Salvage Radical Prostatectomy in Nonmetastatic Castration-Resistant Prostate Cancer.

OBJECTIVE: To analyze the perioperatory and short-oncological outcomes in 5 cases with CRPC M0 developed after pRT that underwent salvage laparoscopic RP (sLRP) and review the current evidence. MATERIAL AND METHODS: Perioperatory and oncological outcomes were prospectively analyzed. Inclusion criteria were patients that had received pRT and posteriorly presented with CRPC M0 in standard imagines and positron emission tomography MRI coline. Evidence was reviewed in PUBMED database. RESULTS: No surgical complications and blood transfusion were reported. Two patients required an endoscopic urethrotomy due to bladder neck contracture (Clavien IIIb). Final pathological findings were T3 or more, multifocal with 3 positive surgical margins. Four patients reach undetectable PSA after surgery except one that continuous under ADT without disease progression. After 12 months follow-up, 4 patients persist with undetectable PSA and one with stable disease under ADT. Current evidence demonstrated that CRPC M0 treated with open, laparoscopic or robotic RP a biochemical recurrence of 68.7% as a hormone-sensitive PC; however, 17.4% were disease-free after 4 years of follow-up. CONCLUSION: Our serie, 4 cases are disease free after 12 months follow-up. Current evidence is a retrospective and multicenter experience with few cases and intermediate oncological follow-up. More cases with longer follow-up and better evidence are required to opt for this treatment as a first line.

Remission of progressive metastatic castration-resistant prostate cancer during abiraterone therapy following unilateral adrenalectomy for a functioning adrenal adenoma.

Despite advances and introduction of new therapies in the last decade, metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. The development of androgen axis-targeted therapies such as abiraterone acetate, enzalutamide and darolutamide can prolong survival in mCPRC; however, resistance remains a barrier to prolonged response, necessitating exploration into resistance mechanisms and locoregional therapies. Here, we describe a patient with mCRPC that was progressing on abiraterone acetate. He was also found to have primary hyperaldosteronism from a functional adrenal adenoma, and thus he had a partial adrenalectomy to remove this tumour. Pathology confirmed an aldosterone-producing adrenal adenoma. After his adrenalectomy, he had a sharp decline in both his PSA (prostate specific antigen) and testosterone levels, and he enjoyed a year-long period of remission after his adrenalectomy. We propose several explanations for his response, the most likely being that his adenoma was producing both aldosterone and androgens. This is a unique case of mCRPC responding to partial adrenalectomy from a functional adrenal adenoma, and it raises insights that warrant further investigation into underlying mechanisms of resistance to androgen-targeted therapies.

Spine Stereotactic Body Radiotherapy for Prostate Cancer Metastases and the Impact of Hormone Sensitivity Status on Local Control.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is used to deliver ablative dose of radiation to spinal metastases. OBJECTIVE: To report the first dedicated series of spine SBRT specific to prostate cancer (PCa) metastases with outcomes reported according to hormone sensitivity status. METHODS: A prospective database was reviewed identifying patients with PCa treated with spine SBRT. This included those with hormone-sensitive PCa (HSPC) and castrate-resistant PCa (CRPC). The primary end point was MRI-based local control (LC). RESULTS: A total of 183 spine segments in 93 patients were identified; 146 segments had no prior radiation and 37 had been previously radiated; 27 segments were postoperative. The median follow-up was 31 months. At the time of SBRT, 50 patients had HSPC and the remaining 43 had CRPC. The most common fractionation scheme was 24-28 Gy in 2 SBRT fractions (76%). LC rates at 1 and 2 years were 99% and 95% and 94% and 78% for the HSPC and CRPC cohorts, respectively. For patients treated with de novo SBRT, a higher risk of local failure was observed in patients with CRPC (P = .0425). The 1-year and 2-year overall survival rates were significantly longer at 98% and 95% in the HSPC cohort compared with 79% and 65% in the CRPC cohort (P = .0005). The cumulative risk of vertebral compression fracture at 2 years was 10%. CONCLUSION: Favorable LC rates were observed after spine SBRT for PCa metastases; strategies to improve long-term LC in patients with CRPC require further investigation.

[Pelvic exenteration in patients with locally advanced, symptomatic castration-resistant prostate cancer]. / Radikale pelvine Tumorchirurgie bei Patienten mit einem lokal fortgeschrittenen, symptomatischen kastrationsresistenten Prostatakarzinom.

