Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies.

Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-naïve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

Stroma-specific gene expression signature identifies prostate cancer subtype with high recurrence risk.

Current prognostic tools cannot clearly distinguish indolent and aggressive prostate cancer (PC). We hypothesized that analyzing individual contributions of epithelial and stromal components in localized PC (LPC) could improve risk stratification, as stromal subtypes may have been overlooked due to the emphasis on malignant epithelial cells. Hence, we derived molecular subtypes of PC using gene expression analysis of LPC samples from prostatectomy patients (cohort 1, n = 127) and validated these subtypes in two independent prostatectomy cohorts (cohort 2, n = 406, cohort 3, n = 126). Stroma and epithelium-specific signatures were established from laser-capture microdissection data and non-negative matrix factorization was used to identify subtypes based on these signatures. Subtypes were functionally characterized by gene set and cell type enrichment analyses, and survival analysis was conducted. Three epithelial (E1-E3) and three stromal (S1-S3) PC subtypes were identified. While subtyping based on epithelial signatures showed inconsistent associations to biochemical recurrence (BCR), subtyping by stromal signatures was significantly associated with BCR in all three cohorts, with subtype S3 indicating high BCR risk. Subtype S3 exhibited distinct features, including significantly decreased cell-polarity and myogenesis, significantly increased infiltration of M2-polarized macrophages and CD8 + T-cells compared to subtype S1. For patients clinically classified as CAPRA-S intermediate risk, S3 improved prediction of BCR. This study demonstrates the potential of stromal signatures in identification of clinically relevant PC subtypes, and further indicated that stromal characterization may enhance risk stratification in LPC and may be particularly promising in cases with high prognostic ambiguity based on clinical parameters.

Exergaming Improves Cardiac Risk Factors in Prostate Cancer Patients: A Single-Blinded Randomized Controlled Trial.

Purpose: Androgen deprivation therapy (ADT) may induce unfavorable changes in metabolic outcomes, insulin sensitivity, insulin-like growth factors (IGFs), and in serum levels of adipocyte-derived hormones. In this preplanned randomized ancillary study, we aimed to investigate the ability of exercise to counteract alterations in triglyceride, cholesterol, waist circumference, and insulin caused by ADT in men with locally advanced and metastatic prostate cancer (PCa). Materials and Methods: Forty-six PCa patients undergoing treatment were randomized to 12 weeks of 180 minutes of weekly unsupervised home-based exergaming or usual care. Blood glucose, lipids, cholesterol, adiponectin, leptin, insulin sensitivity, and the insulin growth factor axis were measured at baseline, and after 12 and 24 weeks. Biomarkers were analyzed using a linear mixed-effect model of the difference between the groups from baseline to week 24. In addition, blood pressure, body mass index, body weight, and waist circumference were measured at baseline and after 12 weeks/end of intervention and analyzed using adjusted linear regression analysis. Results: After 24 weeks, a significant difference was seen between the intervention and usual care groups in plasma triglyceride (diff: 0.5 mmol/L, P = 0.02) and high-density lipoprotein (HDL; diff: 0.2 mmol/L, P = 0.01) favoring the intervention group, whereas IGF-binding protein-3 (diff: 148 µg/L, P = 0.01) favored the usual care group. The remaining outcomes were unaffected. Conclusion: Improvement in HDL cholesterol could be used as a primary biomarker in future randomized controlled trials investigating the cardiovascular protecting properties of exergaming.

Cumulative incidence of second primary cancers in a large nationwide cohort of Danish cancer survivors: a population-based retrospective cohort study.

