Localized Adenocarcinoma Of Prostate Research Articles

Abstract 1947: Rovalpituzumab tesirine as a therapeutic agent for neuroendocrine prostate cancer

Abstract Background: Delta-like protein 3 (DLL3) is expressed on the surface of small cell lung cancer (SCLC) tumor-initiating cells, and the DLL3 targeted antibody-drug conjugate, Rovalpituzumab tesirine (Rova-T™; SC16LD6.5), has shown promise for patients with SCLC. Neuroendocrine prostate cancer (NEPC) is an emerging late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rovalpituzumab tesirine in NEPC xenografts. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 361 patients (552 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and castration resistant NEPC and correlated with pathologic and genomic features. mRNA was assessed by RNAseq. Protein was assessed by immunohistochemistry (DLL3 SP347 antibody). Prostate cancer cell lines were engrafted in mice and treated with SC16LD6.5 in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/132 Benign (0%), 1/254 (0.4%) PCA, 10/90 (11.1%) CRPC and 47/76 (61.8%) NEPC samples. DLL3 IHC was of higher intensity in NEPC and co-localized with classical neuroendocrine (NE) markers. DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p=<0.0001, fold change=71), and positively correlated with ASCL1 expression (r= 0.88) and RB1 genomic loss (83%), and inversely with AR expression. siRNA knockdown of DLL3 did not alter AR signaling or NE score. In vivo treatment of the NEPC, NCI-H660, xenografts with vehicle, IgG1LD6.5, or SC16LD6.5 (0.3mg/Kg, intraperitoneal single dose) showed complete responses to SC16LD6.5 with no recurring tumors after 100 days; while the tumor developed from the CRPC line, DU145, which do not express DLL3, continued growing despite the treatment and were sacrified when tumors reached the maximum size allowed by our IACUC protocol. Conclusions: DLL3 is expressed on the surface of the majority of NEPC cases evaluated and is not expressed in primary prostate cancer or benign tissues. Modulation of DLL3 expression does not appear to affect AR or NEPC signaling in cell lines. SC16LD6.5 (Rova-T) demonstrates preferential preclinical activity in NEPC that express DLL3 compared to CRPC-adenocarcinoma that are DLL3 negative, in vivo. A Phase 1 Basket trial investigating Rova-T is now open with a dedicated NEPC arm (NCT02709889). Citation Format: Loredana Puca, Verena Sailor, Katie Gavyert, Etienne Dardenne, Kumiko Isse, Michael Sigouros, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran. Rovalpituzumab tesirine as a therapeutic agent for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1947.

PO-520 Comprehensive molecular classification of localised prostate adenocarcinoma reveals a tumour subtype predictive of a non-aggressive disease

IntroductionManagement of localised prostate cancer is a major clinical challenge since most of these cancers won’t evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that prostate cancer can be classified according to their genomic alterations but none of the published prostate cancer molecular classifications could identify a subtype corresponding to non-evolutive tumours.Material and methodsMulti-omics molecular profiling was performed on post-radical prostatectomy material from a cohort of 130 patients with localised PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas (TCGA) cohort were used to characterise the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned.Results and discussionsWe describe three prostate cancer molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 726 samples from five distinct cohorts (p=9.45 × 10-9, n=726 tumour samples), and showed that our subtyping approach outperforms the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 39 transcriptomic biomarkers which robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localised prostate cancer tumours.ConclusionAt least 20% of patients with localised prostate cancer can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo invasive surgery and rather be placed under active surveillance.

Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results From a Multi-institutional Consortium Study

Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n=38) between 2000 and 2013.Propensity scores were included ascovariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. The median follow-up period was 4.9years overall (3.9years for RP, 4.8years for EBRT, and 5.7years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P<.01 by χ2 test), though the durations were similar (median, 24months vs 22.5months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048). To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5years after treatment.

DNA Damage Response in Prostate Cancer.

