• antitumoral
• cholesterol
• mevalonate pathway
• prostate cancer
• statins

• Male
• Humans
• Prostatic Neoplasms, Castration-Resistant/pathology
• Mevalonic Acid
• Prostatic Neoplasms/metabolism
• Receptors, Androgen/metabolism
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use

• T69_23R Government of Aragon
• S.R-Z was supported by a Margarita Salas Fellowship for the Requalification of the Spanish university system 2021-2023 from the University of Zaragoza the European Union-NextGenerationEU

• Malignity
• Multiparametric magnetic resonance imaging
• PI-RADS 3
• Plasma atherogenic index
• Prostate cancer

• Male
• Humans
• Prostatic Neoplasms/pathology
• Prostate-Specific Antigen
• Prostate/pathology
• Magnetic Resonance Imaging/methods
• Retrospective Studies
• Image-Guided Biopsy/methods
• Kidney Neoplasms/pathology

Hypolipidemic drugs are among the most frequently prescribed medications in the Western world. Since many studies have indicated their role in carcinogenesis, this work aimed to investigate their association with the occurrence of a second primary malignancy in colorectal cancer survivors. The overall incidence of a second neoplasm was not linked to hypolipidemic medication; however, a subgroup analysis revealed a lower incidence of secondary neoplasia in statin users. When stratified by cancer types, a significant increase in gastric and bladder cancer was detected among colorectal cancer patients using hypolipidemic drugs. Survival outcomes in patients with early-stage colorectal carcinoma who suffered second cancer were significantly worse if treated with hypolipidemic drugs. Although our results do not provide evidence for a causative relationship between hypolipidemic medication and carcinogenesis, these correlations might steer the direction of tertiary prevention care towards specific risk factors shared between cardiovascular diseases and cancer.

An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan−Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.

• Active surveillance
• Diet
• Metformin
• Prostate cancer
• Statins

• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Metformin/therapeutic use
• Prostatic Neoplasms/diet therapy
• Prostatic Neoplasms/therapy
• Secondary Prevention
• Watchful Waiting

• castration-resistant prostate cancer
• cholesterol uptake
• patient survival
• prostate cancer
• scavenger receptor Class B type I high-density lipoproteins

Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.

• Statins
• Cancer
• Pleiotropic effects
• Risk reduction
• Clinical trials
• 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase
• Mevalonate pathway

• aged
• humans
• male
• middle aged
• cause of death
• disease progression
• erectile dysfunction
• erectile dysfunction/epidemiology
• palliative care
• postoperative complications
• postoperative complications/epidemiology
• prostatectomy
• prostatectomy/adverse effects
• prostatectomy/methods
• prostatectomy/mortality
• prostatic neoplasms
• prostatic neoplasms/mortality
• prostatic neoplasms/pathology
• prostatic neoplasms/surgery
• prostatic neoplasms/therapy
• quality of life
• randomized controlled trials as topic
• urinary incontinence
• urinary incontinence/epidemiology
• watchful waiting

• Aged
• Cause of Death
• Disease Progression
• Erectile Dysfunction/epidemiology
• Humans
• Male
• Middle Aged
• Palliative Care
• Postoperative Complications/epidemiology
• Prostatectomy/adverse effects
• Prostatectomy/methods
• Prostatectomy/mortality
• Prostatic Neoplasms/mortality
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/surgery
• Prostatic Neoplasms/therapy
• Quality of Life
• Randomized Controlled Trials as Topic
• Urinary Incontinence/epidemiology
• Watchful Waiting

