Androgen Deprivation Treatment Research Articles

Abstract 1725: Role of PRMT5 in neuroendocrine prostate cancer development

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20-30% of castration resistant prostate cancer (CRPC) deaths. While NEPC can arise de novo, the majority of these cases emerge as treatment-induced NEPC (tNEPC). Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Methods: Here we generated an in vitro cell culture model and mouse model to mimic the clinical conditions in androgen signaling inhibitor (ASI) or androgen deprivation treatment (ADT) We developed an in vitro cell culture and in vivo model to mimic the clinical conditions in enzalutamide-resistant prostate cancer. Regulation and role of protein arginine methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) were determined by treating cells and mice tumors with doxycycline inducible-shRNAs and catalytic inhibitors followed by analysis of cell viability, neurite growth, and effects on neuroendocrine related gene transcription. Pro-NEPC development effects were analyzed by immunofluorescence, immunohistochemical analysis, and western blot. PRMT5:MEP50-dependent methyltransferase activity was further validated by observing histone deposition levels via western blot and ChIP-qPCR. For clinical correlation, PRMT5 and MEP50 expression levels were comprehensively analyzed in both CRPC and NEPC patient prostate tissue samples. Results: Our clinical and computational analyses have identified increased expression of PRMT5:MEP50 in NEPC. Overexpression of PRMT5 and MEP50 in prostate cancer cells is sufficient to induce neuroendocrine differentiation (NED) in prostate cancer cells. Gene depletion of PRMT5 and MEP50 prevented the NE phenotype induced by androgen receptor inhibition and resensitized the prostate cancer cells to ASI/ADT. PRMT5 and MEP50 facilitate chromatin modulation through the dimethylation of H4R3, which is highly correlated with the NED phenotype. Moreover, overexpression of PRMT5 and MEP50 in mouse prostate induces NEPC development, and gene downregulation can prevent NED in a xenograft mouse model. Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving ADT and their recurrence probability after the treatment. Conclusion: Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Citation Format: Hye Seung Nam, Xuehong Deng, Chang-Deng Hu. Role of PRMT5 in neuroendocrine prostate cancer development [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 1725.

Patient preference on once-daily oral versus injectable androgen deprivation therapy for Asian patients with advanced prostate cancer.

The study aimed at investigating prostate cancer patients' choice of androgen deprivation treatment (ADT) and possible factors that would affect their preferences of ADT. This was a single-centre cross-sectional study investigating the usage and preferences of ADT. Consecutives prostate cancer patients who were receiving injectable luteinizing hormone-releasing hormone (LHRH) agonist or antagonist were recruited from the prostate cancer clinic in a tertiary academic hospital. Patients who received bilateral orchidectomy or those who could not consent to the study were excluded. Disease characteristics, treatment information and patient background were documented. The survey collected information related to their change in ADT regimen, preferences on drug usage (routes and frequency of administration) and their reasons. A hypothetical set of three drug formularies was designed. Questions regarding patient preference and the contributing reasons raised in the format of questionnaire. 100 patients completed the survey. Most patients started with more frequent injections (3-monthly, 54%; 1-monthly, 38%) and switched to 6-monthly injections (89%) at the time of the survey. Primary reasons for the change were healthcare opinion (72%) and less frequent treatment (51%). Three options of ADT (oral daily, 1-monthly and 6-monthly injection) with the same efficacies and side effect profile were offered: 61% preferred 6-monthly injection, 1% preferred 1-monthly injection and 38% preferred oral regimen. When patients were informed of lower cardiovascular side effects in 1-monthly injection or daily oral drug, patients' preference was 56% (6-monthly), 6% (1-monthly), and 39% (oral). Patients with polypharmacy (more than 5 regular medications) were more inclined to choose injections (p = 0.025). Patient age, educational background, employment status, marriage status and disease status were not found to be statistically significant contributing factors to patient preference. 6-monthly ADT injection was the preferred ADT despite greater cardiovascular risks. Among 1-monthly or daily oral LHRH antagonist, more patients prefer oral option. Convenience factor was highly valued.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Apalutamide toxicity and tolerability: A real-world multicentre experience in metastatic hormone-sensitive prostate cancer (MHSPC) in the United Kingdom (UK).

