Androgen Deprivation Treatment Research Articles

Estrogen induces androgen-repressed SOX4 expression to promote progression of prostate cancer cells.

The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor β (ERβ), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERβ and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERβ and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17β-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERβ and AR. Knockdown of AR or ERβ blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERβ and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERβ expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. These findings suggest that SOX4 is a novel DHT-repressed AR-target gene. E2 could promote proliferation of PCa cells through the up-regulation of SOX4 under androgen-depleted environment. Our data provides a possible molecular basis for the overexpression of SOX4 in CRPC and may facilitate the detection and prevention of the emergence of CRPC.

562 The effect of intermittent androgen deprivation treatment in progression to castration resistant prostate cancer, compared with continuous androgen deprivation treatment

562 The effect of intermittent androgen deprivation treatment in progression to castration resistant prostate cancer, compared with continuous androgen deprivation treatment

Prolonged androgen deprivation may influence the autoregulation of estrogen receptors in the brain and pelvic floor muscles of male rats

Androgen deprivation in males has detrimental effects on various tissues and bodily functions, some of which can be restored by estradiol (E2) administration. We investigated how the duration of androgen deprivation affects the autoregulation of estrogen receptors (ERs) levels in core brain areas associated with sexual behavior and cognition, as well as in pelvic floor muscles (PFM). We also measured c-Fos levels in brain areas associated with sexual behavior shortly after the rats mated.Prolonged castration increases ERα levels in the preoptic area (POA) and E2 treatment reverses these effects. In the POA, c-Fos levels after mating are not affected by the duration of androgen deprivation and/or E2 treatment. ERβ levels in the POA as well as c-Fos levels in the POA and the core area of nucleus accumbens correlate with the mounting frequency for E2-treated Short-Term castrates. Additionally, ERβ levels in the medial amygdala are positively correlated with the mounting frequency of Long-Term castrates that received E2 treatment. In the hippocampus, ERs are downregulated only when E2 is administered early after castration, whereas downregulation of ERα in the prefrontal cortex only occurs with delayed E2 treatment. Early, but not delayed, E2 treatment after castration increases ERβ levels in the bulbocavernosus and ERα levels in the levator ani of male rats.Our data suggest that the duration of androgen deprivation may influence the autoregulation of ERs by E2 treatment in select brain areas and pelvic floor muscles of male rats.

Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.

277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.

The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway.

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1α in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.

SEOM clinical guidelines for the treatment of metastatic prostate cancer.

Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years. Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required.

Androgen deprivation and radiotherapy in patients with prostate cancer and cardiovascular risk factors: clinical controversies.

Recent reports of an association between androgen deprivation treatment (ADT) and increased risk of cardiovascular (CV) events have generated debate on the use of ADT in patients with prostate cancer (PCa) and CV comorbidities. This study aims to describe the recommendations of radiation oncologists in the most controversial aspects of treating such patients. The project involved 61 oncologists and comprised 4 phases: (1) selection of the most controversial aspects in the administration of ADT in patients with a history of CV disease and PCa, (2) selection of the most relevant published evidence, (3) preparation of case reports, (4) critical reading and discussion. Therapeutic procedures were classified as "highly recommendable", "recommendable in some cases", or "not recommendable/not applicable". For each item assessed, the mode of the scores given, and the percentage of experts who selected each score were calculated. The panel recommended that patients with high/very high-risk PCa and a history of CV disease should receive gonadotropin-releasing hormone agonists (GnRHa). ADT with GnRHa for 24-36 months + radiotherapy (RT) was also considered highly recommendable. In intermediate-risk PCa and a history of CV, ADT with GnRHa for 6-8 months + RT, and not administering ADT were considered highly recommendable. Studies are necessary to investigate the impact of ADT on CV mortality in patients who benefit most from adjuvant ADT in terms of survival. In the meantime, the experts believe that clinical evidence on the proven therapeutic benefits of ADT should override concerns about potential cardiac toxicity.