BACKGROUND: A new primary cancer is a serious late effect of a pre-existing cancer diagnosis, and can be attributed to hereditary cancer syndromes, immune or hormonal factors, cancer treatment, or modifiable lifestyle or environmental factors. We investigated the absolute and relative incidence of second primary cancers in a large cohort of Danish cancer survivors. Furthermore, we examined the association between alcohol-related, smoking-related, virus-related, and hormone-related first and second primary cancers. METHODS: In this retrospective cohort study, we identified a cohort of Danish adults (aged ≥40 years) diagnosed with cancer from Jan 1, 1997, to Dec 31, 2014 and alive 1 year after diagnosis. Follow-up was from date of first cancer diagnosis and lasted up to 24 years, ending on Dec 31, 2020. Cohort identification and information on second primary cancers was obtained from the Danish Cancer Registry, and comorbidity and sociodemographic information was obtained from Danish population-based registries. Overall, and for 27 cancer types, cumulative incidence functions and Cox proportional hazard regression models were used to estimate the incidence of second primary cancer and death, and hazard ratios (HRs) and 95% CIs of second primary cancer adjusted for sex, age and year of diagnosis, cohabitation status, income, and comorbidity. FINDINGS: 457 334 Danish adults were included in our study (230 150 [50·3%] male individuals and 227 184 [49·7%] female individuals; median age at diagnosis 68·3 years, IQR 59·7-76·6; median follow-up 3·6 years, IQR 0·6-9·3). The cumulative incidence of second primary cancer increased over time from 6·3% (95% CI 6·2-6·4) 5 years after diagnosis to 10·5% (10·4-10·6) 10 years after diagnosis and to 13·5% (13·4-13·7) 15 years after diagnosis. The highest cumulative incidence of second primary cancer 10 years after diagnosis was observed in survivors of cancers in the larynx (21·8%, 20·5-23·1), oropharynx and oral cavity (19·5%, 18·7-20·3), and bladder and urinary tract (18·5%, 18·0-19·0). Survivors of cancers related to alcohol (HR 1·09, 95% CI 1·06-1·13), smoking (1·73, 1·68-1·78), diet high in red or processed meat (1·32, 1·24-1·39), or virus (1·23, 1·13-1·35) were at increased risk of developing a second cancer with the same aetiology, whereas having had a hormone-related first cancer was associated with lower risk of a second hormone-related cancer (0·77, 0·73-0·81). INTERPRETATION: Our results could help optimise prevention efforts targeting modifiable risk factors to reduce risk of developing a second primary cancer. FUNDING: Nordic Cancer Union and The Health Foundation (Helsefonden).

Association between copy number alterations estimated using low-pass whole genome sequencing of formalin-fixed paraffin-embedded prostate tumor tissue and cancer-specific clinical parameters.

Copy number alterations (CNAs) are frequently observed in early-stage prostate cancer and are associated with disease recurrence and tumor aggressiveness. Cost-effective assessment of CNAs could enhance clinical utility of CNAs. Here, we combined the cost-effectiveness of low-pass (low coverage) whole genome sequencing (LPWGS) and the routine availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for assessing CNAs in a cohort of 187 men with early-stage localised prostate cancer. We detected well known CNAs in 8p, 8q, 13q and 16q and recurrent gains of the oncogene MYC and losses of the tumor suppressor genes NKX3-1, PTEN and RB1, indicating assay reliability. The estimated burden of CNAs was significantly associated with Gleason score, pathological T stage, surgical margin status and biochemical recurrence. Further, genomic losses or gains in specific chromosomal arms were significantly associated with worse BCR-free survival. Copy number signatures extracted from the LPWGS data showed potential for risk stratifying patients, where signatures S1 and S2 showed significant association to worse BCR-free survival compared to S3. Our study provides clinical validation of the associations between CNAs and tumor aggressiveness in an independent and representative RP cohort, while demonstrating the feasibility of performing LPWGS of FFPE tumor tissue for cost-effective assessment of CNAs.

Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer.

The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06-2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02-2.39), P = 0.04] and shorter OS [HR 1.99, (1.12-3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage.

Danish Prostate Cancer Consortium Study 1 (DPCC-1) protocol: Multicentre prospective validation of the urine-based three-microRNA biomarker model uCaP.

