bluuebunny/crossref_metadata_2025 huggingface dataset:
A quantitative image analysis model of prostate biopsies for predicting clinical risk in men enrolled in an active surveillance program.
Authors: Khan Faisal M , Fernandez Gerardo , Scott Richard , Lance Raymond S. , Cordon-Cardo Carlos , Klotz Laurence , Donovan Michael J.
Published: February 2017

111

Background: Quantitative image analysis of the prostate needle biopsy (PNB) has proven to be a robust and predictive platform for prostate cancer (PCa) prognosis. We sought to determine the performance of quantitative metrics in identifying which patients enrolled in an active surveillance (AS) program are most likely to present with significant clinical risk, including subsequent biopsy Gleason grade (GG) upgrading and/or a short (less than 24 month) prostate-specific antigen (PSA) doubling time (PSADT). Methods: One hundred sixty two AS patients (median age 70, 94% cT1-T2a, 85% <=GS6, median PSA 5.9 ng/mL) with overall 8 year median follow up and available diagnostic PNB specimens were analyzed. Computerized image analysis derived quantitative biometric features representing PCa morphology and immunofluorescent (IF) biomarkers from the PNB. Multivariate models predicting either GG upgrading on a subsequent PNB or a PSADT less than 24 months were evaluated. The AUC/concordance index (CI), sensitivity, specificity and hazard ratio (HR) were used to assess performance. Results: Univariate distribution of selective features, notably expression levels of AR and Ki67, were reflective of a low risk cohort.A multivariate model with three quantitative imaging metrics was trained with a CI of 0.77. Men at high risk within 24 months of the PNB were identified with 80% sensitivity and 73% specificity, HR of 5.7. The most important feature measured the relative proportion of tumor epithelial nuclei that were both Androgen Receptor and alpha-methylacyl-CoA racemase positive. The other two features were morphological assessments of epithelial cellular area compared to luminal area. Of note, clinical features such as age, GG and PSA were not selected in competition with the imaging metrics. Conclusions: Quantitative image analysis of morphology and IF biomarker expression in the PNB outperformed standard clinical features in a multivariate model to accurately predict which AS patients are at risk for Gleason upgrading and/or a shortened PSADT. Identifying such patients may prove beneficial in the primary treatment decision process.
Predictive factors associated with Gleason score underestimation on prostate biopsy in a monocentric cohort of 3,062 patients treated by mini-invasive radical prostatectomy.
Authors: Audenet Francois , Rozet Francois , Resche-Rigon Matthieu , Bernard Rémy , Lizee Daphne , Lacarriere Emeric , Prapotnich Dominique , Sanchez-Salas Rafael , Galiano Marc , Barret Eric , Cathelineau Xavier
Published: February 2017

113

Background: Gleason score (GS) on prostate biopsy is a critical factor in the initial evaluation of patients with prostate cancer (PC), and can lead to different therapeutic options. However, it may differ from the final pathologic result on radical prostatectomy (RP) specimen in up to 30 to 50% of cases. The aim of this study was to explore the clinicopathological features and outcomes associated with Gleason upgrading from biopsy to RP in a contemporary cohort and to develop an upgrading risk tool available preoperatively. Methods: Using a monocentric prospectively maintained database, we included 3,062 patients who underwent minimally invasive RP between 2005 and 2012. All biopsies and surgical specimens were analyzed by dedicated pathologists. We explored clinicopathological features and outcomes associated with Gleason upgrading from biopsy to RP. A multivariate logistic regression was used to develop a nomogram predicting upgrading for Gleason 6 PC. Results: The median number of biopsy cores was 12 (10 to 13). The GS on biopsy was respectively 6, 7, and more than 7 in 58.5%, 37.4%, and 4.1%. The GS on biopsy was consistent with the specimen in 42.7%. The GS was upgraded in 37.8% and the primary pattern was upgraded in 14.1%. Patients upgraded from biopsy Gleason 6 to Gleason 7 on RP had a longer time to biochemical recurrence than those with Gleason 7 on both biopsy and RP, but a shorter time to BCR than those who remained Gleason 6 on RP (p<0,0001). On multivariate analysis, variables predicting upgrading for Gleason 6 PC were: age (p=0.0014), abnormal digital rectal examination (p<0.0001), prostate-specific antigen density (p<0.0001), percentage of positive cores (p<0.0001) and body-mass index (p=0.037). A nomogram was generated and validated internally. Conclusions: Biopsy GS is misleading in one third of cases. Gleason upgrading from biopsy to PR seems to have consequences on the clinical outcomes. A nomogram using clinicopathological features can be useful to recognize the probability of upgrading in patients with Gleason 6 PC at initial evaluation. This could help to better choose therapeutic options in low-risk PC.
A study of two ODM-201 formulations with a safety and tolerability extension phase in patients with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).
Authors: Massard Christophe , Tammela Teuvo L. J. , Vjaters Egils , Lietuvietis Vilnis , Bono Petri , Penttinen Heidi , Nykänen Pirjo , Snapir Amir , Mattila Leena , Fizazi Karim
Published: February 2017

