Clinical Features Of Prostate Cancer Research Articles

Bioinformatics-based analysis of the effect of general Transcription Factor IIH on prognosis of Prostate cancer

Objective: To investigate the genetic and expression characteristics of transcription factor IIH (TFIIH) in pre-initiationcomplex in prostate cancer (PCa) and its relationship with prostate cancer progression. Methods: Analyzing the expression characteristics and clinical signification of TFIIH subunits about 495 cases of PCa and 52 cases of adjacent cancer in The Cancer Genome Atlas-Prostate adenocarcinoma (TCGA-PRAD) database. PCa microarray chip was used to verify the correlation between the key factor General Transcription Factor IIH Subunit 4 (GTF2H4) in TFIIH and clinical features. Results: The 495 patients with PCa were (61.01±6.82) years old.The mRNA expression of ERCC3、GTF2H4 and MNAT1 were high in PCa tissues with GS≥8(P<0.05). The expression of GTF2H4 and MNAT1 were relevant to the pathological stages(P<0.05). High expression of GTF2H4 has higher biochemical recurrence (BCR) rate in PCa patients(HR=2.47, 95%CI:1.62-3.77, P<0.001), which has better predictive effect of BCR in PCa patients(The 3rd, 5th, and 7th year AUC all>0.7) than other subunits, and it has been verified in four additional databases. Single-factor Cox regression analysis showed that GTF2H4 were risk factors for BCR (HR=2.470, 95%CI:1.620-3.767, P<0.001) and GTF2H5 were protective factors(HR=0.506,95%CI: 0.336-0.762, P=0.001). The results of immunohistochemical staining showed that the protein expression of GTF2H4 was correlated with the clinical features of PCa patients.The differences of the above results were statistically significant. Conclusion: GTF2H4, the key factor of TFIIH, is highly expressed in PCa and indicates a poor prognosis.

Clinical features of prostate cancer by polygenic risk score.

Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual's risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use. Our study aimed to investigate associations between PRS and clinical factors in affected individuals, including age of diagnosis, metastases, histology, International Society of Urological Pathology (ISUP) Grade Group (GG) and family history of prostate cancer, while taking into account germline genetic testing in known prostate cancer related genes. To evaluate the relationship between these clinical factors and PRS, a quantitative retrospective chart review of 250 individuals of European ancestry diagnosed with prostate cancer who received genetic counseling services at The Ohio State University's Genitourinary Cancer Genetics Clinic and a 72-SNV PRS through Ambry Genetics, was performed. We found significant associations between higher PRS and younger age of diagnosis (p = 0.002), lower frequency of metastases (p = 0.006), and having a first-degree relative diagnosed with prostate cancer (p = 0.024). We did not observe significant associations between PRS and ISUP GG, histology or a having a second-degree relative with prostate cancer. These findings provide insights into features associated with higher PRS, but larger multi-ancestral studies using PRS that are informative across populations are needed to understand its clinical utility.

Zinc supplement use and risk of aggressive prostate cancer: a 30-year follow-up study.

Zinc supplementation was hypothesized to have therapeutic potential against prostate cancer, but its influence on prostate cancer incidence especially at high doses is controversial. A total of 47,240 men from the Health Professionals Follow-up Study were followed from 1986 to 2016. Men reported their zinc supplement use at baseline and biennially thereafter. Clinical features of prostate cancer included stage, grade, lethal and aggressive (T4 or N1 or M1 or Gleason 8-10) outcome. Multivariable Cox proportional hazards models were used to evaluate the association between zinc supplement use and incidence of prostate cancer. During a median follow-up of 28.3 years, we documented 6,980 incident prostate cancer cases including 1,053 lethal and 1,143 aggressive. Zinc supplement use was not associated with overall, localized, low- and intermediate-grade prostate cancer. However, compared to never-users, men who used supplement zinc more than 75mg/day were at higher risk for lethal (HR: 1.76, 95% CI: 1.16-2.66, Ptrend = 0.001) and aggressive prostate cancer (HR: 1.80, 95% CI: 1.19-2.73, Ptrend = 0.006). Similarly, men who took supplemental zinc for 15 or more years had a higher risk for lethal (HR: 1.91, 95% CI: 1.28-2.85, Ptrend <0.001) and aggressive prostate cancer (HR: 1.55, 95% CI: 1.03-2.33, Ptrend = 0.004). Zinc supplementation of more than 75mg per day or over 15 years may substantially increase risk of lethal and aggressive prostate cancer. Caution is warranted regarding excessive usage of zinc supplements among adult men.

