Biochemical Recurrence-free Survival Research Articles

The Effect of Perineural Invasion on Biochemical Recurrence-free Survival Following Nerve-sparing Radical Prostatectomy

The Effect of Perineural Invasion on Biochemical Recurrence-free Survival Following Nerve-sparing Radical Prostatectomy

Ten-year functional and oncological outcomes of a prospective randomized controlled trial comparing laparoscopic versus robot-assisted radical prostatectomy.

Among prostate cancer (PCa) treatment options, mini-invasive surgical approaches have gained a wide diffusion in the last decades. The aim of this study was to present oncological, functional, and quality of life data after 10 years of follow-up of a prospective randomized controlled trial (RCT) (ISRCTN11552140) comparing robot-assisted radical prostatectomy (RARP) versus laparoscopic radical prostatectomy (LRP) for the treatment of PCa. Patients with localized PCa were randomized to undergo LRP or RARP between January 2010 and January 2011. Functional (continence and potency) and oncological (prostate-specific antigen, biochemical recurrence [BCR] and BCR-free survival [BCRFS]) variables were evaluated. BCRFS curves were estimated by the Kaplan-Meier method and compared using the log-rank test. Machine learning partial least square-discriminant analysis (PLS-DA) was used to identify the variables characterizing more the patients who underwent RARP or LRP. Seventy-five of the originally enrolled 120 patients remained on follow-up for 10 years; 40 (53%) underwent RARP and 35 (47%) LRP. Continence and potency recovery rates did not show significant differences (p = 0.068 and p = 0.56, respectively), despite a Δ12% for continence and Δ8% for potency in favor of the robotic approach. However, the quality of continence (in terms of International Consultation on Incontinence Questionnaire-Short Form [ICIQ-SF] score) and erection (in terms of International Index of Erectile Function-5 [IIEF-5] score) was significantly better after 10 years in the robotic group (p = 0.02 and p < 0.001). PLS-DA revealed that LRP was characterized by the worst functional-related outcomes analyzing the entire follow-up period. Four (10%) and six (17%) patients experienced BCR in RARP and LRP groups, respectively (p = 0.36), with an overall 10-year BCR-free survival of 88% and 78% (p = 0.16). Comparable continence and potency rates were observed between RARP and LRP after a 10-year follow-up. However, the RARP group exhibited superior totally dry rate and erection quality. No difference in terms of oncological outcomes was found.

Development of risk-score model in patients with negative surgical margin after robot-assisted radical prostatectomy

A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0–43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70–6.03, P < 0.001), lymphovascular invasion (HR 2.03, 95% CI 1.00–4.12, P = 0.049), perineural invasion (HR 10.7, 95% CI 1.45–79.9, P = 0.020), and maximum tumor diameter (MTD) > 20 mm (HR 1.9, 95% CI 1.01–3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors.

Salvage Androgen Deprivation Therapy as Potential Treatment for Recurrence after Robot-Assisted Radical Prostatectomy.

The efficacy of intermittent androgen deprivation therapy (ADT) for biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) is unknown, and its usefulness in Japanese practice needs to be investigated. We conducted a retrospective analysis of 85 patients who underwent RARP and were selected for intermittent ADT for postoperative recurrence at Kanazawa University Hospital between 2009 and 2019. Intermittent ADT was administered for 2 years. If prostate-specific antigen levels increased post-treatment, intermittent ADT was reinitiated. The median follow-up period was 47 months. The 73 patients had completed the initial course of ADT, and 12 were under initial ADT. The 5-year castration-resistant prostate-cancer-free survival rates, cancer-specific survival, and overall survival were 92.7%, 98.3%, and 94.7%, respectively. A subgroup analysis of 69 patients who completed intermittent ADT was conducted to evaluate the BCR rate following initial ADT. The 5-year BCR-free survival rate was 53.2%. Multivariate analysis identified testosterone ≤ 0.03 ng/mL during ADT as the sole predictor of BCR after ADT. Salvage intermittent ADT may be an effective treatment option for BCR after RARP. In addition, it would be useful to confirm strong testosterone suppression as a criterion for transition to intermittent therapy.

