trial indicate that combining a Stockholm3 test with systematic biopsies is comparable with MRI-based screening with PSA levels and systematic and targeted biopsies for detection of clinically significant prostate cancer, but this approach resulted in more biopsies as well as detection of a greater number of indolent cancers. In regions where access to MRI is lacking, the Stockholm3 test can aid in selecting patients for systematic prostate biopsy. Trial Registration: ClinicalTrials.gov Identifier: NCT03377881.

Prediagnostic Prostate-specific Antigen Testing and Clinical Characteristics in Men with Lethal Prostate Cancer.

Background and objective: Prostate cancer (PC) is the fifth leading cause of cancer-related mortality in men worldwide. Opportunistic testing with prostate-specific antigen (PSA) has limited impact on PC mortality. Our objective was to assess prediagnostic PSA testing patterns and clinical characteristics at diagnosis in men with lethal PC. Methods: We conducted a population-based observational study of all men dying from PC in Stockholm County, Sweden, from 2015 to 2019. Data were retrieved from the National Prostate Cancer Register and the Stockholm PSA and Biopsy Register. If the first PSA was registered within 1 yr before diagnosis, men were categorised as PSA naïve. If an elevated PSA level was registered >1 yr before diagnosis without leading to prostate biopsy or repeating PSA within 1 yr, men were categorised as having delayed diagnosis. If a normal PSA level was registered within 5 yr before diagnosis, followed by an elevated PSA level that resulted in PC diagnosis within 1 yr, men were categorised as PSA tested. Clinical characteristics at diagnosis were stratified with D'Amico risk group classification. Key findings and limitations: Among 1473 men dying from PC, PSA test history was available for 995. Of these men, 60% (n = 592) were PSA naïve, 25% (n = 250) received delayed diagnosis, and 15% (n = 153) were PSA tested. After examining all 1473 men, 25% (n = 350) were diagnosed with low- or intermediate-risk cancer, 48% (n = 687) with high-risk cancer, and 27% (n = 385) with metastatic disease. Limitations include the retrospective design. Conclusions and clinical implications: Many men with lethal PC lacked PSA testing before diagnosis or had been tested without subsequent follow-up. Nearly half of the study population was diagnosed with high-risk cancer and almost one-third with metastatic disease. These findings suggest further evaluation of the current opportunistic PSA testing approach. Patient summary: Data from a population-based observational study of men dying from prostate cancer showed that many of them did not undergo either prostate-specific antigen (PSA) testing before diagnosis or subsequent follow-up if tested. These findings implicate deficiencies in the current opportunistic PSA testing approach.

Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors.

PURPOSE: The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade ≥ 2). METHODS: This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients. RESULTS: 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naïve (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG ≥ 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS ≥ 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively. CONCLUSIONS: Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions. TRIAL REGISTRATION: The present study was registered at ClinicalTrials.gov number: NCT05078359.

Biochemical Recurrence and Risk of Mortality Following Radiotherapy or Radical Prostatectomy.

Importance: Stratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments. Objective: To evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM. Design, Setting, and Participants: This population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023. Main Outcomes and Measures: Primary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria. Exposures: Radical prostatectomy or radiotherapy. Results: A total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category. Conclusions and Relevance: These findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression.

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A "consensus" classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters.

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a "consensus" classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.

Association of 5α-Reductase Inhibitors With Prostate Cancer Mortality.

Importance: There is evidence that 5α-reductase inhibitors (5-ARIs), a standard treatment of benign prostate hyperplasia, are associated with a decrease in the incidence of prostate cancer (PCa). However, studies to date have had conflicting results regarding the association with prostate cancer mortality (PCM). Objective: To evaluate the association of treatment with 5-ARIs with PCM in men without a prior diagnosis of PCa. Design, Setting, and Participants: This population-based cohort study was conducted in Stockholm, Sweden, between January 1, 2007, and December 31, 2018, and included 429 977 men with a prostate-specific antigen (PSA) test within the study period. Study entry was set to 1 year after the first PSA test. Data were analyzed from September 2021 to December 2021. Exposures: After their initial PSA test, men with 2 or more newly dispensed prescriptions of 5-ARI, finasteride, or dutasteride were considered 5-ARI users (n = 26 190). Main Outcomes and Measures: Primary outcome was PCM. Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs for all-cause mortality and PCM. Results: The study cohort included 349 152 men. The median (IQR) age for those with 2 or more filled prescriptions of 5-ARI was 66 (61-73) years and 57 (50-64) years for those without. The median follow-up time was 8.2 (IQR, 4.9-10) years with 2 257 619 person-years for the unexposed group and 124 008 person-years for the exposed group. The median exposure to treatment with 5-ARI was 4.5 (IQR, 2.1-7.4) years. During follow-up, 35 767 men (8.3%) died, with 852 deaths associated with PCa. The adjusted multivariable survival analysis showed a lower risk of PCM in the 5-ARI group with longer exposure times (0.1-2.0 years: adjusted HR, 0.89; 95% CI, 0.64-1.25; >8 years: adjusted HR, 0.44; 95% CI, 0.27-0.74). No statistically significant differences were seen in all-cause mortality between the exposed and unexposed group. Men treated with 5-ARIs underwent more PSA tests and biopsies per year than the unexposed group (median of 0.63 vs 0.33 and 0.22 vs 0.12, respectively). Conclusions and Relevance: The results of this cohort study suggest that there was no association between treatment with 5-ARI and increased PCM in a large population-based cohort of men without a previous PCa diagnosis. Additionally, a time-dependent association was seen with decreased risk of PCM with longer 5-ARI treatment. Further research is needed to determine whether the differences are because of intrinsic drug effects or PCa testing differences.

Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer.

PURPOSE: To evaluate clinical variables, including magnetic resonance imaging (MRI) predictive of adverse pathology (AP) at radical prostatectomy (RP) in men initially enrolled in active surveillance (AS). METHODS: A population-based cohort study of men diagnosed with low-risk prostate cancer (PCa), in Stockholm County, Sweden, during 2008-2017 enrolled in AS their intended primary treatment followed by RP. AP was defined as ISUP grade group ≥ 3 and/or pT-stage ≥ T3. Association between clinical variables at diagnosis and time to AP was evaluated using Cox regression and multivariate logistic regression to evaluate the association between AP and clinical variables at last biopsy before RP. RESULTS: In a cohort of 6021 patients with low-risk PCa, 3116 were selected for AS and 216 underwent RP. Follow-up was 10 years, with a median time on AS of 23 months. 37.7% of patients had AP at RP. Clinical T-stage [Hazard ratio (HR): 1.81, 95% confidence interval (CI) 1.04-3.18] and PSA (HR: 1.31, 95% CI 1.17-1.46) at diagnosis and age [Odds Ratio (OR): 1.09, 95% CI 1.02-1.18), PSA (OR: 1.22, 95% CI 1.07-1.41), and PI-RADS (OR 1.66, 95% CI 1.11-2.55)] at last re-biopsy were significantly associated with AP. CONCLUSION: PI-RADS score is significantly associated with AP at RP and support current guidelines recommending MRI before enrollment in AS. Furthermore, age, cT-stage, and PSA are significantly associated with AP.