Higher Risk Of Biochemical Recurrence Research Articles

Development of a redox-related prognostic signature for predicting biochemical-recurrence-free survival of prostate cancer*

Abstract Objective Prostate cancer (PCa) is one of the most common malignancies among elderly males. However, effective prognostic biomarkers are currently lacking. Bioinformatic analysis was used to identify patients at high risk of biochemical recurrence (BCR). Methods In our study, RNA sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) dataset to serve as the training and internal validation sets. The GSE84042 dataset was used as the external validation set. Batch effects were removed and normalized for the two datasets using “sva” package. Univariate Cox, least absolute shrinkage and selection operator (LASSO) Cox, and multivariate Cox regression analyses were successively performed to identify the redox-related gene (RRG) signature. After performing univariate Cox, LASSO Cox, and multivariate Cox regression analyses, a signature consisting of seven RRGs was established to predict BCR of patients with PCa, which included TP53, ADH5, SRRT, SLC24A2, COL1A1, CSF3R, and TEX19. Kaplan-Meier and receiver operating characteristic curve analyses showed good performance for the prognostic signature in the training and validation datasets. Results Univariate and multivariate Cox analyses showed that the RRG signature was an independent prognostic factor for BCR of patients with PCa. Thereafter, the nomogram results revealed that it was able to predict BCR of patients with PCa with high efficiency. Conclusion This study identified an independent prognostic signature and established a nomogram to predict BCR in PCa. This signature can be used to identify patients with PCa with a high risk of BCR, and personalized treatment can be applied.

MP20-05 LATROPHILINS AS DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR INDUCE PROSTATE CANCER PROGRESSION

You have accessJournal of UrologyCME1 Apr 2023MP20-05 LATROPHILINS AS DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR INDUCE PROSTATE CANCER PROGRESSION Yuki Teramoto, Takuro Goto, Masato Yasui, and Hiroshi Miyamoto Yuki TeramotoYuki Teramoto More articles by this author , Takuro GotoTakuro Goto More articles by this author , Masato YasuiMasato Yasui More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Latrophilins (LPHNs), including LPHN1, LPHN2, and LPHN3, are a group of the G-protein-coupled receptor where a spider venom latrotoxin (LTX) is known to bind. Alterations in their encoded genes (e.g. ADGRL1, ADGRL2, ADGRL3) have been linked to susceptibility to attention deficit hyperactivity disorder (ADHD). Interestingly, ADHD is diagnosed approximately 3 times more often in boys than in girls, and prenatal exposure to excess androgens has been suggested to increase its risk. However, LPHNs remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHNs in the progression of prostate cancer. METHODS: In human prostate cancer lines, we assessed the effects of androgen receptor (AR) ligands and LPHN ligands (e.g. LTX, FLRT3) or silencing of each LPHN via shRNA virus infection on the expression of LPHNs and the cell growth/expression of related proteins, respectively. In 150 radical prostatectomy cases, we immunohistochemically stained for LPHN1/LPHN2/LPHN3. RESULTS: In AR-positive LNCaP/C4-2/CWR22Rv1 cells, dihydrotestosterone treatment considerably increased the expression levels of LPHN1, LPHN2, and LPHN3, which was at least partially restored by AR inhibitors, bicalutamide and enzalutamide. Chromatin immunoprecipitation assay further revealed the binding of endogenous ARs, including ARv7, to the promoter region of each LPHN in prostate cancer cells. Treatment with LTX or FLRT3 resulted in induction in the cell viability and migration of AR-positive lines, as well as the expression of prostate-specific antigen, and reduction in apoptosis. LTX/FLRT3 also enhanced the expression of phosphorylated forms of JAK2 and STAT3, as well as Bcl-2. Meanwhile, knockdown of LPHN1, LPHN2, or LPHN3 showed opposite effects on all of those described above for LTX/FLRT3 treatment. In addition, similar stimulation by LTX/FLRT3 treatment or inhibition by knockdown of each LPHN was seen in AR-negative PC-3 and DU145 cells. In immunohistochemistry, high LPHN1 (H-score >200; HR=3.706, p=0.006)/LPHN2 (>100; HR=6.023, p=0.002)/LPHN3 (>200; HR=4.265, p=0.004) was associated with a significantly higher risk of biochemical recurrence after prostatectomy even in a multivariate setting. CONCLUSIONS: These findings indicate that LPHNs, as downstream effectors of the ARs, promote the growth of prostate cancer. LPHNs could thus be independent prognosticators in prostate cancer patients undergoing radical prostatectomy, as well as therapeutic targets for both androgen-sensitive and castration-resistant tumors. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e276 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuki Teramoto More articles by this author Takuro Goto More articles by this author Masato Yasui More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement PDF downloadLoading ...