Prostatic adenocarcinoma (PCa) remains a significant health concern. Although localized PCa can be effectively treated, disseminated disease remains uniformly fatal. PCa is reliant on androgen receptor (AR); as such, first-line therapy for metastatic PCa entails suppression of AR signaling. Although initially effective, recurrent tumors reactivate AR function, leading to a lethal stage of disease termed castration-resistant PCa (CRPC). Recent findings implicate AR signaling in control of DNA repair and show that alterations in DNA damage repair pathways are strongly associated with disease progression and poor outcome. This review will address the DNA repair alterations observed in the clinical setting, explore the anticipated molecular and cellular consequence of DNA repair dysfunction, and consider clinical strategies for targeting tumors with altered DNA repair.

Transcriptomic heterogeneity of androgen receptor activity in primary prostate cancer: Identification and characterization of a low AR-active subclass.

2 Background: Significant genomic diversity exists in the androgen receptor ( AR) and its activity (AR-A) in mCRPC. In localized prostate cancer, the biologic, prognostic, and therapeutic clinical implications of AR-A heterogeneity have yet to be interrogated Methods: Genome-wide expression profiles of FFPE RP or biopsy tumor samples were evaluated from a prospective registry cohort (n = 5,239, NCT02609269) and six retrospective institutional cohorts (n = 1,170). AR-A was calculated based on expression of 9 targets of AR.. Results: Utilizing 6,409 localized prostate adenocarcinomas with full transcriptomic data, we found there was marked inter-individual transcriptomic diversity in AR and AR-A expression, and weak correlation between them (r = 0.08 to 0.36 based on cohort), in contrast to mCRPC that has a strong correlation between AR and AR-A expression (r = 0.76). Additionally, serum PSA had no correlation to intratumoral AR-A (r = 0.06). Unsupervised hierarchical clustering identified a distinct subclass of low AR-A prostate tumors, which had increased markers of immunogenicity (decreased T-regs and MDSCs, and increased CD3 effector T-cells), increased neuroendocrine marker expression ( NCAM1, ENO2, and SCG2), and decreased DNA repair pathway expression (all p &lt; 0.001). Clinically, low AR-A tumors had more rapid development of metastatic disease in three independent cohorts, were more prone to develop resistance to hormonal therapy and develop CRPC, and were found at an increased frequency in African-American men. Interrogating in vitro drug sensitivity analyses utilizing the NCI-60 panel, low AR-A tumors appear more sensitive to platinum chemotherapy and PARP inhibition, and less sensitive to hormone therapy and taxanes. Conclusions: The diversity in AR-signaling in localized prostate cancer represents important biological heterogeneity that is both prognostic and predictive of treatment response. These findings are provocative in that low AR-A tumors may be more susceptible to immunotherapy, PARP inhibition, platinum chemotherapy, and/or radiotherapy. Patients with low AR-A tumors warrant dedicated biomarker enhanced clinical trials.

Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of &lt; 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p &lt; 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.

Novel Clinical Tools to Guide Management of Prostate Cancer: Preoperative Predictive Models to Identify Patients at Risk for Needing Adjuvant Radiation (T3 or +margin) or Having Detectable Postoperative PSA