115^

Background: This open phase I trial assessed the bioavailability, and the effect of food on the bioavailability of ODM-201 600mg tablets compared to a 600mg capsule formulation. Efficacy, safety, and tolerability of ODM-201 were studied in the extension period. Methods: The study had two parts: a pharmacokinetic (PK), and a safety and tolerability part. Dosing was 600mg bid with or without food. In the PK part, three single doses of ODM-201 were given over 3 weeks. In the extension part patients could continue treatment until disease progression or until an intolerable adverse event or condition that prevented further dosing of ODM-201. Results: Thirty men with metastatic chemotherapy-naïve castration-resistant prostate cancer (CRPC) were enrolled, the median age was 68. The median prostate-specific antigen (PSA) was 18.2 ng/mL and testosterone 23.1 ng/dL at baseline. Food interaction was observed when ODM-201 formulations were administered after a high fat content breakfast compared to administration at fast. AUC and Cmaxvalues were about 50% lower after fast. Twenty nine patients have completed the 4-week visit. The PSA response rate (50% or more PSA decline) was 86%, with a median PSA decrease of -66% (-96, 5) at week 4 (N=18/21). Most commonly reported adverse events so far are fatigue, abdominal pain, diarrhea, hematuria, and nausea. Conclusions: ODM-201 600mg bid as tablets has comparable PK to capsules used in the phase II ARADES trial. It is well tolerated and has good PSA response in chemotherapy-naïve patients with CRPC . Clinical trial information: NCT01784757.
Preferences for treatment to delay bone metastases (BM) in patients with castration-resistant prostate cancer (CRPC) at high risk of developing BM.
Authors: Qian Yi , Hauber A. Brett , Gonzalez Juan Marcos , Posner Joshua , Mohamed Ateesha F , Tombal Bertrand , Body Jean-Jacques , Gatta Francesca , Arellano Jorge
Published: February 2017

117

Background: Limited treatments are available for patients with non-metastatic CRPC. Prophylactic treatment may be associated with adverse events (AE). We evaluated patient preferences for a medication delaying bone metastases (BM) with a risk of AE.Methods: UK and Swedish adults with CRPC at high risk for BM (on androgen-deprivation or hormone therapy for ≥ 3 yrs) completed an online discrete-choice experiment with 10 choice questions. Patients were asked if they would prefer to receive a hypothetical prophylactic medication (HPM) with a risk of osteonecrosis of the jaw (ONJ) to prevent BM or to decline HPM thus not receiving any treatment benefit or risk. HPMs were defined by delay in BM (0-23 months) and risk of ONJ (0-9%). The proportion of patients who chose HPM with different combinations of BM delay and ONJ risk was calculated. To further evaluate the impact of BM to patients, time tradeoff was used to assess patients’ willingness to trade off between life years with and without bone complications (i.e., skeletal-related events, including spinal cord compression, surgery or radiation to bone, and pathologic fracture).Results: A total of 201 UK patients and 200 Swedish patients completed the survey. As shown in the table, even a HPM with the lowest level of BM delay (5 months) and the highest level of ONJ risk (9%) was acceptable to the majority of patients in both countries. Furthermore, when asked about the tradeoff between life years with and without bone complications, 52% of UK patients and 26% of Swedish patients were willing to trade off 5 months of survival to avoid bone complications; nearly three-quarters of the patients were willing to trade off 3 months of survival to avoid bone complications. Conclusions: A majority of patients in the UK and Sweden were willing to take HPMs to delay BM, despite a treatment-related risk of ONJ and were willing to trade off 3 to 5 months of survival to avoid bone complications. [Table: see text]
Feasibility of multimodal molecular characterization of the androgen receptor (AR) in circulating tumor cells (CTCs) from patients with castrate-resistant prostate cancer (CRPC).
Authors: VanderWeele David James , Isikbay Masis , Reyes Edwin , Duggan Ryan , Wyche Alicia J. , Stadler Walter Michael , Vander Griend Donald , Szmulewitz Russell Zelig
Published: February 2017

