Publications by authors named "Markus Aly"

55 Publications

Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label, non-inferiority trial.

Lancet Oncol 2021 09 13;22(9):1240-1249. Epub 2021 Aug 13.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Capio St Göran's Hospital, Stockholm, Sweden.

Background: Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies.

Methods: We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881.

Findings: Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p<0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group.

Interpretation: The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer.

Funding: The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.
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http://dx.doi.org/10.1016/S1470-2045(21)00348-XDOI Listing
September 2021

Identifying Prostate Cancer Among Men with Lower Urinary Tract Symptoms.

Eur Urol Open Sci 2021 Feb 1;24:11-16. Epub 2021 Jan 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: In men aged above 50 yr, lower urinary tract symptoms (LUTS), benign prostate hyperplasia, and prostate cancer are common urological conditions. Current guidelines for general practitioners frequently recommend prostate-specific antigen (PSA) testing in patients with LUTS for the detection of prostate cancer.

Objective: To assess the performance of PSA, PSA density, and the Stockholm3 blood test for identification of prostate cancer among men with LUTS.

Design Setting And Participants: In this post hoc analysis of a population-based diagnostic trial (STHLM3,  = 58 588), 4588 men aged 50-69 yr, without previous prostate cancer, with International Prostate Symptom Score (IPSS) data, and having PSA ≥ 3 ng/mL were identified. Men with at least moderate LUTS, defined as an IPSS score of ≥8, were included. PSA density and Stockholm3 scores were calculated.

Intervention: Participants underwent 10-12-core systematic prostate biopsies.

Outcome Measurements And Statistical Analysis: The primary outcome was significant prostate cancer (sPCa) defined as International Society of Urological Pathology (ISUP) grade ≥2. Logistic regression analysis adjusted for age and previous biopsy status was performed. The area under the receiver operating characteristic curve (AUC) was calculated, and decision curve analysis was performed.

Results And Limitations: Out of 4588 men, 1544 (34%) reported at least moderate LUTS. The median age was 64 yr, and 11% had undergone a previous prostate biopsy. The Stockholm3 test showed superior discrimination for sPCa to PSA density, which in turn showed superior discrimination to PSA (AUC 0.77 vs 0.70 vs 0.61,  <  0.02). Calibration of the Stockholm3 test was adequate. Performing biopsy only in men with PSA ≥5 ng/mL saved 64% of biopsies, but resulted in missing 52% of detectable sPCa. Recommending biopsy for men with PSA density ≥0.07 resulted in sparing 26% of biopsy procedures and delaying the diagnosis of 12% of sPCa cases, with a 6.1% risk of sPCa among unbiopsied men. Recommending men with Stockholm3 ≥ 0.11 for biopsy resulted in sparing 53% of biopsy procedures and delaying the diagnosis of 20% of sPCa cases, with a 5.1% risk of finding sPCa in unbiopsied men.

Conclusions: PSA density and the Stockholm3 blood test were superior to PSA for the identification of prostate cancer among men with LUTS.

Patient Summary: In this analysis of a large Swedish study, we find that the use of prostate-specific antigen (PSA) density or the Stockholm3 blood test instead of only PSA might improve the detection of prostate cancer among men with lower urinary tract symptoms.
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http://dx.doi.org/10.1016/j.euros.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317798PMC
February 2021

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening.

N Engl J Med 2021 09 9;385(10):908-920. Epub 2021 Jul 9.

From the Departments of Medical Epidemiology and Biostatistics (M.E., A.D., M.B., H.G., T.N.) and Molecular Medicine and Surgery (F.J., M. Aly, S.C.), and the Department of Clinical Sciences at Danderyd Hospital (T.N.), Karolinska Institutet, the Department of Diagnostic Radiology (F.J.), the Department of Surgery (M.B., H.G.) and the Department of Clinical Pathology and Cytology, Unilabs (A.G.), Capio St. Göran's Hospital, C-Medical Urology Odenplan (M. Annerstedt), and the Department of Urology, Karolinska University Hospital Solna (M. Aly, S.C.) - all in Stockholm.

Background: High rates of overdiagnosis are a critical barrier to organized prostate cancer screening. Magnetic resonance imaging (MRI) with targeted biopsy has shown the potential to address this challenge, but the implications of its use in the context of organized prostate cancer screening are unknown.

Methods: We conducted a population-based noninferiority trial of prostate cancer screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with prostate-specific antigen (PSA) levels of 3 ng per milliliter or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer (experimental biopsy group). The primary outcome was the proportion of men in the intention-to-treat population in whom clinically significant cancer (Gleason score ≥7) was diagnosed. A key secondary outcome was the detection of clinically insignificant cancers (Gleason score 6).

Results: Of 12,750 men enrolled, 1532 had PSA levels of 3 ng per milliliter or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group. In the intention-to-treat analysis, clinically significant cancer was diagnosed in 192 men (21%) in the experimental biopsy group, as compared with 106 men (18%) in the standard biopsy group (difference, 3 percentage points; 95% confidence interval [CI], -1 to 7; P<0.001 for noninferiority). The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4% [41 participants] vs. 12% [73 participants]; difference, -8 percentage points; 95% CI, -11 to -5).

