Hematological changes during androgen deprivation therapy.
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ABSTRACT:
SUBMITTER: Grossmann M
PROVIDER: S-EPMC3735076 | biostudies-other | 2012 Mar
REPOSITORIES: biostudies-other
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Project description:Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (<? 70 years versus ?? 70 years), prior duration of ADT (?? 6 months versus > 6 months), and baseline BTM (?? median versus >? median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was -90% in the denosumab group and -3% in the placebo group (p? <? 0.0001). The median change in TRAP-5b levels at month 1 was -55% in the denosumab group and -3% in the placebo group (p?<? 0.0001). The maximal median change in P1NP was -64% in the denosumab group and -11% in the placebo group, (p ?<? 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.
| S-EPMC3222788 | biostudies-literature
Project description:PurposeTo characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).Patients and methodsWe prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).ResultsMedian ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).ConclusionIn men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
| S-EPMC3434987 | biostudies-literature
Project description:Androgen deprivation therapy induces apoptosis or cell cycle arrest in prostate cancer (PCa) cells. Here we set out to analyze whether MCL1, a known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is upregulated in androgen-deprived PCa cells. Regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed. Moreover, clonogenicity of primary basal PCa cells is efficiently inhibited by Obatoclax. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling.
| S-EPMC4467425 | biostudies-literature
Project description:Opinion statementProstate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.
| S-EPMC8053026 | biostudies-literature
Project description:BackgroundProstate cancer (PC) is the most frequent neoplasia in the male population and androgen deprivation therapy (ADT) is frequently used in the management of the disease.AimTo evaluate the effect of ADT exposure on cognitive status, grey matter volume (GMV) and white matter lesion (WML) load.MethodsFifty ADT patients and fifteen PC-non-ADT (control) patients were included in the study. A neuropsychological evaluation was performed and a magnetic resonance imaging (MRI), with anatomical T1 and FLAIR sequences, was performed to evaluate the GMV and the WML burden.ResultsMost of the patients included in the study presented a significant cognitive impairment (CI). No significant differences were identified in the cognitive assessment between the studied groups, but when considering the educational background intragroup differences were found.No significant difference of GMV and WML volume were identified between groups, but a negative relationship between the ADT period and the GMV was identified. Furthermore, a significant positive association between the age and the lesion volume was found in the ADT group (β=.406; p=.004).ConclusionPC patients exposed to ADT present an acceleration of age-related brain changes, such as WML development and GMV loss.
| S-EPMC6710035 | biostudies-literature
Project description:The aim of the present work is to describe the differences in rs-fMRI measures (Amplitude of low frequency fluctuations [ALFF], Regional Homogeneity [ReHo] and Functional Connectivity [FC]) between patients exposed to Androgen deprivation therapy (ADT) and a control group. Forty-nine ADT patients and fifteen PC-non-ADT patients (Controls) were included in the study. A neuropsychological evaluation and a resting-state fMRI was performed to evaluate differences in ALFF and ReHo. Region of interest (ROI) analysis was also performed. ROIs were selected among those whose androgen receptor expression (at RNA-level) was the highest. FC analysis was performed using the same ROIs. Higher ALFF in frontal regions and temporal regions was identified in Controls than in ADT patients. In the ROI analysis, higher activity for Controls than ADT patients was shown in the left inferior frontal gyrus and in the left precentral gyrus. Lower ALFF in the right hippocampus and the lateral geniculate nucleus of the right thalamus was identified for Controls than ADT patients. Higher ReHo was observed in Controls in the left parietal-occipital area. Finally, ADT patients presented an increase of FC in more regions than Controls. These differences may reflect an impairment in brain functioning in ADT users.
| S-EPMC8639725 | biostudies-literature
Project description:Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients. We retrospectively reviewed 20,328 patients with PC diagnosed during 1991-2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort. With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence-free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17-0.49) for BC recurrence. This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence.
| S-EPMC4350350 | biostudies-literature
Project description:Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFß activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFß-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.
| S-EPMC5352374 | biostudies-literature
Project description:The data generated here in relates to the research article "CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer". A model of prostate cancer (PCa) progression to castration resistance was employed, with untreated androgen sensitive LNCaP cell line alongside two androgen deprived (bicalutamide) sublines, either 10 days (LNCaP-ADT) or 2 years (LNCaP-ABL) treatment, in addition to androgen insensitive PC3. With this PCa model, qPCR was used to examined fold change in markers linked to androgen resistance, androgen receptor (AR) and neuron specific enolase (NSE), observing an increase under androgen deprivation. In addition, the gene expression of a range of calcium channels was measured, with only the L-type Voltage gated calcium channel, CACNA1D, demonstrating an increase during androgen deprivation. With CACNA1D knockdown the channel was found not to influence the gene expression of calcium channels, ORAI1 and STIM1. The calcium channel blocker (CCB), nifedipine, was employed to determine the impact of CaV1.3 on the observed store release and calcium entry measured via Fura-2AM ratiometric dye in our outlined PCa model. In both the presence and absence of androgen deprivation, nifedipine was found to have no impact on store release induced by thapsigargin (Tg) in 0mM Ca2+ nor store operated calcium entry (SOCE) following the addition of 2mM Ca2+. However, CACNA1D siRNA knockdown was able to reduce SOCE in PC3 cells. The effect of nifedipine on CaV1.3 in PCa biology was measured through cell proliferation assay, with no observed change in the presence of CCB. While siCACNA1D reduced PC3 cell proliferation. This data can be reused to inform new studies investigating altered calcium handling in androgen resistant prostate cancer. It provides insight into the mechanism of CaV1.3 and its functional properties in altered calcium in cancer, which can be of use to researchers investigating this channel in disease. Furthermore, it could be helpful in interpreting studies investigating CCB's as a therapeutic and in the development of future drugs targeting CaV1.3.
| S-EPMC9046638 | biostudies-literature
Project description:PurposeTo test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer's disease risk.MethodsWe used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer's disease using 1:5 propensity score-matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer's disease risk.ResultsThere were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow-up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score-matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer's disease risk. We also observed a statistically significant increased risk of Alzheimer's disease with increasing duration of ADT (P = .016).ConclusionOur results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer's disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence.
| S-EPMC5070576 | biostudies-literature