After Androgen Deprivation Therapy Research Articles

Diagnostic efficacy and interobserver agreement among readers with variable experience of the Prostate Imaging for Recurrence Reporting system with whole-mount histology after androgen deprivation therapy as a reference.

The Prostate Imaging for Recurrence Reporting (PI-RR) system was recently proposed to assess the local recurrence of prostate cancer (PCa), but its exact performance for the prostate after radiotherapy or radical prostatectomy is difficult to determine. We aimed to evaluate the diagnostic performance and interreader agreement of this system using whole-mount histology of the prostate after androgen deprivation therapy (ADT) as the standard of reference. In total, 119 patients with PCa post-ADT underwent multiparametric magnetic resonance imaging (mp-MRI) before prostatectomy. Three radiologists analyzed the MRI images independently, scoring imaging findings according to PI-RR. Spearman correlation was performed to assess the relationship between the percentage of sectors with residual cancer and PI-RR score. The diagnostic performance for detection of residual cancer was assessed on a per-sector basis. The chi-squared test was used to compare the cancer detection rate (CDR) among readers. Overall and pairwise interreader agreement in assigning PI-RR categories and residual cancer sectors with a score ≥3 or ≥4 were evaluated with the Cohen kappa coefficient. Histology revealed 209 sectors with residual cancer. The percentage of pathologically positive sectors increased with the increase in PI-RR score for all readers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at a cutoff of score 3 ranged from 74.2% to 83.7%, 86.4% to 92.7%, 51.3% to 64.3%, and 95.4% to 96.9%, respectively, and at a cutoff of score 4, they ranged from 47.4% to 56.5%, 97.9% to 98.6%, 82.5% to 85.3%, and 91.6% to 92.9%, respectively. There was no significant difference among the CDR of readers. In PI-RR categories and detection of residual cancer sectors, overall interreader agreement was moderate for all readers, but agreement was higher between the more experienced readers (moderate to substantial) than between the more and less experienced readers (fair to moderate). MRI scoring with the PI-RR assessment provided accurate evaluation of PCa after ADT, but readers' experience influenced interreader agreement and cancer diagnosis.

Sexual experiences and information needs among patients with prostate cancer: a qualitative study.

Less is known about the sexual life and information seeking of Chinese patients with prostate cancer (PCa) after androgen deprivation therapy (ADT) treatment. To identify the experiences of sex and information needs among Chinese patients with PCa after ADT treatment. This qualitative study included 15 Chinese patients with PCa in urology inpatient wards, selected via a purposive sampling method. Semistructured interviews were conducted face-to-face or by telephone regarding sexual experiences and information needs after ADT treatment. Themes and subthemes were assessed among patients with PCa. Two themes and 5 subthemes emerged from the interview data. The first theme was "altered sexual life and attitude" with 3 subthemes: (1) undesirable sexual function and altered sexuality, (2) sexual attitudes and sociocultural cognition, and (3) behavior adjustment and intimacy. The second theme was "scarce information sources" with 2 subthemes: (1) uncertainty and lack of information support and (2) barriers to access sexual information. The present findings suggest that the following may help patients with PCa manage treatment and develop appropriate sexual attitudes: a tailored sexual health education program, well-equipped consultations rooms, and information delivery innovations. Strengths of this study included adding unique evidence among patients with PCa within an Asian context to reveal the understudied topic of sexual health and information needs after ADT treatment. This study was limited in being representative of all Chinese patients with PCa, with different marital statuses, treatment therapies, sexual orientations, and barriers of information seeking. Sexual life and attitude among patients with PCa were affected by their sociocultural cognition and ADT treatment, and most patients received insufficient information and sexual health education from health care providers.

Longer time to testosterone recovery impacts favorably on outcomes for prostate cancer following androgen deprivation and radiotherapy.