Conclusions: MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was noninferior to standard biopsy for detecting clinically significant prostate cancer in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer. (Funded by the Swedish Research Council and others; STHLM3-MRI ClinicalTrials.gov number, NCT03377881.).
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http://dx.doi.org/10.1056/NEJMoa2100852DOI Listing
September 2021

The 90-day cause-specific mortality after radical prostatectomy: a nationwide population-based study.

BJU Int 2021 Jun 30. Epub 2021 Jun 30.

Urology, The Institution for Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objective: To investigate the cause-specific mortality in the postoperative period after radical prostatectomy (RP) for prostate cancer (PCa).

Methods: In the National Prostate Cancer Register of Sweden (NPCR), we identified all men who died within 90 days after RP performed 1998-2018 and we assessed cause of death in a chart review. We compared the adjudications of death from our medical record review with those in in the Swedish Cause of Death Registry (CDR).

Results: Out of 44 635, 58 (0.13%) men who had undergone RP from 1998 through 2018 died within 90 days after RP. Per medical record review the most common causes of death were cardiac disease (30%) and venous thromboembolic events (VTE; 21%). No men died of metastatic PCa as was first indicated in the CDR. After robot-assisted RP (RARP) or open retropubic RP (RRP), the postoperative mortality was 0.09% (19/21 520) and 0.19% (37/19 635), respectively. The effect off modality was confounded mainly by year of surgery, age at surgery, Charlson Comorbidity Index score and the concomitant pelvic lymph node dissection.

Conclusion: The validated absolute 90-day mortality after RP was 1.3/1000 during the 21-year study period. Cardiovascular diseases were the most common causes of death after RP. Our validation of the CDR refuted the occurrence of postoperative deaths from metastatic PCa. There were differences in rates and type of mortality between RRP and RARP, but the RARP cohort was more recent than the RRP cohort, which likely explain the differences.
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http://dx.doi.org/10.1111/bju.15533DOI Listing
June 2021

Real world treatment utilization patterns in patients with castration-resistant prostate cancer.

Scand J Urol 2021 Aug 7;55(4):299-306. Epub 2021 Jun 7.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016.

Methods: We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described.

Results: Treatment for men with de novo metastatic disease ( = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis ( = 66) was 44%, treatment for men with nonmetastatic CRPC ( = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis ( = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006-2009 for metastatic cancer to 50% in 2013-2015 ( < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2-0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 - 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 - 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 - 5.8).

Conclusions: Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.
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http://dx.doi.org/10.1080/21681805.2021.1936626DOI Listing
August 2021

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Eur Urol Oncol 2021 Aug 9;4(4):570-579. Epub 2021 Jan 9.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

Objective: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

Design, Setting, And Participants: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.

Outcome Measurements And Statistical Analysis: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.

Results And Limitations: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).

Conclusions: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.

Patient Summary: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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http://dx.doi.org/10.1016/j.euo.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233PMC
August 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

The CanMoRe trial - evaluating the effects of an exercise intervention after robotic-assisted radical cystectomy for urinary bladder cancer: the study protocol of a randomised controlled trial.

BMC Cancer 2020 Aug 26;20(1):805. Epub 2020 Aug 26.

Department of Neurobiology, Care sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.

Background: Patients who have undergone radical cystectomy for urinary bladder cancer are not sufficiently physically active and therefore may suffer complications leading to readmissions. A physical rehabilitation programme early postoperatively might prevent or at least alleviate these potential complications and improve physical function. The main aim of the CanMoRe trial is to evaluate the impact of a standardised and individually adapted exercise intervention in primary health care to improve physical function (primary outcome) and habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications in patients undergoing robotic-assisted radical cystectomy for urinary bladder cancer.

Methods: In total, 120 patients will be included and assigned to either intervention or control arm of the study. All patients will receive preoperative information on the importance of early mobilisation and during the hospital stay they will follow a standard protocol for enhanced mobilisation. The intervention group will be given a referral to a physiotherapist in primary health care close to their home. Within the third week after discharge, the intervention group will begin 12 weeks of biweekly exercise. The exercise programme includes aerobic and strengthening exercises. The control group will receive oral and written information about a home-based exercise programme. Physical function will serve as the primary outcome and will be measured using the Six-minute walk test. Secondary outcomes are gait speed, handgrip strength, leg strength, habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications. The measurements will be conducted at discharge (i.e. baseline), post-intervention and 1 year after surgery. To evaluate the effects of the intervention mixed or linear regression models according to the intention to treat procedure will be used.

Discussion: This proposed randomised controlled trial has the potential to provide new knowledge within rehabilitation after radical cystectomy for urinary bladder cancer. The programme should be easy to apply to other patient groups undergoing abdominal surgery for cancer and has the potential to change the health care chain for these patients.

Trial Registration: ClinicalTrials.gov. Clinical trial registration number NCT03998579 . First posted June 26, 2019.
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http://dx.doi.org/10.1186/s12885-020-07140-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448437PMC
August 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in Sweden.

