Shorter Biochemical Recurrence-free Survival Research Articles

Prognostic value of pretreatment inflammatory markers in localised prostate cancer before radical prostatectomy

PurposeThere is growing evidence of an association between inflammatory processes and cancer development and progression. In different solid tumor entities, a pronounced inflammatory response is associated with worse oncological outcome. In this study, we aim to evaluate the prognostic role of clinically established pretreatment inflammatory markers in patients with localised prostate cancer (PCa) before radical prostatectomy (RP).MethodsA total of 641 men met our inclusion criteria and were followed prospectively for a median of 2.85 years. Univariable logistic and Cox regression analysis were performed to analyse associations between preoperative inflammatory markers and tumor characteristics, and biochemical recurrence free survival (BRFS).ResultsMedian age at RP was 64 years. Gleason Score (GS) 7a (263, 41%) was the most prevalent histology, whereas high-risk PCa (≥ GS 8) was present in 156 (24%) patients. Lympho-nodal metastasis and positive surgical margin (PSM) were detected in 69 (11%) and 180 (28%) patients, respectively. No statistically relevant association could be shown between pretreatment inflammatory markers with worse pathological features like higher tumor stage or grade, nodal positive disease or PSM (for all p > 0.05). Additionally, pretreatment inflammatory markers were not associated with a shorter BRFS (p > 0.05). Known risk factors (tumor grade, tumor stage, nodal positivity and positive surgical margins) were all associated with a shorter BRFS (for all p < 0.0001).ConclusionIn this large prospective cohort, preoperative inflammatory markers were not associated with worse outcome.

Safety and efficiency of repeat salvage lymph node dissection for recurrence of prostate cancer using PSMA-radioguided surgery (RGS) after prior salvage lymph node dissection with or without initial RGS support.

Metastasis-directed therapy is a feasible option for low PSA, recurrent locoregional metastatic prostate cancer. After initial salvage surgery, patients with good response might consider a repeat salvage surgery in case of recurrent, isolated, and PSMA-positive metastases. This analysis aimed to evaluate the oncological outcome and safety of repeat PSMA-targeted radioguided surgery (RGS) after either prior RGS or "standard" salvage lymph node dissection (SLND). We identified 37 patients undergoing repeat RGS after prior SLND (n = 21) (SLND-RGS) or prior RGS (n = 16) (RGS-RGS) between 2014 and 2021 after initial radical prostatectomy with or without pelvic radiation therapy at two German tertiary referral centers. Kaplan-Meier analyses and uni-/multivariable Cox regression models were used to investigate factors associated with biochemical recurrence-free survival (BRFS) and treatment-free survival (TFS) after repeat salvage surgery. Complete Biochemical Response (cBR, PSA < 0.2ng/ml) was observed in 20/32 patients (5 NA). Median overall BRFS [95% confidence interval (CI)] after repeat salvage surgery was 10.8months (mo) (5.3-22). On multivariable regression, only age (HR 1.09, 95% CI 1.01-1.17) and preoperative PSA (HR 1.23, 95% CI 1.01-1.50) were associated with shorter BRFS, although PSA (HR 1.16, 95% CI 0.99-1.36) did not achieve significant predictor status in univariable analysis before (p value = 0.07). Overall, one year after second salvage surgery, 89% of the patients (number at risk: 19) did not receive additional treatment and median TFS was not reached. Clavien-Dindo grade > 3a complications were observed in 8% (3/37 patients). Limitations are the retrospective evaluation, heterogeneous SLND procedures, lack of long-term follow-up data, and small cohort size. In this study, repeat RGS was safe and provided clinically meaningful biochemical recurrence- and treatment-free intervals for selected cases. Patients having low preoperative PSA seemed to benefit most of repeat RGS, irrespective of prior SLND or RGS or the time from initial RP/first salvage surgery.

Identification and validation of cancer-associated fibroblast-related subtypes and the prognosis model of biochemical recurrence in prostate cancer based on single-cell and bulk RNA sequencing.