To evaluate the impact of sustained hypogonadism after androgen deprivation therapy (ADT) associated with radiotherapy in prostate cancer (PCa) patients with biochemical relapse-free survival (bRFS). Aretrospective cohort analysis of 213consecutive PCa patients referred for radiotherapy plus ADT was carried out. Follow-up times including time to testosterone recovery (TTR) and bRFS were calculated from the end of ADT. Univariate and multivariate Cox regression analyses predicting bRFS were used. The optimal cutoffs for TTR and duration of ADT were determined using the maximally selected rank statistics (MSRS). After amedian follow-up of 104 months, 18patients relapsed among those who had recovered testosterone levels and 9 among those who did not. Median ADT duration was 36months. The optimal cutoff for TTR was determined using MSRS. TTR >48months was significantly associated with better bRFS (logrank, p < 0.0027). Five-year bRFS was 100% for >48months vs. 85% for <48months. TTR was the only significant variable for bRFS in multivariate Cox analysis. Our data show an association between longer TTR and bRFS values among PCa patients treated with ADT.

Polyphyllin I induces ferroptosis in castration-resistant prostate cancer cells through the ERK/DNMT1/ACSL4 axis.

Castration-resistant prostate cancer (CRPC) inevitably arises after androgen deprivation therapy (ADT). Therefore, there is an urgent need to search for novel treatment strategies for CRPC. Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been shown to have an anticancer effect. This study investigated the role and mechanism of PPI in CRPC cell ferroptosis. Protein levels of GPX4, p-extracellular regulated protein kinases (ERK), ERK, DNMT1, and ACSL4 were measured by Western blot. DNMT1 and ACSL4 mRNA expression was analyzed byreverse transcription-quantitative polymerase chain reaction (RT-qPCR). Prostate cancer cells (DU145, PC3) were treated with PPI. Cell viability was assessed utilizing Cell Counting Kit-8 (CCK-8) assay. The role of PPI in regulating ferroptosis was determined by analyzing lipid reactive oxygen species (ROS), malonyl dialdehyde (MDA), iron (Fe2+ ), and glutathione (GSH) content. Chromatin immunoprecipitation (ChIP) assay verified the effect of DNMT1 on the ACSL4 promoter. The methylation level of ACSL4 promoter was assessed utilizing MSP. A nude mice xenograft was adopted to detect the effect of PPI in vivo. PPI inhibited CRPC cell proliferation, reduced levels of GSH and GPX4, and increased levels of MDA, Fe2+ , and ROS, while ERK inhibitor reversed the effect of PPI on ferroptosis. PPI repressed the methylation level of ACSL4 promoter by inhibiting DNMT1. DNMT1 knockdown promoted CRPC cell ferroptosis by regulating ACSL4. PPI induced ferroptosis and suppressed CRPC growth in nude mice. PPI can be used as a ferroptosis inducer to induce ferroptosis in CRPC cells via the ERK/DNMT1/ACSL4 axis, suggesting that PPI may be a new strategy for CRPC treatment.

The expression of PKM1 and PKM2 in benign and cancerous prostatic tissues.

e17058 Background: Prostate cancer (PCa) is the most diagnosed cancers in American men. After androgen deprivation therapy (ADT) fails, there is an increase in the aggressive neuroendocrine (NE) phenotype. Currently, there is no effective treatment for NE prostate cancer (NEPC). The metabolic reprogramming, one of the cancer hallmarks, regulates PCa progression and therapy resistance. However, the energy metabolism in NEPC has not been well studied yet. Pyruvate kinase (PK), catalyzing the final step of glycolysis, has PKM1, PKM2, PKL and PKR four isoforms. PKL and PKR are expressed in the liver and erythrocytes, respectively. Alternative splicing of PKM results in two isoforms, PKM1 and PKM2, which are expressed in most tissues. In prostate adenocarcinoma, loss of PKM1 promotes PCa progression whereas loss of PKM2 suppresses tumor growth. However, the expression pattern of PKM1 and PKM2 in NEPCa remains largely unknown. Methods: Immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR were conducted to examine the expression of PKM1 and PKM2 in both murine and human prostatic tissues. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE). Results: TRAMP is a widely used PCa mouse model. TRAMP mice develop prostatic intraepithelial neoplasia (PIN) and the tumors progress into NEPC following castration. We found that PKM1 expression was detected in normal prostate but not in the PIN lesions. In the TRAMP NEPC tumors, PKM1 expression was detected in the NE areas but not in the adjacent PIN lesions. Compared with the adjacent PIN, NEPC cells displayed lower PKM2 expression. Further, we examined the expression of PKM1 and PKM2 in human prostatic tissues including benign prostatic hyperplasia (BPH), low-grade adenocarcinomas (AdPCa), high-grade AdPCa, and NEPC. We found that in BPH, basal epithelial cells express both PKM1 and PKM2. In PCa, PKM1 was robustly expressed in the stromal cells but its expression was absent in the cancer cells in majority of the specimens examined except a small number of samples where low level of PKM1 was detected in the cancer cells. However, PKM1 expression was detected in 9 out of 12 NEPC samples and colocalized with NE marker chromogranin A. This co-expression was also detected in the NE cells scattered on the prostate adenocarcinoma tissues. As for PKM2, its expression was detected in all the samples examined. However, different from previous report, PKM2 expression levels did not correlate with cancer grade in this cohort. Conclusions: PKM1 is expressed in the basal epithelial cells of benign prostates, a small subset of prostate adenocarcinomas, and 75% NEPC tumors. PKM2 is expressed throughout prostate development, in both benign and cancerous prostate. However, PKM2 expression does not correlate with tumor grade.