Scand J Urol 2020 Apr 8;54(2):115-121. Epub 2020 Apr 8.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

This study investigated prostate cancer (PC)-specific survival and overall survival (OS) in a population-based castration-resistant PC (CRPC) cohort. Data from Stockholm Prostate-Specific Antigen (PSA) and Biopsy Register patients with increasing PSA despite gonadotropin-releasing hormone treatment or surgical castration ( = 1,712) included PSA values and biopsies from 2003 to 2015 and were linked to the National Prostate Cancer Register and Prescribed Drug Register. Kaplan-Meier method estimated PC-specific survival and OS, stratified by metastasis at PC diagnosis, and Cox regression estimated hazard ratios (HRs) for Gleason score and T-stage at PC diagnosis and for age and calendar period at CRPC onset by metastasis status at diagnosis. Median OS after CRPC onset was 23.2 months (95% CI = 21.0-25.9) among patients without metastases (M0) at primary diagnosis, and 13.2 months (11.3-14.5) among patients with metastases (M1). Median PC-specific survival from CRPC onset was 30.3 (27.5-34.1) months and 13.3 (12.1-15.8) months for M0 and M1 patients, respectively. Biopsy Gleason score ≥ 8 was associated with higher all-cause mortality than ≤6 (HR = 2.07 [95% CI = 1.43-3.01]) and PC-specific mortality (2.07 [1.27-3.40]) after CRPC among patients with M0 disease. Patients developing CRPC from 2012 onward had lower all-cause mortality (HR = 0.71 [95% CI = 0.60-0.85] [M0]; 0.60 [0.47-0.77] [M1]) and PC-specific mortality (0.73 [0.57-0.94] [M0]; 0.62 [0.46-0.84] [M1]) compared with those prior to 2012. M1 disease at PC diagnosis was associated with worse survival after CRPC onset versus M0. Higher Gleason score at diagnosis was associated with higher mortality after CRPC onset in M0 patients at diagnosis.
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http://dx.doi.org/10.1080/21681805.2020.1739139DOI Listing
April 2020

Lower urinary tract symptoms (LUTS) are not associated with an increased risk of prostate cancer in men 50-69 years with PSA ≥3 ng/ml.

Scand J Urol 2020 Feb 26;54(1):1-6. Epub 2019 Dec 26.

Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.

There is conflicting evidence about the association between prostate cancer and Lower Urinary Tract Symptoms (LUTS). We aimed to describe the prevalence of LUTS and its association with prostate cancer risk. We studied the association between International Prostate Symptom Score (IPSS) and prostate cancer in a population-based sample of men ( = 45,595) aged 50-69 years from the Stockholm3 study. Men with PSA ≥3 ng/ml ( = 4579) underwent systematic prostate biopsies. We used the International Society of Urological Pathology Gleason Grading (ISUP grade) and performed regression analysis for risk of any cancer ( = 1797), ISUP grade ≥2 ( = 840) and advanced cancer, defined as ISUP grade ≥3 or cT ≥3 ( = 353). 74.6% of all men had no or mild LUTS (IPSS ≤7) and 3.2% had severe LUTS (IPSS >19). Men with any, ISUP grade ≥2 or advanced cancer had lower median IPSS compared to men with benign biopsy (any cancer: 4 (IQR 2-9); ISUP grade ≥2: 4 (2-8); advanced cancer: 4 (2-8); benign biopsy: 6 (3-11);  < 0.05). IPSS was not associated with increased risk of cancer in multivariate analyses (OR (any cancer) 0.97; 95% CI 0.96-0.98; OR (ISUP grade ≥2) 0.97; 95% CI 0.96-0.99; OR (advanced cancer) 0.99; 95% CI 0.99-1.01). Three-quarters of men aged 50-69 years report no or mild LUTS. Our data do not support any clinically meaningful association between LUTS and prostate cancer. Specifically, men with advanced prostate cancer did not exhibit more urinary symptoms than men without cancer.
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http://dx.doi.org/10.1080/21681805.2019.1703806DOI Listing
February 2020

Association Between Antidiabetic Medications and Prostate-Specific Antigen Levels and Biopsy Results.

JAMA Netw Open 2019 11 1;2(11):e1914689. Epub 2019 Nov 1.

Translational Oncology and Urology Research, Comprehensive Cancer Centre, King's College London, London, United Kingdom.

Importance: Diabetic men appear to have a lower risk of prostate cancer. Whether antidiabetic medications are protective or potentially mask prostate cancer by lowering prostate-specific antigen (PSA) levels is unclear.

Objective: To examine the associations of antidiabetic medication use with (1) PSA levels, (2) frequency of PSA testing, (3) receipt of biopsy following elevated PSA results, and (4) prostate cancer detection at biopsy.

Design, Setting, And Participants: Population-based cohort study using data from the Stockholm PSA and Biopsy Register. Participants were all prostate cancer-free men aged 40 to 79 years residing in Stockholm County, Sweden, between January 1, 2006, and December 31, 2015. Data were analyzed from November 2018 to March 2019.