GOAL: The retrospective evaluation of clinical outcomes after palliative pelvic exenteration (PPE) in patients with subvesical and supravesical complications due to symptomatic locally advanced castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: In all, 84 patients with locally advanced and symptomatic CRPC underwent radical cystoprostatectomy (n = 71, 83.3%) or anterior and posterior exenteration (n = 13, 16.7%). Local staging was done via pelvic MRI (magnetic resonance imaging), cystoscopy, and rectoscopy. Systemic staging was performed by computed tomography of the thorax, abdomen pelvis, and skeletal scintigraphy. Perioperative complications were evaluated using the Clavien-Dindo classification. The primary study objective was symptom-free survival defined as absence of lower or upper urinary tract symptoms and absence of endoluminal or percutaneous intervention. RESULTS: After a median follow-up of 43.5 (3-139) months, symptom-free survival at 1 and 3 years was 95.2% and 86.7%, respectively. In all, 86.7% of patients remained symptom-free for their remaining lifetime with respect to local symptoms. Overall survival at 1 and 3 years was 92.9% and 54.7%, respectively. Clavien-Dindo grade 2, 3, and 4 complications occurred in 19 (22.6%), 7 (8.3%), and 3 (3.6%) patients, respectively. CONCLUSION: With adequate patient selection, PPE is possible with a low complication rate and results in significant symptom relief in the lower or upper genitourinary tract in about 90% of patients, of whom more than 80% remain symptom-free for the remainder of their lives. Prerequisites for favorable surgical outcomes are patient selection, an interdisciplinary approach, and appropriate surgical expertise.

PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. METHODS: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis. RESULTS: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. CONCLUSIONS: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.

Cell-free DNA concentration and fragment size as a biomarker for prostate cancer.

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5ng/mL = 1.34, P = 0.027) or to being a control (OR5ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.

Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.

PURPOSE: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. EXPERIMENTAL DESIGN: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. RESULTS: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. CONCLUSIONS: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

Tissue Expression of Androgen Receptor Splice Variant 7 at Radical Prostatectomy Predicts Risk of Progression in Untreated Nonmetastatic Prostate Cancer.

BACKGROUND: Androgen receptor splice variant V7 (AR-V7) was recently detected in circulating tumor cells of castration-resistant prostate cancer (PC) patients and its expression correlated with resistance to new-generation androgen signaling inhibitors. OBJECTIVES: We retrospectively analyzed whether AR-V7 expression was detectable on radical prostatectomy (RP) specimens of untreated nonmetastatic PC cases, and whether it could be associated with progression after surgery. METHOD: The expression of AR-V7 and AR-FL (full length) was separately evaluated by immunohistochemistry using a streptavidin-biotin-peroxidase system with 2 anti-AR-V7 and anti-AR-FL rabbit monoclonal antibodies. RESULTS: 56 PC cases, classified by their clinical risk, were analyzed. Positive expression was found in 24/32 cases in the high-risk group, 4/13 in the intermediate-risk group, and only 2/11 in the low-risk group. We found a significant correlation between AR-V7 positivity and both risk classification (p < 0.001) and progression after surgery (p < 0.001). CONCLUSIONS: In our population of untreated nonmetastatic PC, AR-V7 is detectable by immunohistochemistry in more than 50% of cases. At this early stage, AR-V7 positivity is associated with risk classification and it can predict progression after surgery.

Outcomes of Salvage Radical Prostatectomy for M0 Castration-resistant Recurrent Prostate Cancer: A Reasonable Option in the Era of New Antiandrogen Therapies?