107 Background: Apalutamide became available for mHSPC along with androgen deprivation treatment (ADT) in the UK in November 2021. We present here, to our best knowledge the first real world multicentre experience of Apalutamide use in mHSPC patients from three tertiary cancer centres from the UK. Our primary aim was to assess for toxicity and tolerability at this stage. Methods: We collected retrospective data from hospital prescription registries including all patients with mHSPC receiving Apalutamide between November 2021 and January 2023. Median period of follow up in our cohort was 14 months. Results: Two hundreds and ten patients received Apalutamide for mHSPC from three centres. The median age was 73 years. A total of 16.4% of the patients had recurrent mHSPC previously treated for localised PC and 83% were de novo metastatic. Of all patients, 43.3% had high-volume disease, and 56.7% had low-volume disease. The median presenting Prostate Specific Antigen (PSA) was 62 ng/l at diagnosis (range 0.87 to 5580). Undetectable PSA achieved in 43.3% of patient after starting Apalutamide and ADT. For those who have detectable PSA, median value was 0.22. Ninety percent of patients maintained their performance status (PS) at 0 or 1 on treatment. Most common side effects were fatigue (35.7%) and rash (11.4%). Cardiac adverse effects were recorded in 1.9% and thromboembolic events in 0.4%. Overall grade 3 and 4 toxicity was 5.2% across all symptoms assessed. To date, 83.3% patients continue on Apalutamide, 7.6 % discontinued due to toxicity and 9.1% had progressive disease (PD). Three deaths were recorded and all due to PD. Conclusions: In this multicentre retrospective analysis we found that Apalutamide and ADT is well tolerated in the real-world setting. Our patients are older and had lower volume metastasis compared with patients from the registry Trial (TITAN). Fatigue is more prevalent. Majority patients continue on Apalutamide with manageable side effects and good PS.

Case report: Squamous cell carcinoma of the prostate-a clinicopathological and genomic sequencing-based investigation

Squamous differentiation of prostate cancer, which accounts for less than 1% of all cases, is typically associated with androgen deprivation treatment (ADT) or radiotherapy. This entity is aggressive and exhibits poor prognosis due to limited response to traditional treatment. However, the underlying molecular mechanisms and etiology are not fully understood. Previous findings suggest that squamous cell differentiation may potentially arise from prostate adenocarcinoma (AC), but further validation is required to confirm this hypothesis. This paper presents a case of advanced prostate cancer with a combined histologic pattern, including keratinizing SCC and AC. The study utilized whole-exome sequencing (WES) data to analyze both subtypes and identified a significant overlap in driver gene mutations between them. This suggests that the two components shared a common origin of clones. These findings emphasize the importance of personalized clinical management for prostate SCC, and specific molecular findings can help optimize treatment strategies.

The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer.

Metastatic prostate cancer (PCa) poses a significant public health concern. While radiation therapy (RT) is commonly utilized in the treatment of synchronous oligometastatic hormone sensitive prostate cancer (OM-HSPC), the occurrence of biochemical recurrence still remains. To deepen our understanding and optimize the outcome of OM-HSPC, we conducted this study to investigate the characteristics of PCa progression and explore potential synergistic mechanisms involving carbon-ion radiotherapy (CIRT) and neoadjuvant androgen deprivation treatment (naADT) in OM-HSPC. Metabolomic analysis was conducted with 72 urinary samples (at different timepoints) from 33 Patients (T2-3N0M0-1b) and 18 healthy volunteers by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). MetaboAnalyst website and R software were employed for metabolomic analysis and visualization (using the criteria of p value < 0.05 and |FC|>1.5). The impact of CIRT on metabolism were further verified and explored through in vitro and in vivo experiments. We found that most metabolites (223 out of 233) were upregulated in treatment-naïve PCa samples compared to healthy samples. After naADT, 60 core risk metabolites were still significantly related to PCa's progression, and the glutamine level which was significantly higher in OM-HSPC compared to other groups. Remarkably, after CIRT treatment, the glutamine levels in OM-HSPC were significantly reduced to the level of healthy samples. Experiments further confirmed CIRT's ability to suppress glutamine levels in PCa tumors and its potential enhancement with glutamine deprivation intervention. CIRT with naADT might synergistically inhibit HS-OMPC development, progression and even the ADT resistance through glutamine metabolism repression, moreover, the glutamine metabolism might be a novel target to further improved the efficacy of CIRT.