Cancer-associated fibroblasts (CAFs) are an essential component of the tumor immune microenvironment that are involved in extracellular matrix (ECM) remodeling. We aim to investigate the characteristics of CAFs in prostate cancer and develop a biochemical recurrence (BCR)-related CAF signature for predicting the prognosis of PCa patients. The bulk RNA-seq and relevant clinical information were obtained from the TCGA and GEO databases, respectively. The infiltration scores of CAFs in prostate cancer patients were calculated using the MCP counter and EPIC algorithms. The single-cell RNA sequencing (scRNA-seq) was downloaded from the GEO database. Subsequently, univariate Cox regression analysis was employed to identify prognostic genes associated with CAFs. We identified two subtypes (C1 and C2) of prostate cancer that were associated with CAFs via non-negative matrix factorization (NMF) clustering. In addition, the BCR-related CAF signatures were constructed using Lasso regression analysis. Finally, a nomogram model was established based on the risk score and clinical characteristics of the patients. Initially, we found that patients with high CAF infiltration scores had shorter biochemical recurrence-free survival (BCRFS) times. Subsequently, CAFs in four pairs of tumors and paracancerous tissues were identified. We discovered 253 significantly differentially expressed genes, of which 13 had prognostic significance. Using NMF clustering, we divided PCa patients into C1 and C2 subgroups, with the C1 subgroup having a worse prognosis and substantially enriched cell cycle, homologous recombination, and mismatch repair pathways. Furthermore, a BCR-related CAFs signature was established. Multivariate COX regression analysis confirmed that the BCR-related CAFs signature was an independent prognostic factor for BCR in PCa. In addition, the nomogram was based on the clinical characteristics and risk scores of the patient and demonstrated high accuracy and reliability for predicting BCR. Lastly, our findings indicate that the risk score may be a useful tool for predicting PCa patients' sensitivity to immunotherapy and drug treatment. NMF clustering based on CAF-related genes revealed distinct TME immune characteristics between groups. The BCR-related CAF signature accurately predicted prognosis and immunotherapy response in prostate cancer patients, offering a promising new approach to cancer treatment.

The tumor volume after radical prostatectomy and its clinical impact on the prognosis of patients with localized prostate cancer

We evaluated the contribution of tumor volume (TV) to localized prostate cancer (PCa) patients’ prognosis. We retrospectively analyzed the data of 2394 patients who underwent radical prostatectomy (RP) for localized PCa. The effect of TV and tumor prostate ratio (TV/PV) on PCa patients' prognosis was analyzed through Kaplan–Meier and Cox-proportional analysis. The mean prostate volume for all patients was 36.5 ± 15.4 cc, and the mean TV was 5.9 ± 8.3 cc. A significant positive relationship was observed between the classification by risk group in D’ Amico risk classification and the National Comprehensive Cancer Network risk group (P < 0.001). The high TV showed significantly worse pathologic outcomes than the low TV in terms of high rates of extra-capsular extension, seminal vesicle invasion, and positive surgical margin (P < 0.05). The patients with high TV and TV/PV had significantly shorter biochemical recurrence-free survivals than those with low TV and TV/PV (P < 0.001). Finally, based on multivariate Cox-proportional analyses, TV and TV/PV was an independent predictor to predict shorter biochemical recurrence-free survival as both a TV (HR: 1.04, 95% CI 1.04–1.05, P < 0.001) and TV/PV (HR: 1.42, 95% CI 1.13–1.78, P = 0.003). TV was revealed to be an independent prognostic factor in the postoperative biochemical recurrence. Patients with a high number of positive core and longer tumor length were significantly related to higher TV.

Cribriform architecture outperforms Gleason pattern 4 percentage and tertiary Gleason pattern 5 in predicting the outcome of Grade Group 2 prostate cancer patients.

AimsGleason pattern 4 (GP4) percentage, invasive cribriform and/or intraductal carcinoma (IC/IDC) and the presence of tertiary Gleason pattern 5 (TP5) in radical prostatectomy (RP) specimens all aid in the risk stratification of Grade Group (GG) 2 prostate cancer patients. However, it is unclear to what extent these pathological features are mutually related and what are their individual values if they are investigated simultaneously. The aims of this study were: (i) to determine the mutual relationships of the GP4 percentage, IC/IDC and TP5 in GG2 RP specimens; and (ii) to assess their prognostic value for biochemical recurrence‐free survival (BCRFS).Methods and resultsOf 1064 RP specimens, 472 (44.4%) showed GG2 prostate cancer. Patients with ≥25% GP4 more frequently had IC/IDC (67.0% versus 43.9%; P < 0.001) and TP5 (20.6% versus 5.8%; P < 0.001) than those with <25% GP4. In unadjusted analysis, an increased GP4 percentage [hazard ratio (HR) 1.3; 95% confidence interval (CI) 1.0–1.6; P = 0.04] and IC/IDC (log rank P < 0.001) were associated with shorter BCRFS, whereas TP5 (P = 0.12) and a dichotomised (<25%, ≥25%) GP4 percentage (P = 0.10) were not. In multivariable analysis, IC/IDC was an independent prognostic factor (HR 1.9; 95% CI 1.2–2.9; P = 0.005) for BCRFS, whereas a continuous or dichotomised GP4 percentage and TP5 were not independent prognostic factors.ConclusionIn conclusion, a higher GP4 percentage in RP specimens was associated with more frequent IC/IDC and TP5. IC/IDC was an independent predictor for BCRFS, whereas the GP4 percentage and TP5 were not. These findings underscore the importance of routinely including the presence of IC/IDC in RP pathology reports.