133

Background: Despite the wealth of agents targeting the androgen receptor (AR) signaling pathway in castrate-resistant prostate cancer (CRPC), emergence of resistance is common. Mechanisms for resistance are diverse and likely include quantitative alterations in AR as well as alterations in nuclear localization. Clinical interrogation of such events is challenged by difficulties in biopsying metastatic sites and limitations in available circulating tumor cell (CTC) platforms. We set out to explore different methodologies of AR interrogation within CTCs. Methods: CTCs and cultured prostate cancer cells were isolated from nucleated blood cells using fluorescence associated cell sorting (FACS) targeting the Epithelial Cell Adhesion Molecule (EpCAM) with CD45 negative selection. In addition to standard immunofluorescence imaging, ImageStreamX spectral flow analysis was used to analyze AR protein expression and nuclear localization. Targeted DNA sequencing and TaqMan copy number evaluation were used for downstream analysis of AR alterations. Patients with highly refractory disease were enrolled for these assay development studies. Results: Thirteen of 15 (87%) patients in an initial feasibility cohort had CTCs isolated for downstream evaluation. Targeted DNA sequencing of as few as 10 C4-2 cells isolated from nucleated blood cells confirmed specificity for prostate cells by identifying a known AR mutation. TaqMan copy number evaluation revealed AR amplification in two out of four evaluable patients. Fluorescence microscopy demonstrated feasibility of AR staining, with 10 of 10 patients exhibiting AR staining above negative control and 50% staining above that of AR+ LAPC4 cells. Though the numeric variability in AR expression using ImageJ software was high, AR protein interrogation with ImageStreamX allowed for more precise evaluation of nuclear localization of the AR revealing that in CRPC patients there can be distinct CTC populations with respect to AR localization. Conclusions: Identifying mechanisms of AR derangement is crucial for the precision management of advanced prostate cancer. CTCs are a promising way to evaluate molecular characteristics of AR in patients with late stage disease.
The effect of prior abiraterone (Abi) treatment on subsequent response to docetaxel in men with castrate resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Zhou Xian Chong , Wang Hao , Bassi Sunakshi , Carducci Michael Anthony , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: February 2017

136

Background: Taxanes are hypothesized to mediate their effect in CRPC, at least in part, by disrupting androgen receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents (e.g., Abi) and Tax. Methods: We retrospectively evaluated Tax efficacy in CRPC patients (N=119) who did (Abi+Tax; n=24) or did not (Tax; n=95) receive prior Abi. To ensure a contemporaneous control group, this analysis only included men who started Tax between 12/2007 (the date we began using Abi at our center) and 5/2013. Univariate and propensity score-weighted multivariable analyses for PSA progression-free survival (PSA-PFS) and all-cause progression-free survival (PFS) were conducted to evaluate the effect of prior Abi on responses to Tax. Results: Men in the Abi+Tax group had a significantly higher risk of progression than those in the Tax group. In univariate analysis, PSA-PFS was shorter in the Abi+Tax group (HR 2.00; 95%CI 1.13–3.52; P=0.016), as was PFS (HR 1.97; 95%CI 1.13–3.41; P=0.016). Median PSA-PFS was 4.1 mo in the Abi+Tax group and 6.3 mo in the Tax group (P=0.014). Median PFS was also shorter in the Abi+Tax group (4.1 vs 6.8 mo; P=0.014). In multivariable analysis, prior Abi treatment remained a predictor of shorter PSA-PFS and PFS (Table). PSA declines ≥50% were also less frequent in the Abi+Tax group (37% vs 63%, P=0.04). Conclusions: Men receiving Abi prior to Tax were more likely to develop progression on Tax (and less likely to have a PSA response) than Abi-naive patients. Cross-resistance between Abi and Tax may limit taxane efficacy in Abi-pretreated patients. [Table: see text]
Outcomes after post-operative radiation therapy.
Authors: Nguyen Hao , Cary Clint , Appa Ayesha , Cowan Janet E. , Welty Christopher J , Roach Mack , Shinohara Katsuto , Carroll Peter
Published: February 2017

