Androgen Blockade Research Articles

The prognostic value of neutrophil to lymphocyte ratio on prostate cancer patients treated with maximal androgen blockade

Objective To evaluate the prognostic value of pretreatment neutrophil to lymphocyte ratio (NLR) on prostate cancer patients treated with maximal androgen blockade (MAB). Methods The clinical data of 249 prostate cancer patients treated with MAB in our hospital from October 2007 to March 2017 were retrospectively analyzed. Among all the patients, the median age was 72 years old (ranged 48 to 89 years). The BMI was 14.5-31.8kg/m2 (median 23.0 kg/m2). The PSA was 1.00-758.21 ng/ml (median 60.04 ng/ml). 216 patients’ tumor invaded surrounding tissues; lymph node metastasis occurred in 157 patients; and distant organ metastasis occurred in the remaining 174 patients. The Gleason score was 3-10 (median 7). Coprimary end points were progression-free survival (PFS) and cancer-specific survival (CSS). The best cutoff value of NLR was calculated by receiver operating characteristic (ROC) curve. The prognostic analysis of NLR on prostate cancer patients treated with MAB was estimated using Cox proportional hazards models and Kaplan-Meier analysis. Results The ideal cutoff value of the pretreatment NLR was 2.29 (95%CI 0.603-0.737, P<0.001) determined by the ROC curve according to the survived and deceased cases at the end point of CSS, by which the 249 patients was divided into the high NLR group of 119 patients (47.8%) and the low NLR group of 130 patients (52.2%). High NLR was significantly associated with high Gleason score (P=0.019), higher clinical T stage (P=0.001), N stage (P<0.001), M stage (P<0.001) and more neutrophil count (P<0.001). The median follow-up time was 29 months (ranged 5 to 124). During this period, 115 patients died, and the whole fatality rate was 46.2%. 40 patients died in low NLR group (30.8%), while the figures for the high NLR group were 75(63.0%). Kaplan-Meier analysis demonstrated that patients with NLR ≥2.29 had a poor outcome both in PFS (P<0.001) and CSS (P<0.001). The multivariate Cox analysis showed that NLR, Gleason score, clinical TNM stage and ECOG score were independent predictors for PFS and CSS. Conclusion Pretreatment NLR could be an independent prognostic biomarker for PFS and CSS in prostate cancer patients undergoing MAB. Key words: Prostatic neoplasms; Maximal androgen blockade; Neutrophil to lymphocyte ratio; Prognosis

Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07)

Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54Gy in 1.8Gy fractions with up to 66Gy in 2.2Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7±6.5years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1year did not worsen significantly. The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.

Incidence of second tumours in high risk prostate cancer patients according to the primary treatment applied

Introduction and objectivesThe onset of second primary tumours should be considered in high-risk prostate cancer patients in the natural course of the disease. Our aim was to evaluate the influence of primary treatment with curative intent for these patients on the development of second primary tumours. Material and methodsA retrospective study of 286 patients diagnosed between 1996 and 2008, treated by radical prostatectomy (n=145) or radiotherapy and androgen blockade (n=141). The homogeneity of both series was analyzed using the Chi-squared test for the qualitative variables, and the Student's t-test for the quantitative variables. A multivariate Cox regression analysis was performed to assess whether the type of primary treatment influenced the development of second tumours. ResultsThe median age was 66 years, and the median follow-up was 117.5 months. At the end of follow-up, 60 patients (21%) had developed a second primary tumour. In the prostatectomy group it was located in the pelvis in 13 (9%) cases, and those treated with radiotherapy and hormonotherapy in 8 (5.7%) cases (p=0.29). The most common organ sites were: colo-rectal in 17 (28.3%) patients, the lung in 11 (18.3%), and the bladder in 6 (10%) patients. In the multivariable analysis, the risk of a second tumour doubled for those treated with radiotherapy and hormonotherapy (HR=2.41, 95% CI: 1.31–4.34, p=0.005) compared to the patients treated by prostatectomy. Age and rescue radiotherapy did not behave as independent predictive factors. ConclusionsThe onset of a second primary tumour was related with the primary treatment given; thus the risk for those treated with radiotherapy and androgen deprivation therapy more than doubled.

