Hormone Ablation Research Articles

Effect of hormonal therapy on bone mineral density of breast cancer women

Background: Aromatase inhibitor (AI) was received by breast cancer women with estrogen receptor-positive. The estrogen is the main stimulator for receptor-positive breast cancer cells development and growth, the adjuvant hormone ablation targeting estrogen can decrease the likelihood of cancer recurrence and prolong cancer-free survival. Objective: To determine the effect of this therapy on bone mineral density of women who received it. Patients and Methods: It was identified 100 women with local or regional breast cancer diagnosed and who received AI therapy in the January 2022 to February 2023 from Baqubah teaching hospital/Oncology Centre. It was used DEXA scan to determine the bone minerals density of 50 women after different years from receiving hormonal therapy and other 50 breast cancer women before receiving hormonal therapy. Results: It was shown that there is a significant difference (p<0.0001) in the spine and hip density of breast cancer women who received AIs compare with the bone density of other breast cancer women who did not receive it. Conclusion: It can conclude that Als plays an essential role for osteoporosis that reduce the quality of health and increase the risk of fraction in the breast cancer women.

Abstract 709: Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy

Abstract Current treatments for prostate cancer primarily rely on radiation and hormone deprivation therapy, yet they often lack effective immunotherapeutic effects. Furthermore, long-term hormone ablation has side effects, such as, impotency and osteoporosis. Addressing this gap, we introduce an innovative dual-frequency focused ultrasound (FUS) platform for non-ablative focal therapy, which induces protein unfolding, ER stress, and increases heat-shock protein expression along with translocation of endoplasmic reticular chaperone proteins (e.g., calreticulin) on the tumor cell surface, thereby sensitizing them for phagocytosis by dendritic cells for efficient antigen presentation and cross priming. We hypothesized that FUS-mediated acoustic immune priming can be combined with ablative therapies, such as, hormone ablation and/or radiation therapy (RT) for induction of tumor-specific adaptive immune response and better tumor control than monotherapy in murine prostate cancer models. Utilizing murine prostate cancer cell lines, MyC-CaP and RM1, we explored the cellular responses to androgen deprivation, observing distinct sensitivities. Twenty-four hours after FUS treatment tumor cells experienced mechano-thermal stress response with 15-fold increase in Hspa1a expression. Transmission Electron Microscopy studies showed formation of myelin figures, nuclear membrane deformation, and lipid droplet formation. In vivo, the combination of FUS (220w/cm2 intensity for 3 sec at focal point) and RT (8-10 Gy daily x two fractions) markedly delayed tumor growth and achieved complete cure in 14-17% of animals. Through multicolor flow cytometry, we detected significant alterations in the immune microenvironment, including increased CD8+ T cell infiltration and reduced tumor-associated macrophages in the tumor bed. However, we also observed a compensatory rise in pro-tumor immune cells such as PMN-MDSCs and Tregs with significant suppression of eosinophils (p<0.05). Interestingly, there was suppression of splenic PMN-MDSCs, Mo-MDSCs, and tumor draining lymph node macrophages, suggesting systemic immune modulation in peripheral lymphoid organs of FUS+RT-treated tumor-bearing animals. Our findings reveal that the combination therapy of FUS and RT improves tumor control in murine prostate cancer and significantly modulates the systemic and tumor immune microenvironment. This approach offers new avenues for immunotherapy, potentially transforming the treatment landscape for prostate cancer, typically resistant to conventional immunotherapeutic strategies. Citation Format: Soumya Chatterjee, Saurabh Singh, Stephen Barry, Chandan Guha. Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy [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 709.

Abstract 1069: Interrogating the role of the cGAS/STING pathway fallopian tube transformation

