Publications by authors named "Henrik Gronberg"

302 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

The STHLM3-model, Risk-based Prostate Cancer Testing Identifies Men at High Risk Without Inducing Negative Psychosocial Effects.

Eur Urol Open Sci 2021 Feb 7;24:43-51. Epub 2021 Jan 7.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: The new STHLM3 test, combining protein markers, genetic markers, and clinical data to assess a man's prostate cancer (PCa) risk, has been investigated in Sweden within the frame of the STHLM3 trial.

Objective: To assess whether the STHLM3 test influences men's worry level, PCa knowledge, attitude, and health-related quality of life (HRQoL).

Design Setting And Participants: Invitations with login to the web survey were mailed to 10 000 men, 50-69 yr of age, who were eligible for the STHLM3 trial. The survey was sent 3 mo invitation to the STHLM3 trial (baseline) and 5 mo STHLM3 (follow-up). At baseline, the men were unaware of the upcoming invitation to STHLM3. The survey covered the following: PCa-specific worry and perceived vulnerability, knowledge about PCa, attitude toward PCa testing and health behavior, and HRQoL.

Outcome Measurements And Statistical Analysis: Survey scores were compared between baseline and follow-up by using the nonparametric Wilcoxon-signed rank tests for paired samples. Analysis of covariance was performed for PCa risk group comparisons.

Results And Limitations: A total of 994 men (10%) responded to our survey at baseline and follow-up, and were assessed as follows: low risk: 421 men; intermediate risk: 421 men; and high risk:152, of whom 59 were diagnosed with PCa after further investigation. In men assessed as having low and intermediate risk, level of worrying decreased at follow-up ( <  0.001), whereas no changes were observed in men at high risk. Moreover, no HRQoL changes were observed over time. The low response rate is the main limitation.

Conclusions: We found that the STHLM3 model, a risk-based PCa test, showed no negative impact on the well-being of men.

Patient Summary: Since our results suggest that the risk-based screening as used in STHLM3 did not induce negative psychological effects on the participants, we can recommend this risk-based approach for population-based prostate cancer screening.
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http://dx.doi.org/10.1016/j.euros.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317863PMC
February 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

Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification.

Eur Urol Open Sci 2020 Oct 13;21:51-60. Epub 2020 Oct 13.

Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo and Oslo University Hospital, Oslo, Norway.

Background: More accurate risk assessments are needed to improve prostate cancer management.

Objective: To identify blood-based protein biomarkers that provided prognostic information for risk stratification.

Design Setting And Participants: Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were performed in four independent cohorts retrospectively collected between 1988 and 2015.

Outcome Measurements And Statistical Analysis: The primary outcome objectives were progression-free survival, prostate cancer-specific survival (PCSS), and overall survival. Statistical analyses to assess survival and model performance were performed.

Results And Limitation: Serum leucine-rich α-2-glycoprotein 1 (LRG1) was found to be elevated in fatal prostate cancer. LRG1 provided prognostic information independent of metastasis and increased the accuracy in predicting PCSS, particularly in the first 3 yr. A high LRG1 level is associated with an average of two-fold higher risk of disease-progression and mortality in both high-risk and metastatic patients. However, our study design, with a retrospective analysis of samples spanning several decades back, limits the assessment of the clinical utility of LRG1 in today's clinical practice. Thus, independent prospective studies are needed to establish LRG1 as a clinically useful biomarker for patient management.

Conclusions: High blood levels of LRG1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer, and LRG1 increased the accuracy of risk stratification of prostate cancer patients.

Patient Summary: High blood levels of leucine-rich α-2-glycoprotein 1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.euros.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317831PMC
October 2020

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

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 04 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Mar 30;13(7). Epub 2021 Mar 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC ( = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02-2.84), = 0.04, and OS HR (95%CI): 2.5 (1.06-5.71), = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.
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http://dx.doi.org/10.3390/cancers13071588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037684PMC
March 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML.

Blood Adv 2021 02;5(4):1003-1016

Hematology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss ≥200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
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http://dx.doi.org/10.1182/bloodadvances.2020002517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903223PMC
February 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

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 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

Biomarker discrimination and calibration with MRI-targeted biopsies: an analysis with the Stockholm3 test.

Prostate Cancer Prostatic Dis 2021 06 9;24(2):457-464. Epub 2020 Nov 9.

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

Background: The 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.

Methods: A 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).

Results: Median 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.

Conclusions: Stockholm3 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.
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http://dx.doi.org/10.1038/s41391-020-00297-xDOI Listing
June 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

Incorporating Magnetic Resonance Imaging and Biomarkers in Active Surveillance Protocols - Results From the Prospective Stockholm3 Active Surveillance Trial (STHLM3AS).

J Natl Cancer Inst 2021 May;113(5):632-640

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

Background: Active surveillance (AS) for men with low-risk prostate cancer (PC) can lead to patient morbidity and healthcare overutilization. The aim of this study was to evaluate an AS protocol using the Stockholm3 test and magnetic resonance imaging (MRI) to reduce biopsy intensity.

Methods: We conducted a prospective multicenter study of 280 invited men from a contemporary screening study (STHLM3), with Gleason Score (GS) 3 + 3 PC on a current AS protocol. Patients underwent prostate-MRI and blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic variants, and clinical variables to predict risk of GS ≥3 + 4 PC followed by systematic biopsies and targeted biopsies (for Prostate Imaging Reporting and Data System version 2 ≥3 lesions) in all men. Primary outcomes were reclassification to GS ≥3 + 4 PC and clinically significant PC (csPCa), including unfavorable intermediate risk PC or higher based on National Comprehensive Cancer Network guidelines.

Results: Adding MRI-targeted biopsies to systematic biopsies increased sensitivity of GS ≥3 + 4 PC compared with systematic biopsies alone (relative sensitivity [RS] = 1.52, 95% confidence interval [CI] = 1.28 to 1.85). Performing biopsies in only MRI positive increased sensitivity of GS ≥3 + 4 PC (RS = 1.30, 95% CI = 1.04 to 1.67) and reduced number of biopsy procedures by 49.3% while missing 7.2% GS ≥3 + 4 PC and 1.4% csPCa. Excluding men with negative Stockholm3 test reduced the number of MRI investigations at follow-up by 22.5% and biopsies by 56.8% while missing 6.9% GS ≥3 + 4 PC and 1.3% csPCa.

Conclusion: Including MRI and targeted/systematic biopsies in the follow-up for men on AS increased sensitivity of PC reclassification. Incorporation of risk prediction models including biomarkers may reduce the need for MRI use in men with low-risk PC.
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http://dx.doi.org/10.1093/jnci/djaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096373PMC
May 2021

A Nordic initiative for a more personal and accurate diagnostic pathway for prostate cancer.

Scand J Prim Health Care 2020 Sep;38(3):249-250

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

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http://dx.doi.org/10.1080/02813432.2020.1801148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470020PMC
September 2020

Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer.

World J Urol 2021 Jun 30;39(6):1797-1804. Epub 2020 Jul 30.

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

Purpose: To evaluate clinical variables, including magnetic resonance imaging (MRI) predictive of adverse pathology (AP) at radical prostatectomy (RP) in men initially enrolled in active surveillance (AS).

Methods: A population-based cohort study of men diagnosed with low-risk prostate cancer (PCa), in Stockholm County, Sweden, during 2008-2017 enrolled in AS their intended primary treatment followed by RP. AP was defined as ISUP grade group  ≥ 3 and/or pT-stage ≥ T3. Association between clinical variables at diagnosis and time to AP was evaluated using Cox regression and multivariate logistic regression to evaluate the association between AP and clinical variables at last biopsy before RP.

Results: In a cohort of 6021 patients with low-risk PCa, 3116 were selected for AS and 216 underwent RP. Follow-up was 10 years, with a median time on AS of 23 months. 37.7% of patients had AP at RP. Clinical T-stage [Hazard ratio (HR): 1.81, 95% confidence interval (CI) 1.04-3.18] and PSA (HR: 1.31, 95% CI 1.17-1.46) at diagnosis and age [Odds Ratio (OR): 1.09, 95% CI 1.02-1.18), PSA (OR: 1.22, 95% CI 1.07-1.41), and PI-RADS (OR 1.66, 95% CI 1.11-2.55)] at last re-biopsy were significantly associated with AP.

Conclusion: PI-RADS score is significantly associated with AP at RP and support current guidelines recommending MRI before enrollment in AS. Furthermore, age, cT-stage, and PSA are significantly associated with AP.
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http://dx.doi.org/10.1007/s00345-020-03394-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217019PMC
June 2021

Ethnic variation in prostate cancer detection: a feasibility study for use of the Stockholm3 test in a multiethnic U.S. cohort.

Prostate Cancer Prostatic Dis 2021 03 8;24(1):120-127. Epub 2020 Jul 8.

Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Background: The Stockholm3 test improves Gleason Grade Group ≥2 (GG ≥ 2) prostate cancer (PC) detection, however it has not been evaluated in an American cohort where clinical practice patterns and ethnicity differ. We aimed to identify subgroups within a Stockholm population with PC risk profiles matching American ethnicity-specific subgroups and compare the detection of PC and describe Stockholm3 performance within these subgroups.

Methods: All men age 49-70 years presenting for prostate biopsies were evaluated at UIC from 2016 to 2019, as well as men in Stockholm from 2012 to 2014 in the STHLM3 study. Propensity scores (PS) were estimated for each person using logistic regression for age, PSA, prostate volume, family history of PC, 5-alpha reductase inhibitor use, and prior biopsy. 3:1 PS matching was performed for Stockholm to Chicago ethnicity-specific cohorts and odds ratios (OR) were computed to compare detection of GG ≥ 2 PC between groups.

Results: 504 Chicago men and 6980 Stockholm men were included. In African American (AA) men, 51% had GG ≥ 2 PC detected, while in risk-matched Stockholm men, 34% had GG ≥ 2 PC detected (OR: 2.1, p < 0.001). There was no statistical difference in GG ≥ 2 PC detected when matching Stockholm men to non-Hispanic Caucasian men (31% vs. 24%, OR: 0.7, p = 0.30) or Hispanic Caucasian men (31% vs. 27%, OR: 1.2, p = 0.42). The AUC for the Stockholm3 test of the matched Stockholm cohorts for AA, non-Hispanic Caucasian, and Hispanic Caucasian men was 0.85, 0.89, and 0.90, respectively.

Conclusions: Using statistical techniques to simulate a multi-ethnic Chicago cohort within the STHLM3 population, we found an excess risk of GG ≥ 2 PC among AA men. Our hypothesis that the Stockholm3 may have good predictive value in a multiethnic cohort is strengthened, and that recalibration to at least AA men seems likely to be needed to obtain well-calibrated predictions.
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http://dx.doi.org/10.1038/s41391-020-0250-2DOI Listing
March 2021

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer.

Trials 2020 Jun 26;21(1):579. Epub 2020 Jun 26.

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

Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.

Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.

Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.

Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.

Trial Registration: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.
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http://dx.doi.org/10.1186/s13063-020-04515-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318749PMC
June 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

Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia.

Blood Cancer J 2020 06 11;10(6):67. Epub 2020 Jun 11.

Department of Medical Sciences, Hematology, Uppsala University, Uppsala, Sweden.

Relevant molecular tools for treatment stratification of patients ≥65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients ≥65 years. Intensively treated patients with NPM1 and IDH2 mutations had longer overall survival (OS), whereas mutated TP53 conferred lower CR rates and shorter OS. FLT3-ITD and TP53 mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutated TP53, compared to 97% CR in low-risk patients defined by high expression of ZBTB7A and EEPD1 without TP53 mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
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http://dx.doi.org/10.1038/s41408-020-0332-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289793PMC
June 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

The economic burden of prostate cancer - a Swedish prevalence-based register study.

BMC Health Serv Res 2020 May 20;20(1):448. Epub 2020 May 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65, Stockholm, Sweden.

Background: Incidence and prevalence of prostate cancer in Sweden have increased markedly due to prostate-specific antigen (PSA) testing. Moreover, new diagnostic tests and treatment technologies are expected to further increase the overall costs. Our aims were (i) to estimate the societal costs for existing testing, diagnosis, management and treatment of prostate cancer, and (ii) to provide reference values for future cost-effectiveness analyses of prostate cancer screening and treatment.

Methods: Taking a societal perspective, this study aimed to investigate the annual cost of prostate cancer in Sweden using a prevalence-based cost-of-illness approach. Resource utilisation and related costs within Stockholm Region during 2016 were quantified using data from the Stockholm PSA and Biopsy Register and other health and population registers. Costs included: (i) direct medical costs for health care utilisation at primary care, hospitals, palliative care and prescribed drugs; (ii) informal care; and (iii) indirect costs due to morbidity and premature mortality. The resource utilisation was valued using unit costs for direct medical costs and the human capital method for informal care and indirect costs. Costs for the Stockholm region were extrapolated to Sweden based on cancer prevalence and the average costs by age and resource type.

Results: The societal costs due to prostate cancer in Stockholm in 2016 were estimated to be €64 million Euro (€Mn), of which the direct medical costs, informal care and productivity losses represented 62, 28 and 10% of the total costs, respectively. The total annual costs extrapolated to Sweden were calculated to be €281 Mn. The average direct medical cost, average costs for informal care and productivity losses per prevalent case were €1510, €828 and €271, respectively. These estimates were sensitive to assumptions related to the proportion of primary care visits associated with PSA testing and the valuation method for informal care.

Conclusion: The societal costs due to prostate cancer were substantial and constitute a considerable burden to Swedish society. Data from this study are relevant for future cost-effectiveness evaluations of prostate cancer screening and treatment.
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http://dx.doi.org/10.1186/s12913-020-05265-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238534PMC
May 2020

Prognostic value of perineural invasion in prostate needle biopsies: a population-based study of patients treated by radical prostatectomy.

J Clin Pathol 2020 Oct 7;73(10):630-635. Epub 2020 Feb 7.

Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Aims: Despite being one of the major pathways for the spread of malignant tumours, perineural invasion (PNI) has not conclusively been shown to have an independent prognostic value for prostate cancer. Prostatic biopsy constitutes the major pathology workload in prostate cancer and is the foundation for primary treatment decisions and for this reason we aimed to estimate the prognostic value of PNI in biopsies.

Methods: We followed 918 men who underwent radical prostatectomy (RP) from the prospective and population based STHLM3 study until biochemical recurrence with a median follow-up of 4.1 years. To strengthen the evidence, we combined the estimates from the largest studies targeting the prognostic value of PNI in the biopsy. We also estimated the OR of advanced stage as radical prostatectomy for PNI positive and negative men.

Results: The estimated prognostic value based on our data suggested an approximately 50% increased risk of biochemical recurrence if PNI was present in the biopsy (p=0.06). Even though not statistically significant on the 5% level, this estimate is consistent with similar studies, and by combining the estimates there is in fact strong evidence in support of an independent prognostic value of PNI in the biopsy (p<0.0001). There was also an independent increased risk of advanced stage at RP for positive men (OR 1.85, p=0.005).

Conclusions: The evidence supporting a clinically relevant and independent prognostic value of PNI is strong enough to be considered for pathology reporting guidelines.
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http://dx.doi.org/10.1136/jclinpath-2019-206300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513266PMC
October 2020

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.

Lancet Oncol 2020 02 8;21(2):222-232. Epub 2020 Jan 8.

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

Background: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading.

Methods: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa.

Findings: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73).

Interpretation: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist.

Funding: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.
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http://dx.doi.org/10.1016/S1470-2045(19)30738-7DOI Listing
February 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

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Eur Urol 2019 12 16;76(6):831-842. Epub 2019 Sep 16.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

Design, Setting, And Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.

Outcome Measurements And Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.

Results And Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).

Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.

Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
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http://dx.doi.org/10.1016/j.eururo.2019.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880781PMC
December 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
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