Androgen Deprivation Therapy for Patients With Localized Prostate Cancer Treated With High-Dose-Rate Brachytherapy Boost

Purpose/Objective(s): To evaluate the effectiveness and tolerability of neo-adjuvant/concomitant/adjuvant androgen deprivation therapy (ADT) for patients treated with external beam radiation therapy (EBRT) combined with high-dose-rate (HDR) brachytherapy boost for localized prostate cancer. Our hypothesis was that ADT does not add to the efficacy of the combined treatments. Materials/Methods: This is a retrospective cohort study conducted in a Canadian academic oncology center. All patients treated at our institution with EBRT followed by 192Ir HDR brachytherapy boost for localized prostate cancer between 1998 and 2010 were included in the study. Data on patients’ age, disease severity at diagnosis, androgen deprivation and radiation treatments received and follow up were collected from the patients’ medical records. The primary outcome was biochemical recurrence-free survival (bRFS). The secondary outcomes were genitourinary and gastrointestinal toxicities. Biochemical recurrence was determined according to the Phoenix consensus definition. Survival curves were calculated with the Kaplan-Meier method and compared between the two groups (ADT versus no ADT) with a logrank test. Multivariate Cox regressions were also performed to take into account potentially confounding variables such as age, PSA at diagnosis, TNM stage, Gleason score, biologically effective dose and type and duration of ADT. Genitourinary toxicities were assessed with the IPSS tool and compared between groups with student t-tests. Gastrointestinal toxicities (diarrhea, tenesmus, rectal bleeding) were evaluated with a three points scale (0: never, 1: occasionally, 2: frequently) and compared between groups with chi-squared tests. Results: Six hundred thirty-eight patients were treated with EBRT and HDR brachytherapy boost. Of those, 186 received ADT and 452 received no ADT. Doses ranged from 40 to 45 Gy in 20 to 25 fractions for EBRT and from 15 to 20 Gy in 1 to 3 fractions for the boost. According to NCCN risk classification, 7.8% of patients were low risk, 81.8% were intermediate risk and 10.3% were high risk. Median follow-up was 53 months. There was no significant difference in bRFS between groups in univariate (HR: 0.83; 95% CI: 0.51-1.38; p Z 0.48) and in multivariate analyses (HR: 0.72; 95% CI: 0.42-1.26; p Z 0.20). bRFS at 7 years was 86% in the ADT group and 92% in the no-ADT group (p Z 0.48). We observed no significant difference between groups in mean global IPSS scores at 3 months (ADT: 11.17 vs. no-ADT: 10.4; pZ 0.49) and at 12 months (ADT: 9.64 vs. no-ADT: 10.75; p Z 0.28) post-radiation therapy as well as in gastrointestinal toxicities at 3 and 12 months. Conclusions: For patients with a localized prostate cancer treated with EBRT combined with HDR brachytherapy boost, the addition of ADT does not seem to yield to a significant increased in bRFS neither to be associated with increased genitourinary and gastrointestinal toxicities. Author Disclosure: S. Magnan: None. P. Despres: None. W. Foster: None. A. Martin: None. E. Vigneault: None.

Postimplant Multiparametric MRI-Based Dosimetry After Permanent Iodine Seed Prostate Brachytherapy: The Impact of the Dose Delivered to the Dominant Intraprostatic Lesion on Prostate-Specific Antigen Bounce

