Effects Of Androgen Deprivation Therapy Research Articles

Prostate cancer cancer-associated fibroblasts with stable markers post-androgen deprivation therapy associated with tumor progression and castration resistant prostate cancer.

The specificity and clinical relevance of cancer-associated fibroblasts (CAFs) in prostate cancer (PCa), as well as the effect of androgen deprivation therapy (ADT) on CAFs, remain to be fully elucidated. Using cell lineage diversity and weighted gene co-expression network analysis (WGCNA), we pinpointed a unique CAF signature exclusive to PCa. The specificity of this CAF signature was validated through single-cell RNA sequencing (scRNA-seq), cell line RNA sequencing, and immunohistochemistry. This signature associates CAFs with tumor progression, elevated Gleason scores, and the emergence of castration resistant prostate cancer (CRPC). Using scRNA-seq on collected samples, we demonstrated that the CAF-specific signature is not altered by ADT, maintaining its peak signal output. Identifying a PCa-specific CAF signature and observing signaling changes in CAFs after ADT lay essential groundwork for further PCa studies.

Impact of neoadjuvant relugolix on patient-reported sexual function and bother.

Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT). Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage. The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother. In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Shared Decision-Making and Cardiovascular Complications of Androgen Deprivation Therapy: an Educational Initiative for Oncology Team Members in Colorado, USA.

Patients with prostate cancer may experience side effects of androgen deprivation therapy (ADT) such as cardiovascular (CV) complications. Oncology team members should actively communicate with patients about these complications. On the other hand, shared decision-making (SDM) has been shown to improve patient-physician communication. We developed brochures focused on CV complications of ADT and SDM. We proceeded to deliver these brochures to participating oncology offices and then carried out a survey of team members in these offices. We obtained responses from 31 oncology team members. Our survey revealed that about half of the participants (48%) rarely applied SDM in their oncology practice, and only about one-third (32%) sometimes applied SDM. After reading our brochures, the majority of respondents could correctly answer questions about SDM and CV complications of ADT. Improvement in scores after reading our materials was significant for both CV complications of ADT and SDM (e.g., CV complications of ADT: z = 6.153, p-value < 0.001, and SDM z = 6.456, p-value < 0.001). Implementation of SDM and an improved awareness of the CV complications of ADT can lead to significant benefits. It is therefore important to take steps to further raise such implementation and awareness among oncology team members in other geographic locations and clinical settings.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Perspectives on the Cardiovascular and Metabolic Effects of Androgen Deprivation Therapy in Prostate Cancer.

Cardiovascular disease (CVD) is the leading cause of non-cancer mortality in men with prostate cancer. This review summarizes the existing and emerging literature examining the cardiometabolic effects of androgen deprivation therapy (ADT) in prostate cancer. The evidence behind the metabolic effects of ADT is derived from older studies and has not been validated in modern cohorts. Most of the newer studies focus on the risk of cardiovascular disease (CVD) with ADT. Recently published studies like the HERO and PRONOUNCE trials have once again sparked debate about the effects of different types and durations of ADT on cardiovascular outcomes. The link between ADT and CVD is inherently complex with a majority of the evidence collected from population-based or non-randomized trials without enriching for high-risk populations. Ongoing clinical trials may provide more informative data to guide the cardiovascular care of prostate cancer survivors.

Effects of androgen deprivation therapy on elderly men with high-risk prostate cancer: PROSARC observational study

IntroductionProstatic carcinoma (PC) is a frequent neoplasm in elderly patients. Although androgen deprivation is associated with survival benefits, it is also related to adverse effects such as osteoporosis, frailty, or sarcopenia, which can negatively affect the patient’s quality of life. This study aims to quantify and evaluate the prevalence of osteoporosis, frailty, or sarcopenia in elderly PC patients before and after androgen deprivation. We present data from an interim analysis. Materials and methodsPROSARC is a national (Spain) prospective observational study (May-2022–May-2025) still in progress in 2 hospitals. It includes patients with high-risk PC, aged ≥70 years, non-candidates for local treatment and scheduled to start androgen deprivation therapy. The following variables are analyzed: comorbidity, frailty (Fried frailty phenotype criteria), osteoporosis, sarcopenia (EWGSOP2), fat mass and muscle mass, before treatment and after 6 months of follow-up. ResultsA 6-month follow-up was completed by 12/25 included patients (mean age, 84 years), with a high baseline prevalence of pre-frailty/frailty (67.7%), sarcopenia (66.7%) and osteoporosis (25%). Treatment did not significantly alter these variables or comorbidity. We observed changes in body mass index (p=0.666), decreased mean value of appendicular muscle mass (p=0.01) and increased percentage of fat mass (p=0.012). ConclusionIn patients with high-risk PC, advanced age and a considerable prevalence of osteoporosis, frailty and sarcopenia, androgen deprivation (ADT; 6 months) produces decreased muscle mass without impact on the incidence of the known adverse effects of androgen deprivation.