The assessment of the risk of biochemical recurrence (BCR) is critical in the management of males with prostate cancer (PC). Over the past decades, a comprehensive effort has been focusing on improving risk stratification; a variety of models have been constructed using PC-associated pathological features and molecular alterations occurring at the genome, protein and RNA level. Alterations in RNA expression (lncRNA, miRNA and mRNA) constitute the largest proportion of the biomarkers of BCR. In this article, we systemically review RNA-based BCR biomarkers reported in PubMed according to the PRISMA guidelines. Individual miRNAs, mRNAs, lncRNAs and multi-gene panels, including the commercially available signatures, Oncotype DX and Prolaris, will be discussed; details related to cohort size, hazard ratio and 95% confidence intervals will be provided. Mechanistically, these individual biomarkers affect multiple pathways critical to tumorigenesis and progression, including epithelial-mesenchymal transition (EMT), phosphatase and tensin homolog (PTEN), Wnt, growth factor receptor, cell proliferation, immune checkpoints and others. This variety in the mechanisms involved not only validates their associations with BCR, but also highlights the need for the coverage of multiple pathways in order to effectively stratify the risk of BCR. Updates of novel biomarkers and their mechanistic insights are considered, which suggests new avenues to pursue in the prediction of BCR. Additionally, the management of patients with BCR and the potential utility of the stratification of the risk of BCR in salvage treatment decision making for these patients are briefly covered. Limitations will also be discussed.

To evaluate the association between the use of statins and/or metformin and patient survival in prostate cancer patients in Taiwan.

Newly diagnosed prostate cancer patients who had hyperlipidemia and received radiotherapy were identified from the National Health Insurance Research Database 2000–2010. The survival rate was estimated by the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were performed to examine the association of mortality. Sensitivity analysis was performed to assess the risk of mortality in patients with diabetes.

The study included 567 patients. Patients who used statins or metformin after prostate cancer diagnosis had longer average survival times (9.3 years and 8.1 years, respectively; P=0.001) compared with patients who persistently used or used the medicines prior to cancer diagnosis. Multivariate Cox regression analysis found that patients treated with statins after cancer diagnosis were significantly associated with a lower risk of mortality (aHR =0.24, 95% CI =0.09–0.66) compared to patients who did not use statins during the study period. Patients treated with metformin after cancer diagnosis were significantly associated more with an increased risk of mortality (aHR =6.78, 95% CI =2.45–18.77) compared to patients who did not use metformin during the study period. Sensitivity analysis revealed that the average survival time was similar among different medicine use groups in patients with diabetes.

The finding suggests that statins and metformin use after prostate cancer diagnosis may increase survival in patients with hyperlipidemia and radiotherapy.

• hyperlipidemia
• metformin
• mortality
• prostate cancer
• statin
• survival

Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to investigate the association between MetS‐components, C‐reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig‐PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS‐diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig‐PCa was associated to MetS, greater number of MetS‐components and higher CRP levels (odds‐ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS‐components or CRP levels >2.5 mg/L with an increased Sig‐PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology.

• C-reactive protein
• inflammation
• metabolic syndrome
• significant prostate cancer
• testosterone

Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p<0.001) whereas statin intake showed an odds ratio of 0.49 (p=0.005) indicating a negative association with high-risk PC. Despite a limited number of patients using statins (~9.5%), adjusted and weighed multivariate logistic regression models revealed that preoperative hypercholesterolemia is associated with a diagnosis of high-risk PC which is negatively influenced by statin intake.

• biomarker
• cholesterol
• prostate cancer
• statin therapy
• tumor biology

• chemoprevention
• epidemiology
• pharmacoepidemiology
• prostate cancer
• statins

Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA-independent, study-mandated prostate biopsies.

We conducted a post-hoc analysis of data from 4,974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. ≥7), were examined using multivariable logistic regression.

High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR_per10mg/dl 1.05; 95% CI 1.00-1.09; p=0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values>0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values>0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR_per10mg/dl 1.08; 95% CI 1.01-1.16; p=0.033) and high-grade prostate cancer (OR_per10mg/dl 1.14; 95% CI 1.01-1.28; p=0.034).

In REDUCE, where all men received PSA-independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.

Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth. Immunomodulatory roles of commonly used cholesterol-lowering medications, atorvastatin and other statins, are widely documented. We have previously shown that atorvastatin can inhibit HIV-1 infection and replication. Here, for the very first time we discovered that atorvastatin also regulates activated T cell function by mediating downregulation of multiple co-inhibitory receptors, which corresponded with increased IL-2 production by stimulated T cells. In addition, we found that atorvastatin treatment reduces expression of mTOR and downstream T cell effector genes. We demonstrate a novel mechanism showing that atorvastatin inhibition of Ras-activated MAPK and PI3K-Akt pathways, and subsequent mTOR signalling promotes gross downregulation of co-inhibitory receptors. Thus, our results suggest that statins may hold particular promise in reinvigorating T cell function in chronic conditions.