Racial Distribution of Neighborhood-Level Social Deprivation in a Retrospective Cohort of Prostate Cancer Survivors.

Background: A better understanding of neighborhood-level factors’ contribution is needed in order to increase the precision of cancer control interventions that target geographic determinants of cancer health disparities. This study characterized the distribution of neighborhood deprivation in a racially diverse cohort of prostate cancer survivors. Methods: A retrospective cohort of 253 prostate cancer patients who were treated with radical prostatectomy from 2011 to 2019 was established at the Medical University of South Carolina. Individual-level data on clinical variables (e.g., stage, grade) and race were abstracted. Social Deprivation Index (SDI) and Healthcare Professional Shortage (HPS) status was obtained from the Robert Graham Center and assigned to participants based on their residential census tract. Data were analyzed with descriptive statistics and multivariable logistic regression. Results: The cohort of 253 men consisted of 168 white, 81 African American, 1 Hispanic and 3 multiracial men. Approximately 49% of 249 men lived in areas with high SDI (e.g., SDI score of 48 to 98). The mean for SDI was 44.5 (+27.4), and the range was 97 (1–98) for all study participants. African American men had a significantly greater likelihood of living in a socially deprived neighborhood compared to white men (OR = 3.7, 95% C.I. 2.1–6.7, p < 0.01), while men who lived in areas with higher HPS shortage status were significantly more likely to live in a neighborhood that had high SDI compared to men who lived in areas with lower HPS shortages (OR = 4.7, 95% C.I. = 2.1–10.7, p < 0.01). African Americans had a higher likelihood of developing biochemical reoccurrence (OR = 3.7, 95% C.I. = 1.7–8.0) compared with white men. There were no significant association between SDI and clinical characteristics of prostate cancer. Conclusions: This study demonstrates that SDI varies considerably by race among men with prostate cancer treated with radical prostatectomy. Using SDI to understand the social environment could be -particularly useful as part of precision medicine and precision public health approaches and could be used by cancer centers, public health providers, and other health care specialists to inform operational decisions about how to target health promotion and disease prevention efforts in catchment areas and patient populations.

Regular, Long-Duration Multivitamin Use and Risk of Overall and Aggressive Prostate Cancer in the Health Professionals Follow-Up Study.

Multivitamin supplement is commonly used among older adults in the United States. Evidence on multivitamin use and prostate cancer risk is limited, and some suggested potential risk for clinically important subtypes of cancer. A total of 48,137 men from the Health Professionals Follow-up Study were followed from 1986 to 2017. Multivitamin use and frequency were self-reported at baseline and updated biennially. Clinical features of prostate cancer included advanced, lethal and high-grade outcomes. Cox proportional hazards models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of multivitamin use and incidence of prostate cancer. The median followup for men without prostate cancer diagnosis or death was 30.7 years. We documented 7,108 incident prostate cancer cases including 564 advanced and 1,065 lethal. Overall, we observed a null association between multivitamin use and risk of prostate cancer. Compared to never-users, men who used multivitamin 10 or more tablets per week had similar risk of advanced (HR: 1.14, 95% CI: 0.77-1.70, Ptrend=0.46) or lethal (HR: 1.07, 95% CI: 0.80-1.44, Ptrend=0.59) prostate cancer, and multivitamin use of 15 years or more was not associated with risk of advanced (HR: 1.10, 95% CI: 0.80-1.50, Ptrend=0.46) or lethal (HR: 1.04, 95% CI: 0.83-1.31, Ptrend=0.13) prostate cancer. Regular or long-duration multivitamin use among older, generally well-nourished men was not associated with either increased or lower risk of overall or aggressive prostate cancer.

