Androgen Deprivation Therapy For Advanced Prostate Cancer Research Articles

Utilizing metformin to prevent metabolic syndrome due to androgen deprivation therapy (ADT): a randomized phase II study of metformin in non-diabetic men initiating ADT for advanced prostate cancer

Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation.To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase.36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase.In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.

Genome-wide association studies in advanced prostate cancer: KYUCOG-1401-A study.

Androgen deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (PFS) at 1 year and adverse events including de novo diabetes mellitus, arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with radiographic PFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and overall survival in ADT. In addition, GWAS showed that several SNPs were associated with de novo diabetes mellitus, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

MP34-07 A QUALITATIVE ASSESSMENT OF ANDROGEN DEPRIVATION THERAPY DOCUMENTATION AND ADHERENCE PATTERNS IN A MULTIDISCIPLINARY SETTING

You have accessJournal of UrologyHealth Services Research: Quality Improvement & Patient Safety II (MP34)1 Sep 2021MP34-07 A QUALITATIVE ASSESSMENT OF ANDROGEN DEPRIVATION THERAPY DOCUMENTATION AND ADHERENCE PATTERNS IN A MULTIDISCIPLINARY SETTING Emily Bochner, Robert Den, Nathan Handley, and Edouard J Trabulsi Emily BochnerEmily Bochner More articles by this author , Robert DenRobert Den More articles by this author , Nathan HandleyNathan Handley More articles by this author , and Edouard J TrabulsiEdouard J Trabulsi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002043.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Adherence to scheduled androgen deprivation therapy (ADT) has been shown to influence disease outcomes and overall survival. We evaluated ADT documentation and adherence patterns for patients undergoing ADT for advanced prostate cancer to assess for care discoordination and quality improvement opportunities in multidisciplinary clinical practice. METHODS: We performed a retrospective analysis of patients undergoing ADT for advanced prostate cancer at Sidney Kimmel Cancer Center from 7/2/2019-7/20/2020 as part of a quality improvement project. Electronic medical records were reviewed, and ADT care plan documentation was evaluated. Dose records were examined for missed doses. The ADT care plan was considered documented if the duration of ADT (intermittent ADT, continuous ADT, short duration ADT [6 months], or long duration ADT [2 years]) was clearly stated. Qualitative analyses were performed. RESULTS: One hundred randomly selected patients receiving ADT were included in the study. 70% of patients were White, 24% of patients were African American, 5% of patients were Asian, and 1% of patients were Hispanic. Fifty-five patients (55%) did not have a documented care plan for ADT. Ninety-eight patients (98%) received luteinizing hormone releasing hormone (LHRH) agonist or antagonist therapy (3 patients (3%) received Eligard, 92 patients (94%) received Lupron, and 3 patients (3%) received Firmagon). Of the 98 patients on LHRH agonist or antagonist therapy, 7 patients (7.1%) had a documented missed dose of the LHRH agonist. CONCLUSIONS: For patients undergoing ADT, proper documentation and close follow up are essential steps in maximizing ADT adherence. While 7.1% of patients in this study missed a dose of LHRH agonist therapy, only 45% of patients had an ADT care plan documented. The percentage of patients with a missed dose may have been subsequently underestimated in this study, as 55% of patients did not have an ADT care plan documented. Careful documentation of missed doses of LHRH agonist therapy is particularly important, as studies have shown delayed dosing of ADT has a negative impact on ADT efficacy and testosterone suppression (Crawford et al, Journal of Urology, 2020). Improving documentation patterns may help to improve ADT adherence and subsequent ADT-related outcomes. Further investigations into the effect of late or missed LHRH agonist doses should be performed. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e618-e619 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emily Bochner More articles by this author Robert Den More articles by this author Nathan Handley More articles by this author Edouard J Trabulsi More articles by this author Expand All Advertisement Loading ...

