GnRH Research Articles

Profiling of Skeletal Muscle and Adipose Tissue Depots in Men with Advanced Prostate Cancer Receiving Different Forms of Androgen Deprivation Therapy

BackgroundAndrogen deprivation therapy (ADT) is a common treatment modality for men with prostate cancer. Increases in adipose tissue mass and decreases in skeletal muscle mass are known on-target adverse effects of standard ADT. The effects of newer agents such as abiraterone acetate (ABI) and enzalutamide (ENZA) on body composition and how these compare with standard luteinizing hormone-releasing hormone agonists (aLHRHs) are unclear. ObjectiveTo assess the effects of different forms of androgen deprivation therapy on body composition in men with prostate cancer. Design, setting, and participantsUsing a retrospective design, 229 patients receiving aLHRHs alone (n = 120) or in combination with ABI (n = 53) or ENZA (n = 56) were studied. Outcome measurements and statistical analysisMuscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were assessed at baseline, 6 mo, and 18 mo after initiating therapy using a cross-sectional densitometry analysis performed on standard of care computed tomography images. Response trajectories for all treatment groups were calculated via a two-way analysis of variance post hoc test, for both within-group and between-group differences. Results and limitationsTreatment with aLHRHs, ABI, and ENZA was associated with a median muscle volume loss of –1.4%, –4.8%, and –5.5% at 6 mo, and –7.1%, –8.1%, and –8.3% at 18 mo, respectively. Therapy with aLHRHs was associated with minimal changes in VAT (0.3% at 6 mo and –0.1% at 18 mo). ABI therapy was associated with significant increases in VAT at 6 mo (4.9%) but not at 18 mo (0.5%), and ENZA therapy was associated with significant decreases in VAT (–4.6% at 6 mo and –5.4% at 18 mo). With respect to SAT, treatment with aLHRHs was associated with increases over time (8.6% at 6 mo and 4.7% at 18 mo), ABI was associated with decreases over time (–3.6% at 6 mo and –6.8% at 18 mo), and ENZA had no clear effects (1.7% at 6 mo and 3.3% at 18 mo). ConclusionsADT regimens cause significant short-term losses in muscle mass, with the most rapid effects occurring with ABI and ENZA. The three regimens have disparate effects on SAT and VAT, suggesting distinct roles of androgens in these tissues. Patient summaryAndrogen deprivation therapy alters body composition in men with prostate cancer. Abiraterone and enzalutamide are associated with losses in muscle mass compared with luteinizing hormone-releasing hormone agonists. These treatments impact subcutaneous and visceral fat mass, suggesting distinct roles of androgens in these tissues.

Effect of human chorionic gonadotrophin (HCG) and luteinizing hormone releasing hormone A3 (LHRH-A3) on reproduction and development of brood pouch in Hippocampus erectus

Syngnathid fishes (seahorses and pipefish) are unique in reproduction, with males becoming pregnant and giving birth. The brood pouch provides osmoregulation, gas exchange, waste transport, immunoprotection and nutrition supply. However, the function of hormone trafficking is rarely studied. By injecting the mixture liquor of human chorionic gonadotrophin (HCG, 2 IU/g) and luteinizing hormone-releasing hormone A3 (LHRH-A3, 5 ng/g) into the brood pouch of Hippocampus erectus, we found the reproductive interactions accelerated dramatically, and 4 pairs were successfully mated. After 24 h, the inner epithelium was highly folded and the loose connective tissue layer was highly distended. In the inner tissue layer of the brood pouch, fibroblasts secreted vigorously, blood vessels multiplied and expanded, indicating the physiological structure of the brood pouch modified hastily from the unpregnant stage to the progravid phase. Correspondingly, transcriptome results revealed the gene expression of circadian, epitheliogenesis, angiogenesis, lipid transfer, and spermiogenesis were significantly up-regulated. We innovatively found that macromolecule exogenous hormone (HCG) can be not only efficiently transported from brood pouch to body, but also promote mating and the physiological changes of the brood pouch.