138

Background: Adjuvant radiotherapy following radical prostatectomy has been shown to improve prostate-specific antigen (PSA) recurrence free survival for patients with high-risk pathologic features. However, an alternative strategy is careful follow-up after surgery and selective salvage radiation therapy. We aim to investigate voiding and sexual function, and oncological outcomes of patients who underwent adjuvant radiotherapy (ARD) or salvage radiotherapy (SRT) after radical prostatectomy (RP). Methods: We conducted a retrospective analysis of patients with localized prostate cancer treated with open or robotic assisted laparoscopic RP at the University of California, San Francisco (UCSF) from 2002 to 2013. Primary outcomes were voiding and sexual function, PSA recurrence-free survival (PRFS), combined bone metastasis free-survival/cancer-specific survival (BMFS/CSS), and overall survival (OS). Survival outcomes were analyzed using the Kaplan-Meier method. Results: Among 2,908 men in the study, mean age was 60, median PSA was 5.9 ng/ml, and median PSA density was 0.19 at diagnosis. Median follow-up was 28 months (IQR 8-61). Of those with high risk pathologic features, 1,086 patients did not undergo post-RP radiation (NRT), 109 had ART, and 156 had SRT. All patients had comparable pre-treatment sexual and voiding function. However, patients treated with ART or SRT had worse sexual function (SHIM scores) at 4 years post-RP compared to patients without radiation (5.2 (ART/SRT) versus 11.1 (NRT), p=0.01). There were no differences in voiding function at 4 years between the three groups. PRFS at 4 years was 92% for NRT, 82% for ART, and 55% for SRT cohort, log-rank p<0.01. Four-year BMFS/CSS and OS both were 98% and were similar for all groups. In a sub-analysis of men with stage pT2/3a, positive margins, and negative lymph nodes, PRFS were 86% (NRT) and 90% (ART). The PRFS following SRT was 63%. Conclusions: This study provides novel information on both oncological and functional outcomes for men managed with surgery and post-operative radiation therapy at UCSF. Such information allows for better pre- and post-operative counseling of men. Further analyses are required to better determine which men benefit from immediate adjuvant radiation as compared to a strategy of surveillance followed by selective salvage radiation.
The effect of pathologic T-stage and Gleason score on cancer-specific survival in patients with positive surgical margins after surgery for high-risk prostate cancer.
Authors: Tosco Lorenzo , Van Poppel Hendrik , Van den Broeck Thomas , Bastian Patrick , Briganti Alberto , Chun Felix K. , Gontero Paolo , Hsu Chien Yeh , Karnes R. Jeffrey , Marchioro Giansilvio , Sanchez-Salas Rafael , Spahn Martin , Tombal Bertrand , Van Der Poel Henk , Joniau Steven
Published: February 2017

140

Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach but patients with positive section margins (R1) disease have not always the same cancer-specific survival (CSS). The current study aims to analyze current postoperative pathological features in order to predict CSS of HRPC patients with R1, but with negative lymph nodes (pN0), treated with surgery. Methods: From a multi-institutional retrospective cohort of 5,876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1541 patients with pN0 and R1 were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and p-Gleason score (pGS≥8 and pGS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age at surgery was 66 years (42-89). Of all patients, 399 (25.9%) had GS≥8 and 999 (64.8%) had pT≥3 at definitive histopathology. Patients were classified as COMBO groups: C1 (423; 27.4%; GS<8,pT<3), C2 (674; 43.7%; GS<8, pT≥3), C3 (83; 5.4%; GS≥8, pT<3), C4 (362; 23.5%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 3%/5%, C2 15%/21%, C3 21%/20%, C4 28%/40%. Kaplan-Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97%, C2 93.8%, C3 85.1% and C4 77.3% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide margin-positive, pN0 HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]
Greatest percent involved core length and the risk of death from prostate cancer in men with highest Gleason score 7 or higher.
Authors: Cheney Matthew David , Chen Ming-Hui , Zhang Danjie , Phillips John Gary , Loffredo Marian J. , D'Amico Anthony Victor
Published: February 2017