Purpose/Objective(s): To evaluate the effectiveness and tolerability of neo-adjuvant/concomitant/adjuvant androgen deprivation therapy (ADT) for patients treated with external beam radiation therapy (EBRT) combined with high-dose-rate (HDR) brachytherapy boost for localized prostate cancer. Our hypothesis was that ADT does not add to the efficacy of the combined treatments. Materials/Methods: This is a retrospective cohort study conducted in a Canadian academic oncology center. All patients treated at our institution with EBRT followed by 192Ir HDR brachytherapy boost for localized prostate cancer between 1998 and 2010 were included in the study. Data on patients’ age, disease severity at diagnosis, androgen deprivation and radiation treatments received and follow up were collected from the patients’ medical records. The primary outcome was biochemical recurrence-free survival (bRFS). The secondary outcomes were genitourinary and gastrointestinal toxicities. Biochemical recurrence was determined according to the Phoenix consensus definition. Survival curves were calculated with the Kaplan-Meier method and compared between the two groups (ADT versus no ADT) with a logrank test. Multivariate Cox regressions were also performed to take into account potentially confounding variables such as age, PSA at diagnosis, TNM stage, Gleason score, biologically effective dose and type and duration of ADT. Genitourinary toxicities were assessed with the IPSS tool and compared between groups with student t-tests. Gastrointestinal toxicities (diarrhea, tenesmus, rectal bleeding) were evaluated with a three points scale (0: never, 1: occasionally, 2: frequently) and compared between groups with chi-squared tests. Results: Six hundred thirty-eight patients were treated with EBRT and HDR brachytherapy boost. Of those, 186 received ADT and 452 received no ADT. Doses ranged from 40 to 45 Gy in 20 to 25 fractions for EBRT and from 15 to 20 Gy in 1 to 3 fractions for the boost. According to NCCN risk classification, 7.8% of patients were low risk, 81.8% were intermediate risk and 10.3% were high risk. Median follow-up was 53 months. There was no significant difference in bRFS between groups in univariate (HR: 0.83; 95% CI: 0.51-1.38; p Z 0.48) and in multivariate analyses (HR: 0.72; 95% CI: 0.42-1.26; p Z 0.20). bRFS at 7 years was 86% in the ADT group and 92% in the no-ADT group (p Z 0.48). We observed no significant difference between groups in mean global IPSS scores at 3 months (ADT: 11.17 vs. no-ADT: 10.4; pZ 0.49) and at 12 months (ADT: 9.64 vs. no-ADT: 10.75; p Z 0.28) post-radiation therapy as well as in gastrointestinal toxicities at 3 and 12 months. Conclusions: For patients with a localized prostate cancer treated with EBRT combined with HDR brachytherapy boost, the addition of ADT does not seem to yield to a significant increased in bRFS neither to be associated with increased genitourinary and gastrointestinal toxicities. Author Disclosure: S. Magnan: None. P. Despres: None. W. Foster: None. A. Martin: None. E. Vigneault: None.

Medical treatment for biochemical relapse after radiotherapy

This article's purpose was to review the medical data justifying the use of a medical treatment for biochemical relapse after external beam radiotherapy. The MEDLINE database was searched to identify relevant information with the following medical subject headings: “prostate cancer”, “radiotherapy” and “biochemical relapse”. Prognostic factors affecting the overall survival of patients with a biochemical relapse after external beam radiotherapy have been identified: short prostate specific antigen (PSA)-doubling time (<12months), high PSA value (>10ng/mL) and short interval between treatment and biochemical relapse (<18months). If a second local treatment is not feasible, timing to initiate a salvage medical treatment is not defined. Particularly, randomized trials did not demonstrate a significant benefit of an early initiation of androgen deprivation treatment. Some retrospective studies suggest that an early androgen deprivation is justified if poor prognostic factors are found. However, if an androgen deprivation treatment is prescribed, intermittent schedule is non-inferior to a continuous administration and seems to offer a better quality of life. Many non-hormonal treatments have also been evaluated in this setting: only 5-alpha-reductase inhibitors could be proposed in some specific situations. In conclusion, the judicious use of a medical treatment for biochemical relapse is still debated. Given the natural history of this clinical situation, a simple surveillance is justified in many cases.

Osteoporosis and prostate cancer: a cross-sectional study of Danish men with prostate cancer before androgen deprivation therapy

Objective. The aim of this study was to analyse the prevalence of osteoporosis and risk factors of osteoporotic fractures before androgen deprivation in Danish men. Treatment and prognosis of prostate cancer necessitate management of long-term consequences of androgen deprivation therapy (ADT), including accelerated bone loss resulting in osteoporosis. Osteoporotic fractures are associated with excess morbidity and mortality. Material and methods. Patients with prostate cancer awaiting initiation of ADT were consecutively included. Half of the patients had localized disease and were referred for curative intended radiation, and the remaining patients had disseminated disease. Blood samples were collected, a questionnaire was administered and a dual-energy X-ray absorptiometry (DXA) scan was performed before initiating ADT. The patients were included between January 2010 and March 2012. The study was approved by the local ethics committee. None of the patients had received prior androgen deprivation or osteoporosis treatment. Results. In total, 105 individuals were included. The mean age of the participants was 70 years (range 53–91 years, SD 6.3). The median prostate-specific antigen level was 30.5 g/l (1–5714 g/l). The average Gleason score was 7.8 (range 5–10, SD 1.1). Fifty patients had localized prostate cancer and the other 55 patients had disseminated disease. The prevalence of osteoporosis was 10% and the prevalence of osteopenia was 58% before ADT. There was no significant difference between the two subgroups concerning osteoporosis. Smoking use was the only factor that was significantly associated with an increased prevalence of osteoporosis in the study population. Conclusion. Two-thirds of patients with prostate cancer awaiting ADT had osteoporosis or reduced bone mass. Further awareness regarding osteoporosis and bone health in prostate cancer is needed. It is suggested that patients with prostate cancer undergo a DXA scan before starting ADT.