Single Dose vs. Fractionated High-Dose Rate Brachytherapy in Localized Prostate Cancer: Long Term Results

To evaluate long-term freedom from biochemical relapse (FFbR) and overall survival (OS) after single-dose high-dose-rate brachytherapy (HDR-BT) compared with 2 or 3 fraction schedules. HDR-BT, delivering 1 × 19 Gy or 1 × 20 Gy (A = 49), 2 × 13 Gy (B = 138) or 3 × 10.5 Gy (C = 106), was given to patients with intermediate or high-risk prostate cancer as their sole treatment. Patients were staged with pelvic MRI and isotope bone scan. Transperineal transrectal ultrasound guided implantation was followed by MRI based CTV definition based on GEC ESTRO guidelines. Biochemical relapse was assessed using the Phœnix definition (PSA nadir plus 2 µg/L). Patients were evaluated prospectively from 6 months after implant and bi-annually thereafter. Estimates of freedom from biochemical relapse, and overall survival (OS) were calculated using the Kaplan-Meier (K-M) method and the log-rank test to test for significance. Univariate and multivariate hazard ratios (HR) were obtained using Cox's proportional hazard model. For multivariate modelling a stepwise reduction method was used. Median follow-up was 123, 116 and 120 months (p = 0.4), (A, B, C, respectively). Neo-adjuvant and adjuvant androgen deprivation treatment was given to 80% of all patients, median duration was 9 months for A and 6 months for B and C. K-M estimates of FFbR, at 8 and 10 years, were 67% and 64% (Group A), 78% and 72% (Group B), and 80% and 76% (Group C). Differences in FFbR between dose groups was not significant (p = 0.2). Similarly, no significant difference was seen in OS. Eight and 10-year estimates were 81% and 75% (A), 85% and 74% (B), and 90% and 83% (C); p = 0.5. Hazard Ratios for risk of biochemical recurrence were significant for ADT administration (yes/no) and overall risk category, in multivariate analyses. Only the latter was significant in univariate analysis for risk of death, Gleason risk (low, intermediate, high), MRI tumor stage risk and overall risk category were significant in univariate analyses. Only tumor stage and Gleason risk were significant in multivariate analyses. Concerns around the efficacy of 19-20 Gy single dose HDR BT as monotherapy, based on early data, may have been unfounded. Long-term outcome data up to 10 years show no significant difference in PSA control and overall survival compared to 2 and 3 fractions of HDR-BT.

Testosterone and Peripheral Arterial Disease.

Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidaemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycaemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the haematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

The PRIME-CUT study: A single-arm phase 2 study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

e17089 Background: Overall survival of patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) is improved with androgen deprivation therapy (ADT) and treatment intensification. Initially, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules. These effects diminish as castration-resistant prostate cancer (CRPC) invariably develops. We report the first results of the phase 2 PRIME-CUT study (modulating the PRostate cancer Immune MicroEnvironment with ChemoimmUnoTherapy for metastatic prostate cancer). Methods: Eligible pts had newly diagnosed mHSPC, ECOG performance status (PS) 0 or 1, serum testosterone levels &gt; 150 ng/dL, agreed to undergo serial metastatic tumor biopsies, and had not received ADT in the prior 6 months. Treatment consisted of ADT (degarelix 240 mg subcutaneously (SC) for one dose, followed by leuprolide 22.5 mg SC every 12 weeks) followed by anti-PD-1 antibody (cemiplimab 350 mg IV every 3 weeks) beginning four weeks after ADT initiation. With the intent of immune priming, a two-cycle lead-in of anti-PD-1 therapy was administered prior to standard of care docetaxel (75 mg/m2 every 3 weeks for six cycles). Participants received ADT and cemiplimab until study completion (52 weeks) or until a lack of clinical benefit or intolerable side effects. The primary endpoint was the rate of undetectable PSA at 6 months after chemotherapy initiation (week 37) and compared to the historical rate from the phase III CHAARTED trial (32%). Subjects were monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Results: The study completed accrual of 20 pts (median age 62 years) from Columbia University Irving Medical Center in Aug 17, 2022. Among them, 7 self-identified race as Black and 12 self-identified their ethnicity as Hispanic. Baseline PSA ranged from 8.15 to &gt; 5000 ng/dL (median 2513.1 ng/dL). Site of metastatic disease included: 17/20 bone, 12/20 lymph nodes, 11/20 visceral organs. Overall, 14 of 20 patients received at least 4 cycles of docetaxel. Of the 12 patients that were still on-study at 37 weeks, 2 had an undetectable PSA, and 4 additional pts had PSA &lt; 1.0 ng/dL. Twelve pts experienced ≥ Grade 3 adverse events (AEs), 6 AEs were attributed to study intervention including cytopenias (3), hypotension (1), pneumonitis (1), and stenosis of gastrointestinal stoma (1). Unfortunately, two patients deceased on-study (myocardial infarction after 13 weeks, severe SARS-CoV-2 infection after 19 weeks). Conclusions: The Prime-Cut study did not meet its primary endpoint. However, PSA kinetics and results from the pre-planned correlative science demonstrate ongoing role for immunotherapeutic approaches in mHSPC. No new safety signals were observed. Clinical trial information: NCT03951831 .