(060) Chronology of Endogenous Testosterone Recovery Following Androgen Deprivation Therapy Cessation – Results From a Prospective Analysis

Abstract Introduction Testosterone (T) recovery after androgen deprivation therapy (ADT) is reported in the literature from 7 to 96%, with data mainly from retrospective studies using variable definitions for this event. Age, Diabetes and ADT duration may affect the timing and completeness of recovery Objective Prospectively evaluate the chronology of T recovery following ADT cessation Methods This is a secondary analysis of a prospective oncological study designed to evaluate the impact of neoadjuvant use of ADT in combination with abiraterone acetate and prednisone with or without apalutamide in patients with high-risk prostate cancer. Both regimens were administered for 3 months before radical prostatectomy (RP). Early morning Total T (TT) levels were collected (immunoassay) at baseline and periodically (3, 6 and 12 months) after ADT cessation. 3 outcomes for T recovery were evaluated: return to non-castrate level (TT &amp;gt;50 ng/dL), to normal T (TT ≥ 300 ng/dL) and back to baseline level (BTB –TT≥ baseline level). We performed a time-to-event analysis and reported the cumulative incidence of each outcome. Multivariable analysis was conducted to investigate predictors of recovery Results In this preliminary report, from 64 initially enrolled patients, 1 year follow-up T data from 50 pts were available. Mean age was 64.6 ± 5.89 years, 28% had type 2 diabetes (DM) and 61% hypertension (HTN). Mean TT levels were 450 ± 170ng/dl at baseline, 112. 7± 96.9 at 3m, 208.5 ±197 at 6m, 337.7 ± 170 at 9m and 378.2 ± 166 at 12 m. Figure 1 shows the cumulative incidence of each outcome according to time. Median time to achieve T&amp;gt;50 was 5 m, to achieve T&amp;gt;300 was 9.1m and BTB 13.13 m. At 1 year, 98% had returned back from castrate-level, 76% had TT normalized and 42% had return BTB. In a multivariable analysis including DM, HTN, age and baseline T, only baseline T was associated with a greater chance of recovery, with 88.5% of those with baseline T &amp;gt; 450 ng/dl achieving normal T at 1y vs 46.9% for patients with baseline T &amp;lt; 450 ng/dl (HR: 3.56, p&amp;lt; 0.001) Conclusions In this prospective analysis of a population exposed to neoadjuvant short-term ADT, T recovery rates after 1 year showed that the vast majority (98%) had returned back from castrate level (median time 5m), about 2/3 recovered back to normal levels (median time 9,1m) and less than half returned to BTB level. Baseline TT was the only predictor of T recovery Disclosure Yes, this is sponsored by industry/sponsor: Source of Funding: Janssen-Cilag Farmacêutica Ltda Clarification Industry funding only - investigator initiated and executed study

(298) MRI Measurement of Perineal and Pelvic Muscles as a Novel Imaging Marker for Hypogonadism

