Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

OBJECTIVE: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. MATERIALS AND METHODS: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. RESULTS: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. CONCLUSION: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.

Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI: The ProScreen Randomized Trial.

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.

Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study.

PURPOSE: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). METHODS: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. RESULTS: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). CONCLUSIONS: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Do LUTS Predict Mortality? An Analysis Using Random Forest Algorithms.

Purpose: To evaluate a random forest (RF) algorithm of lower urinary tract symptoms (LUTS) as a predictor of all-cause mortality in a population-based cohort. Materials and Methods: A population-based cohort of 3143 men born in 1924, 1934, and 1944 was evaluated using a mailed questionnaire including the Danish Prostatic Symptom Score (DAN-PSS-1) to assess LUTS as well as questions on medical conditions and behavioral and sociodemographic factors. Surveys were repeated in 1994, 1999, 2004, 2009 and 2015. The cohort was followed-up for vital status until the end of 2018. RF uses an ensemble of classification trees for prediction with a good flexibility and without overfitting. RF algorithms were developed to predict the five-year mortality using LUTS, demographic, medical, and behavioral factors alone and in combinations. Results: A total of 2663 men were included in the study, of whom 917 (34%) died during follow-up (median follow-up time 15.0 years). The LUTS-based RF algorithm showed an area under the curve (AUC) 0.60 (95% CI 0.52-0.69) for five-year mortality. An expanded RF algorithm, including LUTS, medical history, and behavioral and sociodemographic factors, yielded an AUC 0.73 (0.65-0.81), while an algorithm excluding LUTS yielded an AUC 0.71 (0.62-0.78). Conclusion: An exploratory RF algorithm using LUTS can predict all-cause mortality with acceptable discrimination at the group level. In clinical practice, it is unlikely that LUTS will improve the accuracy to predict death if the patient's background is well known.

Do men adapt to lower urinary tract symptoms? An 11-year longitudinal study of male urinary urgency and associated bother.

OBJECTIVE: The study objective is to evaluate prognosis and predictors of bother caused by urinary urgency among middle-aged and older men. MATERIAL AND METHODS: A population-based sample of men born in 1974, 1964, 1954, 1944, 1934 and 1924 was followed-up from 2004 to 2015. The course of urgency and associated bother was evaluated with the Danish Prostatic Symptom Score at baseline and follow-up. Logistic regression was utilized to explore risk factors of increased bother at follow-up. RESULTS: A total of 2,480 men (39%) who had responded at baseline and follow-up were included in the study. Of them, 1,056 men (43%) had persistent mild urgency and 132 men (5%) persistent moderate or severe urgency at follow-up. The proportions of men experiencing at least moderate bother due to persistent urgency at follow-up were 6% (95% confidence interval 4.5-7.3) of those with mild and 79% (71.7-85.9) of the men with moderate or severe urgency. In multivariable-adjusted logistic regression, moderate to severe urgency was strongly associated with bother (odds ratio, OR 55.2, 95% CI 32.1-95.2). Other predictors of bother included cardiac disease (OR 1.8, 95% CI 1.0-31.1), pulmonary disease (OR 1.9, 95% CI 1.1-3.5) and medical treatment (OR 2.7, 95% CI 1.6-4.6). CONCLUSIONS: Most men with urinary urgency have mild symptoms and bother. Only one out of five men with persistent moderate or severe urgency adapt to the symptoms. Men with a history of medical treatment for lower urinary tract symptoms (LUTS) or impaired cardiopulmonary health are more likely to experience bother from urinary urgency.

Early detection of clinically significant prostate cancer: protocol summary and statistical analysis plan for the ProScreen randomised trial.

INTRODUCTION: Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and overtreatment. However, diagnostic accuracy studies have shown that detection of clinically insignificant prostate cancer can be reduced by MRI combined with targeted biopsies.The aim of the paper is to describe the analysis of the ProScreen randomised trial to assess the performance of the novel screening algorithm in terms of the primary outcome, prostate cancer mortality and secondary outcomes as intermediate indicators of screening benefits and harms of screening. METHODS: The trial aims to recruit at least 111 000 men to achieve sufficient statistical power for the primary outcome. Men will be allocated in a 1:3 ratio to the screening and control arms. Interim analysis is planned at 10 years of follow-up, and the final analysis at 15 years. Difference between the trial arms in prostate cancer mortality will be assessed by Gray's test using intention-to-screen analysis of randomised men. Secondary outcomes will be the incidence of prostate cancer by disease aggressiveness, progression to advanced prostate cancer, death due to any cause and cost-effectiveness of screening. ETHICS AND DISSEMINATION: The trial protocol was reviewed by the ethical committee of the Helsinki University Hospital (2910/2017). Results will be disseminated through publications in international peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: NCT03423303.