Cardiometabolic healthcare for men with prostate cancer: an MD Anderson Cancer Center experience

BackgroundMen diagnosed with prostate cancer are at risk for competing morbidity and mortality due to cardiometabolic disease given their advanced age at diagnosis, high prevalence of pre-existing risk factors, and receipt of systemic therapy that targets the androgen receptor (AR). Expert panels have stressed the importance of cardiometabolic risk assessment in the clinic and proposed evaluating key risks using consensus paradigms. Yet, there is a gap in real-world evidence for implementation of comprehensive cardiometabolic care for men with prostate cancer.MethodsThis is a retrospective, descriptive study of patients with prostate cancer who were referred and evaluated in the Healthy Heart Program at MD Anderson Cancer Center, which was established to mitigate cardiometabolic risks in men with prostate cancer. Patients were seen by a cardiologist and exercise physiologist to evaluate and manage cardiometabolic risk factors, including blood pressure, cholesterol, blood glucose, tobacco use, and coronary artery disease, concurrent with management of their cancer by a medical oncologist.ResultsFrom December 2018 through October 2021, the Healthy Heart Program enrolled 55 men with prostate cancer, out of which 35 had biochemical, locoregional recurrence or distant metastases, while all received at least a single dose of a luteinizing hormone-releasing hormone (LHRH) analog. Ninety-three percent of men were overweight or obese, and 51% had an intermediate or high risk of atherosclerotic cardiovascular disease at 10 years based on the pooled cohort equation. Most men had an overlap of two or more cardiometabolic diseases (84%), and 25% had an overlap of at least 4 cardiometabolic diseases. Although uncontrolled hypertension and hyperlipidemia were common among the cohort (45% and 26%, respectively), only 29% of men followed up with the clinic.ConclusionsMen with prostate cancer have a high burden of concurrent cardiometabolic risk factors. At a tertiary cancer center, the Healthy Heart Program was implemented to address this need, yet the utility of the program was limited by poor follow-up possibly due to outside cardiometabolic care and inconvenient appointment logistics, a lack of cardiometabolic labs at the time of visits, and telemedicine visits.

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).

HISTORY OF CANCER HORMONOTHERAPY

breast cancer, epidemiology, risk factors, classification, diagnosis, prognosis, marker, treatment, Lobular carcinoma in situ ((DCIS), time to progression (TTP), complete regression, partial regression, metastatic breast cancer (MBC), median progression-free survival (PFS), overall response, LH-RH agonists and antagonists, receptor estrogen, LH-releasing hormone, Gonadotropin-releasing-hormone-receptor antagonists, overall survival, prostate cancer, Castration-resistant prostate cancer (CRPC), receptor androgens, prostate-specific antigen (PSA)

Efficacy of Degarelix in the Neoadjuvant Setting in Managing Locally Advanced Prostate Cancer.