Abstract Introduction Low serum testosterone (T) in the presence of clinical symptoms of hypogonadism is essential in determining who may benefit from T replacement therapy. However, clinical symptoms associated with hypogonadism are non-specific and challenging to discriminate from other etiologies. While low bone mineral density is an objective primary end-organ effect of low testosterone, DEXA scans are not recommended by national guidelines due to poor sensitivity and specificity, and the limitation that these changes likely manifest over a prolonged period of time. Notably, prior studies have demonstrated that perineal ultrasound of the bulbocavernosus muscle (BCM) can be an effective surrogate to evaluate end-organ activity of hypogonadism. However, it is unclear if low BCM area is secondary to or rather correlated with hypogonadism, and longitudinal studies assessing men in both the eugonadal and hypogonadal state are lacking. Objective To report an initial experience with measuring the androgen-sensitive BCM, ischiocavernosus muscle (ICM), and levator ani muscles (LAM) on MRI in men before and after androgen deprivation therapy (ADT) as a novel imaging marker for end-organ effects of hypogonadism. Methods Data was collected from treatment-naive patients with intermediate or high-risk localized prostate cancer enrolled in a clinical trial involving six months of neoadjuvant treatment with goserelin and enzalutamide prior to prostatectomy. Patients underwent 3-Tesla multiparametric MRI of the prostate prior to treatment and again immediately prior to prostatectomy. An expert genitourinary trained radiologist retrospectively assessed MR images and measured width of the bilateral BCM, ICM, and LAM on coronal T2W MRI (Figure 1). Paired t-tests were performed to evaluate changes in muscle width before and after ADT. Linear regression was performed to evaluate the relationship between change in total testosterone levels and change in muscle width. The lower detection limit of testosterone was 20 ng/dL, and T less than 20 ng/dL was set to 0 for statistical analysis. Results 38 patients with pre- and post-treatment MRIs were identified with a median time between scans of 6.85 months. Median age at start of trial was 62.5 years (IQR: 58-69). 28/38 patients had documented AUA/IPSS and SHIM questionnaires with median scores of 8 and 19.5, respectively. Mean total testosterone prior to androgen deprivation was 289.5 ng/dL (SD= 121.7). 34/38 patients reached castrate level (T less than 20 ng/dL) after treatment completion, with mean testosterone 4.7 ng/dL (SD= 15.4). Muscle width was significantly reduced in all three muscle groups following ADT (Table 1). Linear regression found that decreases in testosterone significantly predicted decreases in combined perineal muscle (BCM + ICM) width (β = 0.0056, p = 0.032). Conclusions Decreases in testosterone to castrate levels led to significant and rapid decreases in sizes of both perineal and pelvic muscles. This shows initial plausibility in using an image-based approach to assess a short- to intermediate-term objective marker of end-organ effects of hypogonadism. Future prospective studies with larger samples and refinement of MRI sequences may lead to a useful clinical tool in the diagnosis and clinical workup of hypogonadism, and help clinicians better understand who would benefit from testosterone supplementation. Disclosure No