Muscle Cross-sectional Area Improves With Home-based Training During Metastatic Castration-resistant Prostate Cancer

PURPOSE: Exercise training improves regional body composition in localized prostate cancer, but it is unknown if training has similar effects in advanced disease. Goals of this analysis were to determine changes in leg muscle cross-sectional area (CSA) and quality (MQ) values following home-based exercise training during metastatic castration-resistant prostate cancer (mCRPC) and to compare CSA values to healthy controls (CON). METHODS: Sedentary mCRPC patients undergoing androgen deprivation therapy (ADT) including next generation androgen receptor signaling inhibitors (n = 17, age = 71y ± 8, BMI = 32.0 kg/m2 ± 6.5) underwent CSA and MQ analyses using B-mode ultrasound for the vastus lateralis (VL) muscle before and after a 12-week home-based exercise protocol. Age- and BMI-matched CON (n = 17, age = 69y ± 2, BMI = 32.8kg/m2 ± 6.5) completed baseline scans only. RESULTS: At baseline, VL CSA was lower in mCRPC (9.12cm2+ 3.15) relative to CON (36.55cm2 ± 7.04, p<0.001, d=4.95). For mCRPC patients, the 12-week intervention did not change VL MQ, but increased CSA by 15.2% following the intervention (pre: 8.28cm2 ± 2.85, post: 9.54 ± 3.56, p<0.001, d= 0.39) with no change in MQ. CONCLUSIONS: Patients undergoing ADT for advanced prostate cancer exhibit lower muscle size compared to CON; however preliminary results suggest that home-based exercise training induces a moderate degree of regional muscle hypertrophy. The finding of regional hypertrophy is consistent with work conducted in patients with localized disease on ADT and may be an important outcome to monitor if increases in muscle CSA translate into improvements in physical function and quality of life. Supported by Physical Activity and Cancer Survivorship Pilot Funding.

Abstract 3269: Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa)

Abstract Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. Metformin decreases glucose &amp; insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: We analyzed serum and PBMC from a recently completed clinical study of men with advanced PCa on ADT that were randomized 1:1 to metformin at 500mg TID or color matched placebo. Subjects serum insulin/glucose, metformin levels, weight and waist circumference (WC) was assessed at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of metformin vs placebo cohort. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: There were 36 evaluable men. The mean age on study was 68.4. Mean weight, WC and insulin at baseline in metformin cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in placebo cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At week 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. Four men randomized to metformin had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in metformin and 53.3% in placebo cohort achieved undetectable PSA at week 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusion: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Citation Format: Devalingam Mahalingam, Salih Hanni, Christos Fountzilas, Joel Michalek, John Sarantopoulos, Sureshkumar Mulampurath Achuthan Pillai, John Kuhn, Michael Pollak, Ian Thompson. Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269.

Testosterone Reduction of≥ 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy.

Reductions in testosterone concentration play a significant role in the treatment of prostate cancer. We studied the role of testosterone as a prognostic marker for advanced prostate cancer (stage C or higher) treated with primary androgen-deprivation therapy (ADT). A total of 348 patients were treated using ADT as first-line therapy for prostate cancer at Chiba University Hospital between 1999 and 2016. Of these, 222 patients with advanced prostate cancer (stage C or higher) were enrolled onto this study. The prognostic values of serum testosterone level and other clinical factors were evaluated in association with prostate-specific antigen (PSA), progression-free survival during first-line therapy, and overall survival. Median age was 73 years. PSA at baseline was 86 ng/mL. Gleason scores of≤ 6, 7, 8, and≥ 9 were seen in 2.3%, 19.4%, 21.2%, and 41.9%, respectively. Mean follow-up was 60.5 months. Median testosterone at baseline was 482 ng/dL and nadir testosterone was 13 ng/dL. No variable associated with testosterone predicted progression-free survival. With regard to overall survival, multivariate analysis identified nadir testosterone≤ 20 ng/dL (hazard ratio= 0.44, P= .026) and testosterone reduction≥ 480 ng/dL (hazard ratio= 0.35, P= .030) as independent prognostic factors. With regard to progression-free survival, multivariate analysis identified nadir PSA≤ 0.1 ng/mL (hazard ratio= 3.07, P< .001), presence of lymph node metastasis (hazard ratio= 1.67, P= .017), and time to nadir PSA (hazard ratio= 0.30, P< .001) as independent prognostic factors. Our data suggested both nadir testosterone (< 20 ng/dL; P= .026) and testosterone reduction (≥ 480 ng/dL; P= .030) to be key prognostic factors for primary ADT in advanced prostate cancer in Japanese men.