Background Prostate cancer holds a substantial presence in the global cancer landscape, and a considerable proportion of diagnoses occur at late stages, particularly in India. Management of locally advanced prostate cancer necessitates a multimodal treatment strategy. A critical part of this strategy is neoadjuvant androgen deprivation therapy, typically administered via luteinizing hormone-releasing hormone (LHRH) analogs. This study explores the potential of an alternative approach: neoadjuvant therapy with degarelix, an LHRH antagonist, and its impact on perioperative and postoperative outcomes in patients undergoing radical prostatectomy for locally advanced or high-risk prostate cancer. Methodology We conducted a retrospective, non-randomized clinical study at Apollo Hospitals in Chennai, India. Patients diagnosed with locally advanced or high-risk prostate cancer who underwent radical prostatectomy were included. Participants were patients treated with neoadjuvant degarelix and subsequent radical prostatectomy between March 2020 and June 2022. We excluded patients receiving radical radiotherapy, those switching from LHRH agonists to antagonists, and those contraindicated for androgen deprivation therapy due to existing comorbidities. For comparison, we selected a group from the institutional database who received conventional treatment (i.e., without neoadjuvant therapy). Results The study compared two groups, each with 32 patients. The groups had no significant difference in total operative duration and console times. The postoperative pathological assessment showed significantly lower margin positivity rates and notable pathological downstaging in the group receiving neoadjuvant degarelix compared to the control group. The incidence of node positivity, prostate-specific antigen levels at three months postoperative, and number of pads used per day at one month did not differ significantly between the two groups. Conclusions Our study suggests that neoadjuvant degarelix could notably enhance patient outcomes in locally advanced prostate cancer management. The benefits include improved symptom control, significant reductions in margin positivity rates, and facilitated surgical procedures. Neoadjuvant degarelix therapy could potentially enhance the feasibility of the surgical intervention in locally advanced prostate cancer management, thus suggesting a promising pathway for improved patient care.

The Finding of New In Vivo Metabolite Triptorelin (5-10) in Human Urine Using Liquid Chromatography Coupled with Ion Trap/Time-of-Flight Mass Spectrometry with Dimethyl Sulfoxide Additives in the Mobile Phase.

Triptorelin and leuprorelin are synthetic gonadotrophin-releasing hormones (GnRH) that are on the World Anti-Doping Agency (WADA) list of prohibited substances. To investigate the possible in vivo metabolites of triptorelin and leuprorelin in humans compared to previously reported in vitro metabolites, excreted urine from five patients treated with either triptorelin or leuprorelin was analyzed by liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (LC/MS-IT-TOF). The addition of dimethyl sulfoxide (DMSO) to the mobile phase was found to enhance the detection sensitivity of certain GnRH analogs. The method was validated, and the limit of detection (LOD) was found at 0.02-0.08 ng/mL. Using this method, a novel new metabolite of triptorelin was discovered in the urine of all subjects up to 1 month after triptorelin administration, but it was not observed in the urine of subjects before drug administration. The limit of detection was estimated to be 0.05 ng/mL. The structure of the metabolite, triptorelin (5-10), is proposed from bottom-up mass spectrometry analysis. The discovery of in vivo triptorelin (5-10) can possibly be used as supporting evidence of triptorelin misuse in athletes.

Open-label study of darolutamide plus androgen-deprivation therapy (ADT) vs ADT in metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC).

TPS5112 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARASENS study (NCT02799602) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80), with a favorable tolerability and safety profile. In the global (excluding US), phase 3 ARANOTE study (NCT04736199), DARO + ADT vs ADT alone is being evaluated in pts with mHSPC. ARASEC (NCT05059236) will complement ARANOTE by assessing DARO + ADT in US pts. As ADT alone is no longer an acceptable comparator in the US, the external control arm will be derived from the historical US CHAARTED study (NCT00309985). A real-world analysis of electronic health record data from pts with mHSPC (TIMES) indicated that there was minimal risk of historical time bias associated with the use of the external ADT alone arm from CHAARTED as a comparator for ARASEC (Shore N, et al . J Clin Oncol 2022;40(28 Suppl):Abstract 403). Methods: ARASEC is a phase 2, open-label, single-arm study enrolling pts with confirmed mHSPC and no prior systemic therapy. Pts will receive DARO 600 mg orally twice daily + ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The external control arm will be derived from 394 pts with mHSPC treated with ADT alone in CHAARTED. To remove biases in evaluating outcomes that could arise due to differences in baseline profiles between arms, pts will be matched 1:1 using a propensity score (PS) summarizing baseline characteristics relevant to disease outcomes. Baseline variables will include age ( &lt; 70 vs ≥70 years), Eastern Cooperative Oncology Group performance status (0–1 vs 2), CHAARTED-defined extent of disease (low vs high volume + bone metastases only vs high volume + visceral metastases ± bone metastases), and prior therapy (yes vs no; as a proxy for recurrent vs de novo disease). Matching patients with scores within a narrow window across the cohorts will ensure that pts in CHAARTED are representative of pts in the DARO + ADT arm. The primary endpoint is progression-free survival (PFS), as defined in CHAARTED. Secondary endpoints include overall survival, radiographic PFS, time to CRPC, undetectable prostate-specific antigen response rate ( &lt; 0.2 ng/mL) at 6 months, and safety. Target enrollment for the DARO + ADT arm is 200 pts at 30 sites. The study will continue until either the event count threshold triggering the primary endpoint analysis has been met (161 PFS events) or all pts have been followed for ≥2 years, whichever occurs later. As of January 2023, 121 pts have been enrolled. A per-protocol, predefined matching exercise on the first 100 pts enrolled will be conducted to ensure that the planned sample size is adequate. Clinical trial information: NCT05059236 .