Exposures: One or more prescription for metformin, sulfonylurea, or insulin, as recorded in Sweden's National Prescribed Drug Register.

Main Outcomes And Measures: Levels of PSA following first exposure to antidiabetic medications were assessed using multivariable linear regression. Frequency of PSA testing was assessed via multivariable Poisson regression. Biopsy following elevated PSA (≥3.0 ng/mL) and prostate cancer detection at biopsy were assessed via multivariable logistic regression.

Results: The cohort of 564 666 men (median [range] age, 65 [40-79] years) consisted of 4583 men initially exposed to metformin, 1104 exposed to sulfonylurea, and 978 exposed to insulin who were age matched with unexposed men (1:5). Exposed men had lower median (interquartile range) PSA levels before starting antidiabetic medications compared with unexposed men (1.2 [0.7-2.5] vs 1.6 [0.8-3.2] ng/mL). After accounting for baseline differences, PSA levels did not vary from those of unexposed men following exposure to antidiabetic medications. Frequency of PSA testing was higher for those receiving metformin (rate ratio, 1.07; 95% CI, 1.06-1.09) and sulfonylurea (rate ratio, 1.06; 95% CI, 1.03-1.08) but was lower for those receiving insulin (rate ratio, 0.79; 95% CI, 0.77- 0.81). Likelihood of biopsy after elevated PSA was lower among men receiving metformin (odds ratio, 0.87; 95% CI, 0.80-0.96) and insulin (odds ratio, 0.83; 95% CI, 0.74-0.93). There were no differences in prostate cancer detection at biopsy, regardless of PSA levels that triggered the biopsy.

Conclusions And Relevance: This study's findings do not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering PSA levels to mask prostate cancer. They do suggest potential detection bias due to fewer biopsies among men receiving antidiabetic medications, which may explain the lower prostate cancer risk in men with diabetes.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.14689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865613PMC
November 2019

A Unified Prostate Cancer Risk Prediction Model Combining the Stockholm3 Test and Magnetic Resonance Imaging.

Eur Urol Oncol 2019 09 9;2(5):490-496. Epub 2018 Oct 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Risk prediction models and magnetic resonance imaging (MRI) of the prostate can reduce unnecessary biopsies and overdiagnosis of low-risk prostate cancer. However, it is unclear how these tools should be used in concert.

Objective: To develop a unified risk prediction model (S3M-MRI) that combines the Stockholm3 score (based on protein and genetic markers and clinical variables) and Prostate Imaging-Reporting and Data System v.2 scores modified for MRI without contrast (modPI-RADS).

Design, Setting, And Participants: We used data for 532 men from the prospective multicentre STHLM3-MRI diagnostic study to construct S3M-MRI. We compared S3M-MRI to Stockholm3 and modPI-RADS alone with respect to model discrimination, calibration, and net benefit. We also compared clinical outcomes for five diagnostic strategies according to the use of combinations of the three models.

Results And Limitations: The area under the receiver operating characteristic curve (AUC) was 0.88 (95% confidence interval [CI] 0.85-0.91) for S3M-MRI, which was significantly higher (p=0.04) than for Stockholm3 (0.86, 95% CI 0.83-0.89) and modPI-RADS (0.83, 95% CI 0.79-0.87). S3M-MRI had a higher net benefit on decision curve analysis for clinically relevant probability thresholds for biopsy recommendation in comparison to Stockholm3 and modPI-RADS. However, for different diagnostic strategies, sequential use of Stockholm3 followed by MRI only for Stockholm3-positive men resulted in a similar number of unnecessary biopsies (64 vs 69) and diagnosed International Society of Urological Pathology (ISUP) grade group 1 cancers (56 vs 51) at similar sensitivity for ISUP grade group ≥2 cancers, while avoiding 38% of MRI scans. Limitations include the ethnically homogeneous study population.

Conclusions: The unified S3M-MRI model was superior to the Stockholm3 model and modPI-RADS alone. However, the S3M-MRI improvement was marginal compared to sequential use of Stockholm3 followed by MRI, and resulted in 60% more MRI scans.

Patient Summary: A new risk prediction model combining clinical variables, genetic and protein biomarkers, and results from prostate magnetic resonance imaging improved the clinical outcome performance of prostate cancer diagnostics.
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http://dx.doi.org/10.1016/j.euo.2018.09.008DOI Listing
September 2019

Is there any association between prostate-specific antigen screening frequency and uptake of active surveillance in men with low or very low risk prostate cancer?

BMC Urol 2019 Aug 5;19(1):73. Epub 2019 Aug 5.

Translational Oncology & Urology Research, Comprehensive Cancer Centre, King's College London, 3rd Floor, Bermondsey Wing, Guy's Hospital, London, SE1 9RT, UK.