Overexpression of CDCA8 Predicts Poor Prognosis and Promotes Tumor Cell Growth in Prostate Cancer.

Human cell division cycle-related protein 8 (CDCA8) is an essential component of the vertebrate chromosomal passenger complex (CPC). CDCA8 was confirmed to play a role in promoting malignant tumor progression. However, the exact function of CDCA8 in the development and progression of prostate cancer (PCa) remains unclear. In this study, the database GSE69223 was downloaded by the gene expression omnibus (GEO) database, as well as CDCA8 expression differences in multiple tumor tissues and normal tissues were detected by The Cancer Genome Atlas (TCGA), TIMER, Oncomine, and Ualcan databases. Kaplan-Meier and Cox regression methods were used to analyze the correlation between CDCA8 expression and prognosis in PCa. We confirmed the expression of CDCA8 in PCa tissues by HPA. We also analyzed the association of CDCA8 expression with PCa clinical characteristics in the TCGA database. To further understand the role of CDCA8 in PCa, we assessed the effects of CDCA8 on PCa cell growth, proliferation, and migration in vitro studies. As a result, CDCA8 was significantly overexpressed in PCa cells compared with normal prostate cells. High CDCA8 expression predicts poor prognosis in PCa patients, and CDCA8 expression was higher in high-grade PCa. In addition, silencing of CDCA8 significantly inhibited PCa cell proliferation and migration. In summary, CDCA8 promoted the proliferation and migration of PCa cells.

Clinical and pathological features associated with circulating tumor DNA content in real-world patients with metastatic prostate cancer.

BackgroundLiquid biopsy is a powerful tool that can enable treatment decisions for metastatic prostate cancer patients with difficult‐to‐biopsy tumors. However, the detection of genomic alterations via liquid biopsy is limited by the fraction (tumor fraction [TF]) of circulating tumor DNA (ctDNA) within the total cell‐free DNA content. While prior work has preliminarily correlated TF with clinical features of prostate cancer, we sought to validate and provide additional resolution, such that a clinical practitioner might anticipate the probability of successful liquid biopsy profiling leveraging commonly assessed clinical and laboratory features.MethodsA total of 813 liquid biopsy specimens were assessable, with 545 associated with a PSA prostate specific antigen measurement, collected in standard‐of‐care settings across approximately 280 US academic or community‐based cancer clinics from September 2018 to July 2021. Deidentified data were captured into a real‐world clinico‐genomic database (CGDB). Comprehensive genomic profiling (CGP) was performed on extracted cell‐free DNA from liquid biopsy samples.ResultsIn multivariable models, higher PSA level, lower hemoglobin, lower albumin, higher alkaline phosphatase (all p < 0.001), and collection of liquid biopsy blood draw within 60 days of new treatment initiation (p = 0.002) were the most strongly associated features with higher TF. At PSA levels of <5 ng/ml, 43% of patients had a TF of <1% indicating an increased likelihood of unevaluable results. Conversely, at PSA levels of >5 ng/ml, 78% of patients had a TF of at least 1% and 46% had a TF of ≥10%, suggesting improved sensitivity for detection of targetable alterations.ConclusionsUniversal genomic profiling of prostate cancers will require complementary use of liquid biopsy and tumor tissue profiling for suitable patients. The likelihood of adequate ctDNA shedding into plasma is one consideration when deciding whether to pursue CGP via liquid biopsy versus tumor profiling. Our real‐world data suggest that PSA < 5 ng/ml is associated with lower ctDNA yield on liquid biopsy, potentially increasing the incidence of negative results or a need for confirmation with tissue testing.