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

PD11-07 CHRONOLOGY OF ENDOGENOUS TESTOSTERONE RECOVERY FOLLOWING ADT CESSATION – RESULTS FROM A PROSPECTIVE ANALYSIS

You have accessJournal of UrologyCME1 Apr 2023PD11-07 CHRONOLOGY OF ENDOGENOUS TESTOSTERONE RECOVERY FOLLOWING ADT CESSATION – RESULTS FROM A PROSPECTIVE ANALYSIS Bruno Nascimento, Rubens Pedrenho Neto, Pedro C.E. Zandoná, Diogo Assed Bastos, Rafael F. Coelho, Jose Bessa, Feira De Santana, William C. Nahas, Jorge Hallak, Cristiano M. Gomes, and John P. Mulhall Bruno NascimentoBruno Nascimento More articles by this author , Rubens Pedrenho NetoRubens Pedrenho Neto More articles by this author , Pedro C.E. ZandonáPedro C.E. Zandoná More articles by this author , Diogo Assed BastosDiogo Assed Bastos More articles by this author , Rafael F. CoelhoRafael F. Coelho More articles by this author , Jose BessaJose Bessa More articles by this author , Feira De SantanaFeira De Santana More articles by this author , William C. NahasWilliam C. Nahas More articles by this author , Jorge HallakJorge Hallak More articles by this author , Cristiano M. GomesCristiano M. Gomes More articles by this author , and John P. MulhallJohn P. Mulhall More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003251.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testosterone (T) recovery after androgen deprivation therapy (ADT) is reported variably in the literature (7 to 96%), due to variable definitions, follow up periods and with data coming mainly from restrospective studies. Age, diabetes and baseline T are reported as associated factors with recovery. Our aim was to report the chronology of T recovery following ADT cessation. METHODS: This is a secondary analysis of an oncological study with a prospective design evaluating the neoadjuvant use of ADT in combination with abiraterone acetate and prednisone with or without apalutamide in high-risk localized patients. Both regimens were administered for 3 m before radical prostatectomy (RP). Early morning Total T (TT) levels were collected at baseline and periodically (3, 6 and 12 m) after ADT cessation. 3 outcomes for T recovery were evaluated: return to non-castrate level (TT > 50 ng/dL), to normal (TT ≥ 300 ng/dL) and back to baseline level (BTB –TT≥ baseline level). We performed a time-to-event analysis and reported the cumulative incidence of each outcome. Multivariable analysis was conducted to investigate predictors of recovery. RESULTS: In this preliminary report, from 64 initially enrolled patients, 1 year follow-up T data from 50 pts were available. Mean age was 64,6y (± 5,89), 28% had type 2 diabetes (DM) and 61% hypertension (HTN). Mean baseline TT was 450ng/dl (± 170) ng/dL, 112,7 at 3m ( ± 96,9), 208,5 ( ±197) at 6m, 337,7 ( ± 170) at 9m and 378,2 (± 166) at 12 m. Figure 1 represents the cumulative incidence of each outcome according to time. Median time to achieve T>50 was 5 m, to achieve T>300 was 9,1 m and BTB 13,13 m. At 1 year, 98% had return back from castrate-level, 76% had TT normalized and only 42% had return BTB. In multivariable analysis including DM, HTN, age and baseline T, only baseline T was significantly associated with a greater chance of recovery, with 88,5% and 46,9% achieving normal T at 1y for patients with baseline T greater and lower than 450 ng/dl (HR: 3,56, p=0,0008) CONCLUSIONS: In this prospective analysis of a population exposed to neoadjuvant short-term ADT, T recovery rates were relatively high at1 year, with 98% having TT>50 ng/dl, about 2/3 third having TT back to TT>300 ng/dl, but with less than half with BTB level. An effort should be made to measure TT before starting ADT. Source of Funding: Janssen-Cilag Farmacêutica Ltda © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e334 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bruno Nascimento More articles by this author Rubens Pedrenho Neto More articles by this author Pedro C.E. Zandoná More articles by this author Diogo Assed Bastos More articles by this author Rafael F. Coelho More articles by this author Jose Bessa More articles by this author Feira De Santana More articles by this author William C. Nahas More articles by this author Jorge Hallak More articles by this author Cristiano M. Gomes More articles by this author John P. Mulhall More articles by this author Expand All Advertisement PDF downloadLoading ...

The role of 11-oxygenated androgens in prostate cancer.

11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC. Consequently, these steroids are of particular interest in the castration-resistant prostate cancer (CRPC) setting. The principal androgen of the pathway, 11-ketotestosterone (11KT), is a potent AR agonist and the predominant circulating active androgen in CRPC patients. Additionally, several precursor steroids are present in the circulation which can be converted into active androgens by steroidogenic enzymes present in PC cells. In vitro evidence suggests that adaptations frequently observed in CRPC favour the intratumoral accumulation of 11-oxygenated androgens in particular. Still, apparent gaps in our understanding of the physiology and role of the 11-oxygenated androgens remain. In particular, in vivo and clinical evidence supporting these in vitro findings is limited. Despite recent advances, a comprehensive assessment of intratumoral concentrations has not yet been performed. The exact contribution of the 11-oxygenated androgens to CRPC progression therefore remains unclear. This review will focus on the current evidence linking the 11-oxygenated androgens to PC, will highlight current gaps in our knowledge, and will provide insight into the potential clinical importance of the 11-oxygenated androgens in the CRPC setting based on the current evidence.

Radiomics based on biparametric MRI for the detection of significant residual prostate cancer after androgen deprivation therapy: using whole-mount histopathology as reference standard.