Several valuable models use preoperative data to predict organ- confined disease at the time of radical prostatectomy. However, there are no similar tools to predict which patients will qualify for adjuvant radiation therapy (ART), or have a detectable postoperative prostate specific antigen (PSA). We developed logistic regression models to predict risk for extracapsular extension (ECE) and seminal vesicle invasion (SVI) and compared them to others (Roach, CAPRA, Memorial Sloan Kettering, and Partin models). We then created two novel formulas to predict risk for ART (either T3 or +margin) or detectable postoperative PSA. We conducted a retrospective multi-institutional review of patients with clinically localized prostate adenocarcinoma who had radical prostatectomy from 2001-2015 (N=1,676) at Kaiser Permanente in Southern California. Patients treated with preoperative leuprolide or missing data were excluded. Three multivariate models were developed to predict ECE, SVI, and either ECE or SVI. A fourth model was developed to predict ECE/SVI/+margin. A fifth model was developed to predict detectable postoperative PSA (≥0.1). The area under the receiver curve (AUC) was calculated and corrected using bootstrap resampling with 2000 samples. Statistical analysis was performed with R version 3.3.1. Statistically significant factors on multivariate analysis included percent positive biopsy cores, biopsy Gleason score, PSA, and clinical T-stage. Age and year of surgery were not statistically significant. The ECE, SVI, and ECE/SVI models (AUC 0.69-0.81) performed favorably compared to other tools (AUC 0.72-0.79) [Table 1]. Our T3/+margin model performs at corrected AUC 0.75. Our detectable postoperative PSA model performs at corrected AUC 0.81 [Table 1]. We developed three models predicting risk of extraprostatic disease, which compared favorably over other widely used models. We created two novel clinical formulas to predict preoperatively whether patients may require ART or have a detectable postoperative PSA. These tools may help guide the selection of surgery or radiation upfront, and could potentially reduce dual modality treatment. While our novel clinical prediction models performed well in our data set, no known tools exist for comparison, and external validation is needed.Abstract 2630; Table 1RoachCAPRAMSKPartinKaiserECE (25% risk) AUC0.740.740.760.720.69 Sen/Spec1.00/00.63/0.701.00/00.87/0.460.37/0.91 PPV/NPV0.22/ NA0.39/0.860.22/0.830.31/0.920.54/0.84SVI (25% risk) AUC0.760.780.790.760.81 Sen/Spec0.47/0.850.22/0.960.28/0.960.03/0.990.39/0.94 PPV/NPV0.27/0.930.39/0.910.47/0.920.40/0.900.42/0.93ECE/SVI (40% risk) AUC---0.760.79 Sen/Spec---0.64/0.720.52/0.86 PPV/NPV---0.48/0.830.61/0.82ECE, SVI, or +margin (20% risk) AUC----0.75 Sen/Spec----0.91/0.35 PPV/NPV----0.44/0.87Detectable 1st Postop PSA (20% risk) AUC----0.81 Sen/Spec----0.36/0.95 PPV/NPV----0.34/0.96 Open table in a new tab

Supplemental IMRT May Increase the Risk of Rectal Bleeding in Prostate Cancer Patients Treated with Stereotactic Body Radiation Therapy (SBRT)

Late rectal bleeding remains an ongoing clinical challenge for patients treated with external beam radiotherapy for prostate cancer. The goal of this study was to identify patient- or treatment-related characteristics associated with an increased risk of late rectal bleeding following SBRT. From May 2007 to August 2014, patients with clinically localized prostate adenocarcinoma were treated with robotic SBRT in 5 fractions (36.25 Gy) or a boost of 3 fractions (19.5 Gy) followed by fiducial-guided Intensity Modulated Radiotherapy (IMRT) to 45-50.4 Gy on an institutional protocol. Patient and treatment characteristics were recorded for patients with at least 2 years of follow-up. Toxicity was prospectively graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4) at the start of and at 1-6 month intervals after therapy. Grade 2 rectal bleeding was defined as bleeding which required a new medication (i.e. steroid suppository) or up to 2 argon plasma coagulations (APCs). Grade 3 bleeding required > 2 APC procedures, a blood transfusion, or use of hyperbaric oxygen. Supplemental IMRT was selected a priori as a classifier for the toxicity. Chi-squared test was conducted to evaluate categorical data including occurrence of late ≥ grade 2 rectal bleeding in SBRT monotherapy and SBRT boost cohorts. Mann-Whitney U test was used to compare nonparametric continuous variables. We devised a standard binary logistic regression model to predict late ≥ grade 2 rectal bleeding controlling for age, Charlson Comorbidity Index (CCI), anticoagulant and/or antiplatelet use (AC), and supplemental IMRT. An ROC was constructed. 620 patients with a median age of 69 (range 42-94) were treated with SBRT. 459 (74%) received SBRT alone, and 161 (26%) received SBRT plus IMRT. At the start of therapy, 299 patients (48.2%) were on AC (4.8%, 42%, and 1.5% on anticoagulants, antiplatelets, or both, respectively), and 191 patients (30.8%) received Androgen Deprivation Therapy. The cumulative incidence of late ≥ grade 2 rectal bleeding was 2.6%, 2.0% for patients treated with SBRT alone and 4.3% for patients treated with SBRT plus IMRT (P<0.05). Controlling for age and AC use, receiving supplemental IMRT after SBRT predicted for more bleeding events (P=0.015; OR=5.94, 95% CI 1.41-25.01). CCI was itself a significant predictor (P=0.045; OR=1.40, 95% CI 1.01-1.94). The AUC of the ROC constructed from the model’s predicted values was 0.785. Utilization of supplemental IMRT may be associated with an increased risk of late ≥ grade 2 rectal bleeding following SBRT. Further studies should examine whether supplemental IMRT benefits select patient groups and whether interventions such as the use of rectal spacers may reduce this bleeding risk.

Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results from a Multi-institutional Consortium Study

Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis for patients presenting with GS10 PCa are largely unknown due to its rarity. We interrogated a large, multi-institutional consortium of patients with biopsy GS 9-10 disease to identify those with GS 10 PCa and obtain benchmark clinical outcomes data for patients treated with definitive intent. Ninety-eight patients with biopsy GS 10 PCa who received definitive treatment with radical prostatectomy (RP, n = 22), external beam radiotherapy (EBRT, n = 38), and EBRT with a brachytherapy boost (EBRT+BT, n = 38) between 2000 and 2013 were included. Overall survival (OS), cancer-specific survival (CSS), distant metastasis-free survival (DMFS), and biochemical recurrence-free survival (bRFS) were estimated with the Kaplan-Meier method. The median follow-up was 4.9 years. The median age was 67. The T stage distribution was 32 (33%) T1c, 14 (14%) T2a, 13 (13%) T2b, 6 (6%) T2c, 18 (18%) T3a, 5 (5%) T3b, 10 (10%) T4. The median initial prostate-specific antigen was 7.9 (range, 0.4-219). Six patients (27%) who underwent RP received neoadjuvant systemic therapy (mainly androgen deprivation therapy [ADT]), 5% received adjuvant radiotherapy, and 32% received salvage radiotherapy. All patients undergoing EBRT or EBRT+BT received ADT, with median durations of 24 and 22 months, respectively. Systemic salvage therapy rates were 23% among RP patients, 13% among EBRT patients, and 3% among EBRT+BT patients. For the entire cohort, the 5-year and 10-year OS, CSS, DMFS, and bRFS were 77% and 53%, 86% and 69%, 74% and 66%, and 77% and 52%, respectively. Outcomes stratified by treatment type are presented in Table 1. To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Biopsy GS 10 PCas follow a very aggressive natural history with nearly 30% of patients dying of this disease at 10 years. Nonetheless, aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease five years following treatment.Abstract 285; Table 1Outcomes stratified by treatment typeOS (5, 10-yr)CSS (5, 10-yr)DMFS (5, 10-yr)bRFS (5, 10-yr)RP78%, 52%83%, 55%62%, 62%60%, 40%EBRT74%, 54%79%, 70%70%, 55%74%, 48%EBRT-BT80%, 52%93%, 70%84%, 77%88%, 65% Open table in a new tab

Bladder Neck Contracture Following Radical Retropubic versus Robotic-Assisted Laparoscopic Prostatectomy

Introduction: Radical retropubic prostatectomy (RRP) and robotic-assisted laparoscopic prostatectomy (RALP) are co-standard surgical therapies for localized prostatic adenocarcinoma. These surgical modalities offer similar outcomes; however, lower rate of bladder neck contracture (BNC) is amongst the touted benefits of RALP. The differences between approaches are largely elucidated through multiple-surgeon comparisons, which can be biased by differential experience and practice patterns. We aimed to eliminate inter-surgeon bias through this single-surgeon comparison of BNC rates following RRP and RALP. Materials and Methods: We retrospectively reviewed all RRPs and RALPs performed by one surgeon over 4 years. We compared clinical characteristics, intraoperative and postoperative outcomes. Results: RRP patients had more advanced cancer and a higher biochemical recurrence rate. No significant differences were noted between groups in rates of anastomotic leakage, BNC, or 12-month postoperative pad-free continence. Conclusion: RRP offers similar outcomes to RALP with regard to postoperative urinary extravasation, urinary continence, and BNC.

Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC).

5029 Background: TheNotch ligand Delta like ligand 3 (DLL3) is aberrantly expressed on the cell surface of small cell lung cancer (SCLC), and the DLL3-antibody drug conjugate, Rova-T, has shown promise for patients with SCLC (Rudin et al, Lancet Onc 2017). NEPC is a late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rova-T in NEPC. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 395 patients (535 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and NEPC and correlated with pathologic and genomic features. Prostate cancer cell lines and patient-derived organoids were treated with Rova-T (SC16LD6.5) in vitro and in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/143 BEN (0%), 4/266 PCA (1%), 8/76 CRPC (10%), 33/50 NEPC (66%). DLL3 IHC was of higher intensity in NEPC and co-localized with classical NE marker expression (SYP, CGA). DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p = &lt; 0.0001, fold change = 71), correlated with ASCL1 expression (r = 0.88) and RB1 genomic loss (83%), and inversely with AR expression. Although treatment with the Notch inhibitor DAPT suppressed Notch target gene expression in NEPC, DAPT did not have significant effect on cellular proliferation. siRNA knockdown of DLL3 or DAPT did not alter AR signaling or NE markers. Rova-T (SC16LD6.5) was active in DLL3-positive NEPC cell lines with an IC50 of 580pM compared to the control IgG1LD6.5 (IC50 = 6.3nM), whereas CRPC lines were insensitive. Conclusions: DLL3 is a cell surface protein aberrantly expressed in the majority of NEPC and a subset of CRPC, and is not expressed in primary prostate cancer or benign tissues. The DLL3 antibody-drug conjugate Rova-T demonstrates preferential preclinical activity in NEPC compared to prostate adenocarcinoma. These data support further investigation of Rova-T as a potential therapeutic agent for NEPC. A phase I trial with dedicated NEPC arm is currently accruing patients (NCT02709889).

Ureteral Mass in a Patient with Localized Prostate Adenocarcinoma, A Rare Metastatic Location

Ureteral Mass in a Patient with Localized Prostate Adenocarcinoma, A Rare Metastatic Location

Dishevelled segment polarity protein 3 (DVL3): a novel and easily applicable recurrence predictor in localised prostate adenocarcinoma.

To identify new biomarkers for biochemical recurrence (BCR) of prostate adenocarcinoma. Clinical information of 500 patients with prostate adenocarcinoma and their 152 RNA-sequencing and protein-array data from The Cancer Genome Atlas (TCGA) were separated into a discovery set and a validation set. Each dataset was analysed according to the Gleason grade groups reflecting BCR. The results obtained from the analysis using TCGA dataset were confirmed by immunohistochemistry analyses of a confirmation cohort composed of 395 patients with localised prostate adenocarcinoma. TCGA discovery set was subgrouped into lower- and higher-risk groups for recurrence-free survival (RFS) (P < 0.001). Cyclin B1 (CCNB1), dishevelled segment polarity protein 3 (DVL3), paxillin (PXN), RAF1, transferrin, X-ray repair cross complementing 5 (XRCC5) and BIM had lower expression in the lower-risk group than that in the higher-risk group (all, P < 0.05). In TCGA validation set, CCNB1, DVL3, transferrin, XRCC5 and BIM were also differently expressed between the two groups. Immunohistochemically, DVL3 positivity was associated with high prostate-specific antigen (PSA) levels, resection margin involvement, and BCR (all, P < 0.05). Ahigh Gleason score indicated a marginal relationship (P = 0.055). BIM positivity was related to high PSA levels, lymphovascular invasion, and BCR (all, P < 0.05). Both DVL3 positivity (P = 0.010) and BIM positivity (P = 0.024) were associated with shorter RFS, but statistical significance was lost when the multivariate Cox regression model included all patients. In the lower-risk group, the multivariate Cox model confirmed that DVL3 was an independent predictor for poor RFS (hazard ratio 1.80, P = 0.040), and the concordance index (C-index) was 0.805. DVL3 and BIM were expressed in patients with a higher risk of BCR. DVL3 may be a novel and easily applicable recurrence predictor of localised prostate adenocarcinoma.

Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Update of the Long-Term Survival Results of the GETUG-01 Randomized Study

To report the long-term results of the French Genitourinary Study Group (GETUG)-01 study in terms of event-free survival (EFS) and overall survival (OS) and assess the potential interaction between hormonotherapy and pelvic nodes irradiation. Between December 1998 and June 2004, 446 patients with T1b-T3, N0pNx, M0 prostate carcinoma were randomly assigned to either pelvic nodes and prostate or prostate-only radiation therapy. Patients were stratified into 2 groups: "low risk" (T1-T2 and Gleason score 6 and prostate-specific antigen <3× the upper normal limit of the laboratory) (92 patients) versus "high risk" (T3 or Gleason score >6 or prostate-specific antigen >3× the upper normal limit of the laboratory). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for high-risk patients. Radiation therapy was delivered with a 3-dimensional conformal technique, using a 4-field technique for the pelvic volume (46Gy). The total dose recommended to the prostate moved from 66Gy to 70Gy during the course of the study. Criteria for EFS included biologic prostate-specific antigen recurrences and/or a local or metastatic progression. With a median follow-up of 11.4years, the 10-year OS and EFS were similar in the 2 treatment arms. A higher but nonsignificant EFS was observed in the low-risk subgroup in favor of pelvic nodes radiation therapy (77.2% vs 62.5%; P=.18). A post hoc subgroup analysis showed a significant benefit of pelvic irradiation when the risk of lymph node involvement was <15% (Roach formula). This benefit seemed to be limited to patients who did not receive hormonal therapy. Pelvic nodes irradiation did not statistically improve EFS or OS in the whole population but may be beneficial in selected low- and intermediate-risk prostate cancer patients treated with exclusive radiation therapy.

Erratum to: Clinical characteristics and outcomes of HIV-seropositive men treated with surgery for prostate cancer.

The natural history and optimal management strategy for men with human immunodeficiency virus (HIV) and prostate cancer remain to be definitively characterized. This study was conducted to evaluate the clinical characteristics and outcomes of HIV-seropositive men treated with robotic-assisted radical laparoscopic prostatectomy for localized prostate cancer. After Institutional Review Board approval, a prospective database of 2175 operative cases of clinically localized prostate adenocarcinoma was reviewed. Thirteen patients were identified as HIV-positive. Tumor characteristics, operative outcomes, postoperative outcomes, histology (Gleason score), local invasion, biochemical recurrence, and surgical complications were compared with HIV-negative patients. There were no preoperative demographic differences between the HIV-positive and HIV-negative patients. HIV-positive patients had higher prostate specific antigen (PSA) levels at time of diagnosis which was not statistically significant. However, HIV-positive patients had higher D’Amico risk assessment (p < 0.05). There was no postoperative complication. HIV-positive patients treated with robotic prostatectomy had similarly favorable perioperative and short-term biochemical recurrence-free survival outcomes. Our findings show that minimally invasive prostatectomy can be safely considered as a therapeutic option in otherwise eligible HIV-positive patients with clinically significant prostate cancer. Further research is necessary to outline a diagnostic and treatment guideline for HIV-positive men in detection and treatment of prostate cancer.

Impact of androgen-deprivation therapy on the outcome of dose-escalation prostate cancer radiotherapy without elective pelvic irradiation.