Abstract Ovarian Cancer is the deadliest gynecologic malignancy. Despite recent advances in cancer diagnostics, it is a cancer that is often detected late and the vast majority of patients are diagnosed at Stage III and Stage IV. After treatment with debulking surgery and chemotherapy, 80% of patients have tumor relapse with increasing resistance. Early detection efforts have been largely unsuccessful and the only effective prevention strategy in high risk patients is surgical removal of the fallopian tube and ovaries. Careful pathologic studies of prophylactic risk reducing bilateral salpingo-oophorectomy (RRSO) has demonstrated that HGSC originates in the fallopian tube. Within the fallopian tube, secretory cells within the fimbriae are believed to be the origin of HGSC based on numerous lines of correlative evidence including the identification of histologically and molecularly abnormal regions in the fallopian tube called serous tubal intraepithelial cancer (STIC) in 3-5% of patients undergoing RRSO, and the presence of STIC in approximately half of patients undergoing debulking surgeries for HGSC. Finally, p53 mutations have been found to be identical in STIC and in the concurrent invasive disease indicating that HGSC and the STIC likely arise from the same clone. TCGA analysis has demonstrated that HCSC is a disease characterized by genomic and chromosomal instability harboring copy number alteration, including amplifications, deletions and more complex chromosomal rearrangements which impact multiple genes and pathways. Aberrantly segregating chromosomes that lag behind the spindle apparatus fail to become part of the primary nucleus (PN) and are instead enclosed by a self-assembled nuclear membrane, creating a structure called the micronucleus (MN). Spontaneous breakdown of the MN causes cytoplasmic DNA sensing and activation of the cGAS-STING pathway, an important innate cellular defense mechanism to foreign cytoplasmic DNA. To better understand the early genomic and signaling events in the development of HGSC, we are interrogating tissue from our archives from MSKCC patients who have undergone RRSO, hormone ablation surgeries or surgical debulking and were found to have benign fallopian tube, STIC lesions or invasive HGSC with STIC. We have performed a pilot experiment of 20 patient samples of different germline genetic backgrounds. Intriguingly, cGAS signaling was observed only rarely in the STICs indicating low rates of CIN in STICs we have evaluated, however we note that even in early invasive disease, we observe cGAS positivity. Taken together, these data are consistent with a model where CIN and subsequent cGAS/STING pathway activation drives the transition from pre-invasive to invasive disease. Citation Format: Duaa Hassan Al-Rawi, Danguole Norkunaite, Samuel Bakhoum, Sohrab Shah. Interrogating the role of the cGAS/STING pathway fallopian tube transformation [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 1069.

OP70 Treating Patients With Hormone-Sensitive Cancer On Endocrine Therapy With Denosumab (Prolia®): A Systematic Review And Network Meta-Analysis

IntroductionPatients receiving endocrine therapy for hormone-sensitive cancers, such as men with prostate cancer (MPC) on hormone ablation therapy (HAT) and women with breast cancer (WBC) on adjuvant aromatase inhibitor therapy (AAIT), have an increased risk of developing osteoporosis. The aim of this study was to compare the safety and effectiveness of denosumab (Prolia®) with selective estrogen receptor modulators (SERMs) (raloxifene and bazedoxifene), bisphosphonates (zoledronate, ibandronate, alendronate, and risedronate), and placebo for the treatment of osteoporosis in patients receiving endocrine therapy for hormone-sensitive cancer.MethodsSystematic literature searches were conducted in three biomedical databases (PubMed, the Cochrane Library, and Embase) to identify randomized controlled trials (RCTs). Only RCTs that investigated MPC on HAT or WBC on AAIT allocated to denosumab, SERMs, bisphosphonates, or placebo were included. RCTs were appraised using the Cochrane Risk of Bias 2.0 tool. Frequentist network and pairwise meta-analyses were performed on predetermined outcomes of vertebral or nonvertebral fractures, treatment-related adverse events (AEs), bone mineral density (BMD), mortality, withdrawal due to treatment-related AEs, and serious AEs.ResultsA total of 14 RCTs (15 publications, 6,463 participants) were included. Relative to placebo, denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy. Moreover, denosumab, alendronate, and zoledronate increased femoral neck (FN) and lumbar spine (LS) BMD in MPC on HAT, compared with placebo, whereas denosumab, risedronate, and ibandronate improved LS and total hip BMD in WBC on AAIT. Similarly, denosumab and risedronate increased trochanteric BMD in WBC on AAIT, compared with placebo. In WBC on AAIT, only denosumab increased FN BMD relative to placebo.ConclusionsDenosumab was more effective than placebo in preventing vertebral fractures and improving BMD at the LS and FN in MPC on HAT, and in preventing vertebral fractures and improving FN, trochanteric, total hip, and LS BMD in WBC on AAIT. From a policy perspective, the continued reimbursement of denosumab needs to be reviewed.