Paradigm Shift in Prostate Cancer Diagnosis: Pre-Biopsy Prostate Magnetic Resonance Imaging and Targeted Biopsy.

With regard to the indolent clinical characteristics of prostate cancer (PCa), the more selective detection of clinically significant PCa (CSC) has been emphasized in its diagnosis and management. Magnetic resonance imaging (MRI) has advanced technically, and recent international cooperation has provided a standardized imaging and reporting system for prostate MRI. Accordingly, prostate MRI has recently been investigated and utilized as a triage tool before biopsy to guide tissue sampling to increase the detection rate of CSC beyond the staging tool for patients in whom PCa was already confirmed on conventional systematic biopsy. Radiologists must understand the current paradigm shift for better PCa diagnosis and management. This article reviewed the recent literature, demonstrating the diagnostic value of pre-biopsy prostate MRI with targeted biopsy and discussed unsolved issues regarding the paradigm shift in the diagnosis of PCa.

LncRNA PCAT14 Is a Diagnostic Marker for Prostate Cancer and Is Associated with Immune Cell Infiltration.

Objective To investigate the relationship between the long noncoding RNA (lncRNA) Prostate cancer-associated transcription factors 14 (PCAT14) and the clinical characteristics of prostate cancer and immune cell infiltration. Methods The relationship between PCAT14 expression and the clinicopathological characteristics of prostate cancer was analyzed based on The Cancer Genome Atlas (TCGA) database. Receiver operating characteristic (ROC) curves were used to evaluate the value of PCAT14 as a diagnostic marker for prostate cancer. The relationship between PCAT14 and immune cell infiltration was analyzed to explore the effect of PCAT14 on the immune-related functions of prostate cancer. Results The ROC curve showed that PCAT14 had a significant diagnostic ability (area under curve = 0.818) for prostate cancer. A reduced expression of PCAT14 in prostate cancer was related to T stage, N stage, primary therapy outcome, residual tumor, Gleason score, and age. The expression of PCAT14 was independently associated with the progression-free interval in prostate cancer patients. The infiltration of immune cells in prostate cancer showed a significant negative correlation between the expression of PCAT14 and plasmacytoid dendritic cells, activated dendritic cells, regulatory T cells, and neutrophils. Conclusions PCAT14 is highly expressed in prostate cancer and is expected to be a diagnostic marker. PCAT14 might promote the development of prostate cancer through chemokines, antimicrobials, and cytokines that affect the infiltration of immune cells.

Identification of a Hypoxia-Related Gene Signature for Predicting Systemic Metastasis in Prostate Cancer.

Background: Systemic metastasis is the main cause of death in patients with prostate cancer. It is necessary to establish a more accurate model to distinguish and predict patients with a high risk of metastasis to optimize individualized treatment.Methods: In this study, it was determined that hypoxia could affect the metastasis-free survival of patients with prostate cancer, and a hypoxia-related gene signature composed of seven genes for predicting metastasis was established and verified in different cohorts. The study further evaluated the effects of ALDOB expression on the proliferation and invasion of the LNCaP and DU145 cell lines under hypoxia and finally constructed a nomogram containing specific clinical characteristics of prostate cancer combined with the hypoxia gene signature to quantify the metastasis risk of individual patients.Results: The hypoxia-related gene signature was identified as an independent risk factor for metastasis-free survival in patients with prostate cancer. The expression of ALDOB increased under hypoxia and promoted the proliferation and invasion of LNCaP and DU145 cells. In addition, patients with a high risk score showed therapeutic resistance and immunosuppression. Compared with other parameters, the nomogram had the strongest predictive power and net clinical benefit.Conclusion: The study established a hypoxia-related gene signature and a nomogram to distinguish and predict patients with a high risk of prostate cancer metastasis, which may help to optimize individualized treatment and explore possible therapeutic targets.

The emerging landscape of tumor marker panels for the identification of aggressive prostate cancer: the perspective through bibliometric analysis of an Italian translational working group in uro-oncology.