Background: Patient-related factors such as concern about cancer are believed to influence both men's decisions to undergo prostate specific antigen (PSA) testing and to have definitive treatment if diagnosed with low risk prostate cancer (PCa). The potential link between screening frequency and choice of active surveillance (AS) for low risk disease has not been studied previously. Our aim was to investigate whether there is any association between PCa screening frequency or previous negative prostate biopsy and uptake of AS among men with low risk PCa.

Methods: This register-based study included all men ≤75 years from Stockholm who were diagnosed with low risk PCa from 2008 to 2014 (n = 4336). Pre-diagnostic PSA testing and biopsy histories were obtained from the Stockholm PSA and Biopsy Register, a population-based register for the Stockholm country. The association between previous screening/biopsy history and AS uptake (based on primary treatment recorded in the National Prostate Cancer Register) was examined using multivariable logistic regression.

Results: Forty seven percent of men with low risk PCa underwent AS. Uptake was associated with older age, very low risk disease, more recent diagnosis and absence of family history. None of the screening/biopsy measures (testing frequency, mean interval, PSA velocity, highest pre-diagnostic PSA or prior negative biopsy) were associated with uptake of AS among men with low risk PCa. Generalisability to settings with different policies and practices may be limited.

Conclusion: We found no evidence that screening frequency and negative biopsy influence uptake of AS among Swedish men with low risk PCa. Further research is required to determine factors that still present barriers for men taking up AS.
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http://dx.doi.org/10.1186/s12894-019-0502-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683376PMC
August 2019

Does a novel diagnostic pathway including blood-based risk prediction and MRI-targeted biopsies outperform prostate cancer screening using prostate-specific antigen and systematic prostate biopsies? - protocol of the randomised study STHLM3MRI.

BMJ Open 2019 06 14;9(6):e027816. Epub 2019 Jun 14.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.

Introduction: Prostate cancer is a leading cause of cancer death among men in the Western world. Early detection of prostate cancer has been shown to decrease mortality, but has limitations with low specificity leading to unnecessary biopsies and overdiagnosis of low-risk cancers. The STHLM3 trial has paved way for improved specificity in early detection of prostate cancer using the blood-based STHLM3 test for identifying men at increased risk of harbouring significant prostate cancer. Targeted prostate biopsies based on MRI images have shown non-inferior sensitivity to detect significant prostate cancer and decrease the number of biopsies and non-significant cancers among men referred for prostate biopsy in clinical practice. The strategy of the STHLM3-MRI project is to study an improved diagnostic pathway including an improved blood-based test for identification of men with increased risk of prostate cancer and use of MRI to select men for diagnostic workup with targeted prostate biopsies.

Methods: This study compares prostate cancer detection using prostate-specific antigen (PSA) and systematic biopsies to the improved pathway for prostate cancer detection using the STHLM3 test and targeted biopsies in a screening context. The study will recruit 10 000 participants during 1 June 2018 to 1 June 2020 combining a paired and randomised design. Participants are grouped by PSA and Stockholm3 test level. Men with Stockholm3 ≥11% or PSA ≥3 ng/mL are randomised to systematic or MRI-targeted biopsies. This protocol follows SPIRIT guidelines. Endpoints include the number of detected prostate cancers, number of performed biopsy procedures and number of performed MRIs. Additional aims include to assess the health economic consequences and development of automated image-analysis.

Ethics And Dissemination: The study is approved by the regional ethical review board in Stockholm (2017-1280/31). The study findings will be published in peer-review journals. Findings will also be disseminated by conference/departmental presentations and by media.

Trial Registration Number: NCT03377881; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-027816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576112PMC
June 2019

Are Prostate Specific-Antigen (PSA) and age associated with the risk of ISUP Grade 1 prostate cancer? Results from 72 996 individual biopsy cores in 6 083 men from the Stockholm3 study.

PLoS One 2019 13;14(6):e0218280. Epub 2019 Jun 13.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Knowledge about the relationship between PSA, age and ISUP grade group (ISUP) 1 prostate cancer can improve clinical and biological understanding of prostate cancer. We aimed to investigate the associations between PSA and age and the risk of ISUP 1 and ISUP ≥ 2 prostate cancer, respectively.

Methods: We included 6 083 men aged 50-69 biopsied with a total of 72 996 individual biopsy cores from the prospective and population based Stockholm3 diagnostic study. We computed the risk of ISUP 1 and ISUP ≥ 2 prostate cancer and their respective associations with PSA and age. Since lower Gleason grades often are masked by higher grades in the overall Gleason score, we compared associations both for overall Gleason score and for Gleason on individual biopsy cores.

Results: ISUP 1 prostate cancer was not significantly associated with PSA at diagnosis: odds ratios ranged from 0.82 (95%CI: 0.68-1.00) for PSA 3-4 ng/mL, 0.96 (95%CI: 0.79-1.16) for PSA 4-6 ng/mL, 0.95 (95%CI: 0.75-1.21) for PSA 6-10 ng/mL, and 0.92 (95%CI: 0.58-1.45) for PSA 10-15 ng/mL compared with PSA 2-3 ng/mL. Age was not significantly associated with risk of ISUP 1 cancer. This contrasts to the strong relationship between ISUP ≥ 2 prostate cancer and its respective associations with PSA and age.