DNA Ploidy as a Potential Adjunct Prognostic Marker of Low-Risk Prostate Cancer Progression after Radical Prostatectomy.

Post prostatectomy PSA kinetics and General Grade Groups (GGG) are the strongest prognostic markers of biochemical recurrence (BCR) and prostate cancer (PCa)-specific mortality after radical prostatectomy. Despite having low-risk PCa, some patients will experience BCR, for some, clinically significant BCR. There is a need for an objective prognostic marker at the time of prostatectomy to improve risk stratification within this population. In this study, we investigated the prognostic potential of DNA ploidy. Prostatectomy samples from 97 patients with GGG1 and GGG2 with a low-risk CAPRA-S score were included in this study. PCa tissue with the worst Gleason pattern underwent tissue disaggregation, cell isolation and staining with a DNA stoichiometric stain. Using image cytometry, DNA ploidy was measured and a Ploidy Score (PS) was generated. Among the 97 patients, 79 had no BCR, 18 experienced BCR, of which 14 had a PSA doubling time (PSA-DT) >1 year (low-risk group) and 4 had a PSA-DT of <1 year (high-risk group). Using Logistic regression analysis, only pathological T stage (pT) and PS independently predicted BCR with PS being the most significant (p = 0.001). The number of aneuploid cells was significantly higher in the high-risk group compared to the other groups (p = 1.7x10-11). PS combined with GGG diagnosis further stratified risk groups of biochemical recurrence free survival within CAPRA-S low-risk cohort. DNA ploidy is an independent prognostic marker of BCR in low-risk PCa after radical prostatectomy, which could early on identify potentially aggressive PCa recurrences and introduce a more personalized approach to salvage treatments.

Abstract 7645: Differentially expressed genes as prognostic markers in racial disparities of prostate cancer

Abstract Racial disparities in prostate cancer are prevalent, with African American (AA) men experiencing 60% greater incidence and 2 to 3 times higher mortality than Caucasian American (CA) men. Consequently, there is a pressing need for improved means of interrogating race/ethnicity-based prostate cancer biology in order to identify biomarkers to help stratify men at high-risk for prostate cancer-specific progression and death and offer treatment recommendation that would mostly benefit AA men undergoing early aggressive therapies. Current predictive models rely on clinical variables but do not account for these disparities. The overall goal is to construct a race-specific prostate cancer prognostic prediction model for risk assessment. Here we performed comprehensive bioinformatics analysis using the data from 17 pairs of gene expression array from AA and CA cohorts and identified 63 differentially expressed genes (DEGs) by race. Among them, chemokine receptor 4 (CXCR4), viz. p-Akt (Ser473), fatty acid synthase (FASN), interleukin-6 (IL-6) and matrix metallopeptidase 9 (MMP-9) gene expressions were significantly altered in AA groups. Immunohistochemistry was performed on 163 prostate cancer patient specimens to validate DEG expression and immunoreactive scores (IRS) were calculated. CXCR4 exhibited significantly higher expression in AA tumors, with &amp;gt; 85% of AA prostate tumors showing weak to strong CXCR4 expression, compared to &amp;lt; 5% in CA specimens. While immunostaining for IL-6, FASN, MMP9 and p-Akt did not provide a significant distinction between CA and AA cases. IRS analysis confirmed higher expression of CXCR4 in AA cancers, compared to CA prostate cancer (p &amp;lt; 0.001). MMP9 and IL6 expression were moderately higher in AA cancer compared to CA prostate cancer (p &amp;lt; 0.05). In contrast, FASN expression was significantly higher in CA cancer, compared to AA prostate cancer (p &amp;lt; 0.001). We further investigated the impact of these genes on biochemical recurrence-free survival (BCRFS) using Kaplan-Meier analysis to examine the differences between low-risk versus high-risk groups. BCRFS analysis demonstrated that CXCR4 is a determinant factor of recurrence risk in AA prostate cancer patients. The activation of the PI3K-Akt signaling pathway, particularly in AA patients, suggests its role in prostate cancer aggressiveness. Taken together, this study demonstrates the importance of differential expression of biomarkers which constitute the bulk tumors in driving cancer. The distinct gene expression patterns, especially the upregulation of CXCR4, in AA prostate cancer highlight its potential as a prognostic biomarker and a target for personalized treatment strategies. These findings encourage further study into the role of population-specific difference in adding CXCR4 in risk model construction, especially in machine learning models. Citation Format: Amel A. Ahmed, Shiv Verma, Ibrahim M. Atawia, Daniel L. Shen, Gregory T. MacLennan, Pingfu Fu, Sanjay Gupta. Differentially expressed genes as prognostic markers in racial disparities of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7645.