Molecular heterogeneity and availability of different therapeutic strategies are relevant clinical features of prostate cancer. On this basis, there is an urgent need to identify prognostic and predictive biomarkers for an individualized therapeutic approach. In this context, researchers focused their attention on biomarkers able to discriminate potential life-threatening from organ-confined disease. Such biomarker could provide aid in clinical decision making, helping to choose the treatment which ensures the best results in terms of patient survival and quality of life. To address this need, many new laboratory tests have been proposed, with a clear tendency to use panels of combined biomarkers. In this review we evaluate current data on the application in clinical practice of the most promising laboratory tests: Phi, 4K score and Stockholm 3 as circulating biomarkers, Mi-prostate score, Exo DX Prostate and Select MD-X as urinary biomarkers, Confirm MDx, Oncotype Dx, Prolaris and Decipher as tissue biomarkers. In particular, the ability of these tests in the identification of clinically significant PCa and their potential use for precision medicine have been explored in this review.

MP67-18 CLINICAL CHARACTERISTICS OF PROSTATE CANCER PATIENTS IN WEST AND SOUTH AFRICA IN THE MEN OF AFRICAN DESCENT AND CARCINOMA OF THE PROSTATE (MADCAP) CONSORTIUM STUDY

MP67-18 CLINICAL CHARACTERISTICS OF PROSTATE CANCER PATIENTS IN WEST AND SOUTH AFRICA IN THE MEN OF AFRICAN DESCENT AND CARCINOMA OF THE PROSTATE (MADCAP) CONSORTIUM STUDY

Urban-Rural Differences in Clinical Characteristics of Prostate Cancer at Initial Diagnosis: A Single-Center Observational Study in Anhui Province, China.

BackgroundPeople residing in rural areas have higher prostate cancer (PCa) mortality to incidence ratio (M/I) and worse prognosis than those in urban areas of China. Clinical characteristics at initial diagnosis are significantly associated with biochemical recurrence, overall survival, and PCa disease-free survival.ObjectiveThis study aimed at investigating the clinical characteristics at initial diagnosis of urban and rural PCa patients and to establish a logistic regression model for identifying independent predictors for high-grade PCa.Materials and MethodsClinical characteristics for PCa patients were collected from the largest prostate biopsy center in Anhui province, China, from December 2015 to March 2019. First, urban–rural disparities in clinical characteristics were evaluated at initial diagnosis. Second, based on pathological findings, we classified all participants into the benign+ low/intermediate-grade PCa or high-grade PCa groups. Univariate and multivariate logistic regression analyses were performed to identify independent factors for predicting high-grade PCa, while a nomogram for predicting high-grade PCa was generated based on all independent factors. The model was evaluated using area under receiver-operating characteristic (ROC) curve as well as calibration curve analyses and compared to a model without the place of residence factor of individuals.ResultsStatistically significant differences were observed between urban and rural PCa patients with regard to tPSA, PSA density (PSAD), and Gleason score (GS) (p < 0.05). Logistic regression analysis revealed that tPSA [OR = 1.060, 95% confidence interval (CI): 1.024, 1.098], PSAD (OR = 14.678, 95%CI: 4.137, 52.071), place of residence of individuals (OR = 5.900, 95%CI: 1.068, 32.601), and prostate imaging reporting and data system version 2 (PI-RADS v2) (OR = 4.360, 95%CI: 1.953, 9.733) were independent predictive factors for high-grade PCa. The area under the curve (AUC) of the nomogram was greater than that of the model without the place of residence of individuals. The calibration curve of the nomogram indicated that the prediction curve was basically fitted to the standard curve, suggesting that the prediction model had a better calibration ability.ConclusionsCompared to urban PCa patients, rural PCa patients presented elevated tPSA, PSAD levels, and higher pathological grades. The place of residence of the individuals was an independent predictor for high-grade PCa in Anhui Province, China. Therefore, appropriate strategies, such as narrowing urban-rural gaps in access to health care and increasing awareness on the importance of early detection should be implemented to reduce PCa mortality rates.