Clinicopathological characteristics and outcome of very young breast cancer patients at a referral center in Iran.

e12568 Background: Although breast cancer (BC) is the most common type of cancer in women worldwide, in women younger than 35 years old is uncommon and only accounts for 2% of breast cancer diagnosed in western countries. However, there is insufficient data on breast cancer in women younger than 35 years old in Iran. The aim of this study was to assess clinicopathological parameters in these very young breast cancer patients. Methods: In this retrospective cohort study, we have collected the demographic, clinical and histopathological data of women younger than 35 years diagnosed with BC who presented to our tertiary center from 2011 to 2017. Patients were followed at least for four years and the diseases-free survival (DFS) and overall survival (OS) were assessed. Chi-square and multivariate regression tests were conducted to assess the association of mentioned variables. A P-value less than 0.05 was considered to be statistically significant. Results: A total of 334 women with Breast Cancer younger than 35 years old were included in this study, of which 219 patients were between 31 to 35. The most common histopathologic type was hormone receptor positive, HER2 negative 41.6 %. HER2 positive (regardless of hormone receptor status) and triple negative were 30.1% and 24.6% of cases respectively. Grade1 was reported in 5% of cases, grade 2 and 3 were 50.9 % and 43.6% respectively. 16.9% of patients were presented in stage I, 44.4% stage II, 30.5% stage III and 8.2% had de novo metastatic disease. Of 68 patients who received neoadjuvant chemotherapy, 29.4% had complete pathological response. Sixty five percent of 199 patients with hormone positive had received Luteinizing hormone-releasing hormone (LHRH) agonist, this type of treatment significantly improved 4-year OS regardless of HER2 expression. Mean follow up was 71.5±26.6 months, 4-year DFS and OS were 66% and 80% respectively. Four-year overall survival was analyzed by stage, it was 100% for stage I, 89% stage II, 79% stage III, and 11% stage IV. The four-year OS corresponding to the subtypes was as follows; HR+/HER2- (89.5%), HR+/HER2+ (76.9%), HR-/HER2+ (73.3%) and TNBC (75.4%). Conclusions: Breast cancer occurring in very young women constituted 9.5% of all breast cancer cases treated at Shohada Hospital, Iran, and this high rate shows a significant correlation with unpublished data by Health ministry in 2016-2017. This high percentage is an alarm not only in breast clinics but also in early detection of breast cancer. In according to other published data, clinicopathological subtypes in our center was similar to other papers. The associations of subtypes with stage and grade, were significant.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Gonadotrophin-releasing hormone receptors in GtoPdb v.2023.1

GnRH1 and GnRH2 receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [85, 84, 114] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [85, 84, 114]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [58]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [58]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [130] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH1 receptor in complex with elagolix has been elucidated [133].

Efficacy and Safety of Neoadjuvant Luteinizing Hormone-Releasing Hormone Antagonist and Tegafur-Uracil Chemohormonal Therapy for High-Risk Prostate Cancer.