We aimed to study radiomics approach based on biparametric magnetic resonance imaging (MRI) for determining significant residual cancer after androgen deprivation therapy (ADT). Ninety-two post-ADT prostate cancer patients underwent MRI before prostatectomy (62 with significant residual disease and 30 with complete response or minimum residual disease [CR/MRD]). Totally, 100 significant residual, 52 CR/MRD lesions, and 70 benign tissues were selected according to pathology. First, 381 radiomics features were extracted from T2-weighted imaging, diffusion-weighted imaging, and apparent diffusion coefficient (ADC) maps. Optimal features were selected using a support vector machine with a recursive feature elimination algorithm (SVM-RFE). Then, ADC values of significant residual, CR/MRD lesions, and benign tissues were compared by one-way analysis of variance. Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues. Third, the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve (AUC). The ADC value (mean ± standard deviation [s.d.]) of significant residual lesions ([1.10 ± 0.02] × 10-3 mm2 s-1) was significantly lower than that of CR/MRD ([1.17 ± 0.02] × 10-3 mm2 s-1), which was significantly lower than that of benign tissues ([1.30 ± 0.02] × 10-3 mm2 s-1; both P < 0.05). The SVM feature models were comparable to ADC value in distinguishing CR/MRD from benign tissue (AUC: 0.766 vs 0.792) and distinguishing residual from benign tissue (AUC: 0.825 vs 0.835) (both P > 0.05), but superior to ADC value in differentiating significant residual from CR/MRD (AUC: 0.748 vs 0.558; P = 0.041). Radiomics approach with biparametric MRI could promote the detection of significant residual prostate cancer after ADT.

Overexpression of RACGAP1 by E2F1 Promotes Neuroendocrine Differentiation of Prostate Cancer by Stabilizing EZH2 Expression.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It is characterized by the loss of androgen receptor (AR) signaling in neuroendocrine transdifferentiation, and finally, resistance to AR-targeted therapy. With the application of a new generation of potent AR inhibitors, the incidence of NEPC is gradually increasing. The molecular mechanism of neuroendocrine differentiation (NED) after androgen deprivation therapy (ADT) remains largely unclear. In this study, using NEPC-related genome sequencing database analyses, we screened RACGAP1, a common differentially expressed gene. We investigated RACGAP1 expression in clinical prostate cancer specimens by IHC. Regulated pathways were examined by Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation, and immunoprecipitation assays. The corresponding function of RACGAP1 in prostate cancer was analyzed by CCK-8 and Transwell assays. The changes of neuroendocrine markers and AR expression in C4-2-R and C4-2B-R cells were detected in vitro. We confirmed that RACGAP1 contributed to NE transdifferentiation of prostate cancer. Patients with high tumor RACGAP1 expression had shorter relapse-free survival time. The expression of RACGAP1 was induced by E2F1. RACGAP1 promoted neuroendocrine transdifferentiation of prostate cancer by stabilizing EZH2 expression in the ubiquitin-proteasome pathway. Moreover, overexpression of RACGAP1 promoted enzalutamide resistance of castration-resistant prostate cancer (CRPC) cells. Our results showed that the upregulation of RACGAP1 by E2F1 increased EZH2 expression, which drove NEPC progression. This study explored the molecular mechanism of NED and may provide novel methods and ideas for targeted therapy of NEPC.

De novo purely prostatic large-cell neuroendocrine carcinoma with thyroid and adrenal metastases

Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo cases are even more infrequent, with only six cases described. The patient was a 78-year-old man with no history of ADT who presented with cervical lymphadenopathy. Diagnostic approaches included PET/CT, MRI, CT scans, ultrasonography, biopsies, and cytological and immunohistochemical evaluations. Results showed a poorly differentiated carcinoma in the thyroid gland accompanied by cervical lymph node enlargement. Thyroid surgery revealed LCNEC metastasis to the thyroid gland. Additional metastases were identified in both the adrenal glands. Despite appropriate treatment, the patient died of the disease. De novo LCNEC of the prostate is a rare, highly aggressive tumor with a poor prognosis. It is resistant to most therapeutic agents, has a high metastatic potential, and is usually diagnosed at an advanced stage. Further studies are required to characterize this tumor. De novo LCNECs of the prostate gland can metastasize almost anywhere in the body, including the thyroid and adrenal glands. LCNECs of the prostate are usually associated with androgen-depriving therapy, but de novo cases are also notable and should be accounted for. Further studies are required to fully understand and treat LCNECs more effectively.