The benefit of androgen-deprivation therapy (ADT) in combination with dose-escalated radiotherapy (DERT) for localized prostate cancer has not been determined in randomized studies. In this study, the benefit of ADT was assessed in patients uniformly treated with dose-escalated intensity-modulated radiation therapy (IMRT) to the prostate and seminal vesicles but not pelvis. In all, 419 patients with localized prostate adenocarcinoma underwent definitive IMRT (cumulative dose 78 Gy), with 32.6%, 33.1%, 32.1%, and 2.1% having T1 through T4 disease, respectively, and 51.2% having high-risk disease. ADT was given to 76.1% of patients. With a median follow-up of 60 months, 5-year biochemical failure-free, disease-free, and overall survival rates were 87%, 86%, and 87%, respectively. T stage was an independent predictor of all three rates. Five-year pelvic nodal recurrence rate was 2.9%. ADT improved biochemical failure-free and disease-free survival but not overall survival. ADT showed benefit in high-risk disease but not intermediate-risk disease. Late gastrointestinal and genitourinary toxicities ≥ grade 2 occurred in 11.0% and 6.7%, respectively. In conclusion, DERT with 78 Gy yields good disease control and low rate of pelvic nodal recurrence. ADT improves disease-free survival in patients with high-risk but not intermediate-risk disease.

Extended pelvic lymphadenectomy in patients with clinically localized prostate cancer: A prospective observational study

ObjectiveTo determine the frequency of lymph node involvement in patients with clinically localized prostate adenocarcinoma who had radical prostatectomy and extended pelvic lymphadenectomy. Material and methodsA prospective observational study was conducted on 137 patients with clinically localized prostate cancer of low, intermediate or high risk according to the D’Amico classification. All participants underwent radical prostatectomy plus extended pelvic lymphadenectomy in 3 reference centers in Bogota, Colombia, between 2013 and 2014. The following variables were assessed: age, prostate specific antigen levels, Gleason score of the biopsy, probability of lymph node involvement calculated with Partin tables and the histopathology result of the surgical specimen, with the definitive Gleason pattern and the total number of resected and involved lymph nodes per tumor, according to the territory of the dissection. ResultsA total of 2876 lymph nodes were extracted (an average of 20.99 lymph nodes per patient). There was lymph node involvement in 14 (10.22%) patients. The high-risk and intermediate-risk group presented lymph node metastases in 28.57% and 5.25%, respectively. There was no lymph node involvement in the low-risk group. Of the patients at risk of lymph node involvement (≥2% according to the Partin tables), 19.40% had lymph node metastases. ConclusionLymph node involvement in our population is similar to that reported in the worldwide literature. Extended pelvic lymphadenectomy increased the probability of detecting lymph node metastases in our community.

Haralick textural features on T2 -weighted MRI are associated with biochemical recurrence following radiotherapy for peripheral zone prostate cancer.

To explore the association between magnetic resonance imaging (MRI), including Haralick textural features, and biochemical recurrence following prostate cancer radiotherapy. In all, 74 patients with peripheral zone localized prostate adenocarcinoma underwent pretreatment 3.0T MRI before external beam radiotherapy. Median follow-up of 47 months revealed 11 patients with biochemical recurrence. Prostate tumors were segmented on T2 -weighted sequences (T2 -w) and contours were propagated onto the coregistered apparent diffusion coefficient (ADC) images. We extracted 140 image features from normalized T2 -w and ADC images corresponding to first-order (n = 6), gradient-based (n = 4), and second-order Haralick textural features (n = 130). Four geometrical features (tumor diameter, perimeter, area, and volume) were also computed. Correlations between Gleason score and MRI features were assessed. Cox regression analysis and random survival forests (RSF) were performed to assess the association between MRI features and biochemical recurrence. Three T2 -w and one ADC Haralick textural features were significantly correlated with Gleason score (P < 0.05). Twenty-eight T2 -w Haralick features and all four geometrical features were significantly associated with biochemical recurrence (P < 0.05). The most relevant features were Haralick features T2 -w contrast, T2 -w difference variance, ADC median, along with tumor volume and tumor area (C-index from 0.76 to 0.82; P < 0.05). By combining these most powerful features in an RSF model, the obtained C-index was 0.90. T2 -w Haralick features appear to be strongly associated with biochemical recurrence following prostate cancer radiotherapy. 3 J. Magn. Reson. Imaging 2017;45:103-117.