This retrospective single-center cohort study evaluated the efficacy and safety of a combination of neoadjuvant luteinizing hormone-releasing hormone (LHRH) antagonist and tegafur-uracil (UFT) therapy (NCHT) and investigated the medical records of patients with high-risk PCa who underwent robot-assisted radical prostatectomy (RARP). The therapy was followed by RARP for high-risk PCa. The enrolled patients were divided into two groups: low-intermediate-risk PCa patients who underwent RARP without neoadjuvant therapy (non-high-risk) and those who underwent NCHT followed by RARP (high-risk group). This study enrolled 227 patients (126: non-high-risk and 101: high-risk group). Patients in the high-risk-group had high-grade cancer compared to those in the non-high-risk-group. At the median follow-up period of 12.0 months, there were no PCa deaths; two patients (0.9%) died of other causes. Twenty patients developed biochemical recurrence (BCR); the median time until BCR was 9.9 months after surgery. The 2-year biochemical recurrence-free survival rates were 94.2% and 91.1% in the non-high-risk and high-risk-group, respectively (p = 0.465). Grade ≥3 NCHT-related adverse events developed in nine patients (8.9%). This study indicates that combining neoadjuvant LHRH antagonists and UFT followed by RARP may improve oncological outcomes in patients with high-risk PCa.

Androgen Deprivation Therapy in Current Clinical Practice: Challenges and Future Perspective

Androgen deprivation therapy (ADT) has been used for many years for treating advanced prostate cancer (PCa) and remains the backbone of treatment. Luteinising hormone-releasing hormone (LHRH) receptor agonists are the most widely used ADT drugs. However, newer options, including gonadotropin releasing hormone (GnRH) receptor antagonists such as degarelix and relugolix, may be clinically more beneficial for some patients. GnRH antagonists reduce serum testosterone levels more rapidly than LHRH agonists, without an initial testosterone surge or subsequent microsurges. This article summarises a symposium delivered on 11th March 2023 at the 38th European Association of Urology (EAU) Annual Congress in Milan, Italy, where speakers from three different disciplines described challenges and future perspectives for ADT in current clinical practice. Kurt Miller, Urologist, Charité University Hospital, Berlin, Germany, described the evolution of ADT in the treatment of PCa, from early reports of the benefits of surgical castration to the recent development of oral treatment for chemical castration. Miller explained the acceleration in progress in ADT research over recent years, with the development of novel drugs, drug sequences, and combinations, which have transformed outcomes in PCa. Alberto Bossi, Radiation Oncologist, Amethyst Group, Institut Gustav Roussy (IGR), Paris, France, next described current challenges with ADT management, including outstanding questions about the personalisation of ADT. Finally, Patrick Davey, Consultant Cardiologist, Northampton General Hospital, UK, spoke about ways to maintain a healthy heart on hormone treatment, and noted that cardiovascular safety is a major challenge in the use of ADT. The meeting was chaired by Heather Payne, Consultant Clinical Oncologist, University College Hospital, London, UK, who introduced the speakers and co-ordinated a question-and-answer session at the end of the symposium.

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China.

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China.

MP67-14 VARIATION OF HORMONAL AGENT USAGE WITH POSTOPERATIVE RADIATION THERAPY: RESULTS FROM A POPULATION BASED COHORT OF PROSTATE CANCER PATIENTS IN COMMUNITY ONCOLOGY PRACTICES