Risk classification system using the detailed positive surgical margin status for predicting biochemical recurrence after robot-assisted radical prostatectomy.

This study aimed to evaluate the risk classification system using the detailed positive surgical margin (PSM) status to predict biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP). We retrospectively analyzed 427 patients who underwent RARP between January 2016 and March 2020. We investigated risk factors for BCR using univariate and multivariate Cox proportional hazard regression models. The biochemical recurrence-free survival (BRFS) rate was assessed using the Kaplan-Meier method. The median follow-up period was 43.4 months and 99 patients developed BCR. In the multivariate analysis, maximum PSM length>5.0mm and the International Society of Urological Pathology grade group (ISUP GG) at the PSM ≥3 were predictive factors for BCR in patients with a PSM. In the multivariate analysis, these factors were also independent predictive factors in the overall study population, including patients without a PSM. We classified the patients into four groups using these factors and found that the 1-year BRFS rates in the negative surgical margin (NSM) group, low-risk group (PSM and neither factor), intermediate-risk group (either factor), and high-risk group (both factors) were 94.9%, 94.5%, 83.1%, and 52.9%, respectively. The low-risk group showed similar BRFS to the NSM group (p=0.985), while the high-risk group had significantly worse BRFS than the other groups (p<0.001). Maximum PSM length>5.0mm and ISUP GG at the PSM ≥3 were independent predictive factors for BCR after RARP. Risk classification for BCR using these factors is considered to be useful and might help urologists decide on additional treatment after RARP.

Prognostic factors among patients with pathological Grade Group 5 prostate cancer based on robot-associated radical prostatectomy specimens from a large Japanese cohort (MSUG94).

There are no definitive prognostic factors for patients with pathological Grade Group 5 (pGG 5) prostate cancer (PCa) undergoing robot-associated radical prostatectomy (RARP). This study aimed to explore the prognostic factors among patients with pGG 5 PCa in a large Japanese cohort (MSUG94). This retrospective, multi-institutional cohort study was conducted between 2012 and 2021 at ten centers in Japan and included 3195 patients. Patients with clinically metastatic PCa (cN1 or cM1) and those receiving neoadjuvant and/or adjuvant therapy were excluded. Finally, 217 patients with pGG5 PCa were analyzed. The median follow-up period was 28.0months. The 3- and 5-year biochemical recurrence-free survival (BCRFS) rates of the overall population were 66.1% and 57.7%, respectively. The optimal threshold value (47.2%) for the percentage of positive cancer cores (PPCC) with any GG by systematic biopsy was chosen based on receiver operating characteristic curve analysis. Univariate analysis revealed that the prostate-specific antigen level at diagnosis, pT, pN, positive surgical margins (PSMs), lymphovascular invasion, and PPCC were independent prognostic factors for BCRFS. A multivariate analysis revealed that PSMs and PPCC were independent prognostic factors for BCRFS. Using these two predictors, we stratified BCRFS, metastasis-free survival (MFS), and castration-resistant PCa-free survival (CRPC-FS) among patients with pGG 5 PCa. The combination of PSMs and PPCC may be an important predictor of BCRFS, MFS, and CRPC-FS in patients with pGG 5 PCa undergoing RARP.