The impact of the apparent diffusion coefficient for the early prediction of the treatment response after definitive radiotherapy in prostate cancer patients

PurposeWe assessed early changes in apparent diffusion coefficient (ADC) and serum prostate specific antigen (PSA) values after definitive radiotherapy (RT) without androgen deprivation treatment in low- and intermediate-risk prostate cancer (PC) patients. Materials and MethodsThe clinical data and ADC parameters of 229 PC patients were retrospectively evaluated. Pre-treatment and post-treatment serum PSA and primary tumor ADC values were calculated. Post-treatment DW-MRI was performed median 4.1 months after completion of definitive RT. The prognostic factors predicting freedom from biochemical failure (FFBF) and progression-free survival (PFS) were analyzed using univariable and multivariable analyses. ResultsWith a median follow-up time of 80.8 months, the 5-year FFBF and PFS rates were 95.9% and 89.3%, respectively. Eleven patients (4.8%) had PSA relapse, with a median of 34.4 months after the completion of RT. A statistically significant difference in post-treatment ADC values was noted between patients with and without recurrence (0.94 ± 0.07 vs. 1.10 ± 0.20 × 10-3 mm2/sec; p< 0.001). Patients with a Gleason score (GS) of 6 and low-risk disease had significantly higher post-treatment tumor ADC and PSA levels than patients with a GS of 7 and intermediate-risk disease. The 5-year FFBF rate in patients with tumor ADC ≤ 0.96 × 10-3 mm2/sec was significantly lower than patients with tumor ADC > 0.96 × 10-3 mm2/sec (85.5% vs. 100; p< 0.001). In the multivariable analysis, a lower ADC value, GS 4 + 3 and intermediate-risk disease were independent predictors of worse FFBF. In the multivariate analysis, a lower post-treatment ADC value and a GS of 4 + 3 were significant prognostic factors for a lower PFS. ConclusionThese findings suggest that the post-treatment tumor ADC value could be used for early treatment response evaluation after definitive RT in PC patients.

Predictors of Recurrence After Metastasis-directed Therapy in Oligorecurrent Prostate Cancer Following Radical Prostatectomy