Time to progression to castration-resistant prostate cancer after commencing combined androgen blockade for advanced hormone-sensitive prostate cancer.

PurposeThe aim of our retrospective study was to determine the time to progression to castration-resistant prostate cancer (CRPC) in prostate cancer patients who undergo combined androgen blockade (CAB), as well as their prognoses.Materials and MethodsWe examined the overall survival (OS) and disease-specific survival rates, as well as the time to CRPC development, in 387 patients who were treated with CAB for prostate cancer. The disease-specific survival rate and time to CRPC were stratified by prostate-specific antigen (PSA) levels, Gleason score (GS), and presence of metastasis at diagnosis. We designated high-risk patients as those satisfying at least two of the following three criteria: extent of disease of bone metastasis grade ≥2, presence of metastasis at diagnosis, and a GS ≥8.ResultsThe 10- and 15-year OS rates were 74.0% and 50.4%, respectively, while the corresponding disease-specific survival rates were both 86.8%. Metastasis at diagnosis was an independent prognostic factor for disease-specific survival. The median time to CRPC development was 140.7 months. A PSA level ≥20 ng/mL, a GS ≥8, and the presence of metastasis at diagnosis were independent predictors of a shorter time to CRPC development. The 10-year disease-specific survival rate in the high-risk group was significantly lower than that in the low-risk group (approximately 74% vs. 98%), and the time to CRPC development was significantly shorter (median: 20.5 months vs. not reached).ConclusionsThe time to CRPC development was shorter in high-risk prostate cancer patients with metastases. Such patients require alternative novel treatment modalities.

Abiraterone acetate for early stage metastatic prostate cancer: patient selection and special considerations.

In recent years, therapeutic advances, together with new medication sequences and combinations, have improved outcomes for prostate cancer. For a long time, androgen deprivation therapy (ADT) has been the standard of care for newly diagnosed, metastatic prostate cancer, first as a standalone therapy and then in combination with taxane-based regimens. More recently, the addition of abiraterone acetate to ADT to achieve complete androgen blockade has proven beneficial for the treatment of metastatic hormone-resistant prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). In this review, we summarize recent findings on the early use of abiraterone in mHSPC and discuss survival benefits as reported in clinical trials. On the basis of existing data, abiraterone in combination with ADT could be considered a new standard of care for patients affected by mHSPC.

Effect of maximal androgen blockade therapy on hematological, biochemical and bone density in locally advanced prostate cancer

Aim: In the present study we aimed to check the impact of maximal androgen deprivation therapy (MADT) on cellular blood components such as hemoglobin (Hb) and hematocrit (Htc) fasting blood glucose (FBG), serum lipid values and bone mineral density (BMD) in locally advanced prostate cancer.Patients and Methods: Having been treated with maximal androgen blockade therapy, thirty-nine patients' initial values and at the twelfth month values of hemoglobin (Hb), hematocrit (Htc), FBG, total cholesterol (tChol), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and spine BMD were recorded. Statistical comparisons of initial and at the twelfth month values were performed. Results: A statistically significant decrease was recorded in Hb and BMD values after one year MADT. On the other hand, TG, tChol, LDL, HDL and FBG values showed a statistically significant increase. Although Hb levels were significantly reduced, none of our patients developed symptoms of anemia. Fourteen of 37 patients whose FBG levels were under 110 mg/dl before treatment, increased over 110 mg/dl at the twelfth month of treatment. Seven patients developed diabetes mellitus (DM) after treatment. Moreover, T score evaluation revealed newly developed osteoporosis in 4 patients. All of the patients with developed osteoporosis had osteopenic T score values before treatment. No bone fractures occurred in any of our patients. Conclusion: Our study points out the increase of FBG related to the treatment of MADT. Decrease in BMD is higher in previously osteopenic patients. The lack of bone fracture and anemia symptoms might be considered as a result of evaluation of the early data on MADT.