You have accessJournal of UrologyCME1 Apr 2023MP67-14 VARIATION OF HORMONAL AGENT USAGE WITH POSTOPERATIVE RADIATION THERAPY: RESULTS FROM A POPULATION BASED COHORT OF PROSTATE CANCER PATIENTS IN COMMUNITY ONCOLOGY PRACTICES Rodrigo R Pessoa, Tyler Robin, Thomas Flaig, Elizabeth Molina, Boris Gershman, Eric Ballon-Landa, Corbin Eule, Elizabeth Kessler, Brian Chapin, Marc C Smaldone, and Simon P Kim Rodrigo R PessoaRodrigo R Pessoa More articles by this author , Tyler RobinTyler Robin More articles by this author , Thomas FlaigThomas Flaig More articles by this author , Elizabeth MolinaElizabeth Molina More articles by this author , Boris GershmanBoris Gershman More articles by this author , Eric Ballon-LandaEric Ballon-Landa More articles by this author , Corbin EuleCorbin Eule More articles by this author , Elizabeth KesslerElizabeth Kessler More articles by this author , Brian ChapinBrian Chapin More articles by this author , Marc C SmaldoneMarc C Smaldone More articles by this author , and Simon P KimSimon P Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003330.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The optimal hormonal agent for postoperative radiation therapy remains to be defined with either LH-RH agents or androgen receptor blockers. Androgen deprivation therapy appears to be important for some patients receiving postoperative radiation therapy but there are differences in side effects and quality of life. Thus, we used a large national database of community practices to identify practice patterns with hormonal agents in the postoperative radiation therapy settings. METHODS: From the CancerLinQ database, which represents more than a 100 community oncology practices in the U.S., we included all men who underwent radical prostatectomy and then received adjuvant or salvage radiation therapy from 2000 to 2021. The primary outcome was concomitant use of hormonal therapy including luteinizing hormone – releasing hormone (LH-RH) agents or androgen receptor blockers. Multivariable logistic regression analyses were used to elucidate patient characteristics associated with use of each class of hormonal agents. RESULTS: Among the 390 surgically treated patients receiving postoperative radiation therapy, 50.7%(n=198) received no hormonal agents, 23.6 % (n=92) received LH-RH agents, and 22.82% (n=89) received both LH-RH agents and androgen receptor blocker. Only 2.8% (n=11) received androgen receptor blocker alone. Among patients with salvage radiation therapy at PSA>0.7 ng/dl, 51.6% did not receive any form of hormonal therapy. On multivariable analysis, patients with pN1+ compared with pN0 had higher odds of receiving LH-RH agents (OR: 3.21; p=0.01) during postoperative radiation therapy. Conversely, African American men were less likely to receive androgen receptor blockers compared to white men (OR: 0.24; p=0.004). Use of hormonal agents were not associated with postoperative radiation therapy intent. CONCLUSIONS: Among patients treated in community-based oncology practices in the U.S., most are not receiving any form of hormonal agents with postoperative radiation therapy. Racial disparities also exist in the use of androgen receptor blockers during post-prostatectomy radiation therapy. Increased attention is needed to disseminate evidence into clinical practice. Source of Funding: Schramm Foundation © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e948 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rodrigo R Pessoa More articles by this author Tyler Robin More articles by this author Thomas Flaig More articles by this author Elizabeth Molina More articles by this author Boris Gershman More articles by this author Eric Ballon-Landa More articles by this author Corbin Eule More articles by this author Elizabeth Kessler More articles by this author Brian Chapin More articles by this author Marc C Smaldone More articles by this author Simon P Kim More articles by this author Expand All Advertisement PDF downloadLoading ...