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan &amp; Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.

LB03 - Effect of androgen deprivation therapy on pSTAT3 expression in prostate cancer

LB03 - Effect of androgen deprivation therapy on pSTAT3 expression in prostate cancer

Neurocognitive effects of androgen deprivation therapy and new hormonal agents in a sample of patients with metastatic prostate cancer

IntroductionAlthough the growing treatment landscape for metastatic prostate cancer (mPC) has revealed new opportunities, it has also provided challenges, such as undesirable side effects. The aim of the present study was to provide further data on domain-specific cognitive impairments in mPC patients with androgen deprivation therapy (ADT) and new hormonal agents.MethodsFifty-eight patients (71 ± 8 years) with mPC were investigated using a cross-sectional design. All patients had received some form of ADT (93% had received luteinizing hormone-releasing hormone (LHRH) analogs/antagonists), 66% had received chemotherapy, and 84% had received anti-resorptive therapy. We evaluated learning and memory, processing speed, and executive functions, as recommended by the International Cognition and Cancer Task Force, to determine neurocognitive deficits.ResultsPatients treated with ADT scored significantly lower on all neurocognitive tests and showed significantly more neurocognitive deficits (38–62%) than age-adjusted reference samples (16%, p < 0.05). Cognitive deficits were mild in most cases and predominantly affected visuomotor processing speed (48%). Moderate and severe deficits were found in 11% and 5% of patients, respectively, with word fluency as the predominant deficit (23%). No associations were found between the type or duration of treatment and the severity of cognitive deficits.ConclusionsTreatment of mPC with ADT is correlated with neurocognitive deficits in several cognitive domains. Language skills and processing speed were most frequently impaired. However, a consistent pattern of cognitive impairment was not identified. Neurocognitive deficits should be considered in phase III and IV trials.Trial registrationThe study was registered in the German Clinical Trials Registry (DRKS00017727).

The Use of Androgen Deprivation Therapy for Prostate Cancer Lead to Similar Rate of Following Open Angle Glaucoma: A Population-Based Cohort Study.

This study aimed to survey the effect of androgen deprivation therapy (ADT) on the development of open angle glaucoma (OAG) in prostate cancer using the data from national health insurance research database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients were regarded as prostate cancer with ADT according to related diagnostic, procedure and medication codes. Each prostate subject with ADT was matched to one patient with prostate cancer, but without ADT, and two participants without both prostate cancer and ADT; 1791, 1791 and 3582 patients were recruited in each group. The primary outcome was set as the OAG development according to related diagnostic codes. Cox proportional hazard regression was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT for the incidence of OAG. There were 145, 65 and 42 newly developed OAG cases in the control group, prostate cancer without ADT group and prostate cancer with ADT group. The prostate cancer with ADT group showed a significantly lower risk of OAG development compared to the control group (aHR: 0.689, 95% CI: 0.489-0.972, p = 0.0341), and the risk of OAG development in the prostate cancer without ADT group was similar compared to that in the control group (aHR: 0.825, 95% CI: 0.613-1.111, p = 0.2052). In addition, ages older than 50 years old would lead to higher incidence of OAG development, respectively. In conclusion, the use of ADT will lead to a similar or lower rate of OAG development.

Association of Androgen Deprivation Therapy with Osteoporotic Fracture in Patients with Prostate Cancer with Low Tumor Burden Using a Retrospective Population-Based Propensity-Score-Matched Cohort.