BackgroundMetastasis-directed therapy (MDT) is performed to delay systemic treatments for oligorecurrent disease after primary prostate cancer (PCa) treatment. ObjectiveThe aim of this study was to identify the predictors of therapeutic response of MDT for oligorecurrent PCa. Design, setting, and participantsbicentric, retrospective study, including consecutive patients who underwent MDT for oligorecurrent PCa after radical prostatectomy (RP; 2006–2020) was conducted. MDT encompassed stereotactic body radiation therapy (SBRT), salvage lymph node dissection (sLND), whole-pelvis/retroperitoneal radiation therapy (WP[R]RT), or metastasectomy. Outcome measurements and statistical analysisndpoints were 5-yr radiographic progression-free survival (rPFS), metastasis-free survival (MFS), palliative androgen deprivation treatment (pADT)-free survival, and overall survival (OS) together with prognostic factors for MFS following primary MDT. Survival outcomes were studied by Kaplan-Meier survival and univariable Cox regression (UVA). Results and limitationsA total of 211 MDT patients were included; 122 (58%) developed a secondary recurrence. Salvage lymph node dissection was performed in 119 (56%), SBRT in 48 (23%), and WP(R)RT in 31 (15%) of the cases. Two patients received sLND + SBRT and one received sLND + WPRT. Eleven (5%) patients received metastasectomies. The median follow-up since RP was 100 mo, while follow-up after MDT was 42 mo. The 5-yr rPFS, MFS, androgen deprivation treatment(–free survival, castration-resistant prostate cancer–free survival, CSS, and OS after MDT were 23%, 68%, 58%, 82%, 93%, and 87% respectively. There was a statistically significant difference between cN1 (n = 114) and cM+ (n = 97) for 5-yr MFS (83% vs 51%, p < 0.001), pADT-free survival (70% vs 49%, p = 0.014), and CSS (100% vs 86%, p = 0.019). UVA was performed to assess the risk factors (RFs) for MFS in cN1 and cM+. Alpha was set at 10%. RFs for MFS in cN1 were lower initial prostate-specific antigen (PSA) at the time of RP (hazard ratio [95% confidence interval] 0.15 [0.02–1.02], p = 0.053], pN stage at RP (2.91 [0.83–10.24], p = 0.096), nonpersisting PSA after RP (0.47 [0.19–1.12], p = 0.089), higher PSA at primary MDT (2.38 [1.07–5.24], p = 0.032), and number of positive nodes on imaging (1.65 [1.14–2.40], p < 0.01). RFs for MFS in cM+ were higher pathological Gleason score (1.86 [0.93–3.73], p = 0.078), number of lesions on imaging (0.77 [0.57–1.04], p = 0.083), and cM1b/cM1c (non-nodal metastatic recurrence; 2.62 [1.58–4.34], p < 0.001). ConclusionsFollowing MDT, 23% of patients were free of a second recurrence at 5-yr follow-up. Moreover, cM+ patients had significantly worse outcomes in terms of MFS, pADT-free survival, and CSS. The RFs for a metastatic recurrence can be used for counseling patients, to inform prognosis, and potentially select candidates for MDT. Patient summaryIn this paper, we looked at the outcomes of using localized, patient-tailored treatment for imaging-detected recurrent prostate cancer in lymph nodes, bone, or viscera (maximum five recurrences on imaging). Our results showed that targeted treatment of the metastatic lesions could delay the premature use of hormone therapy.

What’s new on the treatment of pedophilia and hebephilia?

IntroductionParaphilias constitute a set of psychiatric conditions that are often chronic and require a combination of treatment approaches, such as pharmacotherapy and psychotherapy. Sexual interest toward prepubescents and pubescents (pedophilia and hebephilia) is frequently identified in criminal settings, within numerous child sexual abuse and child pornography offenses. The high prevalence rates and negative consequences of these acts, causing distress in multiple important areas of health and functioning, reveal the importance of preventing these offenses as a clinical and social matter. Secondary prevention programs, which provide treatment and support for those with paraphilia disorders before sexually abusive behaviors and legal system involvement, show as ethically and socially necessary.ObjectivesWe aim to discuss and bring insights into the knowledge on pedophilia and hebephilia treatments and prevention programs, in the fields of psychotherapy as well as pharmacologic strategies.MethodsWe present a non-systematic review of the updated literature on this subject from the data found on the PubMed and PsycInfo databases.ResultsPreliminary results of recent works show that at-risk individuals with paraphilia disorders are often willing to seek treatment without external pressure from the legal system, and report benefits from early treatments. Most studies found that gonadotropin-releasing hormone agonists reduce the risk of child sexual abuse in men with pedophilia. An injectable form has shown to lower this risk 2 weeks after the initial injection, suggesting its use as a rapid-onset treatment option. Cyproterone acetate and medroxyprogesterone acetate are other anti-androgen drugs that inhibit hypersexual behavior, with important side effects to be considered. The combination of androgen deprivation treatment and psychotherapy has a greater effect on preventing fantasies, urges, and behaviours in paraphilic patients. Cognitive-behavioural psychotherapy shows the best results and should soon be initiated in all patients. Biomolecular studies revealed that serotonin and prolactin inhibit sexual arousal, being SSRIs used as first treatment in younger patients, particularly in less severe cases.ConclusionsEvidence-based treatments from randomized clinical trials for paedophilic and hebephilic disorders are lacking. These current numbers reveal the need for widespread implementation of primary and secondary prevention initiatives, that go beyond the prevention of a repeated offense. There is a need for further research using controlled, randomized trials to examine the effectiveness of sexual offender treatment including psychotherapeutic and pharmacologic interventions. The development of more specific, more effective, and better-tolerated medications for these disorders should be recognized as a program worthy of greater support from government and pharmaceutical industry sources.Disclosure of InterestNone Declared

Potential New Approaches for Prostate Cancer Management in Resource-Limited Countries in Africa.