PD16-06 EXAMINING TESTOSTERONE RECOVERY IN ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD16-06 EXAMINING TESTOSTERONE RECOVERY IN ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER Mark A. Preston, Jessica R. Marden, Noam Kirson, Esmond Nwokeji, Raj Gandhi, Allison Briggs, Katherine Gaburo, Sarah Hanson, and Alicia K. Morgans Mark A. PrestonMark A. Preston More articles by this author , Jessica R. MardenJessica R. Marden More articles by this author , Noam KirsonNoam Kirson More articles by this author , Esmond NwokejiEsmond Nwokeji More articles by this author , Raj GandhiRaj Gandhi More articles by this author , Allison BriggsAllison Briggs More articles by this author , Katherine GaburoKatherine Gaburo More articles by this author , Sarah HansonSarah Hanson More articles by this author , and Alicia K. MorgansAlicia K. Morgans More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) used in prostate cancer (PC) can delay testosterone (T) recovery (TR) after treatment cessation. Data are lacking on the clinical impact of prolonged TR. This real-world study examined clinical events among PC patients with and without TR after discontinuing injectable ADT. METHODS: A retrospective longitudinal cohort study was conducted using electronic medical records (Optum’s de-identified Market Clarity Data, 2010–2021). Eligible patients had a PC diagnosis, initiated first-line ADT monotherapy, and had ≥1 serum T level within 1 year of ADT discontinuation. Patients were classified as having TR (serum T >280 ng/dL) or no TR within 1 year of ADT discontinuation. Clinical outcomes examined included myocardial infarction, cerebrovascular accident, diabetes, depression, hot flashes, sexual dysfunction, and bone complications. The proportion of patients with events at 12 months were reported. Multivariate Cox proportional hazards models estimated hazard ratios (HRs) for TR vs non-TR cohorts, adjusting for demographics and baseline clinical events. RESULTS: 1553 patients were identified in the TR (n=390) and non-TR (n=1163) cohorts. Median age at ADT initiation was 70.3 years with 94.8% receiving a luteinizing hormone-releasing hormone agonist. Baseline median serum T was 254.0 ng/dL among patients with available data. During the 1-year post-ADT discontinuation, median serum T levels were 330.5 ng/dL for TR and 32.7 for non-TR cohorts. At 12 months post-discontinuation, a higher proportion of TR vs non-TR patients had sexual dysfunction, while lower proportions had new onset diabetes and depression (Table 1). Adjusted Cox analyses showed TR patients had a lower risk of diabetes (HR=0.47 [95% CI 0.27–0.79], p=0.005) vs the non-TR cohort and trended toward lower risk of depression (HR=0.58 [0.33–1.02], p=0.059) but a higher risk of sexual dysfunction (HR=1.33 [0.99–1.78], p=0.060). CONCLUSIONS: Patients with recovered serum T within 1 year of ADT discontinuation were less likely to experience diabetes. Trends showed a lower rate of depression and sexual dysfunction as potentially correlated with time to TR. Sexual dysfunction may have been higher among TR patients due to greater levels of sexual interest post ADT. Source of Funding: Myovant Sciences, Inc. in collaboration with Pfizer, Inc © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e491 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mark A. Preston More articles by this author Jessica R. Marden More articles by this author Noam Kirson More articles by this author Esmond Nwokeji More articles by this author Raj Gandhi More articles by this author Allison Briggs More articles by this author Katherine Gaburo More articles by this author Sarah Hanson More articles by this author Alicia K. Morgans More articles by this author Expand All Advertisement PDF downloadLoading ...

Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers.

For many years, luteinizing hormone-releasing hormone or gonadotropin-releasing hormone (GnRH) analogs have been used to treat androgen or estrogen-dependent tumors. However, emerging evidence shows that the GnRH receptor (GnRH-R) is overexpressed in several cancer cells, including ovarian, endometrial, and prostate cancer cells, suggesting that GnRH analogs could exert direct antitumoral actions in tumoral tissues that express GnRH-R. Another recent approach based on this knowledge was the use of GnRH peptides for developing specific targeted therapies, improving the delivery and accumulation of drugs in tumoral cells, and decreasing most side effects of current treatments. In this review, we discuss the conventional uses of GnRH analogs, together with the recent advances in GnRH-based drug delivery for ovarian, breast, and prostatic cancer cells.