SMALL CELL PROSTATE CANCER PRODUCING SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE; A CASE REPORT

A 73-year-old man with progressive prostate cancer visited our hospital after prostate biopsy performed at another hospital. His serum PSA level was 29.02 ng/ml. CT revealed invasion of the bladder, bilateral ureters, and rectum. Otherwise, there was no evidence of metastasis. Pathological findings showed a poorly differentiated adenocarcinoma (Gleason score 4+5) and small cell carcinoma component. Two months after administering combined androgen blockade therapy, he was admitted due to severe hyponatremia caused by the inappropriate secretion of antidiuretic hormone. Furthermore, CT revealed right ureter metastasis, although the PSA levels remained low. Therefore, the patient was put on fluid restriction and sodium administration. After the patient recovered from hyponatremia, chemotherapy, including VP-16 and CDDP, was initiated. However, CT after two chemotherapy cycles revealed disease progression, with multiple bone metastases. Second-line chemotherapy, including CPT-11 and CDDP, was less effective, and the patient died 9 months after the diagnosis.

Two Year Outcomes of Short-Term Potent Androgen Blockade and Definitive Radiation for Intermediate to High Risk Localized Prostate Cancer

Two Year Outcomes of Short-Term Potent Androgen Blockade and Definitive Radiation for Intermediate to High Risk Localized Prostate Cancer

Cardiovascular Mortality Following Long-course Androgen Deprivation in Unfavorable Prostate Cancer Patients Treated with Brachytherapy and/or External Beam Radiation Therapy

To investigate whether long-course androgen deprivation therapy (ADT) is associated with an increased risk of cardiovascular mortality (CVM) in Japanese patients treated with brachytherapy and/or external beam radiotherapy (EBRT) for unfavorable localized prostate cancer. This is a retrospective analysis of prospectively collected data from men treated at Tokyo Medical Center between 2003 and 2012. Data on 1,628 patients treated for intermediate (n=1,234) or high-risk (n=394) prostate cancer with brachytherapy (n=486), EBRT (n=196), and a combination of brachytherapy and EBRT (n=946) were included. In total, 1,005 patients (61.7%) received neoadjuvant, concurrent with or in the absence of adjuvant ADT. Patients were divided into two groups according to the total duration of ADT: a short-course group (n = 803) received ≤ 12 months (median duration 6 months), and a long-course group (n = 202) received > 12 months (median duration 24 months). The primary endpoint of this study was a CVM, which was defined as a death from myocardial infarction, sudden cardiac arrest, coronary artery disease, cardiac ischemia, malignant arrhythmia, or cerebrovascular stroke. Statistical analysis was conducted using Kaplan-Meier estimator. Cox regression analyses were performed to assess whether long-course ADT was associated with CVM after controlling for age, presence of baseline cardiovascular disease or diabetes, radiation modality, and risk groups. After a median follow-up of 7.6 years (range=0.5-14 years), overall survival was 85.1% at 10 years. In total, 194 men died; 53 cardiovascular deaths, 41 prostate cancer deaths, 67 other malignancy deaths, 16 infectious disease deaths, 15 other benign disease deaths, and two unknown causes were observed. In terms of baseline patient characteristics, long-course ADT was significantly associated with younger patients, EBRT treatment, high risk group, and total androgen blockade. The 10-year CVM rate was 4.2% in the no-ADT group, 3.9% in the short-course ADT group, and 12.2% in the long-course ADT group (p<.001). In Cox regression analysis, long-course ADT (adjusted hazard ratio [AHR]=2.94; 95% confidence interval [CI]=1.31 to 6.59; p=.009), age (AHR=1.15; 95% CI=1.10 to 1.21; p<.001), baseline cardiovascular disease (AHR=2.62; 95% CI=1.49 to 4.62; p=.001), and baseline diabetes (AHR=2.71; 95% CI=1.36 to 5.41; p=.005) were associated with statistically significantly increased CVM. Long-course ADT is associated with an increased risk of CVM in Japanese patients undergoing brachytherapy and/or EBRT for unfavorable prostate cancer. Although Japan’s CVM is much lower than that of the USA, CVM appears to increase noticeably after long-course ADT in the otherwise this long-lived Japanese population.

802P - Comparative efficacy and cost-effectiveness of maximum androgen blockade (MAB), docetaxel with androgen deprivation therapy (ADT), and ADT alone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in China

802P - Comparative efficacy and cost-effectiveness of maximum androgen blockade (MAB), docetaxel with androgen deprivation therapy (ADT), and ADT alone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in China

Diferencias en la supervivencia global y supervivencia cáncer específica en pacientes con cáncer de próstata de alto riesgo según el tratamiento primario aplicado

Introduction and objectivesThere is no high-level evidence as to which primary treatment provides an overall survival (OS) or cancer-specific survival (CSS) advantage in high-risk localised prostate cancer (HRLPC).Our aim was to analyse the differences in survival and predictive factors in this group of patients, according to their primary treatment (radical prostatectomy (RP) or radiotherapy and androgen blockade (RT+HT)). Material and methodsA retrospective study of 286 HRLPC patients diagnosed between 1996-2008, treated by RP (n=145) or RT+HT(n=141).Survival was assessed using the Kaplan-Meier method. Significant differences between the different variables were analysed using the log-rank test. A uni and multivariate Cox regression analysis was performed to identify risk factors. Resultsthe median follow-up was 117.5 (IQR 87-158) months. The OS was longer (p=.04) in the RP patients, while there were no differences (P=.44) in CSS between either group.The type of primary treatment was not related to OS or CSS. Age (P=.002), the onset during follow-up of a 2nd tumour (P=.0001), and stage cT3a (P=.009) behaved as independent predictive variables of OS. None of the variables behaved as an independent predictive variable of CSS, although biochemical recurrence after rescue treatment (P=.058), and the onset of a 2nd tumour during follow-up showed a significant trend to statistical significance, the latter reducing specific cancer mortality (HR .16, 95%CI .02-1.18, P=.07). ConclusionsPrimary treatment did not relate to OS or CSS in patients with HRPC.

Salivary ductal adenocarcinoma with complete response to androgen blockade

Salivary ductal adenocarcinoma with complete response to androgen blockade

PSA response following the 'steroid switch' in patients with castration-resistant prostate cancer treated with abiraterone: A case report.

A 69-year-old man presented initially with back pain and incomplete bilateral lower limb paralysis. The level of prostate-specific antigen (PSA) in the patient was elevated to 167.0 ng/ml, and multiple bone metastases were detected. Thoracic laminectomy was performed in an emergency due to spinal decompression. Subsequently, the patient was diagnosed with prostate cancer from an examination of resected bone specimens. Combined androgen blockade with degarelix and bicalutamide was initiated in October 2013. Consequently, the serum PSA level decreased to <1.0 ng/ml, but thereafter gradually increased. Subsequent bicalutamide withdrawal response was not observed, and switch of anti-androgen therapy to flutamide also resulted in a poor response. Then, abiraterone (1,000 mg daily) in combination with prednisolone (10 mg daily) was initiated when the level of PSA increased to 35.9 ng/ml in June 2015. The level of PSA decreased to the lowest point of 4 ng/ml; however, PSA level increased again to 21.7 ng/ml in April 2016. Consequently, a 'steroid switch' was attempted. Abiraterone therapy was continued, but concomitant corticosteroid was switched from prednisone to dexamethasone (1.0 mg per day). Fortunately, serum PSA level decreased promptly to the lowest point of 0.6 ng/ml. In the present case report, a review of recent literature was presented and potential explanations of the mechanism underlying the 'steroid switch' were described. Pharmacokinetic differences between dexamethasone and prednisolone may partially explain why the 'steroid switch' occurs. Other mechanisms may include the activation of the glucocorticoid receptor, mineralocorticoid receptor and/or mutant androgen receptor. Corticosteroids accelerate a number of transcription factors, cellular growth factors and cytokines, which may also be potential mechanisms. The 'steroid switch' at PSA progression might be a feasible option for therapy, which may delay the development of the disease. Although the underlying mechanisms require further study, clinicians should pay attention to this phenomenon.