There is little evidence regarding salvage radical prostatectomy (sRP) for M0 castration-resistant prostate cancer (CRPC). We reviewed oncological results and complications for 23 men with radiographically recurrent M0 CRPC undergoing sRP at six institutions. Sixteen and ten men experienced at least one and one major (Clavien >2) complication, respectively. After sRP, nine men became incontinent, including two with severe incontinence. The majority of men had aggressive extraprostatic disease (≥pT3b 56.5%; pN1 30.4%; Gleason ≥8 65.2%). Postoperatively 69.6% reached undetectable prostate-specific antigen (PSA) without androgen deprivation therapy (ADT). Seven men had postoperative PSA persistence and six had CRPC persistence. Among the others, biochemical recurrence (BCR) occurred in 68.7% and CRPC in 58.8% at a median of 11 and 31 mo from sRP, respectively. At median follow-up of 4 yr, 17.4% were disease-free, 34.4% had died from PC, and 4.3% had died from other causes. sRP for M0 CRPC is feasible although the risk of complications is significant. A minority of patients can be cured and a significant proportion experience prolonged BCR- and CRPC-free status, thus delaying the need for systemic treatments. Further studies are needed to clarify the role of sRP for M0 CRPC in the era of new antiandrogen therapies. PATIENT SUMMARY: Salvage radical prostatectomy for radiorecurrent M0 castration-resistant prostate cancer (CRPC) is feasible, although continence outcomes are suboptimal and the risk of complications is significant. Survival is promising: some men can be cured and others experience a period without evidence of PC or CRPC. More research is needed to confirm our findings and demonstrate survival benefits.

Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells.

The androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating that they may play a role in development of Prostate Cancer (PCa) and CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. By using blast analysis of 826 GPCRs, we identified a GPCR, GPCR 205, which exhibited maximum similarity with the ligand binding domain of the AR. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all twenty-five prostate tumor patient's samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.

Pelvic exenteration surgery in patients with locally advanced castration-naïve and castration-resistant, symptomatic prostate cancer.

OBJECTIVES: To evaluate retrospectively the surgical, symptomatic and oncological outcomes of pelvic exenteration surgery (PES) in men with significant intrapelvic complications of locally advanced castration-sensitive (CSPC) and castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A total of 103 patients with locally advanced progressive and symptomatic CSPC or CRPC underwent PES (radical cystoprostatectomy, n = 71 [68.9%]; radical prostatectomy with continent vesicostomy, n = 9 [8.7%]; total exenteration, n = 23 [22.3%]). All patients underwent local staging via magnetic resonance imaging, cystoscopy and rectoscopy. Systemic staging was carried out with chest, abdominal and pelvic computed tomography scans and bone scans. Peri-operative complications were assessed according to Clavien-Dindo classification. Symptom-free and overall survival were evaluated using the Kaplan-Meier method. Statistical tests were two-tailed with a P value <0.05 taken to indicate statistical significance. RESULTS: After a median (range) follow-up of 36.5 (3-123) months, the symptom-free survival rate at 1 and 3 years was 89.2% (n = 89) and 64.1% (n = 66), respectively. The median symptom-free survival was 27.9 months. A total of 78.6% of the patients were symptom-free during their remaining lifetime. The overall survival rate at 1 and 3 years was 92.2% and 43.7%, respectively, and the median overall survival was 33.6 months. Clavien-Dindo grades 2, 3 and 4 complications developed in 31 (30.6%), 12 (11.6%) and eight patients (8.1%), respectively. CONCLUSION: Pelvic exenteration surgery is technically feasible in well-selected patients, resulting in symptom relief in >90% of patients, covering 80% of their remaining lifetime.

Primary Radical Prostatectomy or Ablative Radiotherapy as Protective Factors for Patients With mCRPC Treated With Radium-223 Dichloride: An Italian Multicenter Study.

BACKGROUND: We investigated, in a real-life setting, the prognostic relevance of previous primary treatment (radical prostatectomy [RP] or external beam radiotherapy [EBRT]) on overall survival for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (223Ra). MATERIALS AND METHODS: In the present multicenter retrospective study, we enrolled 275 consecutive patients. The demographic and clinical data and mCRPC characteristics were recorded and evaluated at baseline and at the end of treatment or progression. 223Ra was administered according to the current label authorization until disease progression or unacceptable toxicity. We divided the whole cohort into 2 groups: those who had undergone primary radical prostatectomy or ablative radiotherapy (RP/EBRT) and those who had not received previous primary treatment (NO). RESULTS: Of the 275 patients, 128 (46.5%) were alive and undergoing monitoring at the last follow-up examination, 103 (37.4%) had stopped treatment because of disease progression or the onset of comorbidities, and 147 (53.5%) had died during the study period. Of the 275 patients, 132 were in the RP/EBRT group (48%), of whom 93 had undergone RP and 76 had undergone ablative EBRT, and 143 patients were in the NO group (52%). The data showed a clear advantage for the patients in the RP/EBRT group compared with those in the NO group, with an estimated median survival of 18 versus 11 months, respectively (P < .001). The results from the multivariate analysis corroborated this trend, with a hazard ratio of 0.7 (P = .0443), confirming the better outcome for the RP/EBRT group. CONCLUSIONS: Previous radical treatment provides a protective role for patients with mCRPC undergoing 223Ra treatment.

HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

Importance: The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC). Objective: To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data. Design, Setting, and Participants: The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018. Interventions: Men were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone. Main Outcomes and Measures: Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype. Results: Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel. Conclusions and Relevance: Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

Castration-resistant prostate cancer without metastasis at presentation may achieve cancer-specific survival in patients who underwent prior radical prostatectomy.

PURPOSE: Radical prostatectomy (RP) is relatively better oncological outcomes in patients with prostate cancer (PCa). However, the incidence of castration-resistant PCa (CRPC) and PCa-specific mortality in patients with biochemical recurrence (BCR) after RP remains unclear. The aim of this study was to evaluate the cancer-specific survival (CSS) in patients with CRPC after RP, in particular those who had metastases or not. METHODS: We retrospectively reviewed the data of 1582 consecutive patients who underwent RP between July 1996 and January 2019. The enrolled patients had histologically confirmed stage T1a-T3b PCa without lymph node involvement or distant metastasis. The endpoints were oncological outcomes, including CSS and BCR, in patients with PCa with or without metastases at the time of diagnosis with CRPC. RESULTS: A total of 1474 patients were enrolled in this study. By the end of the follow-up period, 352 patients (24.6%) in the enrolled patients had BCR after RP. A total of 42 patients (2.9%) developed CRPC and 18 (1.3%) had died of PCa. With regard to metastasis in patients who diagnosed CRPC, the 5-year CSS rate was 100% for nonmetastatic CRPC (nmCRPC) patients and 53.8% for metastatic CRPC (mCRPC) patients after RP. The 5-year CSS rate was 100% for nmCRPC patients and 27.1% for mCRPC patients after the diagnosis with CRPC. CONCLUSIONS: CRPC is one of the lethal causes with PCa death. However, nmCRPC may achieve relatively good prognosis in patients with PCa after RP.

The role of salvage lymph node dissection in nonmetastatic castration-resistant prostate cancer: A single center experience.

OBJECTIVE: To evaluate oncologic outcomes of patients with nonmetastatic, castration-resistant prostate cancer treated with salvage lymph node dissection (sLND) or androgen-deprivation therapy (ADT) for lymph nodes (LN)-only recurrence. MATERIALS AND METHODS: Retrospective analysis of 23 (51.1%) patients who underwent sLND and 22 (48.9%) men who received ADT for LN-only recurrence. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) >0.2 ng/ml with an increased trend and radiological recurrence (RAR) was defined as a positive imaging study after sLND or ADT. Second line systemic therapies (SST) were defined as any systemic therapy administered for progression. Predictors of BCR, RAR, and SST were assessed with Cox regression analyses. RESULTS: Mean PSA reduction was significantly higher after sLND than ADT (62.8% vs. 17.7%; P = 0.04). Clinical outcomes were not statistically different between the 2 groups. However, there was a trend toward a longer time to BCR (13.3 vs. 6 months; P = 0.2) and RAR (21.1 vs. 14.2 months, P = 0.09) in sLND patients than ADT. Median time to SST was longer in the sLND group than ADT (P = 0.04). Univariable Cox regression analyses showed that PSA doubling time and pT stage were associated with RAR and SST (all P < 0.05). CONCLUSIONS: In patients with nonmetastatic, castration-resistant prostate cancer, sLND resulted in greater PSA decrease than ADT. We noted a nonstatistically significant trend toward longer time to BCR and longer time to RAR for patients treated with sLND than ADT. Additionally, sLND may increase time to SST as compared to ADT.

Impact of pre-treatment variables on the completion of 223radium-dichloride therapy in mCRPC patients with bone metastases.