Artificial Propagation of Pomadasys hasta (Bloch, 1790): A Key to Reach Sustainable Aquaculture

Reproduction of Pomadasys hasta was studied in captivity to establish an induced breeding protocol and larvae rearing tactics. Three distinct hormones viz., human chorionic gonadotropin (HCG), luteinizing hormone-releasing hormone analogues (LHRHa) and salmon gonadotropin hormone-releasing hormone (S-GnRHa) were injected to matured brooders in treatment 1 (T1), treatment 2 (T2) and treatment 3 (T3) but only 0.9% NaCl used in T4 as a control. In each treatment, three experimental trails, E1 (♀40:♂20 µg.kg-1), E2 (♀50:♂25 µg.kg-1) and E3 (♀60:♂30 µg.kg-1) were conducted along with three replications of each trail in order to optimize the hormone dose for the target species. The obtained results have aroused much attention as this is the first breakthrough on induced breeding of a grunter in the Indian subcontinent. Variation in fertilization rate, latency period, egg output and hatching rate in response to different treatments and trails were revealed here. Spawning was occurred between 33-48 h of injection in all the experiments at 17-25°C water temperature. Above all, the highest fertilization (95.45±2.34) and hatching (75.45±4.07) rates were observed in E2 of T2. After 22-26 h of fertilization, the larvae emerged from the egg membrane and the newly hatched larvae were 1.6-1.8 mm in length. Turning larvae into juveniles was noticed by 40–45 days post-hatch (dph) with scales on the entire body surface. The total length was recorded as 43.5±2.1 mm and average body weight as 0.7±0.2 g at 95 dph. This investigation unlocked a track for producing seed of P. hasta in a commercial hatchery for a sustainable aquaculture without hampering their wild stock.

Effects of four hormones on the mitigation of ovarian damage in tilapia (Oreochromis niloticus) after copper and cadmium exposure

Female tilapia of the Genetic Improvement of Farmed Tilapia (GIFT) strain were selected as an animal model to study the effects of four hormonal drugs in mitigating ovarian damage following exposure to copper and cadmium. After combined exposure to copper and cadmium in aqueous phase for 30 d, tilapia were randomly injected with oestradiol (E2), human chorionic gonadotropin (HCG), luteinizing hormone releasing hormone (LHRH), or coumestrol and raised in clear water for 7 d Ovarian samples were collected after combined exposure to heavy metals for 30 d and after recovery for 7 d Gonadosomatic index (GSI), copper and cadmium levels in the ovary, reproductive hormone levels in serum, and mRNA expression of key reproductive regulatory factors were determined. After 30 d of exposure to the combined copper and cadmium in aqueous phase, the Cd2+ content in tilapia ovarian tissue increased by 1,242.46% (p < 0.05), whereas the Cu2+ content, body weight, and GSI decreased by 68.48%, 34.46%, and 60.00% (p < 0.05), respectively. Additionally, E2 hormone levels in tilapia serum decreased by 17.55% (p < 0.05). After drug injection and recovery for 7 d, compared to the negative control group, the HCG group exhibited an increase of 39.57% (p < 0.05) in serum vitellogenin levels. Increases of 49.31%, 42.39%, and 45.91% (p < 0.05) in serum E2 levels were observed, and mRNA expression of 3β-HSD increased by 100.64%, 113.16%, and 81.53% (p < 0.05) in the HCG, LHRH, and E2 groups, respectively. The mRNA expression of CYP11A1 in tilapia ovaries increased by 282.26% and 255.08% (p < 0.05) and mRNA expression of 17β-HSD increased by 109.35% and 111.63% in the HCG and LHRH groups, respectively (p < 0.05). All four hormonal drugs, particularly HCG and LHRH, promoted the restoration of tilapia ovarian function to varying degrees after injury induced by combined exposure to copper and cadmium. This study presents the first hormonal treatment protocol for the mitigation of ovarian damage in fish exposed to combined aqueous phases of copper and cadmium as a strategy to prevent and treat fish ovarian damage induced by heavy metals.

Abstract OT2-03-01: heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer

Abstract BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-01.