Abstract 2498: Identification and characterization of the PIK3R1-mutant subtype in PI3K-addicted prostate cancer

Abstract Metastatic castration-resistant metastatic prostate cancer (mCRPC) is incurable. Recent comprehensive genomic characterization of localized and metastatic prostate cancer has identified a long tail of oncogenic driver mutations and demonstrated recurrent alteration of genes involved in phosphoinositide 3-kinase (PI3K) signaling in ~40% mCRPC cases. Alterations in the PI3K-signaling pathway in cancer have led to a surge in the development of PI3K/Akt inhibitors and many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. Therefore, in precision oncology, the identification of advanced prostate cancers with high PI3K activity is critical for treatment selection and eligibility into clinical trials of PI3K/Akt inhibitors. We analyzed panel sequencing data from 2965 prostate cancer patients (1770 localized and 1195 mCRPC cases) from the Memorial Sloan Kettering Cancer Center clinical sequencing cohort (MSK-IMPACT). The MSK-IMPACT panel sequencing includes all protein-coding mutations, copy number alterations, selected promoter mutations and structural rearrangements of 341, 410 and 468 cancer-associated genes (all panels included). Among the PI3K-AKT-mTOR pathway components (19 genes in MSK-IMPACT panel) we identified a significant enrichment of PIK3R1 (regulatory subunit that codes for p85α protein and modulates the catalytic activity of PI3K-pathway) alterations in mCRPC patients compared to localized prostate cancer (5% mCRPC vs 2% localized cases; p&amp;lt;0.0001). Copy number analysis identified more frequent deletion of the PIK3R1 chromosomal region in mCRPC compared to localized disease (Chromosome 5q13.1; 25% vs 15% p&amp;lt; 0.0001). We also observed that loss of PIK3R1 mRNA is associated with shorter biochemical recurrence-free survival of patients in primary prostate cancer cohorts (low vs high quartile; TCGA; HR: 2.8 and Taylor et al, HR: 2.6) indicating that PIK3R1 inactivation may act as a driver of aggressive prostate cancer. Experimentally we showed that RNAi mediated knockdown of PIK3R1 was sufficient to induce Akt-activation and increase cell growth in human prostate cancer cell line (LAPC4 and 22RV1) models. Most importantly we showed that Akt-inhibitors ipatasertib and MS2206 strongly reduced the viability of prostate cancer cells (LAPC4 and 22RV1) with PIK3R1 knockdown or PIK3R1 mutated mCRPC derived organoid (MSKPCa3) compared to PIK3R1 wild type cells irrespective of their PTEN status. In summary, our study identified an association between PIK3R1 alterations and lethal prostate cancer and demonstrated that men with mCRPC who harbor defective PIK3R1 may benefit from Akt inhibitors. Further in-depth studies are warranted to uncover the biological and phenotypic characterization of PIK3R1-altered prostate cancer. Citation Format: Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Sai Harisha Rajanala, Bastien Nguyen, Romina Ghale, Ying Z. Mazzu, Lina E. Jehane, Gwo-Shu Mary Lee, Lorelei A. Mucci, Nikolaus Schultz, Philip W. Kantoff. Identification and characterization of the PIK3R1-mutant subtype in PI3K-addicted prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2498.

Impact of poor glycemic control upon clinical outcomes after radical prostatectomy in localized prostate cancer

To evaluate the clinical impact of preoperative glycemic status upon oncological and functional outcomes after radical prostatectomy in patients with localized prostate cancer, we analyzed the data of 2664 subjects who underwent radical prostatectomy with preoperative measurement of hemoglobin A1c within 6 months before surgery. The possible association between high hemoglobin A1c (≥ 6.5 ng/dL) and oncological/functional outcomes was evaluated. Among all subjects, 449 (16.9%) were categorized as the high hemoglobin A1c group and 2215 (83.1%) as the low hemoglobin A1c group. High hemoglobin A1c was associated with worse pathological outcomes including extra-capsular extension (HR 1.277, 95% CI 1.000–1.630, p = 0.050) and positive surgical margin (HR 1.302, 95% CI 1.012–1.674, p = 0.040) in multi-variate regression tests. Kaplan–Meier analysis showed statistically shorter biochemical recurrence-free survival in the high hemoglobin A1c group (p < 0.001), and subsequent multivariate Cox proportional analyses revealed that high hemoglobin A1c is an independent predictor for shorter BCR-free survival (HR 1.135, 95% CI 1.016–1.267, p = 0.024). Moreover, the high hemoglobin A1c group showed a significantly longer incontinence-free survival than the low hemoglobin A1c group (p = 0.001), and high preoperative hemoglobin A1c was also an independent predictor for longer incontinence-free survival in multivariate Cox analyses (HR 0.929, 95% CI 0.879–0.981, p = 0.008). The high preoperative hemoglobin A1c level was independently associated with worse oncological outcomes and also with inferior recovery of urinary continence after radical prostatectomy.