Robot-assisted vs open retropubic radical prostatectomy: a propensity score-matched comparative analysis based on 15 years and 18,805 patients.

To compare oncological, functional, and surgical outcomes of a large cohort of patients who underwent open retropubic radical prostatectomy (ORP) or robot-assisted radical prostatectomy (RARP). Data from 18,805 RPs performed with either the open or the robot-assisted approaches at a single tertiary referral center between 2008 and 2022 were analyzed. The impact of surgical approach on biochemical recurrence-free survival, salvage radiotherapy-free survival, and metastasis-free survival was analyzed by log-rank test and Kaplan-Meier analysis in a propensity score (PS)-based matched cohort. Intraoperative and postoperative surgical outcomes were assessed. One-week, 3-month, and 12-month continence rates and 12-month erectile function (EF) were analyzed. No statistically significant differences in oncological outcomes were found between ORP and RARP. A slight statistically significant difference in favor of RARP was noted in urinary continence at 3 months (RARP vs. ORP: 81% vs. 77%, p = 0.007) and 12 months (91% vs. 89.3%, p = 0.008), respectively. The rate of EF was statistically significantly higher (60%) after RARP than after ORP (45%, p < 0.001). Both RARP and ORP yielded similar oncological outcomes. RARP offered a slight advantage in terms of continence recovery, but its clinical significance may be less meaningful. RARP resulted in significantly improved postoperative EF, suggesting a potential influence of both surgical experience and minimally invasive approach.

Nadir prostate-specific antigen after salvage cryotherapy as a potential prognostic factor for oncologic outcomes.

To report oncologic outcomes of patients undergoing salvage cryotherapy (SCT) for local recurrence of prostate cancer (PCa) and to establish a nadir PSA (nPSA) value that best defines long-term oncologic success. Retrospective study of men who underwent SCT for local recurrence of PCa between 2008 and 2020. SCT was performed in men with biochemical recurrence (BCR), after primary treatment and with biopsy-proven PCa local recurrence. Survival analysis with Kaplan-Meier and Cox models was performed. We determined the optimal cutoff nPSA value after SCT that best classifies patients depending on prognosis. Seventy-seven men who underwent SCT were included. Survival analysis showed a 5-year biochemical recurrence-free survival (BRFS), androgen deprivation therapy-free survival (AFS), and metastasis-free survival (MFS) after SCT of 48.4%, 62% and 81.3% respectively. On multivariable analysis for perioperative variables associated with BCR, initial ISUP, pre-SCT PSA, pre-SCT prostate volume and post-SCT nPSA emerged as variables associated with BCR. The cutoff analysis revealed an nPSA < 0.5ng/ml to be the optimal threshold that best defines success after SCT. 5-year BRFS for patients achieving an nPSA < 0.5 vs nPSA ≥ 0.5 was 64% and 9.5% respectively (p < 0.001). 5-year AFS for men with nPSA < 0.5 vs ≥ 0.5 was 81.2% and 12.2% (p < 0.001). Improved 5-year MFS for patients who achieved nPSA < 0.5 was also obtained (89.6% vs 60%, p = 0.003). SCT is a feasible rescue alternative for the local recurrence of PCa. Achieving an nPSA < 0.5ng/ml after SCT is associated with higher long-term BRFS, AFS and MFS rates.