Abstract A006: Loss of PMEPA1 gene isoform facilitates the development of hormone and radiation therapies resistance in prostate cancer cells

Abstract Introduction: Nearly all the patients receiving hormone treatment eventually progress into castration resistance stage. In addition, approximately 30% to 40% of patients receiving radiation treatment will develop resistance. The aberrant alterations of androgen receptor (AR) and transforming growth factor-β (TGF-β) signaling play critical roles in such processes. Our studies identified five PMEPA1 (Prostate Transmembrane Protein Androgen Induced 1) gene isoforms in prostate cancer cells. PMEPA1-b isoform was androgen responsive and inhibited androgen signaling. In contrast, PMEPA1 isoforms a and d were TGF-β inducible and suppressed TGF-β signaling. Loss or reduced expressions of PMEPA1 was detected in over 60% of prostate cancer samples. In this study, we investigated the impacts of PMEPA1 isoforms (a, b and d) on the development of hormone and radiation therapies resistance in prostate cancer. Methods: RNA-seq data of unmatched 50 benign and 499 malignant prostate samples from The Cancer Genome Atlas (TCGA) dataset, as well as 101 metastatic castration resistant prostate cancer (mCRPC) biopsy samples from Quigley lab at UCSF (WCDT dataset) were used to study the transcript levels of PMEPA1 isoforms (a, b and d) and their correlations to disease progression. Hormone dependent LNCaP cells and androgen independent PC-3, DU-145 cells were utilized to investigate the impacts of PMEPA1 isoforms (a, b and d) on the responses to of androgen inhibitors (enzalutamide and bicalutamide, 0, 5.0 and 25.0 nM) and radiation (0, 1.0 and 5.0 Gy). The vectors of pcDNA3.1-PMEPA1-a, -b and -d were transfected into prostate cancer cells via Lipofectamine, and endogenous PMEPA1 isoforms were knocked down by isoforms specific siRNAs. The cell growth was assessed by cell counting, BrdU incorporation and cell plating efficiency assays. The protein levels of AR and PSA were evaluated by immunoblotting. The transcript levels of PSA, NKX3.1, NEDD9 and THBS1 were assessed by RT-PCR technology. Results: The reduced transcript levels of PMEPA1 isoforms (a, b and d) were detected in mCRPC group. Lower expression of PMEPA1-b was significantly associated with earlier biochemical recurrence. The growth inhibition and androgen signaling blockage mediated by androgen inhibitors were explicitly reversed by depletion of PMEPA1-b in LNCaP cells. Ectopic PMEPA1-b in isoform b depleted LNCaP cells reinstituted the growth inhibition induced by androgen inhibitors. Knockdown of isoforms a and d conspicuously rescued the decreased cell proliferation and suppressed TGF-β signaling resulted from radiation treatment in PC-3 and DU-145 cells. Similarly, over-expression of PMEPA1-a and -d in siRNA treated cells recapitulated the growth inhibitory effects of radiation treatments. Conclusion: Loss of PMEPA1 gene isoforms (a, b and d) induced the development of resistance to hormone ablation and radiation treatments in prostate cancer cells in vitro through activating androgen and TGF-β signaling. Our research provided a new insight into treatment resistance mechanism of prostate cancer cells. Citation Format: Shashwat Sharad, Hua Li. Loss of PMEPA1 gene isoform facilitates the development of hormone and radiation therapies resistance in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A006.

Systematic Evaluation of Studies in the Fields of Diagnosis and Management of Prostate Cancer in Coronavirus Disease 2019 Era

Background: Prostate cancer is one of the most common cancers worldwide. The proper management of this cancer during the coronavirus disease 2019 (COVID-19) or similar outbreaks could be a serious challenge. Proper timing of surgery, radiotherapy, and other medical modalities are essential in providing the most effective treatment. Objectives: This systematic review aimed at evaluating the proper management of prostate cancer during the COVID-19 outbreak. Methods: This study was conducted from 2019 to 2022. An internet search was conducted using the keywords: Diagnosis, management, radical prostatectomy, radiotherapy, hormone ablation therapy, chemotherapy and prostate cancer, and COVID-19. The visited databases included PubMed, Scopus, Web of Sciences, Google Scholar, and Scientific Information Database. The review was performed based on the preferred reporting items for a systematic review and meta-analyses (PRISMA) guidelines. Results: Postponing the biopsy for up to three months and adopting of non-invasive diagnostic methods were likely reasonable during the COVID-19 pandemic. Patients with cancer were more prone to severe injuries and were more likely to have serious complications. Surgery, radiation therapy, brachytherapy, palliative radiation, hormone ablation therapy, and chemotherapy were among the pre-institutional treatments that had to be performed according to medical protocols as well as health and professional guidelines. Conclusions: It was recommended that the prostate cancer screening should not be performed for asymptomatic men during the COVID-19 outbreak. It was also suggested that the treatment should be performed in the shortest possible time and in the safest way.

Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer.

Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance. We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker. Invitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy. AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance. The funding detail can be found in the Acknowledgements section.

Prostate Cancer: Side-Effect Management for Androgen Deprivation Therapy

Drug-based hormonal ablation is an essential component of therapy in hormone-sensitive advanced prostate cancer and as a backbone in castration resistance. LHRH agonists are among the most widely used medicinal products. Since these are usually given for life, therapy management is very important. Common side-effects typical of the substance class, such as weight gain, cardiovascular problems, hot flushes, erectile dysfunction or osteoporosis, can significantly reduce patients' quality of life and increase morbidity and mortality. This endangers adherence and, hence, treatment success. This paper provides an overview of how to deal with side-effects during LHRH therapy based on current data and practical experience.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

Crosstalk between epigenetics and tumor promoting androgen signaling in prostate cancer.

Prostate cancer (PCa) is one of the major health burdens among all cancer types in men globally. Early diagnosis and efficacious treatment options are highly warranted as far as the incidence of PCa is concerned. Androgen-dependent transcriptional activation of androgen receptor (AR) is central to the prostate tumorigenesis and therefore hormonal ablation therapy remains the first line of treatment for PCa in the clinics. However, the molecular signaling engaged in AR-dependent PCa initiation and progression is infrequent and diverse. Moreover, apart from the genomic changes, non-genomic changes such as epigenetic modifications have also been suggested as critical regulator of PCa development. Among the non-genomic mechanisms, various epigenetic changes such as histones modifications, chromatin methylation and noncoding RNAs regulations etc. play decisive role in the prostate tumorigenesis. Given that epigenetic modifications are reversible using pharmacological modifiers, various promising therapeutic approaches have been designed for the better management of PCa. In this chapter, we discuss the epigenetic control of tumor promoting AR signaling that underlies the mechanism of prostate tumorigenesis and progression. In addition, we have discussed the approaches and opportunities to develop novel epigenetic modifications based therapeutic strategies for targeting PCa including castrate resistant prostate cancer (CRPC).

The Evaluation of Survival Rate in Patients with Prostate Cancer by Bayesian Weibull Parametric Accelerated Failure-Time Model.

Prostate cancer is the most prevalent malignancy in men. This study was carried out to determine effective factors on the survival rate of patients diagnosed with prostate cancer in Kerman, Iran. The present study was conducted as a retrospective cohort of 238 patients diagnosed with prostate cancer from 2011 to 2019 in Kerman, Iran. First, the demographic and clinical information of patients were collected. Then, the information on patient survival up to June 2019 was tracked, and their latest statuses of death or survival were recorded. Kaplan-Meier method, log-rank test, and Bayesian Weibull parametric accelerated failure-time model were used for data analysis. Data analysis was carried out by Stata and SAS. The mean age of patients in the diagnosis was 73.28±10.08 year. The patient's 1, 2, 3 and 5-years of overall survival rates were equal to 78.54%, 65.97%, 56.64% and 49.30, respectively. Patients under surgical therapy relatively held longer survival times compared to the rest of the therapies. Patients under chemotherapy had shorter survival times. Age at diagnosis, occupation, chemotherapy, surgery, education, and smoking variables significantly affected patients' survival (P<0.05). Patients' survival duration increases if the disease is diagnosed at younger ages and its preliminary development stages. Smoking cessation is strongly recommended after diagnosis, as it is associated with a lower survival rate. Patients who underwent radical prostatectomy surgery showed higher survival rates than radiotherapy, hormone ablation, or chemotherapy. Moreover, patients with higher education had more prolonged survival.