Abstract 237: DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer

Abstract Introduction: Fatty acid oxidation (FAO) is the dominant bioenergetic pathway in prostate cancer (PCa). Previous studies have demonstrated efficacy in targeting key FAO enzymes using in vitro and in vivo models of PCa. However, clinical evidence supporting FAO targeting in PCa is lacking. A recent study reported that FAO is upregulated in PCa cells and is essential for cell viability. Here, we demonstrated therapeutic efficacy of targeting FAO in clinical prostate tumors and identified DECR1 as a potential FAO-related survival factor. Methods and Results: To examine the therapeutic efficacy of targeting FAO in a more clinically-relevant setting, patient-derived prostate explants (PDE) were treated with etomoxir (FAO inhibitor). Results showed significant inhibition of cell proliferation (evaluated using Ki67 immunohistochemistry staining) in drug-treated PDE by a mean of 48% (n=13, p&amp;lt;0.05). To identify key targets of FAO in PCa, a meta-analysis was performed using four clinical RNA-sequencing datasets comprising of malignant and matched normal PCa patient tissues. DECR1 – the rate limiting enzyme of polyunsaturated fatty acid (PUFA) oxidation was identified as a robustly overexpressed FAO gene in PCa tissues; its expression is significantly associated with shorter biochemical recurrence-free survival and overall PCa patient survival. Consistent with the vital role of DECR1 in PUFA oxidation, knockdown of DECR1 impaired the cell's capacity to metabolize PUFAs; furthermore, FAO inhibition via DECR1 knockdown is specific to PUFA oxidation. Notably, DECR1 knockdown significantly inhibited PCa cell proliferation, migration, and invasion, and significantly reduced cellular proliferation in tumors. Mechanistically, DECR1 knockdown results in the induction of lipid peroxidation and cell death via ferroptosis in PCa cells. In contrast, overexpression of DECR1 significantly decreased mitochondrial oxidative stress and reduced levels of malondialdehyde. Treatment of PCa cells with ferrostatin successfully rescued PCa cells from death by DECR1 inhibition. Taken together, these data suggest that overexpression of DECR1 may offer PCa cells a survival advantage by protecting the cells from ferroptosis. Conclusion: This study demonstrated for the first time clinically-relevant evidence that targeting FAO is efficacious and provides evidence for the importance of FAO, and specifically PUFA oxidation, in PCa progression. Importantly, this study identified DECR1 as a promising and novel therapeutic target for PCa. Citation Format: Chui Yan Mah, Zeyad D. Nassar, Ingrid J. Burvenich, Swati Irani, Margaret M. Centenera, Max Moldovan, David J. Lynn, Andrew J. Hoy, Johannes V. Swinnen, Lisa M. Butler. DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer [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 237.

Analysis of key genes reveal lysine demethylase 5B promotes prostate cancer progression.

Prostate cancer (PCa) is one of the most common types of cancer in males globally. However, the molecular mechanisms underlying PCa progression remain largely unclear. In the present study, Gene Expression Omnibus (GEO) datasets and datasets from The Cancer Genome Atlas (TCGA) were used to analyze the expression of lysine demethylase 5B (KDM5B) in PCa. Proliferation, cell cycle and migration assays were used to detect the functional roles of KDM5B. It was found KDM5B was upregulated in PCa tissues by analyzing GEO and TCGA datasets. KDM5B knockdown significantly suppressed proliferation and cell cycle progression in PCa cells. In additional, KDM5B knockdown inhibited PCa cell migration. By analyzing a TCGA dataset, KDM5B was found to be upregulated in patients at N1 stage compared with N0 stage PCa, in patients at T3+T4 stages compared with T2 stage and in patients with Gleason score ≥8 compared with those with score ≤7. Kaplan-Meier analysis revealed that higher expression of KDM5B was associated with shorter biochemical recurrence-free survival and overall survival time in patients with PCa. These results suggest that expression of KDM5B may serve as a biomarker to predict the outcome of PCa.

Cohort study of high-intensity focused ultrasound in the treatment of localised prostate cancer treatment: Medium-term results from a single centre.