Conclusions: We find no significant association between the risk of ISUP 1 prostate cancer and PSA and age at diagnosis indicating that PSA contribution from ISUP 1 prostate cancer is closer to that of benign prostate tissue than to that of ISUP ≥ 2 prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6564040PMC
February 2020

Objectively measured mobilisation is enhanced by a new behaviour support tool in patients undergoing abdominal cancer surgery.

Eur J Surg Oncol 2019 Oct 18;45(10):1847-1853. Epub 2019 Apr 18.

Karolinska Institutet, Division of Physiotherapy, Department of Neurobiology, Care Sciences and Society, Alfred Nobels Allé 23, 23100, 141 83, Huddinge, Sweden; Karolinska University Hospital, Function Area Occupational Therapy and Physiotherapy, Allied Health Professionals Function, 171 76, Stockholm, Sweden; Sophiahemmet University, Department of Health Promoting Science, Box 5605, 114 86, Stockholm, Sweden. Electronic address:

Introduction: Mobilisation reduces the risk of complications after abdominal surgery. Despite that, patients spend most of their time immobilised during hospital stay. Hence, the aim of this study was to evaluate a tool called the Activity board, which includes behaviour change techniques, regarding effects on mobilisation and postoperative recovery after abdominal cancer surgery.

Material And Methods: Patients who were planned for abdominal surgery due to colorectal, ovarian or urinary bladder cancer, and at least three postoperative days at Karolinska University Hospital were included in this non-randomised controlled trial, from January 2017 to May 2018. The patients were allocated to Activity board or standard treatment when they were admitted to hospital. Mobilisation was evaluated objectively with activity monitor the first three postoperative days, and postoperative recovery was assessed continuously during hospital stay.

Results: In total, 133 patients, mean (sd) age 68.1 (12.3) years were included. The patients with the Activity board had postoperatively higher levels of mobilisation, compared to standard treatment, as mean value over the first three days, steps, median (min-max) 1057 (3-10433) and 360 (0-6546), respectively (p = 0.001), and for each day separately. Further, the group with the Activity board had a shorter length of stay, 6 (3-13), compared to standard treatment 7 (3-14) (p = 0.027).

Conclusion: The Activity board is an effective tool to enhance mobilisation after abdominal surgery due to cancer, in hospital settings. Using the Activity board could lead to improved postoperative recovery.
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http://dx.doi.org/10.1016/j.ejso.2019.04.013DOI Listing
October 2019

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2019 02;51(2):363

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0330-6DOI Listing
February 2019

Preoperative staging using magnetic resonance imaging and risk of positive surgical margins after prostate-cancer surgery.

Prostate Cancer Prostatic Dis 2019 09 30;22(3):391-398. Epub 2018 Nov 30.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference.

Methods: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting.

Results: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03]).

Conclusions: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.
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http://dx.doi.org/10.1038/s41391-018-0116-zDOI Listing
September 2019

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

Genome Med 2018 11 21;10(1):85. Epub 2018 Nov 21.

Centre for Oncological Research, University of Antwerp, Antwerp, Belgium.

Background: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited.

Methods: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.

Results: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.

Conclusions: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.
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http://dx.doi.org/10.1186/s13073-018-0595-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247769PMC
November 2018

The Stockholm3 blood-test predicts clinically-significant cancer on biopsy: independent validation in a multi-center community cohort.

Prostate Cancer Prostatic Dis 2019 03 31;22(1):137-142. Epub 2018 Aug 31.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Several blood-based tests have been suggested to improve prostate cancer testing. The Stockholm3 test has been shown to reduce the number of prostate biopsies, to decrease detection of low-grade cancer and to maintain the detection rate of ISUP Gleason Group (GG) ≥ 2 cancer in a screening-by-invitation setting. We aimed to validate the performance of the Stockholm3 test in an independent, clinical practice cohort.

Methods: The study-population consisted of 533 men in ages 45-75 without previous diagnosis of prostate cancer scheduled for prostate biopsy at any of three centers in Norway and Sweden. Blood samples for Stockholm3 analysis were drawn prior to systematic prostate biopsies. Clinically significant prostate cancer was defined as any finding of ISUP Grade Group (GG) 2 or higher. We calculated area under the curve (AUC) for predicting prostate cancer at biopsy and calculated. Models including PSA and PSA-density (PSA/prostate volume) were compared to a model including also clinical information, protein levels and single nucleotide polymorphisms (SNP).

Results: 263 of 533 (49%) participants were diagnosed with prostate cancer. 162 men had prostate cancer with GG ≥ 2. The Stockholm3 test discriminated better for GG ≥ 2 prostate cancer than PSA in combination with PSA-density AUC 8.9 (95% CI 82.7-89.2) and AUC 74.8 (95% CI 70.3-79.3). Using a Stockholm3 cut-off of 10% risk of GG ≥ 2 cancer, 38% of the biopsy procedures were saved, however delaying diagnosis for 6% (n = 10) of men with GG ≥ 2 cancer. Using PSA-density 0.1 as cut-off for biopsy saved 35% of biopsies, delaying diagnosis for 16% (n = 26) of men with GG ≥ 2 cancer.