This study evaluated the effect of androgen deprivation therapy (ADT) on osteoporotic fractures (OF) and its prognostic effect on overall survival in patients with localized or regional prostate cancer (PC) using the Korean National Insurance Dataset. A total of 8883 pairs of 1:1 propensity-score-matched patients with localized or regional PC were retrospectively enrolled between 2007 and 2016. All patients underwent at least 1 year of follow-up to evaluate therapeutic outcomes. Multivariate analysis was performed to determine the prognostic effect of ADT on OF. During a mean follow-up of 47.7 months, 977 (3.43%) patients developed OF, and the incidences of hip, spine, and wrist fractures were significantly different between ADT and non-ADT groups (p < 0.05). The ADT group had a significantly higher incidence of OF (hazard ratio 2.055, 95% confidence interval 1.747-2.417) than the non-ADT group (p < 0.05), and the incidence of spine/hip/wrist OF was significantly higher in the ADT group regardless of the PC stage (p < 0.05). Multivariate analysis failed to show any significant difference in overall survival between the two groups (p > 0.05). ADT resulted in a significantly higher incidence of OF among patients with localized and regional PC, but the overall survival did not differ between ADT and non-ADT groups.

Effect of androgen deprivation therapy on plasma irisin levels, muscle strength, and physical functions tests of lower extremities

Objective: Losses in muscle strength and decreases in physical functions, and therefore a decrease in quality of life, have been observed in prostate cancer patients receiving androgen deprivation therapy (ADT). Irisin is a new exercise-induced myokine, released from the muscles. It is predicted that muscle tissue irisin release as a result of muscle loss, may be affected in patients receiving ADT. The aim of this study is to compare irisin levels, together with muscle strength and physical functions, in patients receiving ADT, patients not receiving ADT, and healthy individuals. Material and methods: A total of 21 healthy individuals (control group: CG); 28 local- or local-advanced prostate cancer patients, not receiving ADT (non-ADT group); and seven prostate cancer patients receiving luteinizing hormone releasing hormone agonist (ADT group) were included in the study. Blood biochemistry (lipid profile, hormones, prostate specific antigen, glucose, insulin, and creatine phosphokinase) and irisin analyses were conducted. Physical functions were assessed by using the Five Times Sit to Stand (5TSTS), climbing stairs, walking pace, and functional reach (FRT) tests. Lower extremity isometric muscle strength was measured using an isokinetic dynamometer. Results: It was observed that the 5TSTS test results were higher (p=0.03), but FRT results were lower (p=0.04) in the ADT group. It was found that isometric muscle strength in lower extremities was significantly lower in the ADT group (p˂0.05). Plasma irisin levels did not reveal a significant difference between the groups (p=0.31). Conclusion: It was determined that muscle strength and physical function test performances of prostate cancer patients receiving ADT were worse, but their irisin levels were similar to patients who were not receiving ADT, and the healthy CG. Muscle strength and physical functions of patients who are receiving ADT, and who will start receiving ADT should be monitored, and protective measures should be taken.

Current Update on Prostate Cancer Immunotherapy

Immunotherapy encompasses a wide array of treatment modalities that utilize our natural defense system to fight against cancer and in recent years has contributed to significant improvement in survival and quality of life in patients. However, its use in prostate cancer has been limited due to low efficacy and lack of effective biomarkers. Prostate cancer’s unfavorable tumor microenvironment characterized by T-cell exclusion and expansion of T-reg cells, along with the possible inhibitory effect of androgen deprivation therapy (ADT) on the immune system further explains this poor response to immunotherapy. Here, we review current immunotherapies and ongoing clinical trials as well as potential biomarkers being investigated to predict treatment responses to immunotherapy. Finally, we discuss the conflicting results on the best approach to sequencing immunotherapy in relation to ADT.

Intensity-modulated radiation therapy for intermediate-risk prostate cancer: does ADT still have an impact in the dose-escalated external beam radiation therapy era?

This study aimed to investigate the effect of androgen deprivation therapy (ADT) on the survival of intermediate-risk prostate cancer (IR-PCA) patients treated with dose-escalated external beam radiation therapy (DE-EBRT), and to determine the group that will benefit from ADT. We analysed 620 IR-PCA patients treated with DE-EBRT at two institutions. Variables were adjusted using the stabilised inverse probability of treatment weighting method (sIPTW) between radiation therapy (RT) and RT plus ADT groups. Biochemical relapse-free survival (bRFS) rate and overall survival (OS) rate were compared using Kaplan-Meier analysis and log-rank test. Cox proportional hazard analysis (CPH) was conducted to detect unfavorable risk factors. This study included 405 patients; with 217 and 188 patients in the RT and RT plus ADT groups, respectively. The prescribed radiation dose was 78Gy in 39 fractions. The median follow-up time was 82.0months. After sIPTW-adjustment, 214.3 and 189.7 patients were assigned to the RT and RT plus ADT groups, respectively. The 7-year bRFS and OS were 89.3% and 94.6% in RT group and 92.3% and 91.0% in RT plus ADT group, respectively. Before and after sIPTW adjustment, no statistically significant differences were found in these endpoints between treatment groups. Multivariate CPH for bRFS revealed Gleason score (GS) 4+3 as an unfavorable risk factor, and ADT improved biochemical control of them. ADT may not always be effective in all Japanese IR-PCA patients treated with DE-EBRT, but it can improve biochemical control in patients with GS 4+3.