We report medium-term results in men receiving primary whole-gland HIFU (WG-HIFU) and following salvage treatment. One hundred and twenty-eight patients in a single hospital were enrolled. The enrolled patients were treated with WG-HIFU for primary localized prostate cancer. Salvage treatment include androgen deprivation therapy, secondary HIFU and salvage radiation therapy. Our primary outcomes were biochemical recurrence-free survival, salvage treatment-free survival, and metastasis-free survival. Secondary outcomes included urinary incontinence, de novo erectile dysfunction, acute epididymitis, bladder neck contracture, and urethral stricture. The 5-year biochemical recurrence-free survival rates were 85.7%, 82.7%, and 45.2% for D'Amico low-, intermediate-, and high-risk groups, respectively. Multivariate analysis revealed high risk group is the only predictor of significant shorter biochemical recurrence free survival, salvage treatment free survival, and metastasis free survival. Of 38 patients receiving salvage treatment after biochemical recurrence, 29 (76.3%) became free from biochemical recurrence. Rates of the adverse events of urinary incontinence, acute epididymitis, bladder neck contracture or urethral stricture, and de novo erectile dysfunction were 2.3%, 10.9%, 20.3%, 65.6%, respectively. In conclusion, WG-HIFU is an effective treatment option for localised prostate cancer, especially in D'Amico low- and intermediate-risk cases. The success rate of salvage treatment with radiation therapy and secondary HIFU for biochemical recurrence was acceptable. Fewer adverse events were caused by HIFU, especially incontinence and erectile dysfunction, than by radical prostatectomy and radiotherapy.

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both invitro and invivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Risk Stratification of Prostate Cancer Through Quantitative Assessment of PTEN Loss (qPTEN).

Phosphatase and tensin homolog (PTEN) loss has long been associated with adverse findings in early prostate cancer. Studies to date have yet to employ quantitative methods (qPTEN) for measuring of prognostically relevant amounts of PTEN loss in postsurgical settings and demonstrate its clinical application. PTEN protein levels were measured by immunohistochemistry in radical prostatectomy samples from training (n = 410) and validation (n = 272) cohorts. PTEN loss was quantified per cancer cell and per tissue microarray core. Thresholds for identifying clinically relevant PTEN loss were determined using log-rank statistics in the training cohort. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards) analyses on various subpopulations were performed to assess biochemical recurrence-free survival (BRFS) and were independently validated. All statistical tests were two-sided. PTEN loss in more than 65% cancer cells was most clinically relevant and had statistically significant association with reduced BRFS in training (hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.59 to 3.87; P < .001) and validation cohorts (HR = 4.22, 95% CI = 2.01 to 8.83; P < .001). The qPTEN scoring method identified patients who recurred within 5.4 years after surgery (P < .001). In men with favorable risk of biochemical recurrence (Cancer of the Prostate Risk Assessment - Postsurgical scores <5 and no adverse pathological features), qPTEN identified a subset of patients with shorter BRFS (HR = 5.52, 95% CI = 2.36 to 12.90; P < .001) who may be considered for intensified monitoring and/or adjuvant therapy. Compared with previous qualitative approaches, qPTEN improves risk stratification of postradical prostatectomy patients and may be considered as a complementary tool to guide disease management after surgery.

MP29-10 TRIM36, A NOVEL ANDROGEN-RESPONSIVE GENE, ENHANCES ANTI-ANDROGEN EFFICACY AGAINST PROSTATE CANCER BY INHIBITING MAPK/ERK SIGNALING PATHWAYS

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2018MP29-10 TRIM36, A NOVEL ANDROGEN-RESPONSIVE GENE, ENHANCES ANTI-ANDROGEN EFFICACY AGAINST PROSTATE CANCER BY INHIBITING MAPK/ERK SIGNALING PATHWAYS Jie Li, Chao Liang, Shangqian Wang, Bianjiang Liu, Gong Cheng, Chao Qin, Pengfei Shao, and Zengjun Wang Jie LiJie Li More articles by this author , Chao LiangChao Liang More articles by this author , Shangqian WangShangqian Wang More articles by this author , Bianjiang LiuBianjiang Liu More articles by this author , Gong ChengGong Cheng More articles by this author , Chao QinChao Qin More articles by this author , Pengfei ShaoPengfei Shao More articles by this author , and Zengjun WangZengjun Wang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.930AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hormone therapy drugs, such as bicalutamide and enzalutamide, directed against prostate cancer focus on androgen receptor (AR) signaling and are initially effective, but the disease progresses to lethality as resistance to these drugs develops. A method to prolong the drug response time and improve the drug efficacy is still unavailable. In this study, we investigated the functional analysis and androgen regulation of TRIM36 and its underlying mechanisms enhancing anti-androgen efficacy against prostate cancer (PCa). METHODS TRIM36 expression has been detected by mRNA microarray analysis, quantitative reverse transcription (qRT-PCR), Western blotting and Liquid chromatography-Mass Spectrum (LC-MS/MS) in matched prostate cancer and adjacent normal tissues, and prostate cell lines RWPE-1, C4-2, LNCaP, DU145, PC3. A total of 95 cases of prostate cancer after radical prostatectomy were analysed in a tissue microarray (TMA) for TRIM36 and androgen receptor (AR) protein expression. Prostate cancer cells stably expressing and shRNAs knockdown TRIM36 were used for CCK-8 assay, clone formation assay and xenograft with or without ADT drugs. Androgen regulation was examined by ChIP, dual-luciferase reporter assay, qRT-PCR and Western blot analysis. RESULTS In this study, we found that 63.4% (64/95) of PCa in TMA expressed the TRIM36 protein. Interestingly, patients with negative TRIM36 expression had a shorter biochemical recurrence-free survival. TRIM36 expression was significantly associated with the Gleason score (P=0.005), delayed prostate cancer cell cycle progression and inhibited cell proliferation in vitro and in vivo, and these effects were mediated via inhibition of the MAPK/ERK phosphorylation pathway. Remarkably, we found that rescuing the expression of TRIM36 during anti-androgen therapy could improve the drug efficacy. CONCLUSIONS Collectively, TRIM36 is a novel androgen-responsive gene, and it dramatically enhanced the efficacy of anti-androgen drugs against prostate cancer. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e369 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Jie Li More articles by this author Chao Liang More articles by this author Shangqian Wang More articles by this author Bianjiang Liu More articles by this author Gong Cheng More articles by this author Chao Qin More articles by this author Pengfei Shao More articles by this author Zengjun Wang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Is expanded radiographic criteria for clinically positive lymph nodes associated with outcome in pathologically node positive prostate cancer?