INTRODUCTION: Radium-223 dichloride (223Ra) is an alpha-particle-emitter radiopharmaceutical, approved for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral involvement. Its administration is based on a schedule of intravenous injection (55kBq/kg) every four weeks for up to six cycles. Because the biological effectiveness of 223Ra-therapy is dose-dependent, the main goal is to complete the entire treatment to achieve a better patient outcome. This study aims to identify potential pre-treatment variables that could impact on 223Ra-treatment completion and then be used to improve the clinical and supportive management of mCRPC patients. MATERIALS AND METHODS: 30 consecutive mCRPC patients (mean age 77 years old), who were admitted for Ra223-therapy at our Department from February 2016 to October 2018, were enrolled for the analysis. The population was grouped as patients who completed 223Ra-therapy (group Ra223-C) and patients who do not (group 223Ra-U). For each group, we analyzed the effects of potential pre-treatment variables (age, Gleason Score, tumor burden, "Time From Diagnosis To 223Ra therapy", type and number of previous treatments, hemoglobin level, Alkaline Phosphatase, Prostate Specific Antigen and pain) on the Ra223-therapy completion. Statistical analysis was performed to evaluate the association between the completion of 223Ra therapy and the variables examined. RESULTS: 16/30 (53%) patients were 223Ra-C, conversely 14/30 (47%) patients were 223Ra-U because of an early interrupted treatment. A statistically significant association was found only with tumor burden: 68.7% of patients who completed 223-therapy had less than 20 bone metastases (χ2=4.821, p=0.028). CONCLUSION: Our preliminary analysis demonstrates that the high tumor burden represents the most important pre-treatment factor that could affect treatment completion and that needs to be considered before starting 223Ra-therapy to achieve a better outcome in mCRPC patients.

Class III ß-tubulin expression as a predictor of docetaxel-resistance in metastatic castration-resistant prostate cancer.

About half of the patients treated with docetaxel in the setting of metastatic castration-resistant prostate cancer (CRPC) are non-responders. Therefore, a marker of response would be beneficial for clinical decision-making. We evaluated class III ß-tubulin (ßIII-tubulin) expression as a predictor of resistance in this setting, which previously has been correlated with lack of response to taxanes in other cancers. Patients with CRPC were included if they were treated with at least 3 cycles of docetaxel between 1990 and 2011. ßIII-tubulin expression was assessed by immunostaining, which was performed in tissue samples obtained either via biopsy or prostatectomy at the time of diagnosis. Rates of prostate-specific antigen (PSA) response and overall survival (OS) following docetaxel treatment were compared between patients with high (2+ or 3+ staining) vs. low (0 or 1+ staining) ßIII-tubulin expression. Of 73 patients, 26 (35%) had a high expression of ßIII-tubulin. A PSA decline of 10% or greater occurred in 65% of patients with a high ßIII-tubulin expression vs. 89% with a low ßIII-tubulin expression (p = 0.0267). The median OS for patients with a high ßIII-tubulin expression was 17.4 (95% CI 8.7-21.0) months vs. 19.8 (95% CI 16.6-23.6) months for patients with a low expression (p = 0.039). Our results show that a high ßIII-tubulin expression is a negative prognostic factor in metastatic CRPC patients treated with docetaxel.

Fibroblast as a critical stromal cell type determining prognosis in prostate cancer.

BACKGROUND: Tumor stroma associates with prostate cancer (PCa) progression, but its specific cellular composition and association to patient survival outcome have not been characterized. METHODS: We analyzed stromal composition in human PCa using multiplex immunohistochemistry and quantitative, high-resolution image analysis in two retrospective, formalin-fixed paraffin embedded observational clinical cohorts (Cohort I, n = 117; Cohort II, n = 340) using PCa-specific mortality as outcome measurement. RESULTS: A high proportion of fibroblasts associated with aggressive disease and castration-resistant prostate cancer (CRPC). In a multivariate analysis, increase in fibroblast proportion predicted poor cancer-specific outcome independently in the two clinical cohorts studied. CONCLUSIONS: Fibroblasts were the most important cell type in determining prognosis in PCa and associated with CRPC. Thus, the stromal composition could be critically important in developing diagnostic and therapeutic approaches to aggressive prostate cancer.

Upregulation of Scavenger Receptor B1 Is Required for Steroidogenic and Nonsteroidogenic Cholesterol Metabolism in Prostate Cancer.

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary prostate cancer. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in prostate cancer relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small-molecule SR-B1 antagonist block lipid transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and nonsteroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC. SIGNIFICANCE: These findings highlight SR-B1 as a potential target in primary and castration-resistant prostate cancer that is essential for cholesterol uptake needed to drive steroidogenic and nonsteroidogenic biogenic pathways.