A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a perpetual dispute

To review the literature and present new data of continuous androgen deprivation therapy (ADT) vs intermittent androgen deprivation (IAD) as therapies for prostate cancer in terms of survival and quality of life and clarify practical issues in the use of IAD. We conducted a systematic search on Medline and Embase databases using ″prostatic neoplasm″ and ″intermittent androgen deprivation″ as search terms. We reviewed meta-analyses, randomised controlled trials, reviews, clinical trials and practise guidelines written in English from 2000 and onwards until 01/04/2013. Ten randomized controlled trials were identified. Seven of them published extensive data and results randomizing 4675 patients to IAD versus CAD. Data from the other three randomized trials were limited. Over the last years studies confirmed that IAD is an effective alternative approach to hormonal deprivation providing simultaneously several potential benefits in terms of quality of life and cost effectiveness. Thus, in patients with non metastatic, advanced prostate cancer IAD could be used as standard treatment, while in metastatic prostate cancer IAD role still remains ambiguous. Nowadays, revaluation of the gold standard of ADT in advanced prostate cancer appears essential. Recent data established that IAD should no longer be consi¬dered as investigational, since its effectiveness has been proven, especially in patients suffering from non-metastatic advanced prostate cancer.

Lifestyle Changes for Improving Disease-specific Quality of Life in Sedentary Men on Long-term Androgen-Deprivation Therapy for Advanced Prostate Cancer: A Randomised Controlled Trial

BackgroundProstate cancer is a key driver of cancer-related global disability-adjusted life-years. Androgen-deprivation therapy (ADT) for advanced disease is linked to fatigue, reduced physical function, and quality of life (QoL). ObjectiveTo evaluate the effect of a lifestyle intervention on disease-specific QoL, diastolic blood pressure, and cancer-related fatigue in sedentary men receiving long-term ADT for advanced prostate cancer. Design, setting, and participantsA total of 100 hundred sedentary men with locally advanced or metastatic prostate cancer on long-term ADT were randomised to an intervention or usual care group. InterventionA 12-wk lifestyle intervention consisting of aerobic and resistance exercise with parallel dietary advice. Outcome measurements and statistical analysisDisease-specific QoL was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaires at 12 wk postintervention and at 6 mo following withdrawal of support. Analysis of covariance and mixed regression were conducted. Results and limitationsClinically relevant improvements in FACT-P were seen at 12 wk in the intervention group compared with controls (mean difference: 8.9 points; 95% confidence interval [CI], 3.7–14.2; adjusted p=0.001). No difference was apparent at 6 mo (mean difference: 3.3 points; 95% CI, −2.6 to 9.3; adjusted p=0.27). No difference in diastolic blood pressure was seen at either follow-up (all p > 0.05). Clinically relevant improvements in FACT-F were seen at 12 wk (mean difference: 5.3 points; 95% CI, 2.7–7.9; adjusted p<0.001) and maintained following withdrawal of supervision (mean difference: 3.9 points; 95% CI, 1.1–6.8; adjusted p=0.007). Improvements in exercise tolerance and behaviour were maintained at 6 mo (adjusted p<0.001 and 0.038). ConclusionsA lifestyle intervention resulted in a clinically meaningful improvement in disease-specific QoL that was not maintained postintervention. No effect on blood pressure occurred. Durability of response was seen in fatigue and exercise behaviour. Further evaluation of support structures is essential. Trial registrationISRCTN88605738.