Adverse metabolic consequences of androgen deprivation therapy (ADT) on Asian patients with prostate cancer: Primary results from the real‐life experience of ADT in Asia (READT) study

Androgen deprivation therapy (ADT) use in prostate cancer (PCa) has seen a rising trend. We investigated the relationship between ADT and adverse changes in metabolic parameters in an Asian population. This is an international prospective multicenter single-arm cohort yielded from the real-life experience of ADT in Asia(READT) registry. Consecutive ADT-naïve patients diagnosed of PCa and started on ADT were prospectively recruited from 2016 and analyzed. Baseline patient characteristics, PCa disease status, and metabolic parameters were documented. Patients were followed up at 6-month interval for up to 5 years. Metabolic parameters including body weight, lipid profiles, and glycemic profiles were recorded and analyzed. 589 patients were eligible for analysis. ADT was associated with adverse glycemic profiles, being notable at 6 months upon ADT initiation and persisted beyond 1 year. Comparing to baseline, fasting glucose level and hemoglobin A1c level increased by 4.8% (p < 0.001) and 2.7% (p < 0.001), respectively. Triglycerides level was also elevated by 16.1% at 6th month and by 20.6% at 12th month compared to baseline (p < 0.001). Mean body weight was 1.09 kg above baseline at 18th month (p < 0.001). ADT was associated with adverse metabolic parameters in terms of glycemic profiles, lipid profiles, and body weight in the Asian population. These changes developed early in the treatment and can persist beyond the first year. Regular monitoring of the biochemical profiles during treatment is paramount in safeguarding the patients' metabolic health.

Erythroblast transformation-specific transcription factor fusions in prostate cancer.

224 Background: Common drivers in advanced prostate cancer (PC) involve fusions of the 3’ DNA binding domain-containing region of an Erythroblast Transformation Specific (ETS) transcription factor gene with a 5’ region of another gene, often one that is androgen-regulated. Previous work indicates that PCs harboring TMPRSS2:ERG fusions are more dependent on androgen signaling, and men with such tumors may, therefore, be more responsive to the effects of androgen deprivation therapy than men lacking this fusion. In this study, we examined the frequency of fusions involving ETS-family genes, including TMPRSS2:ERG, and determined how often such fusions would be missed if detection relied solely on DNA sequencing. Methods: To identify fusions and compare DNA-only versus DNA plus RNA sequencing, we utilized the Oncomap ExTra genomic profiling assay. This assay performs whole-exome, whole-transcriptome DNA and RNA sequencing of tumor and matched normal samples to identify somatic alterations in tumors. Single-nucleotide variants, indels, copy number alterations, alternative transcripts, and gene fusions are all detected. We specifically searched for fusions involving ETS transcription factor genes ERG and ETV1- 7. Results: A total of 512 PC patient samples assayed between April 2018 and July 2022 were included in the analysis; 226 ETS fusions were present in 223 (43.6%) patients; 3 patients carried two fusions. There were 196 ERG fusions including 185 (36.1%) patients having the familiar TMPRSS2: ERG fusion and 8 (1.6%) patients with a SLC45A3: ERG fusion, which is known to be associated with particularly poor prognosis. ETV1, 4, and 5 fusions were found in 29 (5.7%) patients and involved 12 different 5’ partner genes, the most common of which were SLC45A3 (6 fusions) and CANT1 (4 fusions). The two partner genes were on the same chromosome in 192 fusions, with 190 requiring a single deletion to create the fusion and 2 requiring a single inversion. For the 34 fusions involving genes on different chromosomes, a single translocation would be sufficient to produce the fusion gene in 23 cases; in 11 cases more than one structural rearrangement would be required. A total of 66 (29.6%) fusions were not detected in the DNA sequencing data, including 40 (21.6%) TMPRSS2: ERG fusions. In addition, 16 fusions were detected only in the DNA data, as RNA could not be sequenced, including 13 TMPRSS2: ERG fusions. Conclusions: In addition to TMPRSS2: ERG, the Oncomap ExTra assay identified several low frequency ETS fusions, all of which could be used to assist patients and physicians to select appropriate treatments. The identification of ETS fusions appears to be limited when using only DNA sequencing. Oncomap ExTra RNA analysis identified 66 additional fusions, representing almost 30% of those present, not identified by whole-exome DNA sequencing, suggesting RNA plus DNA assays detect fusions more reliably than DNA-only assays.