Using Competing Risk of Mortality to Inform the Transition from Prostate Cancer Active Surveillance to Watchful Waiting

BackgroundFor men on active surveillance (AS) for prostate cancer (PCa), disease progression and age-related changes in health may influence decisions about pursuing curative treatment. ObjectiveTo evaluate the predicted PCa and non-PCa mortality at the time of reclassification among men on AS, to identify clinical criteria for considering a transition from AS to watchful waiting (WW). Design, setting, and participantsPatients enrolled in a large AS program who experienced biopsy grade reclassification (Gleason grade increase) were retrospectively examined. All patients who had complete documentation of medical comorbidities at reclassification were included. Outcome measurements and statistical analysisA validated model was used to assess 10- and 15-yr untreated PCa and non-PCa mortalities based on patient comorbidities and PCa clinical characteristics. We compared the ratio of predicted PCa mortality with predicted non-PCa mortality (“predicted mortality ratio”) and divided patients into four risk tiers based on this ratio: (1) tier 1 (ratio: >0.33), (2) tier 2 (ratio 0.33–0.20), (3) tier 3 (ratio 0.20–0.10), and (4) tier 4 (ratio <0.10). Results and limitationsOf the 344 men who were reclassified, 98 (28%) were in risk tier 1, 85 (25%) in tier 2, 93 (27%) in tier 3, and 68 (20%) in tier 4 for 10-yr mortality. Fifteen-year risk tiers were distributed similarly. The 23 (6.7%) men who met the “transition triad” (age >75 yr, Charlson Comorbidity Index >3, and grade group ≤2) had a 14-fold higher non-PCa mortality risk and a lower predicted mortality ratio than those who did not (0.07 vs 0.23, p < 0.001). The primary limitations of our study included its retrospective nature and the use of predicted mortalities. ConclusionsAt reclassification, nearly half of patients had a more than five-fold and one in five patients had a more than ten-fold higher risk of non-PCa death than patients having a risk of untreated PCa death. Despite a more significant cancer diagnosis, a transition to WW for older men with multiple comorbidities and grade group <3 PCa should be considered. Patient summaryMen with favorable-risk prostate cancer and life expectancy of >10 yr are often enrolled in active surveillance, which entails delay of curative treatment until there is evidence of more aggressive disease. We examined a group of men on active surveillance who developed more aggressive disease, and found, nevertheless, that the majority of these men continued to have a dramatically higher risk of death from non–prostate cancer causes than from prostate cancer based on a risk prediction tool. For men older than 75 yr, who have multiple medical conditions and who do not have higher-grade cancer, it may be reasonable to reconsider the need for curative treatment given the low risk of death from prostate cancer compared with the risk of death from other causes.

Prostate cancer clinical characteristics and outcomes in Central Sudan

Prostate cancer clinical characteristics and outcomes in Central Sudan

Antidiabetic Drugs and Prostate Cancer Prognosis in a Finnish Population-Based Cohort.

Hyperinsulemia and glycemic control may play a role as prostate cancer prognostic factors, whereas use of certain antidiabetic drugs, that is metformin, could improve the prognosis. We examined the link between antidiabetic medication use and prostate cancer survival taking into account simultaneous use of multiple drugs. The study cohort composed of 6,537 men in The Finnish Randomized Study of Screening for Prostate Cancer with prostate cancer diagnosed 1996 to 2009. Use of medication was attained from the nationwide prescription database of the Social Insurance Institution of Finland. Median follow-up was 9.2 years postdiagnosis. A total of 1,603 (24,5%) men had used antidiabetic medication. A total of 771 men died of prostate cancer during the follow-up. We used multivariable-adjusted Cox regression to evaluate the risk of prostate cancer death and onset of androgen deprivation therapy (ADT) with adjustment for prostate cancer clinical characteristics, comorbidities and use of other drugs. Separate analyses were further adjusted for blood glucose. Risk of prostate cancer death was higher among antidiabetic drug users overall (HR = 1.42; 95% CI, 1.18-1.70) compared with nonusers, separately among insulin and metformin users. Adjustment for blood glucose level abolished the risk increase. Risk of ADT initiation was increased among the medication users (HR = 1.26; 95% CI, 1.05-1.49). Men with prostate cancer using antidiabetic medication are generally at increased risk of dying from prostate cancer compared with nonusers. The risk association is driven by underlying diabetes, as adjustment for blood glucose level ameliorates the risk increase. Type 2 diabetes should be considered as a risk factor when considering prostate cancer prognosis.