Small cell carcinoma of the prostate

Pure small-cell carcinoma (SCC) of the prostate is a rare entity and one of the most aggressive malignancies of the prostate. Histologically, prostatic SCCs of the prostate are part of a spectrum of anaplastic tumours of the prostate and are similar to SCCs of the lungs. In most cases, SCC of the prostate is associated with conventional prostatic adenocarcinoma. Both components of these mixed tumours frequently share molecular alterations such as ERG gene rearrangements or AURKA and MYCN amplifications, suggesting a common clonal origin. The clinical behaviour of small-cell prostate carcinomas is characterized by extensive local disease, visceral disease, and low PSA levels despite large metastatic burden. Commonly, the emergence of the SCC occurs in patients with high-grade adenocarcinoma who are often treated with androgen deprivation treatment (ADT). However, SCCs do not usually benefit from ADT. A biopsy of accessible lesions is strongly recommended to identify those with SCC pathological features, as management is undoubtedly affected by this finding. Chemotherapy is the standard approach for treating patients with either localized or advanced prostatic SCC. Despite the emergence of more-aggressive treatment modalities, the prognosis of men with prostatic SCC remains dismal.

The Role of Neuroendocrine Cells in Prostate Cancer: A Comprehensive Review of Current Literature and Subsequent Rationale to Broaden and Integrate Current Treatment Modalities

Neuroendocrine prostate carcinoma (NE-PCa) is a heterogeneous disease. Due to a high prevalence of NE (neuroendocrine) differentiation in patients who receive prolonged androgen deprivation treatment, the real incidence of NE-PCa remains unknown. Similarly, the biological steps from prostate carcinoma (PCa) toward NE differentiation are far less than definitive and, consequently, there is a lack of evidence to support any of the treatments as the "gold standard". A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles and review articles regarding NE-PCa . Keywords were "prostate cancer" and "neuroendocrine". Articles published between 1995 and 2013, were reviewed and selected with the consensus of all of the authors. Fifty-one articles were selected by the authors for the purpose of this review. The principle findings were reported into some subsections: Epidemiology, Biological steps of NE differentiation (with some principle articles on animal and in vitro, since there is very little in the literature on human studies); for the treatment options, we had to expand the search on PubMed to a larger timeframe and selection since very little was specifically found in the first criteria: surgery, radiotherapy, ablative techniques, immunomodulation and epigenetic therapy were then reviewed. A multidisciplinary approach, advocated by many authors, although promising, has failed to demonstrate increased survival rates. Limitations of this review include the lack of a clear definition of NE-PCa and consequently, the lack of strong evidence provided by a large series with long-term follow-up. Supported from this extensive review, we propose it is worthwhile to investigate a new multimodal therapeutic approach to address advanced NE-PCa starting from a debulking (with radical intent) of the disease plus epigenetic therapy with stem cell differentiation stage factors (SCDSFs). In addition immunotherapy can be used to treat the cancer presenting phenotype in association with chemomodulation plus ablative therapies, in case of advanced or recurrent diseases. SCDSFs may be utilized to regulate cancer stem cells and possible new phenotypes could also be associated with ablative therapies. Hormonal deprivation, radiotherapy, chemotherapy, ex vivo vaccines and targeted therapies could also be used and reserved in case of failure.