Prostate cancer is a major male malignancy in many sub-Saharan countries in Africa. Because of resource limitations, screening, early detection, diagnosis, and curative treatments are not available for many men on the subcontinent, and there are even barriers to the treatment of advanced-stage metastatic prostate cancer. We are making the case for new approaches to the detection, diagnosis, and treatment of this malignancy in sub-Saharan Africa and other low-resource regions-approaches that differ from the ones available and used in high-income countries. The development of one-step dipstick-type detection assays of serum prostate-specific antigen (PSA) offers an approach to prostate cancer detection, treatment and monitoring that circumvents issues related to laboratory quality control and is also low-cost. Curative-intent treatments of early-stage prostate cancer are often unavailable in low-resource contexts, and most prostate cancers are not detected in Africa until they are at an advanced stage. Hence, androgen deprivation treatments, including orchiectomy and older low-cost drugs, offer feasible and affordable approaches to prolong survival and sustain a reasonable quality of life. However, clinical trials are needed to identify which of these androgen deprivation treatments are most efficacious and best tolerated to make progress in providing medical care for men with prostate cancer in sub-Saharan Africa and other low- and lower-middle-income areas around the world.

Low hemoglobin and PSA kinetics are prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients

The objective of this study was to identify the prognostic factors and to propose a new risk model in metastatic castration-resistant prostate cancer (mCRPC) patients. The clinical data were retrospectively obtained for 102 mCRPC patients who received cancer treatment between 2005 and 2018 at the University of Tokyo Hospital. We investigated clinical and pathological parameters, including prostate-specific antigen (PSA) kinetic profiles under androgen deprivation treatment, and identified predictors of overall survival (OS). The median age and PSA were 73 (Interquartile range [IQR], 68–79) years and 5.00 (IQR, 2.77–13.6) ng/ml. The median follow-up was 34 (IQR, 17–56) months. In univariate analysis, ‘lymph node metastasis’, ‘Hemoglobin (Hb)’, ‘Time to nadir PSA (TNPSA)’, ‘PSA doubling time (PSADT)’, ‘Time to CRPC’, and ‘presence of pain’ were prognostic factors. Multivariate analysis identified ‘Hb < 11 g/dL’, ‘TNPSA < 7 months’ and ‘PSADT < 5 months’ as independent prognostic factors of OS. The high-risk group (patients with two or three factors) demonstrated shorter OS (23 vs. 50 months) with an increased risk of death (HR = 2.997; 95% CI 1.632–5.506; P = 0.0004). The proposed risk stratification model may contribute to the prediction of survival and provide supportive information in treatment decision-making.

Immunosuppressive environment in response to androgen deprivation treatment in prostate cancer.

To invest the role of androgen deprivation therapy (ADT) on the tumor immune microenvironment of prostate cancer. Here we have profiled the transcriptomes of 19,227 single cells from 4 prostate tumors, including two cases who received ADT. To validated the single-cell analysis we use another group of patients receiving neoadjuvant ADT. After receiving ADT treatment, the killing effect of prostate cancer immune cells on tumors is weakened, the interaction between immune cells and tumor cells is weakened, and the proportion of immunosuppressive cells Myeloid-derived suppressor cell (MDSC) and Regulatory T cells (Treg) cells increases. Our results highlight that ADT induces immunosuppressive in the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy.

PMON280 Effect of Gender Affirming Hormone Therapy (GAHT) on Adipose Tissue Morphology and Metabolism in Transgender Individuals