Qualitative study on psychological experience in elderly patients with prostatic cancer after castration

Objective To explore the real psychological experience in elderly patients with prostatic cancer after castration and to offer reference for formulating targeted interventions. Methods Totally 15 elderly prostatic cancer patients who received castration and total androgen blockade in the First Affiliated Hospital of Wenzhou Medical University from October 2014 to June 2016 were selected by convenient sampling and interviewed intensively. The data were analyzed by Colaizzi's seven-step method for qualitative studies. Results Totally 3 topics were summarized: the sense of uncertainty in elderly prostatic cancer patients after castration; changes in social adaptation; self-image disorder. Conclusions Various psychological crises, especially depression, are experienced in elderly prostatic cancer patients after castration. Therefore, continuous and extensive support is required for elderly prostatic cancer patients after castration. Key words: Prostatic neoplasms; Castration; Psychological experience

Incidencia de segundos tumores en pacientes con cáncer de próstata de alto riesgo según el tratamiento primario aplicado

Introduction and objectivesThe onset of second primary tumours should be considered in high-risk prostate cancer patients in the natural course of the disease. Our aim was to evaluate the influence of primary treatment with curative intent for these patients on the development of second primary tumours. Material and methodsA retrospective study of 286 patients diagnosed between 1996 and 2008, treated by radical prostatectomy (n=145) or radiotherapy and androgen blockade (n=141). The homogeneity of both series was analysed using the Chi-squared test for the qualitative variables, and the Student's t-test for the quantitative variables. A multivariate Cox regression analysis was performed to assess whether the type of primary treatment influenced the development of second tumours. ResultsThe median age was 66 years, and the median follow-up was 117.5 months. At the end of follow-up, 60 patients (21%) had developed a second primary tumour. In the prostatectomy group it was located in the pelvis in 13 (9%) cases, and those treated with radiotherapy and hormonotherapy in 8 (5.7%) cases (P=.29). The most common organ sites were: colo-rectal in 17 (28.3%) patients, the lung in 11 (18.3%), and the bladder in 6 (10%) patients. In the multivariable analysis, the risk of a second tumour doubled for those treated with radiotherapy and hormonotherapy (HR=2.41, 95%CI: 1.31-4.34, P=.005) compared to the patients treated by prostatectomy. Age and rescue radiotherapy did not behave as independent predictive factors. ConclusionsThe onset of a second primary tumour was related with the primary treatment given; thus the risk for those treated with radiotherapy and androgen deprivation therapy more than doubled.

Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy.

Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT-treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling-related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis.Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035).Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908-16. ©2018 AACR.

Abstract B097: NRF2 antioxidant signaling mediates the ability of PIM protein kinases to induce resistance of prostate cancer to PI3K inhibitor therapy

Abstract Aberrant activation of the PI3K pathway leading to increases in AKT activity is seen in many prostate cancer patients refractory to androgen blockade therapy. A number of small-molecule inhibitors of PI3K, including BKM120 (Novartis), have entered clinical trials. As with PI3K-AKT activation, highly expressed Pim kinase has been shown to drive the growth of prostate cancer. Recent studies have demonstrated that Pim kinase plays a critical role in promoting resistance of breast cancer to PI3K inhibition. Similarly, when the Pim-1 protein kinase is overexpressed, prostate cancer cell lines become resistant to PI3K inhibitor. In both tissue culture and animal models, the combination of a Pim inhibitor, PIM447, and BKM120 acted synergistically in blocking the survival and growth of prostate cancer cells. We therefore investigated the biochemical mechanism by which Pim-1 mediates cell resistance to the PI3K inhibitor. Previously, we have demonstrated that knockout of Pim kinases led to accumulation of reactive oxygen species (ROS) accompanied by a lower level of expression of ROS scavengers. To explore whether Pim-1 overexpression reverses this phenotype in prostate epithelial cancer, using lentiviral transduction, we expressed Pim-1 in mouse prostate epithelial cancer cells derived from spontaneous prostate adenocarcinomas that arose in a mouse model in which Tp53 and Rb1 are deleted in prostate epithelium. Pim-1 overexpression promoted anchorage-independent growth and formation of mouse prostate epithelial tumors in vivo. Gene expression arrays demonstrated that Pim-1 induced an Nrf2 antioxidant response element gene signature, including increases in Heme oxygenase-1 (Hmox1), NAD(P)H quinone oxidoreductase 1 (Nqo1), and glutathione S-transferase kappa1 (Gstk1) genes. Similarly, overexpression of Pim-1 in human prostate cancer LNCaP cells results in increased expression of Nrf2 and Hmox1 protein. As expected, depletion of Nrf2 with shRNA prevented Pim-1-mediated increases in Hmox1 expression, indicating that Nrf2 activation is required for the Pim-1 induction of ROS scavengers. In line with this result, in Pim-1 overexpressing cell lines knockdown of either Hmox1 or Nrf2 restored sensitivity to BKM120 treatment. A vital role of ROS scavengers in mediating the resistance to BKM120 was further confirmed by the treatment of cells and xenografted tumors with buthionine sulfoximine (inhibitor of glutathione synthesis), which resensitized the Pim-1 overexpressing cells to BKM120 via ROS induction. Our data further demonstrated that Pim-1 overexpression decreases the ubiquitination of Nrf2 protein, thus preventing its degradation, and increasing its half-life. Conversely, inhibition of Pim kinase promoted Nrf2 ubiquitination and proteasomal degradation. Taken together, our results show that the increased expression of Pim kinases in prostate cancer blocks therapeutic efficacy of PI3K inhibitor by inducing Nrf2 and antioxidant scavengers that inhibit the induction of ROS. Citation Format: Jin H. Song, Libia A. Leuvano, Neha Singh, Andrew S. Kraft. NRF2 antioxidant signaling mediates the ability of PIM protein kinases to induce resistance of prostate cancer to PI3K inhibitor therapy [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B097.

Upregulation of Oxytocin Receptor in the Hyperplastic Prostate.

Background: The etiology of benign prostatic hyperplasia (BPH) is complex, both age and androgen are thought to be important. However, the failure of androgen blockade treatments suggests other paracrine/autocrine factors involved in BPH. Oxytocin was found to have a paracrine/autocrine role in prostate in recent years. The influence of BPH on prostatic oxytocin receptor (OTR) expression has never been studied.Material and methods: A testosterone-estradiol induced rat model of BPH was employed and human hyperplastic prostate specimens were harvested. Expressions of OTR, α1-adrenoreceptor subtypes and nitric oxide synthase isoforms were determined via real-time RT-PCR. OTR was further analyzed with Western-Blotting and histological examination. Subsequently, rat epithelial cells, human stromal cells and epithelial cells were cultured in vitro and treated with gradient concentrations of OT from 1 to 5 days. Cell proliferation was tested by Cell Counting Kit-8 and Flow Cytometry.Results: The rat BPH model was validated with significant increased prostate weight. H-E stain revealed a different histopathology between human and rat BPH. Masson's trichrome staining demonstrated that smooth muscle (SM) cells, epithelium cells and collagen fibers were simultaneously augmented in this rat BPH model and human BPH samples. OTR mainly localized in epithelium in rat prostate whereas it mainly localized in stroma in human prostate. OTR gene was upregulated 3.3-fold in rat BPH and 3.0-fold in human BPH, along with increased expression of 2.0-fold α1aARs and 3.0-fold eNOS for rat BPH and 5.0-fold α1aARs for human BPH. The expression of OTR protein was upregulated 1.4-fold in rat BPH and 3.9-fold in human BPH, respectively. Increased concentrations of exogenous OT can accelerate proliferation of rat epithelial cells and human stromal cells but has no impact on human epithelial cells in vitro. Flow Cytometry showed oxytocin could significantly increase G2/M period cell number.Conclusions: Our novel data demonstrates a significant and previously undocumented upregulation of OTR in both rat and human BPH. Moreover, exogenous OT accelerates proliferation of rat prostate epithelial cells and human prostate stromal cells. It is suggested OTR is involved in the development of BPH and OT regulatory system could be a potential new target for the BPH treatment.