Intermittent Versus Continuous Androgen Deprivation Treatment of Prostate Cancer

Intermittent Versus Continuous Androgen Deprivation Treatment of Prostate Cancer

Mise au point : TEP-choline et cancer de la prostate

PET with (18)F-Fluorocholine has authorization for the diagnosis of bone metastases. There are no limitations to the realization of this exam but androgen deprivation treatment should not be initiated or modified before performing TEP-choline. Some studies have shown a good correlation between choline uptake within the prostate and the tumor, if the size is greater than 5 mm; this exam is interesting in case of negative biopsy. In the initial staging of high-risk prostate cancer, metastatic nodes could be detected if there are more than 5 mm, especially those localized outside the lymphadenectomy area. TEP-choline is the most efficient exam that could detect intra-medullary bone metastases. It could realize the staging N and M in one procedure, and it could replace conventional imaging exams to detect lesions at an early stage. In the evaluation of recurrent disease, TEP-choline is able to detect the site of relapse--local, pelvic nodal or bone metastases--from a threshold of 1 ng/mL, less if the velocity value is greater than 1 ng/mL per year or the doubling time less than 6 months. For low PSA value, (around 5 ng/mL), relapse is usually isolated, either be local or nodal or metastatic. TEP-choline could be carried out in a first intention to consider a local salvage treatment. Bladder accumulation of choline can hide local small volume recurrence: overcome this drawback by the administration of Furosemide. In case of high-level PSA, Standard examinations (scintigraphy, CT…) are sufficient to detect the site of relapse.

Preoperative Erectile Function is an Independent Predictor for Decision to Spare Cavernous Nerves During Radical Prostatectomy

Cavernous nerve sparing (NS) is critical for recovery of erectile function (EF) as well as erectile tissue preservation following radical prostatectomy (RP). Clinical experience suggests that surgeons may opt for non-NS RP in patients with impaired baseline EF. This study was performed to define if baseline EF is an independent predictor of NS status during RP. A total of 2,323 mean (mean age 59 ± 7 years) who underwent RP at a tertiary referral academic medical center were retrospectively evaluated. Patients who underwent preoperative radiation therapy or androgen deprivation treatment were excluded. Preoperative parameters evaluated included biopsy pathological characteristics, prostate-specific antigen (PSA) level, patient age, and EF. Baseline EF was graded on a validated five-point patient reported scale. NSS was graded intraoperatively by the surgeon, using a four-point NS score assigned to each nerve where 1 = fully preserved, 2 = partially preserved, 3 = minimally preserved, and 4 = resected. NS surgery was defined as NSS of 1 or 2 on both sides, and nerve resection surgery was defined as NSS of 3 or greater on both sides. On univariate analysis, factors related to nerve resection surgery included (all P < 0.01): increasing age (r = 0.16), Gleason score (r = 0.19), EF score (r = 0.21), percentage biopsy cores positive (r = 0.11), higher preoperative PSA (relative risk [RR] 1.72, 95% confidence interval [CI] 1.23-2.40), and clinical stage ≥T2 (RR 2.17, 95% CI 1.68-2.78). On multivariable analysis, factors independently predicting for non-NS surgery included (all P < 0.01): baseline EF (odds ratio [OR] 1.50, 95% CI 1.33-1.68), biopsy Gleason sum (OR 1.95, 95% CI 1.65-2.36), clinical T stage ≥T2 (OR 1.59, 95% CI 1.15-2.20), patient age (OR 1.07, 95% CI 1.04-1.09), and percentage of biopsy cores positive (OR 1.01, 95% CI 1.00-1.02). While unfavorable clinical and prostate biopsy characteristics predict less NS, we have shown that poorer baseline EF also independently predicts for nerve resection RP. For every point increase in EF score (that is, worsening EF) the odds of not receiving NS during surgery increase by a factor of 1.5. Although NS is not associated with worse cancer outcomes in appropriately selected patients, failure to spare nerves is associated with poor post-operative EF, urinary continence, and increased severity of cavernous venous leak. Patient anxiety related to cancer diagnosis and impending treatment may lead to falsely-worsened apparent EF when recent erections are assessed during a pre-operative planning visit. For these reasons prostatectomists should consider NS based solely on factors other than patient's baseline EF, even when it is impaired.