Screening history and risk of death from prostate cancer: a nested case-control study within the screening arm of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

PURPOSE: We assessed the risk of death from prostate cancer (PCa) in relation to men's screening histories, i.e., screening attendance among men who were offered screening. METHODS: Men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996-2007. Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa. Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis. The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Having ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45-0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51-0.87). The effect by time since last screen for the risk of PCa death was significantly lower 2-7 years since last screen. CONCLUSION: Among men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men.

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. METHODS: Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. RESULTS: All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. CONCLUSIONS: Long-term darolutamide treatment was well tolerated; no new safety signals observed. In patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide.

Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine.

BACKGROUND: Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. METHODS: We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones. RESULTS: In patient GP5, CDK12 inactivation was among the first mutations, leading to a PrCa tandem duplicator phenotype and initiating the cancer around age 50, followed by rapid cancer evolution after age 57, and metastasis around age 59, 5 years prior to prostatectomy. In patient GP12, accelerated cancer progression was detected after age 54, and metastasis occurred around age 56, 3 years prior to prostatectomy. Multiple metastasis-originating events were identified in each patient and tracked anatomically. Metastasis from prostate to lymph nodes occurred strictly ipsilaterally in all 12 detected events. In this pilot, metastatic subclone content analysis appears to substantially enhance the identification of key drivers. Evolutionary analysis' potential impact on therapy selection appears positive in these pilot cases. CONCLUSIONS: PrCa evolutionary analysis allows tracking of anatomic site of origin, timing of cancer origin and spread, and distinction of metastatic-capable from non-metastatic subclones. This enables better identification of actionable targets for therapy. If extended to larger cohorts, it appears likely that similar analyses could add substantial biological insight and clinically relevant value.

Prostate cancer-related sexual dysfunction - the significance of social relations in men's reconstructions of masculinity.

Narrating illness experiences in a culturally acceptable manner is essential for retaining quality of life after the disruptive event of being diagnosed for prostate cancer. Psychological pressures caused by treatment side-effects such as erectile dysfunction require reinterpretation of the meanings and impacts of these side-effects on masculinity. This helps maintain coherence in men's lives. We studied how men employ culturally available discursive strategies (compensation, redefinition, recontextualisation, and normalisation) in reconstructing masculinity and sexuality. Our data consists of 22 interviews of heterosexual Finnish prostate cancer patients who had undergone surgery. The aim was to analyse the ways in which various life situations and social relations shaped and limited the use of these strategies. Discourse analysis revealed that older age, a supportive spouse, children, supportive male friends, and good health - were key elements men used in reconstructing a coherent new self-image and conception of life following cancer treatment. Men with sexually active male friends, men without families, younger men and men with new intimate relationships struggled to develop a new version of their masculinity. Being able to effectively utilise certain aspects of one's life situation in re-constructing masculinity is important in maintaining quality of life despite troublesome treatment side-effects.

Missingness in the expanded prostate cancer index short form (EPIC-26) - prevalence, patterns, and explanatory factors.

BACKGROUND: Researchers and clinicians using common clinical assessments need to attend to the prevalence of missing data to ensure the validity of the information gathered. The Expanded Prostate Cancer Index Short Form (EPIC-26) is a commonly used measurement scale used for assessing patients' quality of life, but the measure lacks comprehensive analysis on missing data. We aimed to explore the quantity of missing answers in EPIC-26 and to characterize patterns and possible explanations of missing data in the survey. METHODS: The survey sample consisted of 625 Finnish prostate cancer patients who participated in a study with a 1-year follow-up with three measurement points (0, 6, and 12 months). Descriptive statistics were used to describe the study population and missingness level. A logistic regression was performed for each EPIC domain to study factors related to missingness during the follow-up. RESULTS: Proportions of missing answers in EPIC-26 were low (3.1-3.9%) between survey rounds. As much as 37% of patients left at least one question unanswered during their follow-up. The hormonal domain produced the most missing answers. Questions about breast tenderness/enlargement (question 13.b.), hot flashes (question 13.a.), frequency of erections (question 10.), and ability to reach orgasm (question 8.b.) were most frequently left unanswered. Higher age, lower education level, no relationship, more severe cancer, lower function scores in some EPIC domains, lower treatment satisfaction or self-rated health were associated with missingness. CONCLUSIONS: Questions 13.b. and 13.a. might be considered female-specific symptoms, thus difficult to comprehend unless patients had already experienced side effects from androgen deprivation therapy. Questions 10. and 8.b. might be difficult to answer if the patient has been sexually inactive. To improve the measure's validity, the questionnaire's hormonal section requires additional explanation that the inquired symptoms are common treatment side effects of anti-androgen therapy; questions 8-10 require a not-applicable category for sexually inactive patients.

