Statin use and outcomes of oncological treatment for castration-resistant prostate cancer.

To compare the effect of statin use in relation to castration-resistant prostate cancer (CRPC) treatment, we assessed the risk of ADT-treated PCa-patients to initiate CRPC treatment by statin use and the outcomes of CRPC treatment by statin use. Our study cohort consisted of 1169 men who participated in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) and initiated androgen deprivation therapy (ADT) during the follow-up (1996-2017). Statin use was associated with slightly decreased risk of initiating CRPC treatment (HR 0.68; 95% CI 0.47-0.97) with a 5.7 years' median follow-up until CRPC for non-users and 7.5 years for statin users. The risk of discontinuation of first or second line CRPC treatment due to inefficacy was not modified by statin use and the results remained similar in subgroup analysis assessing separately patients treated with taxans or androgen receptor signaling inhibitors. We observed an inverse association between statin use and the risk of initiation of the CRPC treatment. No beneficial risk modification by statin use during CRPC treatment was observed. These results suggest that statins might be beneficial during hormone-sensitive phase but not in the later phases of prostate cancer treatment.

Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse.

Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.

Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. A population-based cohort study.

PURPOSE: Statins' cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins' effect on prostate cancer prognosis among patients treated with ADT. MATERIALS AND METHODS: Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. RESULTS: During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65-0.82) and prostate cancer death (HR 0.82; 95% CI 0.69-0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76-1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96-1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85-1.24) were not associated with prostate cancer death, without dose dependency. CONCLUSION: Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.

Outcomes of prostate cancer screening among men using antidiabetic medication.

Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08-1.60 and HR 1.55, 95% CI 1.44-1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8-10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14-1.07 and HR 0.19, 95% CI 0.11-0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.

Anticoagulants and cancer mortality in the Finnish randomized study of screening for prostate cancer.

PURPOSE: Anticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death. METHODS: All anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2- and 3-year lag-time analyses were performed. RESULTS: During a median follow-up of 17.2 years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR = 2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories. CONCLUSION: Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.

Tumor features and survival after radical prostatectomy among antidiabetic drug users.

BACKGROUND: To evaluate the association between use of metformin and other antidiabetic drugs with tumor characteristics and survival in surgically managed prostate cancer (PCa) patients. METHODS: The study population included 1314 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Causes of deaths were collected from the Finnish Cancer Registry. Individual-level data on medication use during 1995-2009 was obtained from national prescription database. Fasting blood glucose and hemoglobin A1c values during the study period were gathered from hospital district database. Gleason grade and pathological stage were compared by drug use before surgery and separately by metformin usage. Risk of biochemical recurrence, all-cause death and PCa-specific death were calculated using Cox proportional hazard regression with adjustment for age, tumor characteristics, glycemic control and use of other drug groups. RESULTS: High-grade tumors were more common among antidiabetic drug users (P=0.032), including metformin users (P=0.012). Despite this, no difference in PSA levels was observed. Men who had used antidiabetic drugs before surgery had an increased risk of Gleason 7-10 disease (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.23). The risk of high-grade PCa was higher among metformin users compared with other antidiabetic drug users (OR 3.11, 95% CI 1.16-8.33). During the median follow-up of 8.6 years after surgery, 551 men had biochemical recurrence and 244 died, 32 owing to PCa. Generally, no association with risk of disease recurrence was observed. Risk of death was increased by preoperative use of antidiabetic drugs (hazard ratio 1.81 95% CI 1.03-3.19), but no survival associations for postoperative use of antidiabetic drugs or metformin were observed. CONCLUSION: Diabetic men have more high-grade PCa at lower PSA levels, but that does not have a clear impact on disease-specific survival in the short term even when glycemic control is being considered.

Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study.

BACKGROUND: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting. PATIENTS AND METHODS: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method. RESULTS: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml. CONCLUSION: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values. CLINICAL TRIAL NUMBER: NCT00672282.

Prostate cancer risk among users of digoxin and other antiarrhythmic drugs in the Finnish Prostate Cancer Screening Trial.

PURPOSE: Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study. METHODS: Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996-2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable. RESULTS: No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94-1.18). Neither sotalol (HR 0.97 95% CI 0.76-1.24) nor digoxin (HR 1.01 95% CI 0.87-1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7-10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7-10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49-1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7-10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12-0.84 for men who had used digoxin for 5 years or longer). CONCLUSION: Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival.

Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data.

BACKGROUND: The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs. METHODS: Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost-effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests. RESULTS: Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained. CONCLUSION: Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis.

Prostate cancer risk and nonsteroidal antiinflammatory drug use in the Finnish prostate cancer screening trial.

BACKGROUND: The association between nonsteroidal antiinflammatory drugs (NSAIDs) and prostate cancer risk remains controversial. We examined the risk among NSAID users in 78 615 men in the Finnish Prostate Cancer Screening Trial. METHODS: We obtained information on NSAID prescription usage from Finnish nationwide prescription database and on over-the-counter use by a questionnaire. Prostate cancer cases were identified from the Finnish Cancer Registry. RESULTS: Prostate cancer risk was elevated among current NSAID prescription users irrespective of screening (hazard ratio (HR)=1.45, confidence interval (95% CI)=1.33-1.59 and HR=1.71, 95% CI=1.58-1.86 in the screening and control arm, respectively), but not for previous use of NSAIDs. The risk increase was similar among coxib and acetaminophen current users, and stronger for metastatic prostate cancer (HR=2.41, 95% CI=1.59-3.67 and HR=3.44, 95% CI=2.60-4.55 in the screening and control arm, respectively). Previous use of NSAIDs, aspirin use and over-the-counter NSAID usage were not associated with prostate cancer. CONCLUSIONS: Differing association for current and previous use suggests that the risk increase is unlikely to be directly caused by the medication, but may be due to the conditions indicating NSAID prescription usage, such as symptoms of undiagnosed prostate cancer. To reduce inconsistency between the study outcomes, future epidemiological studies on NSAID use and prostate cancer risk should assess the indications for NSAID usage.