Concomitant High-Grade Prostatic Intraepithelial Neoplasia Is Associated with Good Prognosis Factors and Oncologic Outcome after Radical Prostatectomy

Objectives: To assess correlations between concomitant high-grade prostatic intraepithelial neoplasia (HGPIN), pathological features and oncologic outcomes after radical prostatectomy (RP). Material and Methods: We prospectively collected a single-institution database of 2,351 patients who underwent RP between 1998 and 2011. Results: 1,272 (54.1%) patients had HGPIN on specimens. The mean follow-up was 28 months. Presence of HGPIN was significantly associated with a favorable preoperative risk status and with pathological factors of poor prognosis in RP specimens. Patients without HGPIN had a worse biochemical recurrence-free survival compared with those with HGPIN in RP specimen (log-rank test: p = 0.015). The 3-year RFS rate was 73.9% for the HGPIN group versus 67.2%. The absence of HGPIN was also significantly correlated with the use of androgen deprivation treatment during the follow-up (p < 0.001). In Cox multivariate analysis, taking into account the other prognostic pathological factors, HGPIN was not an independent predictive factor for PSA failure (p = 0.868). Conclusion: HGPIN is associated with factors of good prognosis but fails to show independent significance when classical pathological prognostic factors are taken into account.

Results of hormone therapy as first-line treatment for high-risk prostate cancer

To assess the current place for androgen deprivation therapy as single modality in locally advanced nonmetastatic situations. One standard of care for node negative locally advanced disease is a combination of external beam with androgen deprivation treatment. Several recent randomized trials have confirmed the key role of a local treatment combined to a systemic one in terms of specific and overall survival. The specific morbidity of this combined modality appears to be minimal. Retrospective data also suggest that a local treatment should be considered in case of positive nodes. Finally, the real place of immediate single hormonal treatment has also been clarified. The limited survival benefit has to be balanced with the side-effects. Therefore, this single modality should be limited to the most aggressive situations when no local treatment is planned. Single hormonal treatment for nonmetastatic advanced prostate cancer appears to be limited to the few patients unfit or unwilling for a local treatment and having a high prostate-specific antigen and a short prostate-specific antigen doubling time. In all other situations, it might represent a clear undertreatment.

Interaction between docetaxel resistance and castration resistance in prostate cancer: Implications of twist1, YB‐1, and androgen receptor

Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy. We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-β, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells. Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naïve prostate cancer may be superior to that of salvage taxane treatment in CRPC.

Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients

BackgroundThe most recent randomized controlled trial in a predominantly prostate-specific antigen-detected prostate cancer (PC) population found a nonsignificant reduction in mortality from radical prostatectomy (RP) compared to conservative management. The optimal treatment for clinically localized prostate cancer is anything but clear. The PC-specific mortality and all-cause mortality were compared between primary androgen-deprivation treatment (PADT) and RP, both as monotherapy, among clinically localized PC patients.MethodsA retrospective cohort study among PC patients in Surveillance, Epidemiology and End Results-Medicare data with a median follow up of 2.87 years in the PADT cohort and 2.95 years in the RP cohort. Propensity score-matching was employed to adjust for the observed selection bias. PC-specific mortality and all-cause mortality were modeled using the Fine and Gray competing risk model and Cox proportional hazards model, respectively. The independent variables in these models included age, race, Gleason score risk groups, T-score, prostate-specific antigen, Charlson comorbidity, and index year of treatment initiation.ResultsAfter propensity score-matching, there were 1624 in the PADT cohort and 1624 in the RP cohort. All baseline values were comparable (all P-values >0.35). There were a total of 266 deaths (16.38%) and 60 (3.69%) PC-specific deaths among PADT recipients, while there were 56 (3.45%) deaths and four (0.25%) PC-specific deaths among RP recipients. According to the Kaplan–Meier estimation, the 8-year survival rate was 43.39% in the PADT cohort and 79.62% in the RP cohort. PADT was associated with increased risk of overall mortality (hazard ratio = 2.98, 95% confidence interval 2.35–3.79; P < 0.001) and increased risk of PC-specific mortality (hazard ratio = 12.47, 95% confidence interval 4.48–34.70; P < 0.001).ConclusionWith adjustment for the observed selection bias, PADT was associated with increased all-cause mortality and PC-specific mortality when compared to RP.