Focal brachytherapy as definitive treatment for localized prostate cancer: A systematic review and meta-analysis

PURPOSEIn this systematic review and meta-analysis, we describe the oncologic and toxicity outcomes of definitive focal brachytherapy for prostate cancer. METHODS AND MATERIALSA PROSPERO registered study (CRD42023410170) was conducted following the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. PubMed, Embase, and The Cochrane Library were searched for studies between 2000 and 2022. Two authors independently performed the initial search. Biochemical recurrence-free survival (bRFS) was defined as the primary endpoint for the meta-analysis. Generalized linear mixed-effects models were conducted to calculate effect size and quantify heterogeneity. We also describe the side effects and local recurrence patterns of focal brachytherapy. RESULTSTen studies were identified and included 315 patients treated using focal brachytherapy as a definitive treatment. Mean (SD) age was 67.65 (7.9) years and mean (SD) PSA was 7.15 (2.7) ng/mL. Most patients (n = 236, 75%) underwent LDR Brachytherapy and 25% received HDR brachytherapy. Among the participants, 147 (46.5%) had a Gleason score ≤6, and 169 (53.5%) had a Gleason score ≥7. Only 11 (3.5%) patients received ADT. Overall, bRFS rate at median follow-up 4 years (Range: 1–6.42 years) was 91% (95% confidence interval [CI], 82–95%). Acute Grade ≤ 2 GU and GI toxicities were reported in 22 (7%) and 11 (3.5%) patients, respectively. Late Grade ≤ 2 GU and GI toxicity were reported in 6 (2%) and 14 (4.4%) patients, respectively. One case of prostate hemorrhage due to improper foley removal was noted but otherwise no acute or late Grade 3 or higher GI or GU toxicity related to radiotherapy was reported. CONCLUSIONOverall, definitive focal brachytherapy has a favorable toxicity profile. Oncologic outcomes are yet to mature. The evidence is limited by the small number of studies with low patients’ number, across study heterogeneity, and possibility of publication bias.

Intermediate-Term Oncological Outcome Assessment for Robotic Assisted Radical Prostatectomy Comparing Retzius Sparing to Standard Approach in a Randomized Control Cohort.

Retzius sparing prostatectomy was promoted with the early continence result. The long-term oncological outcome is still unknown. In this study, we aimed to compare the Intermediate-term oncologic outcomes of these two approaches in patient's cohort who was treated as part of a randomized controlled trial. A total of 120 patients were previously randomized equally to receive retzius sparing (RS-RARP) versus standard robotic assisted laparoscopic radical prostatectomy (S-RARP) between January 2015 to April 2016. Baseline, surgical, and pathological characteristics as well as oncologic outcomes were assessed. The analysis was done based on the treatment received. Sixty-three patients underwent S-RARP while 57 patients underwent RS-RARP. There was no statistically significant difference in the baseline nor surgical characteristics. The median follow up was 71.24 (IQR 59.75 - 75.75). There were more pathological T3 diseases in RS-RARP. There was no significant difference in the positive margin status nor the biochemical recurrence rate among both groups. After S-RARP and RS-RARP, 6 and 10 patients had biochemical recurrence and the 5-years biochemical recurrence free survival were 91% and 85%, respectively. (p= 0.21) Conclusion: In this cohort, there was no difference in biochemical recurrence in the patients who received either technique. Further mutli-institutional studies with a larger sample size and longer follow up are required.

Addition of cribriform pattern 4 and intraductal prostatic carcinoma into the CAPRA-S tool improves post-radical prostatectomy patient stratification in a multi-institutional cohort

AimsPre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we...

Nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiotherapy: A systematic review and meta-analysis.