INTRODUCTION: The primary objective of the Danish Prostate Cancer Consortium Study 1 (DPCC-1) is to provide validation for a novel urine-based microRNA biomarker, called uCaP, for a diagnosis of prostate cancer. METHODS AND ANALYSIS: Eligible participants are biopsy naïve men aged ≥18 years with prostate-specific antigen (PSA) levels ≥3 ng/mL, who are referred to prostate MRI due to suspicion of PC at one of the following three major urology/uroradiology centers: Aarhus University Hospital, Herlev & Gentofte University Hospital, or Odense University Hospital, where MRI and targeted biopsy are implemented in clinical use. Exclusion criteria include previous diagnosis of urogenital cancer, contraindication to MRI, gender reassignment treatment or PSA level >20 ng/mL. The participants will be asked to donate a urine sample in connection with their MRI. The study is observational, uses a diagnostic accuracy testing setup and will integrate into the current diagnostic pathway.We will measure the levels of the three microRNAs in the uCaP model (miR-222-3 p, miR-24-3 p and miR-30c-5p) in extracellular vesicle-enriched cell-free urine samples, to assess if uCaP can improve specificity and retain sensitivity for International Society of Urological Pathology Grade Group ≥2 PC, when used as a reflex test to PSA ≥3 ng/mL. We hypothesise that uCaP can improve selection for prostate MRI and reduce the number of unnecessary scans and biopsies. ETHICS AND DISSEMINATION: This study is approved by the Central Denmark Region Committee on Health Research Ethics (reference number: 1-10-72-85-22). All participants will provide written informed consent. Study results will be published in peer-reviewed journals and presented in scientific meetings. TRIAL REGISTRATION NUMBER: NCT05767307 at clinicaltrials.gov.

Spatial whole transcriptome profiling of primary tumor from patients with metastatic prostate cancer.

Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.

Social inequality in cancer survivorship: Educational differences in health-related quality of life among 27,857 cancer survivors in Denmark.

BACKGROUND: With a growing population of cancer survivors in Denmark, the evaluation of health-related quality of life (HRQoL) has become increasingly important. We describe variations in HRQoL between educational groups in a national population of cancer survivors. METHODS: We conducted a cross-sectional questionnaire study among breast, prostate, lung, and colon cancer survivors diagnosed in 2010-2019 in Denmark. We used the EORTC QLQ-C30 to assess HRQoL including physical, role, emotional, cognitive, social functioning, and symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Information on educational level and clinical data were extracted from national registers and clinical databases. Levels of impaired functioning and severe symptoms were identified using newly established thresholds for clinical importance. Multivariate logistic regression was used to examine associations between education and HRQoL. All statistical tests were 2-sided. RESULTS: In total, 27,857 (42%) participated in the study. Up to 72% and 75% of cancer survivors with short education (≤9 years) reported impaired functioning and severe symptoms, respectively. Cancer survivors with short compared to long education (>12 years) were more likely to report impaired functioning and severe symptoms, with for example significantly higher odds ratios (ORs) for impaired physical function (breast OR = 2.41, 99% CI = 2.01-2.89; prostate OR = 1.81, 99% CI = 1.48-2.21; lung OR = 2.97, 99% CI = 1.95-4.57; and colon cancer OR = 1.69, 99% CI = 1.28-2.24). CONCLUSIONS: Cancer survivors with short education are at greater risk of impaired HRQoL than survivors with long education 2-12 years after diagnosis. This underscores the need for systematic screening and symptom management in cancer aftercare, in order to reach all cancer survivors, also cancer survivors with short education.

Results from the PRIMA Trial: Comparison of the STHLM3 Test and Prostate-specific Antigen in General Practice for Detection of Prostate Cancer in a Biopsy-naïve Population.