126 Background: Patients with pN1 prostate cancer (PCa) have heterogeneous outcomes largely dependent on variables only known post-treatment. Traditionally, the size criteria for clinically positive pelvic adenopathy is axial diameter of 10mm. We employed expanded radiographic criteria (ERC) to evaluate for association with differences in outcome differences. Methods: 187 men treated with RP BPLND for PCa from 2001-2013 were identified as pN1. Imaging studies were re-reviewed by a single radiologist (TB) for nodes that were considered positive if they were 8mm or greater in size OR if they were 6mm or greater in size AND either rounded, asymmetrical OR heterogeneously enhancing. This yielded a group of 34 cN1 patients by ERC. Time to biochemical recurrence (BCR) was compared between cN0 and cN1 patients by K-M method. Cox proportional hazards modeling was used to determine association of baseline PSA, node status, adjuvant therapy, Gleason score, positive margins, and ECR with time to BCR and overall survival (OS). Results: Median age (61 v 59 p = 0.3), baseline PSA (8.7 v 11.1 p = 0.2), and positive margin rate (33% vs 32% p = 0.9) did not differ between cN0 and cN1 patients. Median number of positive LNs was higher in the cN1 group (2.7 v 1.8) p = 0.03. Median biochemical recurrence free survival did not differ between groups (3.3 vs 1.8 years p = 0.3) (Fig1). Only Gleason score was associated with shorter BCR free survival HR 1.3 (95%CI 1.0-1.62, p = 0.047). cN1 disease with expanded radiographic criteria did not predict BCR (HR 1.03, 95CI 0.62-171, p = 0.9) or ACM (HR 0.46, 95CI, 0.1-2.12, p = 0.3). Conclusions: Expanded radiographic criteria for clinically positive lymph nodes was not associated with BCR-free survival or OS in a group of pN1 PCa patients. Further study is required to determine if cN1 status based on expanded clinical criteria or more sensitive imaging methods is associated with outcome differences.

Influence of HOTAIR rs920778 and rs12826786 Genetic Variants on Prostate Cancer Risk and Progression-Free Survival

Evaluate the impact of the single nucleotide polymorphisms rs920778 and rs12826786 in the long noncoding RNA HOTAIR in the susceptibility and prognosis of prostate cancer (PCa) patients. HOTAIR single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism in 151 PCa cases and 180 cancer-free controls. Odds ratio, 95% CIs and prognostic significance were calculated. Our data showed no statistically significant associations between HOTAIR polymorphic variants in rs920778 and rs12826786 and PCa susceptibility. However, the CC genotype in rs12826786 was significantly associated with shorter biochemical recurrence-free survival in pT3-stage PCa patients. Our results indicate that HOTAIR rs12826786 CC genotype may be an independent prognostic biomarker in a particular subset of PCa tumors.

TRIM36, a novel androgen-responsive gene, enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathways

Hormone therapy drugs, such as bicalutamide and enzalutamide, directed against prostate cancer focus on androgen receptor (AR) signaling and are initially effective, but the disease progresses to lethality as resistance to these drugs develops. A method to prolong the drug response time and improve the drug efficacy is still unavailable. TRIM36 was reported as a novel androgen signaling target gene and is upregulated in prostate cancer. In this study, we found that 63.4% (64/95) of PCa in TMA expressed the TRIM36 protein. Interestingly, patients with negative TRIM36 expression had a shorter biochemical recurrence-free survival. TRIM36 expression was significantly associated with the Gleason score (P = 0.005), delayed prostate cancer cell cycle progression and inhibited cell proliferation in vitro and in vivo, and these effects were mediated via inhibition of the MAPK/ERK phosphorylation pathway. Remarkably, we found that rescuing the expression of TRIM36 during anti-androgen therapy could improve the drug efficacy. Collectively, TRIM36 is a novel androgen-responsive gene, and it dramatically enhanced the efficacy of anti-androgen drugs against prostate cancer.