Abstract 806: Interrogating chromosomal instability in the earliest steps of ovarian cancer development

Abstract Ovarian Cancer is the deadliest gynecologic malignancy. Despite recent advances in cancer diagnostics, it is a cancer that is often detected late. After treatment with debulking surgery and chemotherapy, 80% of patients have tumor relapse. Early detection efforts have been largely unsuccessful and the only effective prevention strategy in high risk patients is surgical removal of the fallopian tube and ovaries. Careful pathologic studies of prophylactic risk reducing bilateral salpingo-oophorectomy (RRSO) has demonstrated that the origins of HGSC is likely within secretory cells of the fimbriae in the fallopian tube. This is based on numerous lines of correlative evidence including the identification of abnormal regions in the fallopian tube called serous tubal intraepithelial cancer (STIC) in 10-15% of patients undergoing RRSO, and the presence of STIC in half of patients undergoing debulking surgeries for HGSC. Finally, p53 mutations have been found to be identical in STIC and in the concurrent invasive disease indicating that HGSC and the STIC likely arise from the same clone. TCGA analysis has demonstrated that HCSC is a disease characterized by genomic and chromosomal instability harboring copy number alteration, including amplifications, deletions and more complex chromosomal rearrangements which impact multiple genes and pathways. Aberrantly segregating chromosomes that lag behind the spindle apparatus fail to become part of the primary nucleus (PN) and are instead enclosed by a self-assembled nuclear membrane, creating a structure called the micronucleus (MN). Spontaneous breakdown of the MN causes cytoplasmic DNA sensing and activation of the cGAS-STING pathway an important innate cellular defense mechanism to foreign cytoplasmic DNA. To understand the early genomic and signaling events in the development of HGSC, we are interrogating FFPE tissue from our archives from MSKCC patients who have undergone RRSO, hormone ablation surgeries or surgical debulking and were found to have benign fallopian tube, STIC lesions or invasive disease with STIC. We have performed a pilot experiment of 20 patient samples of different genetic backgrounds. Intriguingly, cGAS signaling was observed only rarely in the STICs indicating low rates of CIN in STICs, however we note that even in early invasive disease, we observe cGAS positivity. Moreover, we observe robust CD8+ T cell localization to early invasive disease. Taken together, these data are consistent with a model where CIN and subsequent cGAS/STING pathway activation drives the transition from pre-invasive to invasive disease with early immune recognition that is lost in invasive disease. We propose a model of ovarian cancer development where fallopian tube secretory transition from a p53 WT SCOUT to p53 mutant state STIL acquire a proliferative capacity forming a STIC and then develop CIN transitioning to invasive disease. Citation Format: Duaa Hassan Al-Rawi, Herman Chui, Sorhab Shah, Samuel Bakhoum. Interrogating chromosomal instability in the earliest steps of ovarian cancer development [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 806.

Salvage radiotherapy (SRT) in combination with pembrolizumab in patients with PSA persistence or biochemical recurrence after radical prostatectomy due to prostate cancer.

TPS212 Background: Goal of our study is to evaluate the efficacy and safety of immunotherapy in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) or prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). The combination of immunotherapy (IO) with radiation therapy might provide a clinical benefit to patients with recurrent prostate cancer due to an induction of increased activity of the immune system against cancerous tissue (abscopal effect). Primary endpoint is complete biochemical response (PSA level below detection level) 60 weeks after start of trial treatment, which further defines prognosis of patients. Further explorative endpoints like radiographic progression-free survival, PSA-nadir level and time to PSA-nadir, time to initiation of subsequent therapy (secondary ADT or NHA) and quality of life as well as adverse events will be evaluated. Methods: The trial is as a phase II, open-label, single arm monocenter trial which evaluates the combination of pembrolizumab as study medication in combination with SRT. Pembrolizumab will be administered in a three-weekly scheme up to one year of treatment. A concomitant ADT is administered in high-risk patients only (PSA &gt; 0.7ng/ml or cN+ in imaging studies). All patients will be staged with PSMA PET-CT, if applicable. Additionally, blood and urine samples will be collected for correlative biomarker studies. A total of 49 patients are planned to be enrolled in this explorative study within 2 years. INCLUSION CRITERIA (excerpt) Histologically confirmed diagnosis of an adenocarcinoma of the prostate and a BCR or PSA persistence after RP. Histology of the RP specimen needs to fulfill the following criteria: adenocarcinoma of the prostate, Gleason score 7-10; pNX or pN0 or pN1 (max. 2 lymph nodes involved). Imaging within 30 days prior to study inclusion is mandatory (([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen and full-body bone scan). PSA value between ≥0.2 and ≤1.0 ng/ml, measured at least six weeks postoperatively. EXCLUSION CRITERIA (excerpt) Prior-therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary hormone ablation or taxan-based chemotherapy). Distant metastases or suspicious lymph nodes outside the lower pelvis in imaging with PSMA PET-CT (patients with PET positive bone lesions that are morphologically not clearly suspicious of metastases and would not change clinical practice can be included). Clinical trial information: NCT04931979.