BACKGROUND: Current management of prostate cancer (PC) lacks biomarker tests and diagnostic procedures that can accurately distinguish clinically significant and clinically insignificant PCs at an early stage of the disease. OBJECTIVE: To compare the Stockholm 3 (STHLM3) test and prostate-specific antigen (PSA) as entry tests for magnetic resonance imaging (MRI) in a prospective study of PC diagnosis in general practice. DESIGN, SETTING, AND PARTICIPANTS: Participants were biopsy-naïve men aged 50-69 yr who had a PSA test in general practice. Participants with PSA 1-10 ng/ml also had an STHLM3 test and were referred for MRI if the STHLM311 test was positive (risk ≥11%) and/or PSA ≥3 ng/ml, and to targeted MRI-guided biopsy (MRGB) if their Prostate Imaging-Reporting and Data System (PI-RADS) score was ≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the number of International Society of Urological Pathology grade group ≥2 (GG ≥2) cases detected with a positive STHLM311 test versus PSA ≥3 ng/ml. Post hoc analysis was performed using a higher STHLM3 test cutoff (risk ≥15%; positive STHLM315 test). RESULTS AND LIMITATIONS: Between January 2018 and December 2021, we recruited 1905 men. The STHLM3 test was performed in 1134 participants. Of these, 437 underwent MRI and 117 underwent MRGB, which detected 38 (32.5%) GG ≥2 and 52 (44.4%) with GG 1 cases. In comparison to PSA ≥3 ng/ml, a positive STHLM311 test increased detection of GG ≥2 from 30 to 37 cases (23.3%, 95% confidence interval [CI] 5.6-52.2%) and detection of GG 1 from 37 to 50 cases (35.1%, 95%CI 11.6-66.7%). STHLM315 positivity did not differ from PSA ≥3 ng/ml regarding detection of GG ≥2 PC (30 vs 32; 6.6%, 95% CI -8.1% to 25.9%), GG 1 PC (37 vs 37; 0.0%, 95% CI -19.6% to 25.0%), or MRGB use (88 vs 83; -5.7%, 95% CI -17.9% to 7.4%), but reduced MRI scans from 320 to 236 (-26.2%, 95% CI -33.1% to -18.9%). CONCLUSIONS: The STHLM311 test improved sensitivity but not specificity for detection of GG ≥2 PC in the clinical setting of nonsystematic PC testing in general practice. Further studies are needed to validate a possible benefit of using a higher cutoff for STHLM3 positivity as an entry test for MRI. PATIENT SUMMARY: We used a test called STHLM3 for detection of prostate cancer in general practice and compared its performance to the conventional PSA (prostate-specific antigen) test. We found that STHLM3 test results of 11% or above were not better at selecting men for MRI (magnetic resonance imaging) scans than the PSA test with a cutoff of 3 ng/ml or above. Analysis suggested that a higher cutoff for a positive STHLM3 test may improve selection of men for MRI scans, but further validation is needed.

Educational differences in healthcare use among survivors after breast, prostate, lung, and colon cancer - a SEQUEL cohort study.

BACKGROUND: Many cancer survivors experience late effects after cancer. Comorbidity, health literacy, late effects, and help-seeking behavior may affect healthcare use and may differ among socioeconomic groups. We examined healthcare use among cancer survivors, compared with cancer-free individuals, and investigated educational differences in healthcare use among cancer survivors. METHODS: A Danish cohort of 127,472 breast, prostate, lung, and colon cancer survivors from the national cancer databases, and 637,258 age- and sex-matched cancer-free individuals was established. Date of entry was 12 months after diagnosis/index date (for cancer-free individuals). Follow-up ended at death, emigration, new primary cancer, December 31st, 2018, or up to 10 years. Information about education and healthcare use, defined as the number of consultations with general practitioner (GP), private practicing specialists (PPS), hospital, and acute healthcare contacts 1-9 years after diagnosis/index date, was extracted from national registers. We used Poisson regression models to compare healthcare use between cancer survivors and cancer-free individuals, and to investigate the association between education and healthcare use among cancer survivors. RESULTS: Cancer survivors had more GP, hospital, and acute healthcare contacts than cancer-free individuals, while the use of PPS were alike. One-to-four-year survivors with short compared to long education had more GP consultations (breast, rate ratios (RR) = 1.28, 95% CI = 1.25-1.30; prostate, RR = 1.14, 95% CI = 1.10-1.18; lung, RR = 1.18, 95% CI = 1.13-1.23; and colon cancer, RR = 1.17, 95% CI = 1.13-1.22) and acute contacts (breast, RR = 1.35, 95% CI = 1.26-1.45; prostate, RR = 1.26, 95% CI = 1.15-1.38; lung, RR = 1.24, 95% CI = 1.16-1.33; and colon cancer, RR = 1.35, 95% CI = 1.14-1.60), even after adjusting for comorbidity. One-to-four-year survivors with short compared to long education had less consultations with PPS, while no association was observed for hospital contacts. CONCLUSION: Cancer survivors used more healthcare than cancer-free individuals. Cancer survivors with short education had more GP and acute healthcare contacts than survivors with long education. To optimize healthcare use after cancer, we need to better understand survivors' healthcare-seeking behaviors and their specific needs, especially among survivors with short education.