MP77-15 INCREASED RISK OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY IN THE ACTIVE SURVEILLANCE ERA

You have accessJournal of UrologyCME1 Apr 2023MP77-15 INCREASED RISK OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY IN THE ACTIVE SURVEILLANCE ERA Sanjay Das, Michael Luu, Stephen Freedland, and Timothy Daskivich Sanjay DasSanjay Das More articles by this author , Michael LuuMichael Luu More articles by this author , Stephen FreedlandStephen Freedland More articles by this author , and Timothy DaskivichTimothy Daskivich More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003351.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In the active surveillance (AS) era, radical prostatectomy (RP) has become more often used for intermediate- and high-risk disease and less for low-risk disease. AS/conservative management became the most common treatment for low-risk disease in the VA in 2010. However, the impact of this shift on risk of biochemical recurrence (BCR) after RP is unknown. We sought to determine how risk of BCR has changed before and after 2010 and to provide contemporary projections for BCR by tumor risk. METHODS: We sampled men who underwent RP for clinically localized disease between 2000 and 2017 from the VA SEARCH database. Kaplan Meier analysis was used to calculate incidence of BCR before and after 2010 overall and across tumor risk subgroups. Multivariable Cox proportional hazard regression analysis including an interaction term between epoch and tumor risk was used to compare risk of BCR before and after 2010 overall and across tumor risk subgroups. RESULTS: Of 5,648 patients, 3,276 (58%) underwent RP in 2010 or prior and 2,372 (42%) after 2010. Of those who underwent RP in 2010 or prior, 1,266 (39%), 503 (15%), 655 (20%), and 712 (22%) had low-, favorable intermediate-, unfavorable intermediate-, and high-risk disease, respectively, compared with 335 (14%), 488 (21%), 768 (32%), and 749 (32%) among those who underwent RP after 2010 (p<0.001). The 7-year risk of BCR in the post-2010 was 43%, compared with 33% in the pre-2010 era (HR 1.15, 95%CI 1.04–1.28). In a multivariable Cox model adjusting for tumor risk, there was a significant interaction between tumor risk and epoch in predicting BCR (p<0.001). Men with favorable intermediate risk (HR 0.71, 95%CI 0.53–0.96) and unfavorable intermediate risk disease (HR 0.74, 95%CI 0.61–0.90) had a lower risk of BCR in the post-2010 era. Men with high-risk disease (HR 1.24, 95%CI 1.06–1.45) had higher risk of BCR in the post-2010 (vs. pre-2010) era. The 5-year risk of BCR in the pre- vs. post-2010 eras were 17% vs. 15%, 23% vs. 20%, 40% vs. 33%, and 46% vs. 52% for low, favorable intermediate, unfavorable intermediate, and high-risk disease, respectively. CONCLUSIONS: Trends toward using RP for higher risk disease have increased the 7-year risk of BCR from 33% to 43% in the pre- vs. post-AS eras, primarily driven by increased risk of BCR in high-risk patients. Source of Funding: This research was supported by Cedars-Sinai Cancer at Cedars-Sinai Medical Center through the Biostatistics Core Voucher Program. Dr. Das was supported by the Patient Centered Outcomes in Urologic and Gynecologic Cancers (PCORT: UroGynCan) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1108 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanjay Das More articles by this author Michael Luu More articles by this author Stephen Freedland More articles by this author Timothy Daskivich More articles by this author Expand All Advertisement PDF downloadLoading ...

Prognostic significance of PI-RADS 5 lesions in patients treated by radical prostatectomy.

To analyse the pathological features and survival of patients with a PI-RADS 5 lesion on pre-biopsy MRI. We extracted from a European multicentre prospectively gathered database the data of patients with a PI-RADS 5 lesion on pre-biopsy MRI, diagnosed using both systematic and targeted biopsies and subsequently treated by radical prostatectomy. The Kaplan-Meier model was used to assess the biochemical-free survival of the whole cohort and univariable and multivariable Cox models were set up to study factors associated with survival. Between 2013 and 2019, 539 consecutive patients with a PI-RADS 5 lesion on pre-biopsy MRI were treated by radical prostatectomy and included in the analysis. Follow-up data were available for 448 patients. Radical prostatectomy and lymph node dissection specimens showed non-organ confined disease in 297/539 (55%), (including 2 patients with a locally staged pT2 lesion and lymph node involvement (LNI)). With a median follow-up of 25months (12-39), the median biochemical recurrence-free survival was 54% at 2years (95% CI 45-61) and 28% at 5years (95% CI 18-39). Among the factors studied, MRI T stage [T3a vs T2 HR 3.57 (95%CI 1.78-7.16); T3b vs T2 HR 6.17 (95% CI 2.99-12.72)] and PSA density (HR 4.47 95% CI 1.55-12.89) were significantly associated with a higher risk of biochemical recurrence in multivariable analysis. Patients with a PI-RADS 5 lesion on pre-biopsy MRI have a high risk of early biochemical recurrence after radical prostatectomy. MRI T stage and PSA density can be used to improve patient selection and counselling.

Cribriform morphology is associated with higher risk of biochemical recurrence after radical prostatectomy in patients with Grade Group 5 prostate cancer.

Grade Group 5 (GG5) prostate cancer (PCa) is associated with a high risk of disease recurrence after radical prostatectomy (~75% at 5 years). However, this is a heterogeneous category that includes neoplasms with different combinations of Gleason pattern (GP) 4 and 5. Within GP4, large cribriform growth has been associated with adverse disease-specific outcomes in GG2-4 PCa. Less is known about the significance of cribriform morphology and the different histologic patterns of GP5 in GG5 PCa. In this study we evaluated the prognostic implications of cribriform morphology (either invasive or intraductal, henceforth "cribriform") and large solid growth or comedonecrosis (comedo/solid) in patients with GG5 PCa. One-hundred and thirty prostatectomies from a single institution were analysed. The presence of comedo/solid components was associated with a higher frequency of concurrent cribriform PCa (85.7% versus 45.9%, P <0.001), lymphovascular invasion (44.6% versus 27%, P=0.04), and biochemical recurrence (48.2% versus 28.4%, P=0.03). The presence of large cribriform growth was associated with a higher frequency of extraprostatic involvement (i.e. pT3a-b; 85.3% versus 68.7%, P=0.02), positive surgical margins (47.6% versus 29.2%, P=0.04) and biochemical recurrence (47.6% versus. 18.7%, P=0.001). Kaplan-Meier analysis demonstrated that GG5 PCa with cribriform or comedo/solid components had a higher probability of biochemical recurrence. Multivariable analysis showed that only cribriform components were an independent predictor of a higher risk of biochemical recurrence in this series. These findings highlight the importance of reporting the presence of cribriform components in GG5 PCa and suggest that cribriform morphology might help decide postsurgical management in these patients.

Index grade group is superior to composite grade group for prediction of biochemical recurrence following radical prostatectomy

The pathological grade of prostate cancer is the strongest predictor of recurrence. It is unclear whether the better predictor is the composite of all carcinomas within the prostate, or the highest grade lesion (index). The purpose of this study was to determine whether composite or index grade group better predicts biochemical recurrence (BCR). We undertook a retrospective analysis from a prospective institutional cohort study of men who underwent radical prostatectomy for localised prostate cancer between 2009 and 2020, in which an index and composite grade group was reported. The index grade in this study was defined as the highest grade of any tumour, usually with the highest stage, regardless of volume. Multivariate analysis and Kaplan-Meier plots were utilised. A total of 2024 men underwent radical prostatectomy during the study period; we analysed 1605 with composite grade group 2 or 3 prostate cancer. Median preoperative prostate specific antigen (PSA) was 5.9 ng/L, mean follow up was 56.8 months, 54% were pT2, 76% had multifocal disease and 16% had discordant index and composite grades. Patients with discordant index grade group had a higher risk of BCR [hazard ratio (HR) 2.22, p<0.0001]. The prevalence of BCR in the discordant group was higher at 1, 3, 5 and 7 years (4.7% vs 8.9%, 8.3% vs 18.1%, 14.5% vs 28.8% and 22.5% vs 49.5%, respectively). In cases of discordance, a higher index grade group is associated with increased rates of BCR after radical prostatectomy. Index rather than composite grade group should be used to counsel men post-operatively regarding prognosis and follow-up.

An autophagy-related gene prognostic index predicting biochemical recurrence, metastasis, and drug resistance for prostate cancer.

Given the dual role of autophagy presenting in tumorigenesis and inhibition, we established an autophagy-related gene prognostic index (ARGPI) with validation to well predict the biochemical recurrence (BCR), metastasis, as well as chemoresistance for patients with prostate cancer (PCa) who underwent radical radiotherapy or prostatectomy. Then, Lasso and COX regression was used to develop the ARGPI. We performed the whole analyses through R packages (version 3.6.3). Secreted phosphoprotein 1 (SPP1), single-minded 2 (SIM2), serine protease inhibitor b5 (SERPINB5), aldehyde dehydrogenase 2 (ALDH2), and acyl-CoA synthetase long-chain 3 (ACSL3) were eventually used to establish the ARGPI score. Patients were divided into two different-risk groups based on the median ARGPI score, high-risk patients with a higher risk of BCR than low-risk patients (hazard ratio [HR]: 5.46, 95% confidence interval [CI]: 3.23-9.24). The risk of metastasis of high-risk patients was higher than low-risk patients (HR: 11.31, 95% CI: 4.89-26.12). In The Cancer Genome Atlas (TCGA) dataset, we observed similar prognostic value of ARGPI in terms of BCR-free survival (HR: 1.79, 95% CI: 1.07-2.99) and metastasis-free survival (HR: 1.80, 95% CI: 1.16-2.78). ARGPI score showed a diagnostic accuracy of 0.703 for drug resistance. Analysis of gene set enrichment analysis (GSEA) indicated that patients in the high-risk group were significantly positively related to interleukin (IL)-18 signaling pathway. Moreover, ARGPI score was significantly related to cancer-related fibroblasts (CAFs; r = 0.36), macrophages (r = 0.28), stromal score (r = 0.38), immune score (r = 0.35), estimate score (r = 0.39), as well as tumor purity (r = -0.39; all P < 0.05). Drug analysis showed that PI-103 was the common sensitive drug and cell line analysis indicated that PC3 was the common cell line of PI-103 and the definitive gene. In conclusion, we found that ARGPI could predict BCR, metastasis, and chemoresistance in PCa patients who underwent radical radiotherapy or prostatectomy.

Impact of Clinicopathological Characteristics and Tissue Inhibitor of Metalloproteinase-3 Polymorphism Rs9619311 on Biochemical Recurrence in Taiwanese Patients with Prostate Cancer.

The tissue inhibitors of metalloproteinases-3 (TIMP3) are not only endogenous regulators of matrix metalloproteinases (MMPs), but also induce apoptosis and inhibit endothelial cell migration and angiogenesis. The focus of this study was to investigate the relationship between TIMP3 genetic polymorphisms and biochemical recurrence and clinicopathological features of prostate cancer. The TIMP3 rs9619311, rs9862, and rs11547635 genetic polymorphisms were analyzed by real-time polymerase chain reaction to determine their genotypic distributions in 579 patients with prostate cancer. This study found that individuals with the TIMP3 rs9619311 TC or TC + CC genotypes have a significantly higher risk of biochemical recurrence of prostate cancer (p = 0.036 and 0.033, respectively). Moreover, in the multivariate analysis, our results showed that pathologic Gleason grade, pathologic T stage, seminal vesicle invasion, lymphovascular invasion, and TIMP3 rs9619311 were associated with increased odds of biochemical recurrence. Patients with a PSA concentration under 7 ng/mL that were found to have the TIMP3 rs9619311 genetic polymorphism were associated with Gleason total score upgrade (p = 0.012) and grade group upgrade (p = 0.023). Compared with the CC homozygous, the TIMP3 rs9862 CT + TT polymorphic variant was found to be associated with clinically advanced tumor stage (p = 0.030) and Gleason total score upgrade (p = 0.002) in prostate cancer patients. In conclusion, the results of our study demonstrated that the TIMP3 rs9619311 genetic polymorphism was significantly associated with susceptibility to biochemical recurrence of prostate cancer. TIMP3 genetic polymorphisms, especially rs9619311, can serve as key predictors of biochemical recurrence and disease prognosis of prostate cancer.

Plasma cell subtypes analyzed using artificial intelligence algorithm for predicting biochemical recurrence, immune escape potential, and immunotherapy response of prostate cancer.

Plasma cells as an important component of immune microenvironment plays a crucial role in immune escape and are closely related to immune therapy response. However, its role for prostate cancer is rarely understood. In this study, we intend to investigate the value of a new plasma cell molecular subtype for predicting the biochemical recurrence, immune escape and immunotherapy response in prostate cancer. Gene expression and clinicopathological data were collected from 481 prostate cancer patients in the Cancer Genome Atlas. Then, the immune characteristics of the patients were analyzed based on plasma cell infiltration fractions. The unsupervised clustering based machine learning algorithm was used to identify the molecular subtypes of the plasma cell. And the characteristic genes of plasma cell subtypes were screened out by three types of machine learning models to establish an artificial neural network for predicting plasma cell subtypes. Finally, the prediction artificial neural network of plasma cell infiltration subtypes was validated in an independent cohort of 449 prostate cancer patients from the Gene Expression Omnibus. The plasma cell fraction in prostate cancer was significantly decreased in tumors with high T stage, high Gleason score and lymph node metastasis. In addition, low plasma cell fraction patients had a higher risk of biochemical recurrence. Based on the differential genes of plasma cells, plasma cell infiltration status of PCa patients were divided into two independent molecular subtypes(subtype 1 and subtype 2). Subtype 1 tends to be immunosuppressive plasma cells infiltrating to the PCa region, with a higher likelihood of biochemical recurrence, more active immune microenvironment, and stronger immune escape potential, leading to a poor response to immunotherapy. Subsequently, 10 characteristic genes of plasma cell subtype were screened out by three machine learning algorithms. Finally, an artificial neural network was constructed by those 10 genes to predict the plasma cell subtype of new patients. This artificial neural network was validated in an independent validation set, and the similar results were gained. Plasma cell infiltration subtypes could provide a potent prognostic predictor for prostate cancer and be an option for potential responders to prostate cancer immunotherapy.

PSOR3 Presentation Time: 11:40 AM: The Role of CAPRA Score as a Predictor of Outcomes in High-Risk Prostate Cancer Patients Treated with EBRT Plus HDR Brachytherapy Boost: A 20-year Single-Institution Experience

<h3>Purpose</h3> The study aimed to report clinical outcomes of high-risk prostate cancer (PCa) patients treated with external beam radiation therapy (EBRT) and high dose-rate boost (HDRB) according to CAPRA score. <h3>Material and Methods</h3> The study sample consisted of 361 high-risk PCa patients stratified according to D'Amico classification and treated with EBRT and HDRB and antiandrogen therapy (ADT) between 1999 and 2016. We conducted retrospective competing-risk survival analyses to compare individuals with a CAPRA score lesser than or equal to five and greater than five on biochemical recurrence (BCR) and metastasis incidence. Kaplan-Meier analysis was performed to assess overall survival (OS). Subsequently, we used ROC curves to compare the performance of the CAPRA model to the MSKCC stratification tool on BCR and metastasis incidence. <h3>Results</h3> The mean age of the patients at treatment time was 69.6±7.3 years. The median follow-up was 55.5 months. Of the 361 individuals, 52,4 % (n=189) had a CAPRA score above five. In comparison to individuals with a CAPRA score lesser than or equal to five, individuals with a CAPRA score above five were deemed at higher risk of BCR (sHR = 2.74, 95% CI: 1.12-6.66, p=0.027) and demonstrated a tendency towards significance in their metastasis incidence trend (sHR 2.33 95% CI: 0.89-6.12, p = 0.085). For 10-year OS, there was a HR for mortality of 1.89 (95% CI: 1.04-3.43, p=0.036) for individuals with a CAPRA score above five. There was no significant difference between either risk stratification strategy in ROC curves analysis. <h3>Conclusions</h3> The data suggest that patients' tumours classified as high-risk using the CAPRA score correlated with a higher risk of BCR, metastasis, and mortality when compared to lower-risk tumours. Further studies are needed to validate the use of the CAPRA score to predict cancer-specific mortality (CSM) as an initial risk stratification tool.

ARNEO: A Randomized Phase II Trial of Neoadjuvant Degarelix with or Without Apalutamide Prior to Radical Prostatectomy for High-risk Prostate Cancer

BackgroundHigh-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP). ObjectiveTo determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo. Design, setting, and participantsARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP. InterventionPatients were randomly assigned at a 1:1 ratio to degarelix (240–80–80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed. Outcome measurements and statistical analysisThe primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored. Results and limitationsPatients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5–11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET–estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET–estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001). ConclusionsIn high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy. Patient summaryIn this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes.

Propensity score matching analysis comparing radical prostatectomy and radiotherapy with androgen deprivation therapy in locally advanced prostate cancer

To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8–87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p < 0.001). After propensity score-matching, there were 68 patients in each group. Among locally advanced PC patients, treatment with RP had a higher risk of biochemical recurrence compared to the RT group. In multivariate Cox regression analysis, treatment with RT plus ADT significantly decreased the risk of biochemical failure (HR 0.162, p < 0.001), but there was no significant difference in local recurrence, distant metastasis and overall survival (p = 0.470, p = 0.268 and p = 0.509, respectively). This information supported a clinical benefit in BCR control for patients undergoing RT plus long-term ADT compared to RP.

Predictive value of CCR3 expression on diagnosis and prognostic classification of the Prostate Adenocarcinoma

Objective: Chemokines are factors secreted from damaged or infected tissues to induce an inflammatory and immunological reaction. Approximately Chemokines have recently been found to be secreted by most cancer cells. The aim of this study is to compare the CCR-3 expression with the clinicopathological variables in patients with prostatic adenocarcinoma(PCa) and benign prostatic hyperplasia(BPH). Material Method: The study included 25 patients with PCa who underwent prostatectomy, 25 patients with BPH. In the study, CCR-3 expression in PCa and BPH tissues was examined by immunohistochemical method, and CCR-3 expression at PCA and BPH tissues was compared with normal prostate tissue at mRNA level by the Real-Time PCR. Results: CCR-3 expression was found to be significantly higher in PCa patients (p=0,001). There was no relationship between Gleason prognostic grade and periprostatic spread and CCR-3 expression (p=0,887, p=0,279). A statistically significant increase was found in total PSA and CCR-3 expression (p=0,001). Conclusion: In prostate cancer, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence. According to this study, the CCR-3 expression may be useful in predicting the diagnosis of PCa and there was a significant relationship between total PSA. The Increasing total PSA was also correlation to increased of the CCR3 expression. However, there was no significant relationship between Gleason prognostic grade.

After ASCENDE-RT: Biochemical and survival outcomes following combined external beam radiotherapy and low-dose-rate brachytherapy for high-risk and unfavourable intermediate-risk prostate cancer, a population-based analysis

PURPOSETo evaluate the outcomes of unfavorable intermediate-risk (UIR) and high-risk (HR) prostate cancer patients treated with combined external beam radiation therapy (EBRT) and low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALSA population-based cohort of 568 prostate cancer patients treated with combined EBRT and LDR-PB from 2010 to 2016 was analyzed. All patients received EBRT followed by LDR-PB boost. Outcomes were compared with the results for the brachytherapy arm of the ASCENDE-RT trial. RESULTSThe median followup was 4.5 years. Sixty-nine percent (N = 391) had HR disease. Ninety-four percent of the HR and 57% of UIR were treated with androgen deprivation therapy (ADT) with a median duration of 12 months. The 5-year K-M biochemical progression-free survival (b-PFS), metastasis-free survival (MFS), and overall survival (OS) were 84 ± 2%, 90 ± 2%, and 88 ± 2%, similar to 89 ± 5%, 94 ± 4%, and 92 ± 4% for the ASCENDE-RT LDR-PB arm. The likelihood of achieving a PSA ≤0.2 ng/mL at 4 years was 88%, similar to 86% in the ASCENDE-RT LDR-PB arm. Thirty-three men (5.8%) would have been ineligible for ASCENDE-RT due to high-risk features. The 5-year K-M b-PFS, MFS and OS estimates were 86 ± 2%, 92 ± 1% and 89 ± 2% for the ASCENDE-RT eligible versus 56 ± 10% (p < 0.001), 73 ± 8% (p < 0.001), and 77 ± 9% (p = 0.098) for the ineligible patients. CONCLUSIONSIn this population-based cohort, combining LDR-PB with pelvic EBRT (+/- ADT) achieves very favorable b-PFS that compares to the LDR-PB arm of the ASCENDE-RT, supporting the generalizability of those results. Men ineligible for ASCENDE-RT, based on prognostic features, have a much higher risk of biochemical recurrence and metastatic relapse.

Abstract 3680: Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer

Abstract Background: Smoking has not been an established risk factor for prostate cancer (PCa), and has not been emphasized in PCa prevention. However, recent studies have shown increasing evidence that there is a higher risk of biochemical recurrence, PCa mortality, and metastasis among current smokers, presenting an urgent need in re-evaluating the association between smoking and aggressive PCa. This study aimed to determine whether smoking increase the likelihood of developing a more aggressive prostate cancer. Methods: Equal numbers of African Americans (AAs) and European Americans (EAs) by smoking status (never/former/current) matched with PCa aggressiveness, BMI, 5-year age group, and year of baseline recruitment, totaling 480 participants, were included in the metabolomics study. For metabolomics analysis, fold change and BH-adjusted p-value from t-test adjusted for age for univariate analysis, and PCA adjusted for age and PLS-DA supervised statistical analysis for multivariate analysis were employed to decipher the underlying metabolomic patterns, and identify significantly dysregulated metabolites for the variables of interest. Results: AA participants were significantly younger (mean=61.4, SD=7.7) compared with EAs (mean=63.5, SD=7.5). Current smokers had a 2.4 times higher risk of high aggressive PCa. When stratified by race, the risk diminished for EAs but increased for AAs. Global metabolic profiles detected a total of 1,487 compounds of known identity. After excluding metabolites with missing values in more than 20% of the samples and with small standard variation, we observed a distinct cluster of participants from AA aggressive PCa patients and current smokers that were separated from EAs and never smokers. With BH-adjusted p-value &amp;lt; 0.05 and fold change &amp;gt; 2, we identified 10 significantly dysregulated metabolites between AA and EA among high aggressive PCa and current smokers. Further, 36 metabolites between current and never smokers among AA high aggressive PCa were significantly dysregulated, but none of them are annotated as tobacco metabolites. Conclusion: Our study presented distinctive metabolomics profiles specific to AA current smokers who had high aggressive PCa. Furthermore, the distinctive patterns were not driven by the tobacco metabolites, with the potential to identify metabolites that might help to understand the relationships between smoking and aggressive PCa in AA. Citation Format: Se-Ran Jun, L. Joseph Su, Eryn Matich, Ping-Ching Hsu. Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3680.

Prognostic differences among Grade Group 4 subgroups in robotic-assisted radical prostatectomy.

ObjectivesTo investigate whether the International Society of Urological Pathology Grade Group 4 (GG 4) subgroups have different oncological outcomes in Japanese prostate cancer (PCa) patients undergoing robotic‐assisted radical prostatectomy (RARP).Patients and MethodsWe conducted a retrospective multicentre cohort study in PCa patients undergoing RARP at 10 institutions in Japan. Pre‐ and post‐operative variables were collected from enrolled patients. We evaluated biochemical recurrence and clinical and pathological variables in the different GG 4 subgroups.ResultsA total of 3195 patients were enrolled in the study. Among them, 298 patients with GG 4 tumours (pathological Gleason scores [GSs] of 3 + 5 [N = 37], 4 + 4 [N = 257] and 5 + 3 [N = 4]) based on RARP specimens were analysed. The median follow‐up period was 25.2 months. The 3‐year biochemical recurrence (BCR)‐free survival (BCRFS) rate in the overall population was 74.5%. The 3‐year BCRFS rates in the pathological GS 3 + 5, GS 4 + 4 and GS 5 + 3 subgroups were 93.8%, 71.9% and 50.0%, respectively (P = 0.01). In multivariate analysis, pathological GS based on RARP specimens, PSA levels at surgery, pathological T stage, pathological N stage and surgical margins were independent risk factors significantly associated with BCRFS. In particular, patients with pathological GSs 4 + 4 and 5 + 3 were at higher risk of BCR than patients with pathological GS 3 + 5 (hazard ratio 4.54, P = 0.03 and hazard ratio 11.2, P = 0.01, respectively). The study limitations include the lack of central pathological specimen evaluation.ConclusionsFor patients with localized PCa undergoing RARP, pathological GS 4 + 4 and GS 5 + 3 were significantly associated with worse BCRFS than pathological GS 3 + 5. Pathological GS 3 + 5 may be overrated in GG 4. This observation emphasizes that primary and secondary GS should be considered to accurately stratify the risk of BCR after RARP.

Roles of m5C RNA Modification Patterns in Biochemical Recurrence and Tumor Microenvironment Characterization of Prostate Adenocarcinoma.

BackgroundProstate cancer is the second most common cancer with a high risk of biochemical recurrence (BCR) among men. Recently, 5-methylcytosine (m5C) modification has attracted more attention as a new layer of RNA post-transcriptional regulation. Hence, we aimed at investigating the potential roles of m5C modification regulators in the BCR of prostate adenocarcinoma (PRAD).MethodsCNV data, mutation annotation data, mRNA expression profiles, and clinical data were downloaded from TCGA and GEO databases. Kaplan-Meier curves analysis, log-rank test, univariate and multivariate Cox regression, and time-dependent ROC curves analysis were performed to evaluate the prognostic factors. Principal components analysis (PCA) was applied to validate the distinction between subgroups. Gene set variation analysis (GSVA) was used to investigate the underlying pathways associated with m5C modification patterns. Single sample gene set enrichment analysis (ssGSEA) was utilized to assess the infiltration of distinct immune cells. Tumor Immune Dysfunction and Exclusion (TIDE) prediction was carried out to assess the potential response to immune checkpoint blockade (ICB) therapy. The m5C modification signature was constructed via LASSO Cox’s proportional hazards regression method.ResultsAfter comprehensively analyzing various types of data from TCGA dataset, and exploring the differential expression and prognostic value of each m5C regulator, we identified m5C modification patterns based on 17 m5C regulators. Two patterns presented a significant difference in the risk of BCR, the tumor microenvironment (TME), and immunotherapy response in PRAD. We found that TET2, which was highly expressed in adjacent normal tissues compared to tumor tissues, was closely associated with many infiltrating immune cells. The m5C modification signature was constructed for the clinical application. Risk score calculated by m5C signature was associated with T stage, N stage, Gleason score, and the possibility of BCR (HR, 4.197; 95% CI, 3.016-5.842; p < 0.001). A higher risk score also represented the possibility of immunotherapy response. Finally, the potential roles of m5C modification signature were validated in the testing dataset.ConclusionsOur study revealed the potential roles of m5C modification in the PRAD BCR and TME diversity, which may provide new insight into the field of prostate cancer in future research.

MP51-16 THE RISK OF RECURRENCE IN CN1 PROSTATE CANCER PATIENTS TREATED WITH RADICAL PROSTATECTOMY VARIES ACCORDING TO THE TYPE PREOPERATIVE STAGING. A COMPARISON BETWEEN 68GA-PSMA-PET VERSUS CONVENTIONAL IMAGING IN A LARGE, MULTI-INSTITUTIONAL STUDY

MP51-16 THE RISK OF RECURRENCE IN CN1 PROSTATE CANCER PATIENTS TREATED WITH RADICAL PROSTATECTOMY VARIES ACCORDING TO THE TYPE PREOPERATIVE STAGING. A COMPARISON BETWEEN 68GA-PSMA-PET VERSUS CONVENTIONAL IMAGING IN A LARGE, MULTI-INSTITUTIONAL STUDY

Radical prostatectomy findings and oncologic outcomes in patients with prostate cancer detected on systematic sextant biopsy only, MRI-targeted biopsy only, or both.

Magnetic resonance imaging-targeted biopsy (T-Bx) has been shown to more accurately detect clinically significant prostate cancer. However, the clinical significance of cancer detection on T-Bx, followed by definitive treatment, needs to be further investigated. We herein investigated unique cohorts of patients with prostate cancer detected on systematic sextant biopsy (S-Bx) and/or T-Bx. We assessed consecutive patients who had undergone T-Bx with concurrent S-Bx (6 sites, ≥12 cores), followed by radical prostatectomy from 2015 to 2019. Within our Surgical Pathology database, we identified a total of 222 men who met the inclusion criteria for prostatic adenocarcinoma on either S-Bx or T-Bx, or both (B-Bx). Radical prostatectomy findings and oncologic outcomes were then compared among groups. Prostate cancer was detected on S-Bx only (n = 32; 14%), T-Bx only (n = 40; 18%), or B-Bx (n = 150; 68%). Compared to cases with cancer detected on S-Bx only, those on T-Bx only or B-Bx showed significantly higher tumor grade (highest Grade Group in each patient) on biopsy and significantly larger estimated tumor volume on prostatectomy. There were no significant differences in tumor volume on biopsy, tumor grade on prostatectomy (except S-Bx vs. B-Bx), pT or pN stage category, surgical margin status, or preoperative prostate-specific antigen level between cases where cancer was detected on S-Bx only vs. T-Bx only or B-Bx. There were also no significant differences in any of these clinicopathologic features between cancers detected on T-Bx only vs. B-Bx. Kaplan-Meier analysis revealed a significantly higher risk of biochemical recurrence after prostatectomy in patients whose cancer was detected on T-Bx only (P = 0.020) or B-Bx (P = 0.032) than in those on S-Bx only. No significant difference in recurrence-free survival between T-Bx only vs. B-Bx cases (P = 0.601) was seen. In multivariate analysis, cancer detection on T-Bx only (vs. S-Bx only) showed significance for recurrence (hazard ratio = 8.482, P = 0.045). Detection of prostate cancer on T-Bx, in addition to or instead of S-Bx, was found to be associated with larger tumor volume as well as worse prognosis. However, no significant clinicopathologic impact of simultaneous tumor detection on S-Bx was indicated in patients with prostate cancer present on T-Bx.

MP53-20 ADDED VALUE OF MPMRI IN THE STRATIFICATION OF PATIENTS WITH HIGH-RISK PATIENTS PROSTATE CANCER TREATED WITH RADICAL PROSTATECTOMY: IMPLICATIONS FOR TAILORED MULTI-MODAL STRATEGIES

MP53-20 ADDED VALUE OF MPMRI IN THE STRATIFICATION OF PATIENTS WITH HIGH-RISK PATIENTS PROSTATE CANCER TREATED WITH RADICAL PROSTATECTOMY: IMPLICATIONS FOR TAILORED MULTI-MODAL STRATEGIES