Individual classes of prostate cancer therapies impact risk of Alzheimer’s disease: A claims‐based retrospective study

AbstractBackgroundProstate cancer is the most prevalent non‐skin cancer in men and the second leading cause of cancer related deaths among men worldwide. There are growing concerns regarding a potential association between androgen targeting therapeutic exposure and Alzheimer’s disease (AD) where the existent literature is limited and highly controversial. The object of this study was to determine whether androgen targeting therapy (ATT) exposure is associated with risk of Alzheimer’s (AD) in men with prostate cancer in the Symphony claims data set.MethodsPatients receiving ATT for prostate cancer treatment were identified and survival analysis, stratified by age and by individual therapeutics, was used to determine the association between EMT exposure and diagnosis of AD. A propensity score approach was used to minimize measured and unmeasured selection bias. Individual classes of ATT were examined to determine risk impact profiles for each therapeutic target of hormone ablation in prostate cancer treatment.ResultsIn this cohort study of propensity score matched men, all ATT class exposure taken together was associated with no impact in diagnosis of neurodegenerative disease (RR, 1.01; 95% CI, 0.96‐1.07; P = 0.56). The class of androgen synthesis inhibitors were associated with a decreased risk of AD (RR, 0.61; 95% CI, 0.46‐0.80; P &lt; 0.001) whereas the class of androgen receptor blockers were associated with an increased risk of AD (RR, 1.29; 95% CI, 1.13‐1.34; P &lt; 0.001). All other classes of ATT were associated with increased AD risk.ConclusionAmong male patients with prostate cancer, exposure to the androgen synthesis inhibitor class of androgen targeting therapy was associated with a decrease in diagnosis of AD and Dementia. All other types of ATT were associated with an increased risk of AD diagnosis. These data help to explain the current controversies in the literature where groups reporting impact of ATT as a composite of each individual drug suggest contradicting results on AD risk. Funding: This study was supported by grants from the Women’s Alzheimer’s Movement, National Institute on Aging grants P01AG026572 Perimenopause in Brain Aging and Alzheimer's Disease and T32AG061897 Translational Research in AD and related Dementias (TRADD) to RDB.

PD13-03 MORTALITY FROM SECONDARY CANCERS IN MEN TREATED WITH RADICAL PROSTATECTOMY FOR PROSTATE CANCER: AN INSIGHT INTO PROSTATE CANCER SURVIVORSHIP AT 15-YEARS OF FOLLOW-UP

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I (PD13)1 Sep 2021PD13-03 MORTALITY FROM SECONDARY CANCERS IN MEN TREATED WITH RADICAL PROSTATECTOMY FOR PROSTATE CANCER: AN INSIGHT INTO PROSTATE CANCER SURVIVORSHIP AT 15-YEARS OF FOLLOW-UP Akshay Sood, Mireya Diaz, Wooju Jeong, Mohit Butaney, Anudeep Mukkamala, James Peabody, Hans Stricker, Craig Rogers, Firas Abdollah, and Mani Menon Akshay SoodAkshay Sood More articles by this author , Mireya DiazMireya Diaz More articles by this author , Wooju JeongWooju Jeong More articles by this author , Mohit ButaneyMohit Butaney More articles by this author , Anudeep MukkamalaAnudeep Mukkamala More articles by this author , James PeabodyJames Peabody More articles by this author , Hans StrickerHans Stricker More articles by this author , Craig RogersCraig Rogers More articles by this author , Firas AbdollahFiras Abdollah More articles by this author , and Mani MenonMani Menon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001989.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With advances in surgical and medical care, and an overall increase in life-expectancy, survivorship in men with prostate cancer (CaP) is of emerging relevance. We sought to examine 15-year secondary cancer and CaP related mortality in men treated with radical prostatectomy (RP) as their initial treatment for CaP. METHODS: Between September 2001 and December 2013, 6,060 men underwent robot-assisted RP (RARP) as first-line therapy for clinically confined CaP at our institution. The patients were stratified by burden of comorbidity (using age-adjusted Charlson comorbidity index [CCI]) and tumor-specific risk (Diaz classification [risk groups 1-5], details in Figure 1) into 12 groups, and mortality from CaP, secondary cancers, non-oncologic causes and unknown causes were estimated using competing risk analysis within these groups. RESULTS: The median follow-up was 8 years. At 15-years, 9% of the patients had developed secondary cancers and 1.5% had died from them. Further, secondary cancers were the leading cause of death in men in Diaz risk groups 1-3 (Figure 1 a-f), with the risk of death increasing with the burden of comorbidity (secondary cancer specific mortality rate at 15-year was between 1.1 and 7.7% depending on the CCI score). The top 3 secondary malignancies were lung, colon, and pancreas and hematologic cancers (the latter two tied for the 3rd place). Family h/o of CaP, family h/o cancers other than CaP, and use of post-RP hormone ablation or radiation therapy were not associated with increased risk of secondary malignancies. CONCLUSIONS: Secondary cancers develop in 9% of post-RP patients with 1.5% dying of them within 15-years. In men with low and favorable intermediate risk CaP, secondary cancers represent the major cause of mortality (none of these men die of CaP). These data have clinical significance with regards to patient counseling, survivorship, and oncologic surveillance in the CaP population that choose RP as their initial treatment. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e210-e210 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Akshay Sood More articles by this author Mireya Diaz More articles by this author Wooju Jeong More articles by this author Mohit Butaney More articles by this author Anudeep Mukkamala More articles by this author James Peabody More articles by this author Hans Stricker More articles by this author Craig Rogers More articles by this author Firas Abdollah More articles by this author Mani Menon More articles by this author Expand All Advertisement PDF downloadLoading ...