722 PREFERRED TREATMENT FREQUENCY IN PATIENTS RECEIVING ANDROGEN DEPRIVATION THERAPY FOR ADVANCED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (I)1 Apr 2013722 PREFERRED TREATMENT FREQUENCY IN PATIENTS RECEIVING ANDROGEN DEPRIVATION THERAPY FOR ADVANCED PROSTATE CANCER Mikkel Fode, Torben Nielsen, Jesper R. Andersen, Henrik Jakobsen, and Jens Sønksen Mikkel FodeMikkel Fode Herlev, Denmark More articles by this author , Torben NielsenTorben Nielsen Herlev, Denmark More articles by this author , Jesper R. AndersenJesper R. Andersen Herlev, Denmark More articles by this author , Henrik JakobsenHenrik Jakobsen Herlev, Denmark More articles by this author , and Jens SønksenJens Sønksen Herlev, Denmark More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.281AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) with GnRH agonists for prostate cancer has typically been administered with 1 or 3 month intervals. New formulations allow for longer injection intervals. The purpose of this study was to assess patient preference regarding the length of intervals between treatment and/or clinical control. METHODS The study was conducted at a large University Hospital between September 2011 and May 2012. Participants were men receiving ADT for advanced prostate cancer. A questionnaire including preferred treatment/control intervals, reasons for wishing either frequent or infrequent treatment/control, as well as satisfaction and side effects with current treatment was developed. A pilot phase where 20 patients filled out the questionnaire and gave comments was carried out to ensure patient understanding. The primary end point was the preferred treatment frequency. Patients were grouped into a frequent-treatment-group (“Every month”, “Every third month”), an infrequent-treatment-group (“Every sixth month”, “Every twelfth month”) and a group for whom the length of treatment intervals made no difference. RESULTS Over all 240 patients were presented with the questionnaire and 178 questionnaires (74%) were available for analysis. Median age of the participants was 77 years. In 49% the disease was considered to be progressing (two consecutively rising PSA values above 2 μg/l). A total of 38% of participants preferred frequent treatment/control, 33% preferred infrequent treatment/control, and 29% stated that it made no difference. The chi square test showed no statistically significant difference in the sizes of the 3 groups (p=0.39). Over all 83.7% were satisfied with treatment while one patient (0.6%) was dissatisfied. Nine percent indicated severe side effects. Taking patient age, disease progression, treatment satisfaction, and side effects into account, a multiple regression analysis showed that patients with stable disease were most likely to prefer infrequent visits (OR 4.1). The most commonly stated reason for wanting frequent visits was that this provided a feeling of security. The most common reasons for wanting less frequent visits were that visits to the hospital served as a reminder of the disease and that hospital visits were impractical. CONCLUSIONS Less frequent ADT treatment may be of benefit for a large group of patients, however, it is not suited for all patients. Longer treatment/control intervals cannot be prescribed blindly without possibly affecting patient satisfaction. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e296-e297 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mikkel Fode Herlev, Denmark More articles by this author Torben Nielsen Herlev, Denmark More articles by this author Jesper R. Andersen Herlev, Denmark More articles by this author Henrik Jakobsen Herlev, Denmark More articles by this author Jens Sønksen Herlev, Denmark More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists

Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.

Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer

BackgroundRadiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC.MethodsUsing mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI.ResultsCompared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density ( VD), and vessel area fraction ( VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores ( AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve ( AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size ( VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such modeling also detected tumor necrosis very strongly.ConclusionsDCE MRI reliably allows non-invasive assessment of tumors’ vascular function. The findings of increased tumor vascularization after ADT encourage further studies into whether these changes are beneficial for combined RT, or if treatment with anti-angiogenic therapy may be a strategy to improve the therapeutic efficacy of ADT in advanced PC.

796 CORTISOL SERUM LEVELS ARE INCREASED AND INDUCE GENOMIC INSTABILITY IN ADVANCED PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Cortisol, also known as stress hormone, is involved with chronic stress; it appears to be associated with higher levels of prostate-specific antigen (PSA) and benign prostate enlargement (BPE). To assess the relationship between cortisol and prostate cancer (PCa), serum cortisol levels were measured in normal men and those with primary or metastatic PCa. In addition, the effect of cortisol on genomic instability was investigated by evaluating DNA mismatch repair (MMR) pathway in androgen-deprived benign or malignant prostate cells. METHODS: Serum cortisol and creatinine levels were determined using ELISA assay. Immunohistochemical staining for MMR proteins was performed on tissue microarray slides. Genomic instability was evaluated by analyzing the microsatellite instability (MSI) using PCR and the National Cancer Institute (NCI)-recommended panel of five MS markers including two mononucleotide repeat (BAT25 and BAT26) and three dinucleotide repeats (D2S123, D5S346, and D17S250). Genomic DNAs for PCR were extracted from AR-positive (LNCaP, E006AA, CWR-22RV1, C4-2B, MDA-PCa2b) and androgeninsensitive (PC-3 and DU145) PCa cell lines and normal prostate epithelial cells that were treated with cortisol and androgen-deprived for 2 to 20 weeks. Purified PCR fragments were separated on ABI 3730XL DNA Analyzer and genotyped using the ABI Gene Mapper ID, V3.2 software. MMR genes and protein expression levels in the cells were examined with qRT-PCR and western blotting, respectively. RESULTS: Serum cortisol levels were in rank order metastatic castrate-resistant prostate cancer (mCRPCa) primary PCa BPE. Serum cortisol levels were higher in African Americans (AAs) than Caucasian Americans (CAs) in BPE, primary PCa, and mCRPCa. Chronic treatment of PCa cells with cortisol increased growth rate and PSA expression. Cortisol induced high-frequency MSI as evidenced by the insertion or deletion of 1-5 bps in at least 2 of 5 MS markers in both androgen-responsive and androgen-insensitive PCa cell lines. Analysis of the DNA mismatch repair pathway in PCa cells and tissues originated from AAs and CAs showed alterations in the expression levels of PMS1, PMS2, MLH1, MSH2, MSH3, MSH6, that belong to the MMR system. CONCLUSIONS: These data support a non-immunological role for cortisol in promoting genomic instability in androgen-deprived PCa cells that might lead to hyper-mutator phenotype or accumulation of adoptive-genetic changes in response to the stress that results from androgen-deprivation therapy for advanced PCa.

LH-receptor polymorphisms and response to androgen deprivation therapy in prostate cancer.

4597 Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer. Our recent data demonstrates an integral role of luteinizing hormone (LH) signaling in androgen synthesis in prostate cancer cells. We therefore hypothesized that genetic variation in the LH receptor may impact the efficiency of signal transduction and influence the degree of castration, the duration of response to ADT and overall course. We now report the association between LH receptor genotype and response to ADT. Methods: Fifty eligible patients had a histopathological diagnosis of prostate cancer and had received ADT for advanced prostate cancer. The blood was collected from each patient after obtaining informed consent. DNA was extracted from blood and genotypes for LHR were assayed using the TaqMan method. The time to castration resistance and level of testosterone suppression were obtained by linking to clinical records. Genotype groups were compared using ANOVA or Kruskal-Wallis tests. Results: The median age at diagnosis was 59 (range 48-69). Of the 50 patients enrolled, 29 were treated for primary metastatic disease, 18 at biochemical recurrence (BCR) and 12 with BCR accompanied by radiographic metastases. The median PSA at initiation of ADT was 109.4 ng/ml for primary metastatic disease and 9.8 ng/ml for recurrent disease. The median time to castration resistance was 12 months in the primary metastatic group and 32.4 months in the recurrent group. In the recurrent group, the presence of minor alleles in the LH receptor genotype was associated with a shorter time to castration resistance with a median of 39 months in men with no minor alleles, 23 months in men with 1 minor allele and 16 months in men with 2 minor alleles (p<.05). Median testosterone levels (T) during ADT were higher for men carrying any minor alleles. Median nadir T was 7 ng/dL for men with no minor alleles compared to 22.5 ng/dL for those with 1-2 minor alleles (p=0.07) with median peak T of 19 ng/dL vs. 43 ng/dL, respectively (p=0.01). Conclusions: Genetic variation in the LH receptor was clearly linked with time to castration resistance and depth of castration and warrants further analysis to define its role as a prognostic and predictive marker.

Effect of toremifene in lowering total cholesterol, LDL, and triglycerides and raising HDL in prostate cancer patients on androgen deprivation therapy

5124 Introduction: Androgen deprivation therapy (ADT) is the standard treatment for men with advanced prostate cancer. ADT has been shown to detrimentally affect lipids (average 9% increase in total cholesterol and 26% increase in triglycerides) and is associated with increased risk of coronary heart disease and myocardial infarction. Toremifene, a selective estrogen receptor modulator (SERM), improves bone mineral density and lipid profiles in women. An ongoing phase III trial will assess the safety and efficacy of toremifene in treating multiple side effects of ADT including osteoporosis, hot flashes, gynecomastia and lipid profiles. Given the emerging recognition of increased cardiovascular risk during ADT, an interim analysis was conducted to assess the effects of toremifene on lipid profiles in the ongoing phase III study. Methods: 1,392 men = 50 years old with histologically documented prostate cancer and receiving ADT were randomized to toremifene (80 mg/day) or placebo. An interim analysis evaluated changes in lipids from baseline to month 12 in the first 197 subjects to complete one-year follow up. The outcomes measured in this interim analysis were total cholesterol, LDL cholesterol, triglycerides, total cholesterol/HDL ratio, and HDL cholesterol. Results: Compared to treatment with placebo, toremifene decreased total cholesterol (7.1%; p=0.001 for between group comparison), LDL cholesterol (9.0%; p=0.003), and triglycerides (20.1%; p=0.009) levels, and the total cholesterol/HDL ratio (11.7%; p&lt;0.001). Toremifene also significantly increased HDL levels (5.4%; p=0.018) compared to placebo. The effects of toremifene were observed in both statin users and nonusers. Conclusions: Toremifene decreases total cholesterol, LDL cholesterol, and triglycerides and increases HDL cholesterol in men receiving ADT for advanced prostate cancer compared to placebo. Conclusions regarding the clinical significance of these observations will be based on the full cohort of patients at the conclusion of the trial. No significant financial relationships to disclose.