Abstract Background Circulating sex hormones exert unique effects on metabolism, leading to sexual dimorphism in white adipose tissue distribution and function. The gender affirming hormone therapy (GAHT) or cross-sex hormone therapy (CSHT) for transgender patients lower the endogenous sex hormones while raising the opposite sex hormones. Sex hormones are known to have a significant impact on white adipose tissue and metabolism. However, long-term metabolic changes with GAHT in transgender individuals have not been studied, nor are the underlying mechanisms properly elucidated. Hypothesis We test the hypothesis that GAHT will result in sexual dimorphic changes in morphology and function of white adipose tissue according to the type of sex hormones used and the native sex of the patients. Aim 1 To study the effect of cross-sex hormones on clinical parameters such as blood pressure, weight, waist-hip circumference ratio, serum lipids, insulin sensitivity Aim 2 To study the changes in human subcutaneous white adipose tissue (SWAT) distribution and expansion with GAHT Aim 3 To study changes in circulating metabolites and adipokines, and pro-inflammatory and pro-fibrotic gene expression in SWAT with GAHT. Methodology 31 hormone-naive patients (19 Male-to-Female; MtF and 12 Female-to-Male; FtM) were enrolled in the longitudinal study and followed up for 3 years. Clinical parameters and blood samples were gathered at baseline and at 6 month intervals. DXA scans and fat biopsies (peri-umbilical SWAT) were performed at baseline and at 1 year intervals. Results The results presented here compare baseline and at 1 year of GAHT. There was an increase in total cholesterol in the MtF group. HOMA-IR, total fat mass and visceral fat mass increased in MtF group, while they decreased in the FtM group. In MtF group, lean mass and bone mineral content (BMC) decreased at 1 year, but no change was observed in the FtM group. On histological assessment, fat cell size increased in MtF group, while it decreased in the FtM group. Conclusion In MtF transgender patients, androgen deprivation and estrogen treatment resulted in reduced insulin sensitivity together with a rise in total cholesterol possibly via a decrease in lean mass and adipose tissue expansion through significant adipocyte hypertrophy. In FtM transgender patients, testosterone treatment caused improved insulin sensitivity possibly via a decrease in total and visceral fat mass. The greatest strengths of our project include its longitudinal nature over 3 years to capture long-term effects in the same patients as well as deeper mechanistic insights into the underlying metabolite, adipokine and gene expression changes. The limitations of our study include the small sample size with heterogeneity of study population in terms of demographics and lifestyles. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Expansion of mouse castration-resistant intermediate prostate stem cells in vitro

BackgroundMost castration-resistant prostate cancers (CRPCs) have a luminal phenotype with high androgen receptor (AR) and prostate-specific antigen (PSA) expression. Currently, it is difficult to culture castration-resistant luminal cells with AR and PSA expression.MethodsWe formulated a custom-made medium and isolated primary cells from the prostate of adult wild-type (WT) and TRAMP mice. The cells were characterized by immunofluorescence staining, transcriptomic analysis, and qRT-PCR verification. Their self-renewal and differentiation potential in vitro and in vivo were examined. We treated the cells with androgen deprivation and enzalutamide and performed immunofluorescence staining and western blotting to analyze their expression of AR and PSA.ResultsWe isolated a novel type of castration-resistant intermediate prostate stem cells (CRIPSCs) from adult WT and TRAMP mice. The mouse CRIPSCs proliferated rapidly in two-dimensional (2D) culture dishes and can be cultured for more than six months. The mouse CRIPSCs expressed luminal markers (AR, PSA, and Dsg4), basal markers (CK5 and p63), Psca, and the intermediate cell marker (Ivl). Transcriptomic analysis showed that the mouse CRIPSCs had upregulated signaling pathways related to cancer development and drug resistance. In the long-term culture, TRAMP CRIPSCs had higher expression of the genes related to stem cells and cancers than WT mice. Both WT and TRAMP CRIPSCs formed organoids in Matrigel. WT CRIPSCs did not form prostate tissues when transplanted in vivo without urogenital sinus mesenchyme (UGM) cells. In contrast, TRAMP CRIPSCs formed prostate ducts in NOG mice without UGM cells and differentiated into luminal, basal, and neuroendocrine cells. Androgens regulated AR translocation between the nucleus and cytoplasm in the mouse CRIPSCs. Treatment of androgen deprivation (ADT) and enzalutamide reduced AR expression in WT and TRAMP CRIPSCs; however, this treatment promoted PSA expression in TRAMP, while not WT CRIPSCs, similar to the clinical observations of CRPC.ConclusionsOur study established a method for isolating and expanding mouse CRIPSCs in 2D culture dishes. Mouse CRIPSCs had markers of basal and luminal cells, including AR and PSA, and can differentiate into prostate organoids and tissues. TRAMP CRIPSCs had elevated PSA expression upon ADT and enzalutamide treatment. Our method can be translated into clinical settings for CRPC precision medicine.