O-145 Green Tea catechins EGCG and pro-drug of EGCG (Pro-EGCG) inhibit endometriosis through targeting molecules regulating macrophages and B cells

Abstract Study question What are the therapeutic targets and mechanisms of green tea EGCG and Pro-EGCG in treating endometriosis? Summary answer EGCG and Pro-EGCG have unique molecular targets to regulate interactions of B cells, macrophages and endometriotic cells and limit the growth and development of endometriosis. What is known already Current treatments of endometriosis are mainly hormonal suppression and surgical ablation or removal. Our previous studies showed EGCG significantly inhibits development of experimental endometriosis in mice. Pro-EGCG is more effective than EGCG in term of anti-endometriosis, anti-angiogenesis and anti-oxidation (Wang, et. al., 2013; Xu, et al., 2011). Dysfunctional immunological activities of macrophages and B cells were found in women with endometriosis. The molecular targets, underlying mechanism and differential therapeutic efficacy of EGCG and Pro-EGCG, as well as their anti-inflammatory activities are still not known. Study design, size, duration Multiplexed Proteome Integral Stability Alteration (PISA) assay (Gaetani et al.,2019), followed by MS/MS was applied to identify the molecular targets of EGCG and Pro-EGCG in endometriotic cells. Pharmacological studies of EGCG and Pro-EGCG on endometriotic cell line and endometriosis models in mice were performed to characterise their anti-endometriosis and anti-inflammatory effects. Gene silencing and over-expression experiments were conducted to confirm the immunoregulatory mechanisms. Participants/materials, setting, methods Endometriotic (Hs832(C)T) cell lines in culture and lysate were treated for chemical proteomics analysis. SiRNA and overexpression vectors were transfected to the cells in vitro and lesions in vivo. Hs832(C).T, monocytic cells (THP-1) and control B cell (Raji null) lines were used for co-culture assays to study the interaction between endometriotic and immune cells in vitro. Endometriosis mice model was established for immunostaining and microarray analysis of lesions to characterise the molecular pathways in vivo. Main results and the role of chance MTDH and PXK were the strongest and most differential targets of EGCG and Pro-EGCG in both cells lysate and cell culture of Hs832(C).T, respectively. Gene silencing and overexpression of the protein targets in vitro and in vivo significantly altered expressions of downstream proteins, including BLK and EGF after PXK, and MYC and AKT after MTDH, as well as endometriosis-related genes such as VEGFC and MMP9. Co-culture assays of Hs832(C).T with Raji null or THP-1 induced macrophages showed that expressions of PXK, MTDH, downstream targets, and immune-related genes were significantly increased after incubation of recombinant proteins, but were significantly decreased after EGCG and Pro-EGCG treatment. M1 and M2 macrophages, as well as B cells were significantly reduced after the treatments in vitro and in vivo. Double immunofluorescent staining of lesions showed that CD68, CD163 or CD20 co-expressed with MTDH, PXK and downstream targets, and numbers of the co-expressed cells were significantly reduced after treatments in vivo. Microarray experiment further identified the upstream and downstream genes of MTDH or PXK contributing to the growth and development of endometriosis. Limitations, reasons for caution Results of this pharmacological and mechanistic study require clinical samples to validate the anti-endometriosis effects of EGCG and Pro-EGCG. Effects of other potential pharmaceuticals targeting the macrophages and B cells on endometriosis are needed. Wider implications of the findings The findings provide pharmacological and mechanistic data for future development of EGCG and Pro-EGCG as new treatment for endometriosis. This study shows that macrophage and B cell could be potential therapeutic targets for treatment of endometriosis, which opens up new horizon for the novel immunotherapy for endometriosis. Trial registration number NA

