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Active surveillance (AS) is standard of care for patients with low-risk prostate cancer (PCa), but its feasibility in intermediate-risk patients is controversial. We compared outcomes of low- and intermediate-risk patients managed with multiparametric magnetic resonance imaging (mpMRI)-supported AS in a community hospital. Of the 433 patients enrolled in AS between 2009 and 2016, 358 complied with AS inclusion criteria (Cancer of the Prostate Risk Assessment (CAPRA) score ≤ 5, Gleason grade group (GGG) ≤ 2, clinical stage ≤ cT2 and prostate-specific antigen (PSA) ≤ 20 ng/ml) and discontinuation criteria (histological-, PSA-, clinical- or radiological disease reclassification). Of the 358 patients, 177 (49%) were low-risk and 181 (51%) were intermediate-risk. Median follow-up was 4.2 years. The estimated 5-year treatment-free survival (TFS) was 56% (95% confidence interval [CI] 51–62%). Intermediate-risk patients had significantly shorter TFS compared with low-risk patients (hazard ratio 2.01, 95% CI 1.47–2.76, p < 0.001). There were no statistically significant differences in the rate of adverse pathology, biochemical recurrence-free survival and overall survival between low- and intermediate-risk patients. Two patients developed metastatic disease and three died of PCa. These results suggest that selected patients with intermediate-risk PCa may be safely managed by mpMRI-supported AS, but longer follow-up is necessary.

IntroductionBlood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins’ efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT.Methods and analysisIn this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial.Ethics and disseminationThis study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.Trial registration numberClinicaltrial.gov: NCT04026230, Eudra-CT: 2016-004774-17, protocol code: ESTO2, protocol date 10 September 2020 and version 6.

Background Current risk stratification tools for prostate cancer patients under active surveillance (AS) may inadequately identify those needing treatment. We investigated DNA ploidy and PTEN as potential biomarkers to predict aggressive disease in AS patients. Methods We assessed DNA ploidy by image cytometry and PTEN protein expression by immunohistochemistry in 3197 tumour-containing tissue blocks from 558 patients followed in AS at a Norwegian local hospital. The primary endpoint was treatment, with treatment failure (biochemical recurrence or initiation of salvage therapy) as the secondary endpoint. Results The combined DNA ploidy and PTEN (DPP) status at diagnosis was associated with treatment-free survival in univariable- and multivariable analysis, with a HR for DPP-aberrant vs. DPP-normal tumours of 2.12 ( p  < 0.0001) and 1.94 ( p  < 0.0001), respectively. Integration of DNA ploidy and PTEN status with the Cancer of the Prostate Risk Assessment (CAPRA) score improved risk stratification (c-index difference = 0.025; p  = 0.0033). Among the treated patients, those with DPP-aberrant tumours exhibited a significantly higher likelihood of treatment failure (HR 2.01; p  = 0.027). Conclusions DNA ploidy and PTEN could serve as additional biomarkers to identify AS patients at increased risk of developing aggressive disease, enabling earlier intervention for nearly 50% of the patients that will eventually receive treatment with current protocol.

Background: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. Methods: We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6–12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies. Results: Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens. Conclusions: Multi-sample analysis should be performed to support clinical treatment decisions.

BackgroundThe validated Stockholm3 test is used to improve PC detection. Stockholm3, however, was developed using systematic biopsies. We aimed to assess Stockholm3 operating performance when using MRI-targeted biopsies for PC detection.MethodsA prospective cohort of 532 men was considered for prostate biopsy during 2016–2017. All men underwent Stockholm3 testing and MRI before biopsy. All PIRADs ≥3 lesion underwent targeted biopsy; all men underwent systematic biopsy. The primary outcome was ISUP Grade Group ≥2 (GG ≥ 2) PC. Detection strategies included: (1) systematic biopsies alone, (2) targeted biopsies alone, (3) targeted with associated systematic biopsies for MRI+, and (4) all biopsies in all men. For each strategy, the Stockholm3 operating characteristics were assessed with discrimination, calibration, and decision curve analysis (DCA).ResultsMedian age was 65 years, median PSA was 6.2 ng/mL, median Stockholm3 score was 16.5%, and overall detection of GG ≥ 2 PC was 36% (193/532). Stockholm3 showed accurate discrimination for separating GG ≥ 2 cancer from benign and GG1, with an area under the curve of 0.84–0.86 depending on the biopsy strategy. Calibration analysis showed that Stockholm3 underestimated risks for GG ≥ 2 PC risk using MRI-targeted biopsies: there was a net benefit over biopsies in all men for Stockholm3 at risk thresholds varying from >3% in systematic biopsies to >15% in targeted with systematic biopsies in MRI+ men. When using a Stockholm3 score of >10% cutoff, a range of 32–38% of biopsies could be avoided while missing 5–11% of GG ≥ 2 PC and 0–3% of GG ≥ 3 PC.ConclusionsStockholm3 shows high discriminatory performance in an MRI-targeted biopsy setting, however risks are underpredicted due to MRI-targeted biopsies being more sensitive than the systematic biopsies for which Stockholm3 was developed. Stockholm3, along with any risk prediction model developed for systematic prostate biopsy decisions, will need recalibration for optimal use in an MRI-driven biopsy setting.