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.

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.

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.

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.

Breast cancer extent and survival among diabetic women in a Finnish nationwide cohort study.

Breast cancer (BC) and diabetes mellitus (DM) are major health problems. We examined the association between DM and BC stage at diagnosis and subsequent survival in a Finnish cohort of female BC patients. All BC cases (N = 73,170) diagnosed in 1995-2013 with dates and causes of death were identified from the Finnish Cancer Registry. Participation in organized mammography screening was obtained from Mass Inspection Registry. Information on DM diagnoses and background conditions recorded during 1995-2013 were obtained from national Care Register for Health Care and merged to data on medication use from the national Prescription Register. Logistic regression with adjustment for mammography screening and age at BC diagnosis was used to evaluate the risk of advanced stage BC at diagnosis. Cox regression was used to evaluate overall and BC survival. Analyses were adjusted for age, background conditions and mammography screening. Survival analyses were further adjusted for tumor extent, histology and primary treatment. Of the cohort 11,676 (16.0%) had DM. Screening participation did not differ by diabetes. Compared to non-diabetic women, diabetics had more often locally advanced (odds ratio, OR 1.26; 95% CI 1.18-1.35) or metastatic BC (OR 1.59; 95% CI 1.44-1.75) at diagnosis. During a median follow-up of 5.8 years after BC diagnosis 10,900 (14.9%) women died of BC. Risk of BC death was higher among diabetic compared to non-diabetic women (HR 1.36; 95% CI 1.27-1.46). Risk of BC death increased with duration of DM. This supports DM as a risk factor for fatal BC.

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.

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.

Intraprostatic inflammation is positively associated with serum PSA in men with PSA <4 ng ml(-1), normal DRE and negative for prostate cancer.

BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.

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.

False-positive screening results in the Finnish prostate cancer screening trial.

BACKGROUND: There is evidence that prostate cancer (PC) screening with prostate-specific antigen (PSA) serum test decreases PC mortality, but screening has adverse effects, such as a high false-positive (FP) rate. We investigated the proportion of FPs in a population-based randomised screening trial in Finland. METHODS: Finland is the largest centre in the European Randomized Study of Screening for Prostate Cancer. We have completed three screening rounds with a 4-year screening interval (mean follow-up time 9.2 years) using a PSA cutoff level of 4.0 ng ml(-1); in addition, men with PSA 3.0-3.9 and a positive auxiliary test were referred. An FP result was defined as a positive screening result without cancer in biopsy within 1 year from the screening test. RESULTS: The proportion of FP screening results varied from 3.3 to 12.1% per round. Of the screened men, 12.5% had at least one FP during three rounds. The risk of next-round PC following an FP result was 12.3-19.7 vs 1.4-3.7% following a screen-negative result (depending on the screening round), risk ratio 3.6-9.9. More than half of the men with one FP result had another one at a subsequent screen. Men with an FP result were 1.5 to 2.0 times more likely to not participate in subsequent rounds compared with men with a normal screening result (21.6-29.6 vs 14.0-16.7%). CONCLUSION: An FP result is a common adverse effect of PC screening and affects at least every eighth man screened repeatedly, even when using a relatively high cutoff level. False-positive men constitute a special group that receives unnecessary interventions but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men.

Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial.

BACKGROUND: The Prostate Cancer Prevention Trial has shown a protective effect of finasteride on prostate cancer in low-risk men. It is uncertain whether similar results can be expected when finasteride is used to treat benign prostatic hyperplasia. METHODS: We performed an observational cohort study within the Finnish Prostate Cancer Screening Trial. Using a comprehensive prescription database on medication reimbursements during 1995-2004 of men using finasteride or alpha-blockers for benign prostatic hyperplasia, we evaluated prostate cancer incidence among 23 320 men screened during 1996-2004. RESULTS: Compared to medication non-users, overall prostate cancer incidence was not significantly affected in finasteride users (hazard ratio 0.87; 95% CI 0.63-1.19). Incidence of Gleason 2-6 tumours, however, was decreased among finasteride users (HR 0.59; 95% CI 0.38-0.91), whereas incidence of Gleason 7-10 tumours was unchanged (HR 1.33; 95% CI 0.77-2.30). The protective effect concerned mainly screen-detected tumours. Overall prostate cancer risk was not significantly reduced among alpha-blocker users relative to non-users, but decreased incidence of high-grade tumours was observed (0.55; 95% CI 0.31-0.96). CONCLUSIONS: The detection of low-grade, early-stage tumours is decreased among men who use finasteride for symptomatic BPH. The protective effect of finasteride can also be expected in men with benign prostatic hyperplasia.