Celebrating the 80th anniversary of hormone ablation for prostate cancer.

In this issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, the combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this special issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.

Multimodal Therapy for Patients with High-Grade, High-Risk Prostate Cancer with Long-Term Follow-up

High risk prostate cancer requires a multimodal approach to treatment. Surgery has played an increasing role for these patients although long-term follow-up and experience with neoadjuvant therapy, a basic tenet of cancer treatment, remains limited. Here we report our experience with neoadjuvant hormonal ablation followed by surgery and postoperative radiation with greater than 20-year follow-up. From 1990-2012, 82 patients with clinically organ-confined prostate cancer and 10 years median follow-up underwent multimodal therapy (MMT) consisting of neoadjuvant hormonal ablation followed by radical retropubic prostatectomy and postoperative radiation. High-risk prostate cancer was defined preoperatively as Gleason Score 8-10 or PSA>20. Patients with negative surgical margins were observed initially and treated with salvage XRT in the instance of recurrence. The MMT protocol was well tolerated in all 82 patients with no treatment-related discontinuation of therapy. Final surgical pathology revealed stage pT3-T4 in 58/82 (71%) and nodal involvement in 7/82 (9%). Distant metastatic disease was identified in 10/82 patients (12%). For patients undergoing MMT at 10, 15 and 20 years, cancer-specific survival was 78/82 (95%), 77 /82 (94%) and 77/82 (94%), overall survival was 68/82 (83%), 66/82 (80%) and 60/82 (73%), and biochemical recurrence was 61/82 (74%), 51/82 (62%) and 35/82 (43%). These findings establish the MMT protocol as an effective treatment strategy for high-risk prostate cancer with excellent long-term cancer-specific survival. Recurrence occurring primarily as a rising PSA as opposed to distant metastatic disease suggests limited morbidity as well among patients treated with this protocol.

ATM Kinase Inhibition Preferentially Sensitises PTEN-Deficient Prostate Tumour Cells to Ionising Radiation.

Simple SummaryProstate cancer is the most frequently diagnosed cancer in men. Despite the importance of radical radiotherapy for the management of this disease, recurrence remains a challenge. PTEN is a tumour suppressor that is frequently inactivated in advanced prostate cancer and has been associated with relapse following radiotherapy. The present study shows that the role of PTEN in response to ionizing radiation is complex. Furthermore, it demonstrates that in the absence of PTEN, an increased response to combined treatment using radiotherapy and the ATM inhibitor KU-60019 can be observed. Our findings provide a strong rationale for evaluating loss of PTEN in prostate cancer as a therapeutic target for ATM inhibitor in combination with radiotherapy in the clinical setting.Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

The Skeletal Effects of Gonadotropin-Releasing Hormone Antagonists: A Concise Review.

Prolonged treatment with Gonadotropin-Releasing Hormone (GnRH) agonists is known to induce bone loss among prostate cancer patients. However, evidence on the skeletal effects of GnRH antagonists is relatively less well-known. This review aims to examine the effects of GnRH antagonists on bone health. GnRH antagonists are an effective treatment for hormone-dependent conditions, such as advanced prostate cancer and endometriosis. They induce a competitive and reversible GnRH-receptor blockage, thereby suppressing the release of gonadotropins and sex hormones. The sex hormone ablation results in undesirable side effects, including accelerated bone loss. In animal studies, treatment with GnRH antagonists is reported to cause deterioration of bone microstructure. Human clinical trials revealed significant bone loss at the spine, hip and femur in patients treated with GnRH antagonists. Thus, osteoporosis and the resultant fragility fractures pose a significant impact on health and quality of life of GnRH antagonist users. Thus, early preventive measures of bone loss are critical in preventing fractures and its associated morbidity in these patients.