Androgen deprivation restores ARHGEF2 to promote neuroendocrine differentiation of prostate cancer

Androgen receptor (AR) plays an important role in the progression of prostate cancer and has been targeted by castration or AR-antagonists. The emergence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) is inevitable. However, it is not entirely clear how ADT fails or how it causes resistance. Through analysis of RNA-seq data, we nominate ARHGEF2 as a pivotal androgen-repressed gene. We show that ARHGEF2 is directly suppressed by androgen/AR. AR occupies the enhancer and communicates with the promoter region of ARHGEF2. Functionally, ARHGEF2 is important for the growth, lethal phenotype, and survival of CRPC cells and tumor xenografts. Correspondingly, AR inhibition or AR antagonist treatment can restore ARHGEF2 expression, thereby allowing prostate cancer cells to induce treatment resistance and tolerance. Overall, our findings provide an explanation for the contradictory clinical results that ADT resistance may be caused by the up-regulation of ARHGEF2 and provide a novel target.

RF07 | PSAT233 The First Case Report of a de-novo Purely Prostatic Large Cell Neuroendocrine Carcinoma with Thyroid and Adrenal Metastases

Abstract Background Large Cell Neuroendocrine Carcinoma (LCNEC) is the rarest neuroendocrine prostatic malignancy. It usually arises after androgen-deprivation therapy (ADT), while de novo cases are even more infrequent with only 6 cases described to date. Case presentation A 78-year-old man with no history of ADT presented with cervical lymphadenopathy. Diagnostic approach included PET/CT, MRI, and CT scans, U/S, biopsies, cytological and immunohistochemical evaluations. CT revealed a non-enriching region on the right lobe of the thyroid gland. An 18F-FDG PET-CT found increased uptake in the thyroid gland and both adrenal glands. Neck ultrasound identified a right thyroid lobe nodule. A fine needle aspiration of the nodule was performed and cytology was consistent with poorly differentiated carcinoma. A total thyroidectomy with central and bilateral lymph node dissection was performed and the pathology report diagnosed a LCNEC metastatic to the thyroid gland. Additional metastases were identified in both adrenal glands. Despite appropriate treatment, the patient succumbed to his disease. Summary We report the first patient with a de novo purely prostatic LCNEC, metastasizing to the thyroid and the adrenal glands. Conclusions De novo LCNECs of the prostate are very rare, highly aggressive tumors with poor prognosis. They are resistant to most therapeutic agents, have high metastatic potential and are usually diagnosed at an advanced stage. Further studies are needed to characterize these tumors. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m.

Efficacy of Novel Hormone Agents in the Treatment of Metastatic Castration-resistant Prostate Cancer: A Real-world Retrospective Study.

Novel hormone agents (NHA) have become important tools for the treatment of advanced prostate cancer. Among them, abiraterone and enzalutamide are two major regimens in the treatment of metastatic castration-resistant prostate cancer (MCRPC). The aim of this study was to evaluate the efficacy of both drugs in patients who had disease progression after androgen deprivation therapy (ADT), using our real-world database. We retrospectively analyzed MCRPC patients who received abiraterone and enzalutamide between October 2010 and October 2021. The associations between baseline demographics and clinical outcomes were evaluated. ADT was defined as luteinizing hormone-releasing hormone (LHRH) agonists, antagonists, or orchiectomy. Of the 324 included patients, the median age was 77 years. Amongst them, 81 patients received chemotherapy-naïve abiraterone, 141 received post-chemotherapy abiraterone, 64 patients received chemotherapy-naïve enzalutamide and 38 patients received post-chemotherapy enzalutamide. The median overall survival was 43.6 months among all NHA-treated MCRPC patients. Pre-MCRPC ADT duration >25.31 months and enzalutamide use were each associated with a decreased risk of death (HR=0.54, 95% CI=0.39-0.75, p<0.001, and HR=0.53, 95% CI=0.33-0.87, p=0.012, respectively), while high-volume disease was associated with an increased risk of death (HR=1.53, 95% CI=1.10-2.21, p=0.007). Upfront chemotherapy and pre-MCRPC ADT duration of >21.03 months were each associated with an increased prostate-specific antigen (PSA) response after NHA treatment (OR=3.18, 95% CI=1.33-7.63, p=0.010, and OR=2.72, 95% CI=1.63-4.54, p<0.001, respectively). Our real-world data revealed the effectiveness of using both abiraterone and enzalutamide in the treatment of MCRPC patients. Long pre-MCRPC ADT duration and enzalutamide use were both associated with a decreased risk of death regardless of four different treatment sequences. Upfront docetaxel and longer pre-MCRPC ADT duration were each associated with an increased NHA PSA response rate.