• atorvastatin
• immune checkpoints
• inhibitory receptors

A possible association between the level of prostate specific antigen (PSA) and the use of some commonly prescribed medications has been reported in recent studies. Most of these studies were carried out in general populations of men who were screened for prostate cancer using the PSA test. We reported on the association between the initial PSA level and the use of statins, metformin and alpha-blockers in patients who were diagnosed with prostate cancer and presented for radiation therapy.

Three hundred and eighty one patients treated between the years of 2000-2005 and 2009-2012 were included in this retrospective study. The information about statin, metformin and alpha-blockers use was recorded immediately prior to treatment. Differences in PSA levels prior to treatment by medication status were estimated using univa-riate and multivariate linear regression on log PSA values.

Compared with men who were not on these medications, the PSA level at presentation was 20% lower for statin users (p = 0.002) and 33% lower for metformin users (p = 0.004). We did not observe statistically significant associations between the use of statins or metformin and cancer stage, National Comprehensive Cancer Network (NCCN) risk score, or therapy outcome. A statistically significant association between the NCCN risk score and the use of alpha-blockers was observed (p = 0.002).

We found that statins and metformin were associated with lower PSA levels in prostate cancer patients to an extent that could influence management decisions. We found no statistically significant associations between the use of these medications and treatment outcomes.

• Metformin
• PSA
• Prostate Cancer
• Statins

• Humans
• Metabolic Networks and Pathways
• Mevalonic Acid/metabolism
• Neoplasms/metabolism
• Signal Transduction

• Anticoagulant drugs
• cohort
• metastasis
• prostate cancer
• risk
• warfarin

The role of statins in preventing prostate cancer is currently a controversial issue. The aim of this review is to investigate the effects of statins use on prostate cancer risk. Electronic databases (the Cochrane Library, PubMed, Medline, Embase, Web of Science, and ClinicalTrials.gov) were searched systematically up to April, 2015. Weighted averages were reported as relative risk (RR) with 95% confidence intervals (CIs). Statistic heterogeneity scores were assessed with the standard Cochran’s Q test and I² statistic. The pooled estimates of randomized controlled trials (RCTs) and retrospective studies suggest that statins have a neutral effect on total prostate cancer (RR = 1·02, 95% CI: 0·90–1·14; and RR = 0·91, 95% CI: 0·79–1·02, respectively). This research provides no evidence to suggest that the use of statins for cholesterol lowering is beneficial for the prevention of low-grade or localized prostate cancer, although a plausible association between statins use and the reduction risk of advanced (RR = 0·87, 95% CI: 0·82–0·91) or high-grade prostate cancer (RR = 0·83, 95% CI: 0·66–0·99) is observed. Furthermore, it shows that prostate cancer risk does not statistically significant benefit from long-term statins use.

• African Americans
• chemoprevention
• epidemiologic studies
• prostate cancer
• statins

• Adult
• Black or African American
• Aged
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
• Incidence
• Male
• Middle Aged
• Neoplasm Grading
• Prostatic Neoplasms/epidemiology
• Prostatic Neoplasms/etiology
• Prostatic Neoplasms/pathology
• Risk Factors
• White People

• R01 CA092447 NCI NIH HHS
• T32 CA009001 NCI NIH HHS

• metabolic syndrome
• prostate cancer
• prostate-specific antigen

• biochemical recurrence
• cholesterol
• postoperative statin use
• prostate cancer

• HMG-CoA reductase
• androgen synthesis
• cholesterol
• prenylation
• prostate cancer
• statin

• Cholesterol/blood
• Cholesterol/metabolism
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Prostatic Neoplasms/blood
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/metabolism
• Randomized Controlled Trials as Topic

• Alcohol trial
• Dutasteride
• Prostate cancer