A single-blinded, multicenter, randomized controlled trial to evaluate NeuroSAFE robotic-assisted radical prostatectomy (RARP) versus standard robotic-assisted radical prostatectomy (RARP) in men with localized prostate cancer: NeuroSAFE PROOF—Trial in progress.

TPS262 Background: Robot-assisted radical prostatectomy (RARP) offers cure for localised prostate cancer but is associated with considerable toxicity. Potency and urinary continence are improved when the neurovascular bundles (NVBs) are preserved during a nerve-sparing (NS) RARP. The NeuroSAFE (intra-operative frozen section examination of the neurovascular structure adjacent prostate margin) seeks to promote optimal NS to maximise the opportunity for functional recovery without jeopardising oncological safety. The NeuroSAFE technique in RP has never been evaluated against a standard of care in an randomised controlled trial. Methods: This is a pragmatic, multicentre, single-blinded randomised controlled trial (RCT) in which men are allocated in a 1:1 ratio to NeuroSAFE RARP or standard RARP. Men in the NeuroSAFE RARP arm will undergo RARP with NS guided by the NeuroSAFE technique. Men in the standard RARP arm will undergo RARP with NS guided by standard current practice (prostate cancer clinical characteristics, multi-parametric magnetic resonance imaging (mpMRI) recommendations and digital rectal examination (DRE)). Eligible men will have operable localised prostate cancer, will be opting for RARP as primary treatment and will have good baseline erectile function (EF) (as defined by an Internatinoal Index of Erectile Function (IIEF)-5 score &gt;21). The primary outcome is the proportion of men who achieve EF recovery at 12-months according to the IIEF. Oncological safety will be ensured by the independent DMC who will routinely review proportions of men with treatment failure (adjuvant therapy or biochemical recurrence (BCR)) in each arm. A sample size of 404 is estimated required. NeuroSAFE PROOF will continue to follow participant recovery for 5 years following treatment. Key secondary outcomes include patient-reported urinary continence recovery, sexual satisfaction, quality of life, and economic analyses. NeuroSAFE PROOF will be the first RCT of frozen section in radical prostatectomy (RP) in the world. Ethics and dissemination: Ethical approval was obtained from the National Research Ethics Committee North London (17/LO/1978). Results of this study will be disseminated through national and international papers, and to study participants. Clinical trial information: NCT03317990.

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.