Identification of long noncoding RNAs with aberrant expression in prostate cancer metastases.

Prostate cancer (PCa) is the second-most common cause of male cancer-related death in western industrialized countries, and the emergence of metastases is a key challenge in the treatment of PCa. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play an important role in the regulation of diverse cellular and molecular processes during the development and progression of cancer. Here, we utilized a unique cohort of castration-resistant prostate cancer metastases (mCRPC) and corresponding localized tumors and RNA sequencing (RNA-seq). First, we showed that patient-to-patient variability accounted for most of the variance in lncRNA expression between the samples, suggesting that genomic alterations in the samples are the main drivers of lncRNA expression in PCa metastasis. Subsequently, we identified 27 lncRNAs with differential expression (DE-lncRNAs) between metastases and corresponding primary tumors, suggesting that they are mCRPC-specific lncRNAs. Analyses of potential regulation by transcription factors (TFs) revealed that approximately half of the DE-lncRNAs have at least one binding site for the androgen receptor in their regulatory regions. In addition, TF enrichment analysis revealed the enrichment of binding sites for PCa-associated TFs, such as FOXA1 and HOXB13, in the regulatory regions of the DE-lncRNAs. In a cohort of prostatectomy-treated prostate tumors, four of the DE-lncRNAs showed association with progression-free time and two of them (lnc-SCFD2-2 and lnc-R3HCC1L-8) were independent prognostic markers. Our study highlights several mCRPC-specific lncRNAs that might be important in the progression of the disease to the metastatic stage and may also serve as potential biomarkers for aggressive PCa.

Psychological recovery and well-being of spouses of patients with prostate cancer 5 years after primary treatment in Finland: a follow-up survey.

OBJECTIVE AND SETTING: To study longitudinally cancer-related experiences of spouses of patients with prostate cancer and the predictors of their psychological recovery and quality of life (QOL) by following the participants of our previous survey at primary cancer treatment in a university hospital. DESIGN: A 5-year longitudinal cohort design. PARTICIPANTS AND PROCEDURE: A follow-up questionnaire was mailed to the female spouses/partners who participated in our previous survey (n=104). We quantitatively explored the spouses' prostate cancer-related experiences since the previous survey and measured their current psychological symptom distress and well-being/QOL. Seventy-seven (74%) of the initial participants responded. OUTCOMES: The main outcome measures were the spouses' psychological recovery (psychological symptoms at the initial survey vs currently) and well-being/QOL (depressive symptoms, domains of QOL) at 5 years. We analysed their predictors with regression analyses. RESULTS: The treatment had been prostatectomy in 70% of the patients. Psychological distress had alleviated in 76% of spouses (p<0.001) and emotional changes decreased (p=0.02), but a deteriorating impact on the partnership (from 4% to 16%) and on sex life ('strong impact' from 23% to 37%) had increased. The outcomes were inversely associated with negative depression-related psychological symptoms and emotional changes either initially or at follow-up. However, some early experiences also predicted the outcomes when other factors were controlled for. Prostate cancer-related information received by the spouses from several sources (leaflets/handouts, TV/radio, internet) predicted better recovery and well-being/QOL, whereas the patients' prostate cancer and treatment-related symptoms (pain, irritability/anger, bowel dysfunction) predicted poorer recovery and well-being/QOL in spouses. CONCLUSIONS: A major negative impact of prostate cancer was experienced by the spouses still 5 years after primary treatment. Early prostate cancer-related experiences predicted long-term psychological recovery and QOL. Responding to the early information needs of spouses and effective symptom management for the patients are likely to enhance the spouses' long-term recovery and well-being.

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation.

Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further.

A randomised, double-blind, dose-finding, phase II multicentre study of ODX in the treatment of patients with castration-resistant prostate cancer and skeletal metastases.

AIMS: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease. METHODS: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period. RESULTS: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety. CONCLUSIONS: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).