Effects of Androgen Deprivation Therapy on Prostate Cancer Outcomes According to Competing Event Risk: Secondary Analysis of a Phase 3 Randomised Trial

BackgroundPrevious studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks. ObjectiveTo determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT. Design, setting, and participantsAn ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted. InterventionShort-term ADT. Outcome measurements and statistical analysisWe applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate-specific antigen (PSA), to stratify patients according to relative hazards for primary cancer-related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score. Results and limitationsT2b, higher GS, and higher PSA were associated with an increased RR for cancer-related versus competing mortality events (a higher omega score); increased age and comorbidity were associated with a decreased omega score. Of 996 patients with low-risk/favourable intermediate-risk (FIR) disease, 286 (28.7%) had a high omega score (≥0.314). Of 768 patients with unfavourable intermediate-risk disease, 175 (22.8%) had a low omega score. The overall discordance in risk classification was 26.1%. Both standard criteria and omega score identified significant interactions for the effect of ADT on cancer-related events and late mortality in low- versus high-risk subgroups. Within the low-risk/FIR subgroup, a higher omega score identified patients in whom ADT significantly reduced cancer events and improved event-free survival. Limitations are the need for external/prospective validation and lower RT doses than contemporary standards. ConclusionsStratification based on competing event risk is useful for identifying prostate cancer patients who selectively benefit from ADT. Patient summaryWe analysed the effectiveness of androgen deprivation therapy (ADT) for localised prostate cancer among patients, defined by the relative risk (RR) for cancer versus noncancer events. Among patients with traditional low-risk/favourable intermediate-risk disease, those with a higher RR benefitted from short-term ADT.

Effects of Androgen Deprivation Therapy on Alzheimer's disease and Related Dementia Risk in the Million Veteran Program

AbstractBackgroundAndrogen deprivation therapy (ADT) for prostate cancer depletes circulating testosterone levels and has been shown to increase risk for Alzheimer’s disease (AD) and related dementias (ADRD). It is unclear whether ADT acts independently to increase ADRD risk, or whether effects of this treatment are exacerbated by the genetic risk for AD. We hypothesized that the effect of ADT on ADRD risk will be moderated by AD polygenic risk.MethodClinical and genetic data were analyzed from 87,060 United States Veterans, who had a diagnosis of prostate cancer and were participants in the Million Veterans Program (MVP) biorepository study. Clinical conditions, including diagnosis codes for ADRD, cancer, Charlson Comorbidity Index conditions, laboratory values (Gleason score, Prostate Specific Antigen levels), cancer treatments, and vital status were obtained from the Veterans Affairs (VA) longitudinal electronic health record data. A polygenic risk score (PRS) for AD was derived based on summary statistics from the Kunkle et al (2019) GWAS of Alzheimer’s disease. The impact of ADT on ADRD was assessed using a time‐varying Fine‐Gray competing risks regression. Death from any cause was considered as a competing event to the development of ADRD.ResultThere were 17,092 (19.6%) patients who received ADT. 72% of the cohort was of white/European ancestry. The average age at prostate cancer diagnosis was 66 years. The median duration of ADT was 360 days. ADT users were more likely to be African American, and had higher PSA levels and Gleason Scores. ADT exposure and the AD PRS each showed significant main effects on ADRD risk, HRs = 1.16 (95% CI: 1.04 ; 1.29) and 1.10 (95% CI: 1.06 ; 1.15) respectively; however, we did not observe a significant interaction effect. Sensitivity analyses indicate that the association was not confounded by including Gleason score, PSA level, income, or education, and results were not altered significantly by excluding or focusing on the effect of the APOE:E4 locus.ConclusionADT significantly increases risk of ADRD, independent of underlying AD genetic risk factors. Further research is necessary in order to determine the mechanism by which androgen depletion contributes to the pathophysiology of ADRD.