Prostate cancer.

This review investigates prostate cancer which with approx. 4,500 new cases annually is the most frequent male cancer, and the incidence is expected to increase due to demographic developments. Prostate cancer can have a natural history without progression to symptomatic or fatal disease, which is why overdiagnosis is one of the disease's biggest challenges. In contrast to potential curable localized clinically significant disease, this is not the case after metastasis. Fortunately, new treatments, and not least combinations thereof, have increased both lifespan and quality of life in these patients significantly.

Long-term risk of benign prostatic hyperplasia-related surgery and acute urinary retention in men treated with 5-alpha reductase inhibitor versus alpha-blocker monotherapy in routine clinical care.

OBJECTIVES: To assess the risk of benign prostatic hyperplasia (BPH)-related surgery and acute urinary retention (AUR) in men treated with 5-alpha-reductase inhibitor (5-ARI) versus alpha-blocker monotherapy in routine clinical care over 15 years of follow-up. METHODS: Using population-based Danish Health registries, we identified all new-users of 5-ARI or alpha-blocker monotherapy in Denmark, 1997-2017. We defined an index date 180 days after the date of first prescription and included men who redeemed at least one additional prescription before the index date. We used multiple imputation to replace missing prostate-specific antigen values. We performed propensity score-weighted Cox regression to estimate weighted hazard ratios (wHRs) and cumulative incidence function to estimate weighted cumulative risks of BPH-related surgery and AUR in intention to treat (ITT) and per protocol (PP) analyses. RESULTS: We included 18,421 and 95,984 men treated with 5-ARI and alpha-blocker monotherapy, respectively. Overall, treatment with 5-ARI monotherapy was associated with a reduced risk of BPH-related surgery (ITT wHR = 0.73 (95% confidence interval [CI]: 0.68-0.78), PP wHR = 0.77 (95% CI: 0.70-0.84) and AUR (ITT wHR = 0.73 (95% CI: 0.67-0.78), PP wHR = 0.75 (95% CI: 0.66-0.84). The 15-year risk of BPH-related surgery in men treated with 5-ARI versus alpha-blocker monotherapy was 14.8% (95% CI: 14.1%-15.5%) versus 19.1% (95% CI: 18.7%-19.5%) in the ITT analysis and 13.8% (95% CI: 12.6%-14.9%) versus 17.5% (95% CI: 16.9%-18.0%) in the PP analysis. The 15-year risk of AUR in men treated with 5-ARI versus alpha-blocker was 13.0% (95% CI: 12.3%-13.6%) versus 16.6% (95% CI: 16.3%-17.0%) in the ITT analysis and 12.6% (95%: 11.3%-14.0%) versus 16.9% (95% CI: 16.3%-17.6%) in the PP analysis. CONCLUSION: Treatment with 5-ARI versus alpha-blocker monotherapy in routine clinical care was associated with a reduced risk of BPH-related surgery and AUR for up to 15 years of follow-up. After 15 years of follow-up, the relative risk reduction was 21%-25% and the absolute risk reduction was 4%.