Maintenance of androgen deprivation therapy or testosterone supplementation in the management of castration-resistant prostate cancer: that is the question

PurposeWhether or not androgen receptor (AR) axis could still be targetable in castration resistant prostate cancer (CRPC) patients with disease progression to next generation hormonal agents (NGHAs) is a controversial issue.ResultsSerum testosterone in CRPC patients has a positive prognostic role and increasing testosterone levels after androgen deprivation therapy (ADT) withdrawal or testosterone supplementation, as part of a bipolar androgen therapy (BAT) strategy, has been shown to potentially restore sensitivity to previous lines of NGHAs.ConclusionThese data suggest that maintenance of ADT in CRPC patients receiving further lines of treatment, as recommended by current international guidelines, could be questionable. Conversely, testosterone supplementation aimed to re-sensitize CRPC to further hormonal manipulation is a strategy worth to be explored in future clinical trials.

Cardiovascular risk of gonadotropin-releasing hormone antagonist versus agonist in men with prostate cancer: an observational study in Taiwan

BackgroundThe impact of gonadotropin-releasing hormone (GnRH) antagonist and agonist (GnRHa) treatment on cardiovascular disease (CVD) risk in prostate cancer (PCa) remains inconclusive due to conflicting findings. We compared the effects of GnRH antagonist and GnRHa treatments on CVD risk in patients with PCa and pre-existing CVD, in a Taiwan population-based database.MethodsWe assessed the risk of major adverse CV events (MACE: ischemic heart disease [IHD], stroke, congestive heart failure [CHF] or all cause deaths) and composite CV events (IHD, stroke, CHF or CV deaths) occurring ≥90 days after androgen deprivation therapy (ADT) initiation in patients with PCa after 90 days of treatment with either GnRH antagonist (degarelix; n = 499) or GnRHa (goserelin, leuprolide, triptorelin; n = 15,127). Patients identified with pre-existing CVD had received cardiac therapy for IHD, reported a stroke or CHF within a year before ADT initiation. Adjusted hazard ratios (aHR) and 95% confidence interval (CI) were obtained for MACE and composite CV events risk after adjusting for age, baseline status of diabetes, hypertension and treatments received.ResultsAll GnRH antagonist-treated patients showed lower risk of composite CV events than the GnRHa-treated patients. The lower composite CV events risk associated with GnRH antagonist was also observed in patients with metastasis at diagnosis (aHR 0.16; 95% CI, 0.04–0.38; p = 0.013) and those receiving ADT for more than six months (aHR 0.30; 95% CI, 0.16–0.54; p < 0.0001). In patients with pre-existing CVD, the MACE risk was 33% lower (aHR 0.67; 95% CI, 0.46–0.96; p = 0.0299) and composite CV events risk was 84% lower (aHR 0.16; 95% CI, 0.05–0.50; p = 0.0017) in GnRH antagonist-treated than the GnRHa-treated patients.ConclusionsIn patients with PCa and pre-existing CVD, GnRH antagonist use was associated with lower risks for composite CV events and MACE compared with GnRHa.

Pre-existing Castration-resistant Prostate Cancer–like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy

BackgroundHormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC). ObjectiveTo understand the mechanisms by which subclones within early PCa develop into CRPC. Design, setting, and participantsWe isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC). Outcome measurements and statistical analysisWe revealed dynamic transcriptional reprogramming that promotes disease progression among 23226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data. Results and limitationsWe identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa. ConclusionsCRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa. Patient summaryHere, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.

Targeting Inflammatory Signaling in Prostate Cancer Castration Resistance.

Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC.