Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.

Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy. METHODS: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes). RESULTS: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis. CONCLUSIONS: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

Effect of Health Service Area on Primary Care Physician Provision of Low-Value Cancer Screening.

BACKGROUND: Using a health systems approach to investigate low-value care (LVC) may provide insights into structural drivers of this pervasive problem. OBJECTIVE: To evaluate the influence of service area practice patterns on low-value mammography and prostate-specific antigen (PSA) testing. DESIGN: Retrospective study analyzing LVC rates between 2008 and 2018, leveraging physician relocation in 3-year intervals of matched physician and patient groups. SETTING: U.S. Medicare claims data. PARTICIPANTS: 8254 physicians and 56 467 patients aged 75 years or older. MEASUREMENTS: LVC rates for physicians staying in their original service area and those relocating to new areas. RESULTS: Physicians relocating from higher-LVC areas to low-LVC areas were more likely to provide lower rates of LVC. For mammography, physicians staying in high-LVC areas (LVC rate, 10.1% [95% CI, 8.8% to 12.2%]) or medium-LVC areas (LVC rate, 10.3% [CI, 9.0% to 12.4%]) provided LVC at a higher rate than physicians relocating from those areas to low-LVC areas (LVC rates, 6.0% [CI, 4.4% to 7.5%] [difference, -4.1 percentage points {CI, -6.7 to -2.3 percentage points}] and 5.9% [CI, 4.6% to 7.8%] [difference, -4.4 percentage points {CI, -6.7 to -2.4 percentage points}], respectively). For PSA testing, physicians staying in high- or moderate-LVC service areas provided LVC at a rate of 17.5% (CI, 14.9% to 20.7%) or 10.6% (CI, 9.6% to 13.2%), respectively, compared with those relocating from those areas to low-LVC areas (LVC rates, 9.9% [CI, 7.5% to 13.2%] [difference, -7.6 percentage points {CI, -10.9 to -3.8 percentage points}] and 6.2% [CI, 3.5% to 9.8%] [difference, -4.4 percentage points {CI, -7.6 to -2.2 percentage points}], respectively). Physicians relocating from lower- to higher-LVC service areas were not more likely to provide LVC at a higher rate. LIMITATION: Use of retrospective observational data, possible unmeasured confounding, and potential for relocating physicians to practice differently from those who stay. CONCLUSION: Physicians relocating to service areas with lower rates of LVC provided less LVC than physicians who stayed in areas with higher rates of LVC. Systemic structures may contribute to LVC. Understanding which factors are contributing may present opportunities for policy and interventions to broadly improve care. PRIMARY FUNDING SOURCE: National Cancer Institute of the National Institutes of Health.

Lifetime Health and Economic Outcomes of Biparametric Magnetic Resonance Imaging as First-Line Screening for Prostate Cancer : A Decision Model Analysis.

BACKGROUND: Contemporary prostate cancer (PCa) screening uses first-line prostate-specific antigen (PSA) testing, possibly followed by multiparametric magnetic resonance imaging (mpMRI) for men with elevated PSA levels. First-line biparametric MRI (bpMRI) screening has been proposed as an alternative. OBJECTIVE: To evaluate the comparative effectiveness and cost-effectiveness of first-line bpMRI versus PSA-based screening. DESIGN: Decision analysis using a microsimulation model. DATA SOURCES: Surveillance, Epidemiology, and End Results database; randomized trials. TARGET POPULATION: U.S. men aged 55 years with no prior screening or PCa diagnosis. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health care system. INTERVENTION: Biennial screening to age 69 years using first-line PSA testing (test-positive threshold, 4 µg/L) with or without second-line mpMRI or first-line bpMRI (test-positive threshold, PI-RADS [Prostate Imaging Reporting and Data System] 3 to 5 or 4 to 5), followed by biopsy guided by MRI or MRI plus transrectal ultrasonography. OUTCOME MEASURES: Screening tests, biopsies, diagnoses, overdiagnoses, treatments, PCa deaths, quality-adjusted and unadjusted life-years saved, and costs. RESULTS OF BASE-CASE ANALYSIS: For 1000 men, first-line bpMRI versus first-line PSA testing prevented 2 to 3 PCa deaths and added 10 to 30 life-years (4 to 11 days per person) but increased the number of biopsies by 1506 to 4174 and the number of overdiagnoses by 38 to 124 depending on the biopsy imaging scheme. At conventional cost-effectiveness thresholds, first-line PSA testing with mpMRI followed by either biopsy approach for PI-RADS 4 to 5 produced the greatest net monetary benefits. RESULTS OF SENSITIVITY ANALYSIS: First-line PSA testing remained more cost-effective even if bpMRI was free, all men with low-risk PCa underwent surveillance, or screening was quadrennial. LIMITATION: Performance of first-line bpMRI was based on second-line mpMRI data. CONCLUSION: Decision analysis suggests that comparative effectiveness and cost-effectiveness of PCa screening are driven by false-positive results and overdiagnoses, favoring first-line PSA testing with mpMRI over first-line bpMRI. PRIMARY FUNDING SOURCE: National Cancer Institute.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Preanalytical stability of molecular forms of prostate-specific antigen in serum samples (PSA, free PSA, [-2]proPSA) and their impact on fPSA/tPSA ratio and PHI.

BACKGROUND: Prostate cancer is a common cancer in men. Detection methods include the measurement of biomarkers: prostate-specific antigen (PSA), free PSA, [-2]proPSA, and the calculated indices: fPSA/tPSA ratio and Prostate Health Index (PHI). Proper preanalytical conditions are crucial for precise measurement and failure to adhere to protocols or regulations can influence the diagnostic algorithm. We assessed the stability of the above-mentioned biomarkers, fPSA/tPSA ratio and PHI, under various pre-analytical conditions. METHODS: Serum samples from 45 males were collected and stored under specific conditions before tPSA, fPSA, and [-2]proPSA were measured. Subsequently, the fPSA/tPSA and PHI were calculated. RESULTS: tPSA, fPSA, and [-2]proPSA remained stable during the two freeze-thaw cycles. Storage at 4°C and 22°C resulted in stable tPSA concentrations. However, fPSA levels decreased and [-2]proPSA levels increased over time. The fPSA/tPSA ratio remained stable for 72 h, at which point a decrease was observed in the samples kept at 4°C and 22°C. A gradual increase in PHI was observed in the samples kept at 4°C and 22°C. CONCLUSIONS: All biomarkers remained stable during two freeze-thaw cycles. tPSA was the most stable analyte when stored at 4°C, as well as at RT. A gradual increase of [-2]proPSA and a slight decrease in fPSA were observed during the storage test. This led to a decrease in the fPSA/tPSA ratio and an elevation in the PHI. We therefore recommend measuring prostate biomarkers promptly following blood collection. IMPACT: Understanding the pre-analytical stability of prostate biomarkers helps prevent false positive results and improve the accuracy of diagnostics for prostate cancer.

Development and validation of an imageless machine-learning algorithm for the initial screening of prostate cancer.

PURPOSE: Prostate specific antigen (PSA) testing is a low-cost screening method for prostate cancer (PCa). However, its accuracy is limited. While progress is being made using medical imaging for PCa screening, PSA testing can still be improved as an easily accessible first step in the screening process. We aimed to develop and validate a new model by further personalizing the analysis of PSA with demographic, medical history, lifestyle parameters, and digital rectal examination (DRE) results. METHODS: Using data from 34,224 patients in the screening arm of the PLCO trial (22,188 for the training set and 12,036 for the validation set), we applied a gradient-boosting model whose features (Model 1) were one PSA value and the personal variables available in the PLCO trial except those that signaled an ex-ante assumption of PCa. A second algorithm (Model 2) included a DRE result. The primary outcome was the occurrence of PCa, while the aggressiveness of PCa was a secondary outcome. ROC analyses were used to compare both models to other initial screening tests. RESULTS: The areas under the curve (AUC) for Model 2 was 0.894 overall and 0.908 for patients with a suspicious DRE, compared to 0.808 for PSA for patients with a suspicious DRE. The AUC for Model 1 was 0.814 compared to 0.821 for PSA. Model 2 predicted 58% more high-risk PCa than PSA ≥4 combined with an abnormal DRE and had a positive predictive value of 74.7% (vs. 50.6%). CONCLUSION: Personalizing the interpretation of PSA values and DRE results with a gradient-boosting model showed promising results as a potential novel, low-cost method for the initial screening of PCa. The importance of DRE, when included in such a model, was also highlighted.

The effect of dose-escalation radiotherapy with simultaneous-integrated-boost on the use of short-term androgen deprivation therapy in patients with intermediate risk prostate cancer.

PURPOSE: To compare the biochemical failure (FFBF) and prostate cancer specific survival (PCSS) rates of patients with intermediate-risk prostate cancer (IR-PC) who were treated with 6 months of androgen deprivation therapy (ADT) with 78 Gy to the prostate, those treated with ADT and focal boost (FB) of 86 Gy to intraprostatic lesion (IPL) using the simultaneous-integrated boost (SIB) technique, and those treated with SIB alone. MATERIALS AND METHODS: A retrospective analysis of 320 IR-PC patients treated between January 2012 and April 2021 was performed. Patients were divided into three groups based on their treatment arm: 78 + ADT (109 patients, 34.1%), 78/86 (102 patients, 31.8%), and 78/86 + ADT. Univariable and multivariable analyses were used to determine prognostic factors for FFBF and PCSS. RESULTS: Median follow-up was 8.8 years. The 8-year FFBF and PCSS rates were 88.6% and 99.0%. Patients who received ADT had significantly higher pretreatment PSA levels and clinical tumor stage. Disease progression occurred in 45 patients (7.3%) at a median of 41.9 months after definitive radiotherapy (RT). Younger age, positive core biopsy (PCB) ≥ 50%, and the absence of ADT were all independent predictors of poor FFBF in multivariate analysis, whereas patients with PCB < 50% who were also given ADT had better PCSS. Patients treated with 78/86 Gy alone had worse FFBF than those treated with 78 Gy and ADT (Hazard ratio [HR] = 3.39 [95% CI = 1.46-7.88]; p = 0.005), as well as than those treated with 78/86 Gy and ADT (HR = 3.21 [95% CI = 1.23-6.46]; p = 0.009). However, FB to IPL has no effect on PCSS in multivariable analysis. There was no significant difference between treatment groups in terms of acute and late Grade ≥2 genitourinary or gastrointestinal toxicity. CONCLUSIONS: Our findings demonstrated that patients who received 78/86 alone did worse than patients who received ADT with either 78 or 78/86 Gy. However, because IR-PC patients are so diverse, additional prospective trials are needed to validate our findings.

The additional value of 68Ga-PSMA PET/CT SUVmax in predicting ISUP GG ≥ 2 and ISUP GG ≥ 3 prostate cancer in biopsy.

BACKGROUND: Prebiopsy magnetic resonance imaging (MRI) increases the detection rate of clinically significant prostate cancer (csPCa). Prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA PET/CT) maximum standardized uptake value (SUVmax) of the prostate may offer additional value in predicting the likelihood of csPCa in biopsy. METHODS: A single-center cohort study involving patients with biopsy-proven PCa who underwent both MRI and PSMA PET/CT between 2020 and 2021. Logistic regression models were developed for International Society of Urological Pathology (ISUP) Grade Group (GG) ≥ 2 and GG ≥ 3 using noninvasive prebiopsy parameters: age, (log-)prostate-specific antigen (PSA) density, PI-RADS 5 lesion presence, extraprostatic extension (EPE) on MRI, and SUVmax of the prostate. Models with and without SUVmax were compared using Likelihood ratio tests and area under the curve (AUC). DeLong's test was used to compare the AUCs. RESULTS: The study included 386 patients, with 262 (68%) having ISUP GG ≥ 2 and 180 (47%) having ISUP GG ≥ 3. Including SUVmax significantly improved both models' goodness of fit (p < 0.001). The GG ≥ 2 model had a higher AUC with SUVmax 89.16% (95% confidence interval [CI]: 86.06%-92.26%) than without 87.34% (95% CI: 83.93%-90.76%) (p = 0.026). Similarly, the GG ≥ 3 model had a higher AUC with SUVmax 82.51% (95% CI: 78.41%-86.6%) than without 79.33% (95% CI: 74.84%-83.83%) (p = 0.003). The SUVmax inclusion improved the GG ≥ 3 model's calibration at higher probabilities. CONCLUSION: SUVmax of the prostate on PSMA PET/CT potentially improves diagnostic accuracy in predicting the likelihood of csPCa in prostate biopsy.

Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67.

BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.

Outcomes of 10 years of PSA screening for prostate cancer in Norwegian men with Lynch syndrome.

BACKGROUND: Pathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA testing from the age of 40. Prospective studies of the outcome of long-term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold >3.0 ng/mL) to evaluate whether our recommendations should be continued. METHODS: This is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI-analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway. RESULTS: Twenty-two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) MSH2 carriers and 8/61 (13.1%) MSH6 carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI-high. SIR was 9.54 (95% CI 5.98-14.45) for all MMR genes, 13.0 (95% CI 6.23-23.9) for MSH2 and 13.74 for MSH6 (95% CI 5.93-27.08). CONCLUSIONS: Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA-threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.

The impact of genomic biomarkers on a clinical risk prediction model for upgrading/upstaging among men with favorable-risk prostate cancer.

BACKGROUND: The challenge of distinguishing indolent from aggressive prostate cancer (PCa) complicates decision-making for men considering active surveillance (AS). Genomic classifiers (GCs) may improve risk stratification by predicting end points such as upgrading or upstaging (UG/US). The aim of this study was to assess the impact of GCs on UG/US risk prediction in a clinicopathologic model. METHODS: Participants had favorable-risk PCa (cT1-2, prostate-specific antigen [PSA] ≤15 ng/mL, and Gleason grade group 1 [GG1]/low-volume GG2). A prediction model was developed for 864 men at the University of California, San Francisco, with standard clinical variables (cohort 1), and the model was validated for 2267 participants from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (cohort 2). Logistic regression was used to compute the area under the receiver operating characteristic curve (AUC) to develop a prediction model for UG/US at prostatectomy. A GC (Oncotype Dx Genomic Prostate Score [GPS] or Prolaris) was then assessed to improve risk prediction. RESULTS: The prediction model included biopsy GG1 versus GG2 (odds ratio [OR], 5.83; 95% confidence interval [CI], 3.73-9.10); PSA (OR, 1.10; 95% CI, 1.01-1.20; per 1 ng/mL), percent positive cores (OR, 1.01; 95% CI, 1.01-1.02; per 1%), prostate volume (OR, 0.98; 95% CI, 0.97-0.99; per mL), and age (OR, 1.05; 95% CI, 1.02-1.07; per year), with AUC 0.70 (cohort 1) and AUC 0.69 (cohort 2). GPS was associated with UG/US (OR, 1.03; 95% CI, 1.01-1.06; p < .01) and AUC 0.72, which indicates a comparable performance to the prediction model. CONCLUSIONS: GCs did not substantially improve a clinical prediction model for UG/US, a short-term and imperfect surrogate for clinically relevant disease outcomes.

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening.

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.).

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Controlled-Release Electrochemiluminescence Biosensor with Strong Self-On Effect by a Multiple Signal Amplification Strategy for Trace Detection of Prostate-Specific Antigen.

The enhancement of sensitivity in biological analysis detection can reduce the probability of false positives of the biosensor. In this work, a novel self-on controlled-release electrochemiluminescence (CRE) biosensor was designed by multiple signal amplification and framework-enhanced stability strategies. As a result, the changes of the ECL signal were enhanced before and after the controlled-release process, achieving sensitive detection of prostate-specific antigen (PSA). Specifically, for one thing, Fe3O4@CeO2-NH2 with two paths for enhancing the generation of coreactant radicals was used as the coreaction accelerator to boost ECL performance. For another, due to the framework stability, zeolitic imidazolate framework-8-NH2 (ZIF-8-NH2) was combined with luminol to make the ECL signal more stable. Based on these strategies, the constructed CRE biosensor showed a strong self-on effect in the presence of PSA and high sensitivity in a series of tests. The detection range and limit of detection (LOD) were 5 fg/mL to 10 ng/mL and 2.8 fg/mL (S/N = 3), respectively, providing a feasible approach for clinical detection of PSA.

Upconversion Nanoparticle-Based Dot-Blot Immunoassay for Quantitative Biomarker Detection.

Dot-blot immunoassays are widely used for the user-friendly detection of clinical biomarkers. However, the majority of dot-blot assays have only limited sensitivity and are only used for qualitative or semiquantitative analysis. To overcome this limitation, we have employed labels based on photon-upconversion nanoparticles (UCNPs) that exhibit anti-Stokes luminescence and can be detected without optical background interference. First, the dot-blot immunoassay on a nitrocellulose membrane was optimized for the quantitative analysis of human serum albumin (HSA), resulting in a limit of detection (LOD) of 0.19 ng/mL and a signal-to-background ratio (S/B) of 722. Commercial quantum dots were used as a reference label, reaching the LOD of 4.32 ng/mL and the S/B of 3, clearly indicating the advantages of UCNPs. In addition, the potential of UCNP-based dot-blot for real sample analysis was confirmed by analyzing spiked urine samples, reaching the LOD of 0.24 ng/mL and recovery rates from 79 to 123%. Furthermore, we demonstrated the versatility and robustness of the assay by adapting it to the detection of two other clinically relevant biomarkers, prostate-specific antigen (PSA) and cardiac troponin (cTn), reaching the LODs in spiked serum of 9.4 pg/mL and 0.62 ng/mL for PSA and cTn, respectively. Finally, clinical samples of patients examined for prostate cancer were analyzed, achieving a strong correlation with the reference electrochemiluminescence immunoassay (recovery rates from 89 to 117%). The achieved results demonstrate that UCNPs are highly sensitive labels that enable the development of dot-blot immunoassays for quantitative analysis of low-abundance biomarkers.

Silica Nanochannels as Nanoreactors for the Confined Synthesis of Ag NPs to Boost Electrochemical Stripping Chemiluminescence of the Luminol-O2 System for the Sensitive Aptasensor.

Herein, we, for the first time, synthesize silver nanoparticles (Ag NPs) within the nanochannels of amino group-functionalized vertically ordered mesoporous silica films (NH2-VMSF) and investigate their coreaction accelerator role in the luminol-dissolved oxygen (O2) electrochemical stripping chemiluminescence (ESCL) system. The synthesized Ag NPs are capable of electrocatalytic reduction of O2 to superoxide radicals, and meanwhile, sliver ions (Ag+) electrochemically stripped from Ag NPs can promote the amount of luminol anion radicals, generating the boosted ECL intensity of the luminol-dissolved O2 system. This proposed Ag NPs@NH2-VMSF on the indium tin oxide electrode was applied to construct the ESCL aptasensor for quantitative determination of prostate-specific antigen (PSA), yielding a low detection limit [0.19 pg/mL (S/N = 3)] and a broad linear dynamic range (1 pg/mL to 100 ng/mL). Furthermore, good analytical performance of PSA in serum with satisfactory recoveries and low relative standard deviation values is achieved by our developed ESCL aptasensor, rendering it a convenient and sensitive method for PSA determination in clinical applications and further broadening the strategy of ESCL techniques.