Prognostic Value of Low-Pass Whole Genome Sequencing of Circulating Tumor DNA in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Multiple treatments are available for metastatic castration-resistant prostate cancer (mCRPC), including androgen receptor signaling inhibitors (ARSI) enzalutamide and abiraterone, but therapy resistance remains a major clinical obstacle. We examined the clinical utility of low-pass whole-genome sequencing (LPWGS) of circulating tumor DNA (ctDNA) for prognostication in mCRPC. METHODS: A total of 200 plasma samples from 143 mCRPC patients collected at the start of first-line ARSI treatment (baseline) and at treatment termination (n = 57, matched) were analyzed by LPWGS (median: 0.50X) to access ctDNA% and copy number alteration (CNA) patterns. The best confirmed prostate specific antigen (PSA) response (≥50% decline [PSA50]), PSA progression-free survival (PFS), and overall survival (OS) were used as endpoints. For external validation, we used plasma LPWGS data from an independent cohort of 70 mCRPC patients receiving first-line ARSI. RESULTS: Baseline ctDNA% ranged from ≤3.0% to 73% (median: 6.6%) and CNA burden from 0% to 82% (median: 13.1%) in the discovery cohort. High ctDNA% and high CNA burden at baseline was associated with poor PSA50 response (P = 0.0123/0.0081), poor PFS (P < 0.0001), and poor OS (P < 0.0001). ctDNA% and CNA burden was higher at PSA progression than at baseline in 32.7% and 42.3% of the patients. High ctDNA% and high CNA burden at baseline was also associated with poor PFS and OS (P ≤ 0.0272) in the validation cohort. CONCLUSIONS: LPWGS of ctDNA provides clinically relevant information about the tumor genome in mCRPC patients. Using LPWGS data, we show that high ctDNA% and CNA burden at baseline is associated with short PFS and OS in 2 independent cohorts.

Acute urinary retention in men: 21-year trends in incidence, subsequent benign prostatic hyperplasia-related treatment and mortality: A Danish population-based cohort study.

OBJECTIVE: To examine trends in incidence of acute urinary retention, subsequent benign prostatic hyperplasia-related treatment and mortality in the era of medical therapy for benign prostatic hyperplasia. Additionally, to compare mortality with the general population. MATERIALS AND METHODS: We conducted a Danish nationwide registry-based study including 70,775 men aged 45 years or older with a first hospitalization for acute urinary retention during 1997-2017. We computed annual standardized incidence rates, subsequent 1-year cumulative incidence of benign prostatic hyperplasia-related surgical and medical treatment, and standardized 3-month and 1-year mortality rates. Finally, we compared standardized all-cause and cause-specific mortality ratios with the general population. RESULTS: The standardized incidence rate of acute urinary retention per 1000 person-years increased transiently from 2.34 to 3.42 during 1997-2004, but gradually declined to 2.95 in 2017. The 1-year cumulative incidence of benign prostatic hyperplasia-related surgery declined from 31.2% to 19.8% and 20.5% to 7.7% after spontaneous and precipitated acute urinary retention, respectively. During 1997-2017, the standardized 1-year mortality declined from 22.2% to 17.2%. Compared with the general population, mortality was 4-5 times higher after 3 months and 2-3 times higher after 1 year of acute urinary retention. The cause-specific standardized mortality ratios were particularly high for deaths attributable to malignancies, urogenital disease, certain infections, chronic pulmonary disease, and diabetes. CONCLUSION: During 1997-2017, we observed a transient increase in the incidence of acute urinary retention. The subsequent use of benign prostatic hyperplasia-related surgery declined considerably and mortality continued to be high, mainly because of deaths from malignancies, urogenital disease, infections, and preexisting comorbidity.

Identification of a high-risk immunogenic prostate cancer patient subset as candidates for T-cell engager immunotherapy and the introduction of a novel albumin-fused anti-CD3 × anti-PSMA bispecific design.