Conclusion: A prediction model including clinical information, protein levels and SNPs was independently validated in a clinical practice cohort and reduces the number of un-necessary biopsies while delaying diagnosis for a limited number of men.
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http://dx.doi.org/10.1038/s41391-018-0082-5DOI Listing
March 2019

Prostate Cancer Diagnostics Using a Combination of the Stockholm3 Blood Test and Multiparametric Magnetic Resonance Imaging.

Eur Urol 2018 12 9;74(6):722-728. Epub 2018 Jul 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: More specific diagnostic for prostate cancer is needed to decrease overdetection and number of diagnostic procedures.

Objective: To assess the performance of combining a blood-based biomarker panel and magnetic resonance imaging (MRI)-targeted biopsies for prostate cancer detection.

Design, Setting, And Participants: We used a prospective, multicenter, paired diagnostic study design. A total of 532 men aged 45-74 yr referred for prostate cancer workup were included during 2016-2017.

Intervention: Participants underwent blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic polymorphisms, and clinical variables; 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to lesions with Prostate Imaging Reporting and Data System version 2 ≥3.

Outcome Measurements And Statistical Analysis: The main outcome was numbers of detected prostate cancer characterized by grade group (GG) and the number of performed biopsies using relative sensitivity (RS).

Results And Limitations: Median prostate-specific antigen was 6.3 ng/ml, and mean age was 63.9 yr. Targeted and systematic biopsies detected 170 and 162 GG ≥2 tumors, respectively (RS 1.05; 95% confidence interval [CI] 0.96-1.14). Compared with performing systematic biopsies on all men, performing targeted and systematic biopsies only on men with >10% risk of GG ≥2 cancer, as predicted by the Stockholm3 test, required 62% (95% CI 58-66) of the biopsy procedures and detected 58% (95% CI 48-70) of GG 1 disease, with increased sensitivity for GG ≥2 detection (RS 1.10; 95% CI 1.02-1.17). Performing only targeted biopsies in men with elevated Stockholm3 test altered these results only slightly. Compared with performing systematic and targeted biopsies on all men, performing this only for men with an elevated Stockholm3 test decreased detection of GG ≥2 cancer slightly (RS 0.92; 95% CI 0.88-0.95). Limitations include lacking knowledge of true disease prevalence.

Conclusions: These findings provide evidence that strategies combining the blood-based Stockholm3 test and MRI-targeted biopsies can be used to inform biopsy decision making.

Patient Summary: In this study, 532 men coming for prostate cancer workup underwent blood sampling, and both traditional and magnetic resonance imaging/fusion-guided prostate biopsies. We report that performing targeted biopsies only in men with an elevated risk as assessed by the Stockholm3 test saved biopsies, decreased overdetection, and maintained the number of detected high-grade cancers.
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http://dx.doi.org/10.1016/j.eururo.2018.06.022DOI Listing
December 2018

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Nat Commun 2018 06 11;9(1):2256. Epub 2018 Jun 11.

Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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http://dx.doi.org/10.1038/s41467-018-04109-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995836PMC
June 2018

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2018 07 11;50(7):928-936. Epub 2018 Jun 11.

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.
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http://dx.doi.org/10.1038/s41588-018-0142-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568012PMC
July 2018

Time-to-event Outcomes in Men with Nonmetastatic Castrate-resistant Prostate Cancer-A Systematic Literature Review and Pooling of Individual Participant Data.

Eur Urol Focus 2019 09 4;5(5):788-798. Epub 2018 Apr 4.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Context: Until recently, there has been a lack of evidence-based treatment alternatives in men with nonmetastatic castrate-resistant prostate cancer (NM-CRPC). However, new evidence-based treatment alternatives are emerging.

Objective: We aimed to describe time-to-event outcomes in NM-CRPC patients based on evidence from both prospective and retrospective studies. Second, we aimed to describe predictors of these outcomes in the same patient population.

Evidence Acquisition: A systematic review was conducted to identify clinical studies (both prospective and retrospective) in NM-CRPC patients. All published Kaplan-Meier curves were digitized, and individual participant data were extracted using a published and validated R code. The following outcomes were considered: overall survival (OS), bone metastasis-free survival (BMFS), time to bone metastasis (TTBM), metastasis-free survival, time to metastasis, time to progression (TTP), progression-free survival, and time to prostate-specific antigen (PSA) progression. Second, we described all predictor/outcome relationships.

Evidence Synthesis: Median survival times, in months, for OS, BMFS, TTBM, and TTP in placebo arms of randomized clinical trials are 45.3 (95% confidence interval [CI]: 43.5-46.8), 31.5 (95% CI: 28-33.4), 28.8 (95% CI: 25.2-31.6), and 22.2 (95% CI: 19.3-24.8), respectively. In general, reported outcomes in retrospective studies seemed to be longer than those reported in clinical trials. Baseline PSA nadir levels, PSA doubling time, PSA velocity, and alkaline phosphatase velocity are reliable predictors of time-to-event outcomes in NM-CRPC patients, whereas Gleason score is not.

Conclusions: NM-CRPC is a long-standing condition where effective treatments to slow down disease progression historically have been lacking. Compared with prospective studies, retrospective studies have had limited ability to correctly identify NM-CRPC patients and estimate time to different outcomes in NM-CRPC patients.

Patient Summary: For patients with nonmetastatic castration-resistant prostate cancer (NM-CRPC), currently no effective treatments resulting in longer survival compared with watchful waiting are available. On average, without additional treatment, half of these patients survive <45 mo after NM-CRPC diagnosis.
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http://dx.doi.org/10.1016/j.euf.2018.03.010DOI Listing
September 2019

Poor Follow-up After Elevated Prostate-specific Antigen Tests: A Population-based Cohort Study.

Eur Urol Focus 2019 09 9;5(5):842-848. Epub 2018 Feb 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background: Although prostate-specific antigen (PSA) testing is common, little is known about the pattern of retesting by either PSA values or subsequent prostate biopsies. Poor follow-up of high PSA values may lead to delayed diagnosis.

Objective: To estimate the probabilities of follow-up (including retesting, prostate biopsies, diagnosis, and cause-specific death) for men undergoing prostate cancer testing at a population level.

Design, Setting, And Participants: Cohort study design for men living in Stockholm with no previous diagnosis of prostate cancer between 2003 and 2015. Men were linked to the national health and population registries in Sweden. We report follow-up for men aged 50-79 yr at 2003 or at their index PSA test.

Outcome Measurements And Statistical Analysis: State probabilities with 95% confidence intervals (CIs) were calculated using multistate Markov models.

Results And Limitations: Among men not previously diagnosed with prostate cancer with an initial PSA value of ≥10ng/ml, the proportions at 1 yr with no subsequent testing or only elevated PSA test values >3ng/ml were 21.7% (95% CI: 19.5, 23.9), 25.2% (95% CI: 23.9, 26.6), and 47.7% (95% CI: 46.2, 49.1) for those aged 50-59, 60-69, and 70-79 yr, respectively. No significant changes were noticed when stratifying by comorbidities. Limitations include the lack of detail from patient medical charts. This detail would have allowed for more accurate assessment of appropriate clinical follow-up.

Conclusions: Regardless of medical history, a large proportion of men with PSA≥10ng/ml were not followed appropriately at 1 yr after the index PSA test. This may partially explain why opportunistic testing is not as effective as screening within trials to reduce prostate cancer mortality.

Patient Summary: For men aged 50-69 yr, who undertake a prostate-specific antigen (PSA) test, a PSA level of >10ng/ml should prompt further investigation. However, we found that one out of 10 of these men did not receive repeat testing within 1 yr of the initial test. This may partially explain why opportunistic prostate cancer testing is less effective than screening trials.
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http://dx.doi.org/10.1016/j.euf.2018.02.001DOI Listing
September 2019

The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker Contribution, and Reflex Test Potential.

Eur Urol 2018 08 10;74(2):204-210. Epub 2018 Jan 10.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: It has been shown that the Stockholm-3 model (S3M) outperforms prostate-specific antigen (PSA) as a screening tool for prostate cancer.

Objective: To update the S3M, to give a detailed account of the value of each predictor in the S3M, and to evaluate the S3M as a reflex test for men with PSA ≥3ng/ml.

Design, Setting, And Participants: During 2012-2015, the Stockholm-3 study evaluated the S3M relative to PSA as tests for Gleason score ≥7 prostate cancers among men aged 50-69 yr. The participants (n=59 159) underwent both tests, and biopsy was recommended if at least one was positive. A total of 5073 men had a biopsy because of elevated PSA (≥3ng/ml).

Outcome Measurements And Statistical Analysis: Logistic regression was used to update the S3M: intact PSA was removed, HOXB13 was included, and the model was fitted to data from the Stockholm-3 training and validation cohorts. To compare S3M with PSA, we fixed the sensitivity for detection of high-grade cancer and evaluated the performance as the number of biopsies needed to achieve that sensitivity for each test.

Results And Limitations: The updated S3M slightly improved the area under the receiver operating characteristic curve compared to previously published results (0.75 vs 0.74). When used as a reflex test for men with PSA ≥3ng/ml, S3M reduced the number of biopsies needed by 34% compared to the use of PSA alone, with equal sensitivity. A limitation is the ethnically homogeneous population.

Conclusions: A major problem with PSA screening-too many unnecessary biopsies-can be mitigated if S3M is used as a reflex test.

Patient Summary: To find aggressive prostate cancer with the minimum number of negative biopsies and detection of clinically insignificant cancers, we evaluated the use of a personalized diagnostic prediction model as a second test for men with a positive prostate-specific antigen (PSA) test. We found that this two-step approach could reduce prostate biopsies by a third compared to using PSA alone.
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http://dx.doi.org/10.1016/j.eururo.2017.12.028DOI Listing
August 2018
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