TMEM45B is a novel predictive biomarker for prostate cancer progression and metastasis.

It is urgently needed to explore the clinical relevance of TMEM45B expression and Prostate cancer(PCa), and determine the predictive significance of TMEM45B as a biomarker for PCa patients.Patient-derived xenograft (PDX) model of PCa with different metastatic potential (LTL-418, LTL-313B, LTL-313H and LTL-331) were developed. The gene expression microarray of LTL-313H and LTL-313B, which derived from a single PCa patient, was performed to identify the candidate biomarker gene, TMRM45B. MSKCC and TCGA PCa patient cohorts were introduced to analyzed the clinical significance of TMEM45B expression. Quantitative Real-Time PCR (qRT-PCR) revealed that there was a significant increase of TMEM45B expression in high metastatic potential tumor lines LTL-313H and LTL-331 compared with the other two low metastatic potential tumor lines(LTL-418, LTL-313B). In MSKCC PCa cohort, the mRNA level of TMEM45B in patients with metastasis was significantly higher than that in primary PCa (P=0.001) and begin prostate hyperplasia (BPH) patients (P<0.001). In addition, the increased TMEM45B expression was positively related with a higher possibility of biochemical recurrence (P=0.016), distant metastasis occurrence(P<0.001) and overall patient survival (P=0.07). Moreover, TMEM45B expression was considered as an independent risk factor for metastasis of PCa based on multivariate logistic regression. Kaplan-Meier analysis showed that patients with elevated TMEM45B had a shorter biochemical recurrence free survival (RFS). For primary PCa patients, subgroup analysis showed that there was a significant association between TMEM45B expression and clinical features in primary PCa cohort. Meanwhile, cases with elevated TMEM45B were more likely to develop metastasis compared to the normal group among N0 primary PCa patients (P=0.010). Primary PCa patient cohort TCGA was used to validate the results, and an obvious relationship was found between TMEM45B and clinical characteristic of PCa (T/N stage, Gleason score, Recurrence / Progress). Furthermore, a significant poor disease free survival (DFS) was investigated in high-level of TMEM45B patients compared with the other remaining cases (P=0.007). Taken together, the increased expression of TMEM45B appears to be significantly associated with prostate carcinoma progression and metastasis which provide a new prognostic biomarker for predicting metastatic potential of PCa patients, especially for primary PCa.

Association between polymorphisms in sex hormones synthesis and metabolism and prostate cancer aggressiveness.

Novel biomarkers for prostate cancer (PCa) diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and PCa risk and aggressiveness. A total of 311 Caucasian men (155 controls and 156 patients) were genotyped for 9 SNPs in AR, CYP17A1, LHCGR, ESR1 and ESR2 genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D´Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan–Meier for the association between SNPs and time to biochemical progression. We found 5 variants (CYP17A1) rs743572, rs6162, rs6163; (LHCGR) rs2293275 and (ESR2) rs1256049 that were statistically significant according to clinical variables (PSA, D´Amico risk and T stage) on a case-case analysis. Moreover, the presence of A and G alleles in rs743572 and rs6162 respectively, increase the risk of higher PSA levels (>10 ng/μl). With respect to D´Amico risk rs743572 (AG-GG), rs6162 (AG-AA) and rs6163 (AC-AA) were associated with an increased risk; and last, AC and AA genotypes for rs6163 were associated with a shorter biochemical recurrence free survival (BRFS) in patients with radical prostatectomy. In multigene analysis, several variants in SNPs rs2293275, rs6152, rs1062577, rs6162, rs6163, rs1256049 and rs1004467 were described to be associated with a more aggressiveness in patients. However, none of the selected SNPs show significant values between patients and controls. In conclusion, this study identified inherited variants in genes CYP17A1, LHCGR and ESR2 related to more aggressiveness and/or a poor progression of the disease. According to this study, new promise PCa biomarkers for clinical management could be included in these previous SNPs.