Clinical characteristics and outcomes of HIV-seropositive men treated with surgery for prostate cancer

The natural history and optimal management strategy for men with human immunodeficiency virus (HIV) and prostate cancer remain to be definitively characterized. This study was conducted to evaluate the clinical characteristics and outcomes of HIV-seropositive men treated with robotic-assisted radical laparoscopic prostatectomy for localized prostate cancer. After Institutional Review Board approval, a prospective database of 2175 operative cases of clinically localized prostate adenocarcinoma was reviewed. Thirteen patients were identified as HIV-positive. Tumor characteristics, operative outcomes, postoperative outcomes, histology (Gleason score), local invasion, biochemical recurrence, and surgical complications were compared with HIV-negative patients. There were no preoperative demographic differences between the HIV-positive and HIV-negative patients. HIV-positive patients had higher prostate specific antigen (PSA) levels at time of diagnosis which was not statistically significant. However, HIV-positive patients had higher D'Amico risk assessment (p<0.05). There was no postoperative complication. HIV-positive patients treated with robotic prostatectomy had similarly favorable perioperative and short-term biochemical recurrence-free survival outcomes. Our findings show that minimally invasive prostatectomy can be safely considered as a therapeutic option in otherwise eligible HIV-positive patients with clinically significant prostate cancer. Further research is necessary to outline a diagnostic and treatment guideline for HIV-positive men in detection and treatment of prostate cancer.

PO-43 - Differential coagulation factor expression in neuroendocrine prostate cancer (PC), metastatic castrate-resistant PC, and localized prostatic adenocarcinoma

Neuroendocrine prostate cancer (NEPC) is an aggressive late-stage variant of PC that is often androgen-receptor negative. Most clinicians believe the VTE rate with NEPC is higher than with standard metastatic castration-resistant PC (mCRPC), but NEPC tends to present with bulkier visceral disease and include platinum chemotherapy unlike standard PC. In many solid tumors, a more aggressive phenotype correlates with increased VTE risk and elevated expression of coagulation factors. We previously reported on the differential expression of thrombin and tissue factor (TF) in NEPC versus localized PC and benign prostate tissue with a small NEPC cohort (N=7), which showed overexpression of prothrombin and reduced expression of TF in NEPC. To compare the expression of coagulation factors of NEPC vs mCRPC (and localized PC control) in an expanded datase. Fresh frozen tissue biopsies were collected and separated into three cohorts based on pathology: localized PC (N=68), standard mCRPC (N=32), and NEPC (N=21). RNA was isolated and next generation paired-end mRNA sequencing was performed on Illumina Sequencers. F2 Prothrombin (F2), tissue factor (F3), carboxypeptidase (CPB2), fibrinogen (FGG, FGA), PAR-1 (F2R), and PAR-2 (F2RL1) were compared by Wilcoxon tests. Prothrombin had significantly higher expression in NEPC versus standard mCRPC (p <0.001). NEPC trended towards higher expression of CPB2 (p=0.1) and lower expression of F3 (p=0.23) and F2RL1 (p=0.14) compared to mCRPC. Compared to localized PC, both types of advanced disease (NEPC and mCRPC) overexpressed F2, FGA, FGB, and CPB2 (p<0.001) and had decreased expression of F3 and F2RL1 (p <0.001). Prothrombin is reliably overexpressed in NEPC vs mCRPC and localized PC. Advanced disease (regardless of subtype) is associated with significantly higher expression of prothrombin, fibrinogen, and carboxypeptidase and lower expression of TF and PAR-2. It is possible that there may be PC-specific differences with aggressive disease associated with the thrombin axis vs the more common TF/PAR2 axis commonly seen in other advanced solid tumors. Further research is required to understand these differences in biology and resulting thrombotic and hemostatic outcomes.