Abstract 1621: Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models

Abstract Background: Prostate cancer (PCa) is one of the most common male-specific malignancies in developed country. The progression of PCa involves complex mechanisms. Contactin 1 (CNTN1) is a neural cell adhesion protein reported to promote lung cancer metastasis and associate with poor prognosis in several cancers. In view of our recent publication reporting CNTN1 as a novel factor promoting PCa metastasis, we have constructed prostate-specific CNTN1 overexpression (CNTN1TG/TG) and PTEN−/− mice to explore CNTN1's role in PC tumorigenesis and progression. Materials and Methods: CNTN1 transgenic C57BL/6 mice was constructed by insertion of a transgene unit into the intron of Rosa26 locus. The CNTN1 transgene (TG) cassette consists of a CAG promoter, a STOP unit flanked by two LoxP sites, followed by CNTN1, which will only be expressed upon removal of the STOP unit by Cre recombinase. The homozygous CNTN1STOP-TG/STOP-TG [without transgene (TG) expression] mice were crossed with prostate-specific Cre mice (PB-Cre4). Prostate expression of CNTN1 was clearly demonstrated only in CNTN1TG/− and CNTN1TG/TG mice but not in CNTN1STOP-TG/STOP-TG animals. In a similar system, PTENflox/flox were crossed with PB-Cre4 to generate prostate-specific PTEN−/- mice. At 21-weeks old when invasive tumors were formed, PTEN−/− mice were surgically castrated and maintained for another 12 weeks to construct the castration-resistant prostate cancer (CRPC) model. Results: At 12-weeks old both CNTN1TG/- and CNTN1TG/TG mice developed hyperplasia in the prostate, evident by an increase in cellularity, nuclear crowding, and mild dysplasia. This supports CNTN1's role in PCa tumorigenesis as prostate epithelial hyperplasia in transgenic mice is a well-regarded precursor of PCa. In line of this observation, immunohistochemistry showed upregulation of proliferation marker Ki67 and AKT phosphorylation at serine 473 (indicative of AKT activation) in the prostate of CNTN1TG/TG compared to control CNTN1STOP-TG/STOP-TG (without Cre) mice. In androgen-sensitive LNCaP cells stably expressing CNTN1, an upregulation of prostate-specific antigen (PSA), a well-regarded AR target, was observed both with and without androgen deprivation. This suggest that CNTN1 likely initiates PCa and contributes to its progression through networks involving AR signaling. The oncogenic role of CNTN1 in association with PTEN deficiency was explored using prostate-specific PTEN−/− mice which recapitulate most clinical features of PCa, including the development of castration-resistant PCa (CRPC). The expression of CNTN1 was undetectable in age-matched C57BL/6 mice but was evident in tumors produced in intact PTEN−/− mice and was further upregulated in CRPC tumors generated in castrated PTEN−/- mice. These observations are consistent with CNTN1-induced AKT activation observed in PCa cells and in CNTN1TG/TG animals. Conclusions: Collectively, these results suggest a role of CNTN1 in promoting PCa tumorigenesis and progression. Evidently, our CNTN1 transgenic mice developed a precancerous lesion of PCa. The oncogenic potential of CNTN1 is further supported by its stimulation of LNCaP cell proliferation. This research provides functional evidence for CNTN1 as an important PCa promoting factor and established a novel transgenic mouse model for PCa; this model may greatly facilitate future PCa research and drug development. Citation Format: Yan Jennifer Gu, Wenjuan Mei, Geoffrey A. Wood, Damu Tang. Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1621.

Antihypertensive drug use and prostate cancer-specific mortality in Finnish men

The aim of this study was to investigate pre- and post-diagnostic use of antihypertensive drugs on prostate cancer (PCa)-specific survival and the initiation of androgen deprivation therapy (ADT). The cohort investigated 8,253 PCa patients with 837 PCa-specific deaths during the median follow-up of 7.6 years after diagnosis. Information on drug use, cancer incidence, clinical features of PCa, and causes of death was collected from Finnish registries. Hazard ratios with 95% confidence intervals were calculated using Cox regression with antihypertensive drug use as a time-dependent variable. Separate analyses were performed on PCa survival related to pre- and post-diagnostic use of drugs and on the initiation of ADT. Antihypertensive drug use overall was associated with an increased risk of PCa-specific death (Pre-PCa: 1.21 (1.04-1.4), Post-PCa: 1.2 (1.02-1.41)). With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 (0.67-0.99)) and diuretics with an increased risk (Post-PCa: 1.25 (1.05-1.49)). The risk of ADT initiation was slightly higher among antihypertensive drug users as compared to non-users. In conclusion, this study supports anti-cancer effect of ATr blockers on PCa prognosis and this should be investigated further in controlled clinical trials.