The EEF1A2 gene expression as risk predictor in localized prostate cancer

BackgroundBesides clinical stage and Gleason score, risk-stratification of prostate cancer in the pretherapeutic setting mainly relies on the serum PSA level. Yet, this is associated with many uncertainties. With regard to therapy decision-making, additional markers are needed to allow an exact risk prediction. Eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) was previously suggested as driver of tumor progression and potential biomarker. In the present study its functional and prognostic relevance in prostate cancer was investigated.MethodsEEF1A2 expression was analyzed in two cohorts of patients (n = 40 and n = 59) with localized PCa. Additionally data from two large expression dataset (MSKCC, Cell, 2010 with n = 131 localized, n = 19 metastatic PCa and TCGA provisional data, n = 499) of PCa patients were reanalyzed. The expression of EEF1A2 was correlated with histopathology features and biochemical recurrence (BCR). To evaluate the influence of EEF1A2 on proliferation and migration of metastatic PC3 cells, siRNA interference was used. Statistical significance was tested with t-test, Mann-Whitney-test, Pearson correlation and log-rank test.ResultsqRT-PCR revealed EEF1A2 to be significantly overexpressed in PCa tissue, with an increase according to tumor stage in one cohort (p = 0.0443). In silico analyses in the MSKCC cohort confirmed the overexpression of EEF1A2 in localized PCa with high Gleason score (p = 0.0142) and in metastatic lesions (p = 0.0038). Patients with EEF1A2 overexpression had a significantly shorter BCR-free survival (p = 0.0028). EEF1A2 expression was not correlated with serum PSA levels. Similar results were seen in the TCGA cohort, where EEF1A2 overexpression only occurred in tumors with Gleason 7 or higher. Patients with elevated EEF1A2 expression had a significantly shorter BCR-free survival (p = 0.043). EEF1A2 knockdown significantly impaired the migration, but not the proliferation of metastatic PC3 cells.ConclusionThe overexpression of EEF1A2 is a frequent event in localized PCa and is associated with histopathology features and a shorter biochemical recurrence-free survival. Due to its independence from serum PSA levels, EEF1A2 could serve as valuable biomarker in risk-stratification of localized PCa.

MP28-12 IMPACT OF LYMPHOVASCULAR INVASION ON LYMPH NODE METASTASIS FOR T3 PATIENTS UNDERGOING RADICAL PROSTATECTOMY IN CONSIDERATION OF RESECTION MARGIN STATUS

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2017MP28-12 IMPACT OF LYMPHOVASCULAR INVASION ON LYMPH NODE METASTASIS FOR T3 PATIENTS UNDERGOING RADICAL PROSTATECTOMY IN CONSIDERATION OF RESECTION MARGIN STATUS Yong Jin Kang, Won Sik Jang, Myung Soo Kim, Won Sik Jung, Cheol Yong Yoon, In Rae Cho, and Young Deuk Choi Yong Jin KangYong Jin Kang More articles by this author , Won Sik JangWon Sik Jang More articles by this author , Myung Soo KimMyung Soo Kim More articles by this author , Won Sik JungWon Sik Jung More articles by this author , Cheol Yong YoonCheol Yong Yoon More articles by this author , In Rae ChoIn Rae Cho More articles by this author , and Young Deuk ChoiYoung Deuk Choi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.825AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To assess an association between the increased risk of biochemical recurrence and lymphovascular invasion in T3 margin positive or negative patients and its association with lymph node metastasis. METHODS 1634 patients who underwent radical prostatectomy from 2005 to 2014 were selected. Patients with bone or distant organ metastasis at the time of operation were excluded. Survival analysis was performed to assess biochemical recurrence, bone metastasis and mortality risks by Kaplan-Meier analysis and multivariate Cox proportional hazard regression. Odds of lymph node metastasis were evaluated by Logistic regression. RESULTS LVI was detected in 118 (7.4%) patients. The median follow-up duration was 33.1 months. In the Kaplan-Meier analysis, lymphovascular invasion was associated with significantly shorter biochemical recurrence free survival (39.3 vs. 82.5 months, p<0.001), bone metastasis-free survival (134.4 vs. 156.7 months, p=0.001) and cancer specific survival (122.7 vs. 152.6 months, p=0.034). When stratified by T stage and resection margin status, lymphovascular invasion resulted in significantly shorter biochemical recurrence-free duration in T3 patients with and without positive surgical margin (p=0.008, 0.005, respectively). In the multivariate Cox regression model lymphovascular invasion resulted in 1.4-fold risk increase (95% CI 1.05-1.75, p=0.031).Lymphovascular invasion was revealed to be strongly associated with lymph node metastasis in the multivariate Logistic regression (OR 4.26, 95% CI 2.07-8.79, p<0.001). CONCLUSIONS Lymphovascular invasion increased the risk of early recurrence in T3 patients regardless of margin status, by accelerating the metastasis. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e342-e343 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Yong Jin Kang More articles by this author Won Sik Jang More articles by this author Myung Soo Kim More articles by this author Won Sik Jung More articles by this author Cheol Yong Yoon More articles by this author In Rae Cho More articles by this author Young Deuk Choi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...