To conduct a meta-analysis to provide the latest evidence of nonsurgical local salvage options in the first-line radiotherapy failure setting for localized prostate cancer patients. Recurrence of localized prostate cancer after primary radiotherapy (RT) remains a clinical challenge. There is no consensus on optimal nonsurgical local salvage therapies, which mainly consist of cryotherapy (CRYO), high-intensity focused ultrasound (HIFU), high/low-dose-rate brachytherapy (HDR/LDR), and stereotactic body radiotherapy (SBRT). Our study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We systematically searched PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov up to September 2023 to identify potentially relevant studies. The risk of bias was assessed using the European Association of Urology (EAU) items. Biochemical recurrence-free survival (bRFS) and genitourinary/gastrointestinal toxicities were the outcomes of interest. Pooled rates with 95% confidence intervals (CIs) were evaluated. A total of 99 studies comprising 8440 patients were included. The pooled rate of 1-year biochemical control (BC) was highest for LDR (0.88, 95%CI 0.72-0.95) and lowest for SBRT (0.68, 95%CI 0.49-0.83). The pooled rate of 5-year BC was highest for CRYO (0.52, 95%CI 0.33-0.69) and lowest for HDR (0.23, 95%CI 0.08-0.51). HIFU presented the worst outcome of grade ≥3 genitourinary toxicities (GU3), with a rate of 0.22 (95%CI 0.12-0.3). Conversely, CRYO (0.09, 95%CI 0.04-0.14), HDR (0.05, 95%CI 0.02-0.07), LDR (0.10, 95%CI 0.06-0.14) and SBRT (0.06, 95%CI 0.03-0.09) presented low rates of GU3. All subgroups induced a quite low incidence of grade ≥3 gastrointestinal toxicities (GI3). Nonsurgical salvage therapies are promising modalities for prostate cancer in the local radiorecurrence setting. Based on the preliminary evidence from this study, CRYO and SBRT might present a relatively steady efficacy of BC with acceptable treatment-related toxicities.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer

PurposeInvestigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer.Material and MethodsMAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay.ResultsMAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001).ConclusionThe present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis.

Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.

Phase II study of pembrolizumab in combination with radiation with or without olaparib in localized high-risk prostate cancer.

TPS351 Background: Definitive radiation therapy (DRT) combined with androgen deprivation therapy (ADT) remains the standard of care in patients with high-risk prostate cancer (HRPC) who do not want surgery. However, up to 50% experience biochemical recurrence (BCR) within 5 years. A phase 3 NCIC group reported the 10-year biochemical recurrence free survival was 63% in ADT plus DRT vs. 27% in ADT alone. There is an urgent need for effective novel combination strategies. We hypothesize combined immune sensitizing effects of PARPi and radiation will result in significant activity of immunotherapy in men with HRPC. Methods: This is a multicenter phase II randomized study to assess biochemical response rates, safety and tolerability of combined therapy in pts with localized HRPC who elected for concurrent DRT. A total of 64 pts will be randomized 1:1 to receive either pembrolizumab (P) combined with olaparib or single agent P in addition to the standard of care ADT with DRT. Hypofractionated IMRT (2.4 to 4 Gy per fraction over 4-6 weeks) will be delivered and all pts will receive adjuvant P for one year and ADT for at least 18 months. All pts will undergo germline testing. Key eligible criteria include biopsy confirmed prostate adenocarcinoma who meets at least one of the four high-risk features: 1) clinical T3a, T3b or T4, 2) N1, 3) Gleason grade group 4 or 5, and 4) PSA &gt;20 ng/ml. Patients with less than 2 cm pelvic nodes and received ADT therapy within 3months prior to study enrollment are allowed. PSA &gt;150 ng/ml and patients with distant metastases will be excluded. The primary endpoint is to assess the proportion of patients who achieve a PSA nadir level of ≤ 0.06 ng/ml within six months after completion of radiation therapy in each arm. The secondary objectives include safety/tolerability, BCR and metastasis-free survival at 3 years. BCR is defined by the Phoenix definition. The study is designed to detect a 15% improvement in PSA nadir ≤ 0.06 ng/mL within 6 months after completion of the combined therapy versus historical control group data Geara FB et al., 2017. Enrollment began in August 2023. Clinical trial information: NCT05568550 .