Pretreatment serum albumin/globulin ratio as a prognostic biomarker in metastatic prostate cancer patients treated with maximal androgen blockade.

The pretreatment serum albumin/globulin ratio (AGR) has been used as a prognostic biomarker for various cancer types. However, the prognostic value of the AGR for prostate cancer, especially for metastatic prostate cancer (mPCa) after maximal androgen blockade (MAB), remains unclear. The aim of this study was to evaluate the prognostic value of the pretreatment serum AGR for mPCa treated with MAB. This retrospective study included 214 mPCa patients receiving MAB from October 2007 to March 2017. The correlation of the AGR with survival was estimated using Kaplan–Meier analysis and Cox proportional hazards models. The cutoff value of the AGR was 1.45 according to the receiver operating characteristic curve. Kaplan–Meier analysis demonstrated that patients with a low AGR (<1.45) had poor outcomes in terms of progression-free survival (PFS) and cancer-specific survival (CSS). Multivariate Cox analyses showed that the AGR was an independent predictor of PFS (hazard ratio [HR] = 0.642; 95% confidence interval [CI]: 0.430–0.957; P = 0.030) and CSS (HR = 0.412; 95% CI: 0.259–0.654; P < 0.001). Furthermore, in a subset of 79 patients with normal serum albumin levels (≥40.0 g l−1), the serum AGR remained an independent predictor of CSS (P = 0.009). The pretreatment AGR was an independent prognostic biomarker for PFS and CSS in patients with mPCa receiving MAB. In addition, the AGR remained effective for the prediction of CSS in patients with normal albumin levels (≥40 g l−1). However, further prospective studies are needed to confirm our conclusions.

Pretreatment systemic inflammation response index as an independent prognostic indicator for prostate cancer patients treated with maximal androgen blockade

Objective To investigate the efficacy of pretreatment systemic inflammation response index (SIRI) in predicting the prognostic of prostate cancer (PCa) patients treated with maximal androgen blockade (MAB). Methods The data of 351 PCa patients who had undergone MAB as first-line therapy between January 2010 and June 2015, were retrospectively analyzed. The age of patients in our cohort ranged from 51 to 89 years old, mean 76 years old. The median value of PSA was 91.60ng/ml, ranging 0.11-1 000.00 ng/ml. 39 cases had a Gleason score of 6, 47 cases had a score of 3+ 4, 89 cases had a score of 4+ 3, 107 cases had a score of 8, and 69 cases had a score of 9-10. 158 cases had bone metastasis. Patients were categorized in two groups using a cut-off point of 1.2 as calculated by the receiver-operating curve analysis. Correlations between SIRI and clinical characteristics were analyzed. Meanwhile, univariate and multivariate cox regression analyses were performed to determine the associations of SIRI with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results The median follow-up duration was 43.0 months, ranging 9-75 months. The disease progression occurred in 162 patients, 91 patients died, including 75 who died because of PCa at the end of the last follow-up. The differences of age, Gleason score and incidence of metastasis between low SIRI group ( 0.05). But the patients in high SIRI group had higher PSA (P=0.046). Multivariate analyses identified SIRI, Gleason score and metastasis as independent prognostic factors for PFS, CSS and OS. Conclusions Pretreatment SIRI≥1.2 was an independent predictor for poor prognosis in PCa patients treated with MAB. Key words: Prostate neoplasms; Maximal androgen blockade; Systemic inflammation response index; Prognosis