BACKGROUND: Cancer immunotherapies such as bispecific T-cell engagers have seen limited adoption in prostate cancer (PC), possibly due to differing levels of cancer receptor expression and effector T-cell infiltration between patients and inherent defects in T-cell engager design. METHODS: CD8+ T-cell infiltration and PSMA expression were determined by RNA sequencing of primary PC tissue samples from 126 patients with localised PC and 17 patients with metastatic PC. Prognostic value was assessed through clinical parameters, including CAPRA-S risk score. A panel of albumin-fused anti-CD3 × anti-PSMA T-cell engagers with different neonatal Fc receptor (FcRn) affinity were characterised by flow cytometry, Bio-Layer Interferometry and functional cellular assays. RESULTS: A subset of patients with localised (30/126 = 24%) and metastatic (10/17 = 59%) PC showed both high PSMA expression and high CD8+ T-cell enrichment. The High/High phenotype in localised PC associated with a clinically high-risk cancer subtype, confirmed in an external patient cohort (n = 550, PRAD/TCGA). The T-cell engagers exhibited tunable FcRn-driven cellular recycling, CD3 and PSMA cellular engagement, T-cell activation and PSMA level-dependent cellular cytotoxicity. CONCLUSION: This work presents an albumin-fused bispecific T-cell engager with programmable FcRn engagement and identifies a high-risk PC patient subset as candidates for treatment with the T-cell engager class of immuno-oncology biologics.

Recurrence rate after radical prostatectomy following primary staging of high-risk prostate cancer with 68Ga-PSMA PET/CT.

BACKGROUND: Accurate primary staging is one of the most important issues for initial management of prostate cancer (PCa) patients to perform an optimal selection of patients for curative intended treatment. 68Ga-Prostate-Specific-Membrane-Antigen (PSMA) PET/CT was found superior to conventional imaging both for detection of recurrence after curative intended treatment and for primary staging. We studied the recurrence rate after radical prostatectomy in high-risk PCa patients primary staged with 68Ga-PSMA PET/CT compared with conventional imaging. MATERIAL AND METHODS: The study included 247 D'Amico high-risk PCa patients treated with radical prostatectomy (RP) after primary staging with 68Ga-PSMA PET/CT and a reference group of 137 high-risk patients with RP after conventional imaging (99mTc bone scintigraphy and CT). Recurrence rates were assessed by Cox regression and Kaplan-Meier analysis. RESULTS: The 5-year recurrence-free survival rate was 71.1% in the 68Ga-PSMA PET/CT cohort compared with 56.4% in the conventional imaging cohort. Primary staging by 68Ga-PSMA PET/CT reduced biochemical recurrence (BCR) risk by 42% (HR = 0.58 (0.41-0.83), p = .004). CONCLUSION: The present data could indicate a lower recurrence rate after RP following primary staging with 68Ga-PSMA PET/CT compared to conventional imaging, likely due to improved selection of patients for surgery.

Predicting Grade group 2 or higher cancer at prostate biopsy by 4Kscore in blood and uCaP microRNA model in urine.

Elevated prostate-specific antigen (PSA) levels often lead to unnecessary and possibly harmful transrectal ultrasound guided biopsy, e.g. when the biopsy is negative or contains only low-grade insignificant cancer, unlikely to become symptomatic in the man's normal lifespan. A model based on four-kallikrein markers in blood (commercialized as 4Kscore) predicts risk of Grade group 2 or higher prostate cancer at biopsy, reducing unnecessary biopsies. We assessed whether these results extend to a single institution prostate biopsy cohort of Danish men and are enhanced by three microRNAs from urine (referred to as uCaP). The 4Kscore measured in cryopreserved blood from 234 men referred for 10+ core biopsy to Aarhus University Hospital, 29 with PSA > 25 ng/ml. We explored uCaP in urine from 157 of these men. Combined with age and DRE findings, both 4Kscore and uCaP could accurately predict Grade group 2 or higher prostate cancer (all patients: AUC = 0.802 and 0.797; PSA ≤ 25: AUC = 0.763 and 0.759). There was no additive effect when combining the 4Kscore and uCaP. Limitations include a study cohort with higher risk than commonly reported for biopsy cohorts. Our findings further support the clinical use of the 4Kscore to predict Grade group 2 or higher cancers in men being considered for biopsy.

A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer.

DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.