Abstract 3657: Mental health disorders among prostate cancer patients in a population-based cohort

Abstract Background. Prostate cancer is the most common malignancy among men in the United States. Few studies evaluate mental health disorders comprehensively among prostate cancer patients with long-term follow-up. The primary aim of our study is to assess the incidence of mental health disorders among prostate cancer patients compared to a general population cohort. A secondary aim is to investigate risk factors for mental health disorders among prostate cancer patients. Methods. Cohorts of 18,134 cancer patients with prostate adenocarcinomas diagnosed between 2004 and 2017 and 73,470 men without cancer matched by age, birth state and follow up time from the general population were identified. Mental health diagnoses were identified from electronic medical records and statewide healthcare facilities data. Cox proportional hazard models were used to estimate hazard ratios (HRs). Results. Prostate cancer patients had increased risks of mental illnesses for the first five years after cancer diagnosis (0-2 years: HR=1.81, 95%CI=1.75-1.87; 2-5 years: HR=1.05, 95%CI=1.01-1.08) compared to the general population, but not in the later follow up periods. Elevated risks of anxiety disorder among prostate cancer patients were observed during across follow-up periods (0-2 years: HR= 1.59, 95% CI= 1.49-1.70; 2-5 years: HR= 1.20, 95% CI= 1.12-1.28; 5-10 years: HR= 1.20, 95% CI= 1.12-1.29; 10- 16 years: HR= 1.29, 95% CI= 1.14-1.45). Likewise, mood disorders, including depressive disorders, among prostate cancer survivors were found for all follow-up periods (0-2 years: HR= 1.59, 95% CI= 1.50-1.69; 2-5 years: HR= 1.21, 95% CI= 1.14-1.29; 5-10 years: HR= 1.20, 95% CI= 1.13-1.28; 10-16 years: HR=1.25, 95% CI= 1.12-1.38).The risks of any mental illness were increased with PSA&amp;gt;20ng/ml, high Gleason score, high-level risk group (intermediate, high, and very high), higher AJCC staging, and androgen deprivation treatment (ADT) therapy within 10 years after prostate cancer diagnosis. Surgery, radiation, ADT and tumor characteristics were also important risk factors for depression at 0-2 years after prostate cancer diagnosis. A baseline Charlson Comorbidity Index score of 1+ and unmarried status were associated with increased risk of any mental illness and depression across all time periods. We also observed that increased risks of any mental illness were associated with Hispanic, black or multiple races, underweight or obese, and family history of prostate cancer for all time periods. Prostate cancer survivors had a 26% increased risk of death associated with a mental illness diagnosis and a 61% increased risk of death with a depression diagnosis. Conclusion. Prostate cancer diagnosis is associated with poor mental health, which was observed as long as 16 years after cancer diagnosis. Providing long-term mental health support may be potentially beneficial to increasing life expectancy for prostate cancer patients. Citation Format: Siqi Hu. Mental health disorders among prostate cancer patients in a population-based cohort [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 3657.

Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

BackgroundAdaptive therapy aims to tackle cancer drug resistance by leveraging resource competition between drug-sensitive and resistant cells. Here, we present a theoretical study of intra-tumoral competition during adaptive therapy, to investigate under which circumstances it will be superior to aggressive treatment.MethodsWe develop and analyse a simple, 2-D, on-lattice, agent-based tumour model in which cells are classified as fully drug-sensitive or resistant. Subsequently, we compare this model to its corresponding non-spatial ordinary differential equation model, and fit it to longitudinal prostate-specific antigen data from 65 prostate cancer patients undergoing intermittent androgen deprivation therapy following biochemical recurrence.ResultsLeveraging the individual-based nature of our model, we explicitly demonstrate competitive suppression of resistance during adaptive therapy, and examine how different factors, such as the initial resistance fraction or resistance costs, alter competition. This not only corroborates our theoretical understanding of adaptive therapy, but also reveals that competition of resistant cells with each other may play a more important role in adaptive therapy in solid tumours than was previously thought. To conclude, we present two case studies, which demonstrate the implications of our work for: (i) mathematical modelling of adaptive therapy, and (ii) the intra-tumoral dynamics in prostate cancer patients during intermittent androgen deprivation treatment, a precursor of adaptive therapy.ConclusionOur work shows that the tumour’s spatial architecture is an important factor in adaptive therapy and provides insights into how adaptive therapy leverages both inter- and intra-specific competition to control resistance.