Size of lymph-node metastases in prostate cancer patients undergoing radical prostatectomy: implication for imaging and oncologic follow-up of 2705 lymph-node positive patients

BackgroundDespite modern imaging modalities, lymph-node staging before radical prostatectomy (RP) remains challenging in patients with prostate cancer (PCa). The visibility of lymph-node metastases (LNMs) is critically influenced by their size.ObjectiveThis study aims to describe the distribution of maximal tumor diameters (i.e., size) in LNMs of pN1-PCa at RP and its consequences on visibility in preoperative imaging and oncological outcomes.Design, setting, and participantsA total of 2705 consecutive patients with pN1-PCa at RP, harboring a cumulative 7510 LNMs, were analyzed. Descriptive and multivariable analyses addressed the risk of micrometastases (MM)-only disease and the visibility of LNMs. Kaplan–Meier curves and Cox analyses were used for biochemical recurrence-free survival (BCRFS) stratified for MM-only disease.ResultsThe median LNM size was 4.5mm (interquartile range (IQR): 2.0–9.0 mm). Of 7510 LNMs, 1966 (26%) were MM (≤ 2mm). On preoperative imaging, 526 patients (19%) showed suspicious findings (PSMA-PET/CT: 169/344, 49%). In multivariable analysis, prostate-specific antigen (PSA) (OR 0.98), age (OR 1.01), a Gleason score greater than 7 at biopsy (OR 0.73), percentage of positive cores at biopsy (OR 0.36), and neoadjuvant treatment (OR 0.51) emerged as independent predictors for less MM-only disease (p < 0.05). Patients with MM-only disease compared to those harboring larger LNMs had a longer BCRFS (median 60 versus 29 months, p < 0.0001).ConclusionOverall, 26% of LNMs were MM (≤ 2mm). Adverse clinical parameters were inversely associated with MM at RP. Consequently, PSMA-PET/CT did not detect a substantial proportion of LNMs. LNM size and count are relevant for prognosis.

Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer

BackgroundCancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present and process antigens in PRAD has not been investigated. In this study, antigen presentation and process-related CAFs (APPCAFs) were identified using bioinformatics, and the clinical implications of APPCAF-related signatures in PRAD were investigated.MethodsSMART technology was used to sequence the transcriptome of primary CAFs isolated from patients undergoing different treatments. Differential expression gene (DEG) screening was conducted. A CD4 + T-cell early activation assay was used to assess the activation degree of CD4 + T cells. The datasets of PRAD were obtained from The Cancer Genome Atlas (TCGA) database and NCBI Gene Expression Omnibus (GEO), and the list of 431 antigen presentation and process-related genes was obtained from the InnateDB database. Subsequently, APP-related CAFs were identified by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses were performed to depict the biological functions. A risk signature based on APPCAF-related genes (APPCAFRS) was developed by least absolute shrinkage and selection operator (LASSO) regression analysis, and the independence of the risk score as a prognostic factor was evaluated by univariate and multivariate Cox regression analyses. Furthermore, a biochemical recurrence-free survival (BCRFS)-related nomogram was established, and immune-related characteristics were assessed using the ssGSEA function. The immune treatment response in PRAD was further analyzed by the Tumor Immune Dysfunction and Exclusion (TIDE) tool. The expression levels of hub genes in APPCAFRS were verified in cell models.ResultsThere were 134 upregulated and 147 downregulated genes, totaling 281 differentially expressed genes among the primary CAFs. The functions and pathways of 147 downregulated DEGs were significantly enriched in antigen processing and presentation processes, MHC class II protein complex and transport vesicle, MHC class II protein complex binding, and intestinal immune network for IgA production. Androgen withdrawal diminished the activation effect of CAFs on T cells. NMF clustering of CAFs was performed by APPRGs, and pseudotime analysis yielded the antigen presentation and process-related CAF subtype CTSK + MRC2 + CAF-C1. CTSK + MRC2 + CAF-C1 cells exhibited ligand‒receptor connections with epithelial cells and T cells. Additionally, we found a strong association between CTSK + MRC2 + CAF-C1 cells and inflammatory CAFs. Through differential gene expression analysis of the CTSK + MRC2 + CAF-C1 and NoneAPP-CAF-C2 subgroups, 55 significant DEGs were identified, namely, APPCAFRGs. Based on the expression profiles of APPCAFRGs, we divided the TCGA-PRAD cohort into two clusters using NMF consistent cluster analysis, with the genetic coefficient serving as the evaluation index. Four APPCAFRGs, THBS2, DPT, COL5A1, and MARCKS, were used to develop a prognostic signature capable of predicting BCR occurrence in PRAD patients. Subsequently, a nomogram with stability and accuracy in predicting BCR was constructed based on Gleason grade (p = n.s.), PSA (p < 0.001), T stage (p < 0.05), and risk score (p < 0.01). The analysis of immune infiltration showed a positive correlation between the abundance of resting memory CD4 + T cells, M1 macrophages, resting dendritic cells, and the risk score. In addition, the mRNA expression levels of THBS2, DPT, COL5A1, and MARCKS in the cell models were consistent with the results of the bioinformatics analysis.ConclusionsAPPCAFRS based on four potential APPCAFRGs was developed, and their interaction with the immune microenvironment may play a crucial role in the progression to castration resistance of PRAD. This novel approach provides valuable insights into the pathogenesis of PRAD and offers unexplored targets for future research.

SARIFA as a new histopathological biomarker is associated with adverse clinicopathological characteristics, tumor-promoting fatty-acid metabolism, and might predict a metastatic pattern in pT3a prostate cancer

BackgroundRecently, we introduced Stroma-AReactive-Invasion-Front-Areas (SARIFA) as a novel hematoxylin–eosin (H&E)-based histopathologic prognostic biomarker for various gastrointestinal cancers, closely related to lipid metabolism. To date, no studies on SARIFA, which is defined as direct tumor-adipocyte-interaction, beyond the alimentary tract exist. Hence, the objective of our current investigation was to study the significance of SARIFA in pT3a prostate cancer (PCa) and explore its association with lipid metabolism in PCa as lipid metabolism plays a key role in PCa development and progression.MethodsTo this end, we evaluated SARIFA-status in 301 radical prostatectomy specimens and examined the relationship between SARIFA-status, clinicopathological characteristics, overall survival, and immunohistochemical expression of FABP4 and CD36 (proteins closely involved in fatty-acid metabolism). Additionally, we investigated the correlation between SARIFA and biochemical recurrence-free survival (BRFS) and PSMA-positive recurrences in PET/CT imaging in a patient subgroup. Moreover, a quantitative SARIFA cut-off was established to further understand the underlying tumor biology.ResultsSARIFA positivity occurred in 59.1% (n = 178) of pT3a PCas. Our analysis demonstrated that SARIFA positivity is strongly associated with established high-risk features, such as R1 status, extraprostatic extension, and higher initial PSA values. Additionally, we observed an upregulation of immunohistochemical CD36 expression specifically at SARIFAs (p = 0.00014). Kaplan–Meier analyses revealed a trend toward poorer outcomes, particularly in terms of BRFS (p = 0.1). More extensive tumor-adipocyte interaction, assessed as quantity-dependent SARIFA-status on H&E slides, is also significantly associated with high-risk features, such as lymph node metastasis, and seems to be associated with worse survival outcomes (p = 0.16). Moreover, SARIFA positivity appeared to be linked to more distant lymph node and bone metastasis, although statistical significance was slightly not achieved (both p > 0.05).ConclusionsThis is the first study to introduce SARIFA as easy-and-fast-to-assess H&E-based biomarker in locally advanced PCa. SARIFA as the histopathologic correlate of a distinct tumor biology, closely related to lipid metabolism, could pave the way to a more detailed patient stratification and to the development of novel drugs targeting lipid metabolism in pT3a PCa. On the basis of this biomarker discovery study, further research efforts on the prognostic and predictive role of SARIFA in PCa can be designed.