164

Background: Men with highest Gleason Score (GS) ≥ 7 and a lower GS (Combo GS) have a decreased risk of prostate cancer (PC) specific mortality (PCSM) following radiation therapy (RT) or RT and androgen deprivation therapy (ADT). Whether this risk is modulated based on the greatest percent involved core length (GPC) is unknown and investigated in the current study. Methods: The study cohort consisted of 333 men with GS ≥ 7 PC consecutively treated between 12/1989 and 7/2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%). Biopsy core and tumor lengths were used to calculate the GPC. Competing risks regression assessed whether increasing GPC was associated with an increased risk of PCSM in men with or without ComboGS adjusting for prognostic factors, age, and treatment. Results: After a median follow-up of 5.36 years (IQR: 3.22-7.61 years) 92 (28%) men died, 28 (30%) from PC. Increasing GPC was significantly associated with an increased risk of PCSM (AHR: 1.02; 95%CI: 1.00, 1.03; p=0.02) (Table). Men with GPC ≥ 50% vs. < 50% had significantly higher estimates of PCSM when ComboGS was present (p< 0.001) vs. absent (p=0.55). Of the 127 men with ComboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; none in men with GS 7 and favorable intermediate-risk PC. Conclusions: Men treated with RT for ComboGS, GPC < 50%, GS 7 and favorable intermediate-risk PC may not require ADT to reduce the risk of PCSM. [Table: see text]
Pelvic exenteration in patients with nonmetastatic, locally advanced castration-resistant prostate cancer.
Authors: Donahue Timothy F. , Morris Michael J. , Hilton William M. , Scher Howard I. , Bochner Bernard H.
Published: February 2017

168

Background: A subset of patients who present with localized prostate cancer (PCa) do not develop metastatic disease and recur locally after definitive primary therapy, local salvage therapy, hormones, and systemic intervention. We report our experience in patients with non-metastatic, locally advanced castration resistant prostate cancer (CRPC) treated with radical cystectomy or pelvic exenteration (RC/PEx). Methods: Institutional review board (IRB) approved retrospective review of all patients undergoing RC/PEx for non-metastatic, locally recurrent CRPC after definitive and salvage therapies. Patients were excluded if RC/PEx was for complications of definitive therapy alone. Results: Of 31 patients who had RC/PEx for PCa, 20 met inclusion criteria. Initial therapy was RP (4), XRT (6), brachytherapy (4), brachy/XRT (3), ADT/chemo (2), and ADT alone (1). Five patients had salvage XRT. All received ADT at relapse and 11 had chemotherapy prior to RC/PEx. RC/PEx was performed a median of 8.16 years (0.7 to 24.5) after PCa diagnosis. Patients had pT2b (1), pT3 (5), and pT4 (14) disease at surgery. Lymph nodes were clinically negative in all patients but pathologically positive in six, negative in nine, and not resected in five. Concurrent resections included rectum (12), pelvic wall (6), pubis (1), and iliac vein (1). Eighty five percent of patients had symptoms attributable to locally progressive PCa at RC/PEx including pain, genitourinary or gastrointestinal obstruction and bleeding. All symptomatic patients had relief of disease-related symptoms until recurrence. After a median follow-up of 3.12 years (0.7 to 13.4), nine patients are alive (four have no evidence of disease, five alive with disease), nine dead of disease, and two dead of other causes. Median time to death after RC/PEx was 2.8 years (0.8 to 5.9). For 14 patients who relapsed, metastases developed a median of 398 days (110 to 1,679) after RC/PEx. Ten patients received chemotherapy and 16 had androgen-deprivation therapy after surgery for local recurrence or distant metastases. Median time to chemotherapy after RC/PEx was 346 days (96 to 1,709). Conclusions: For patients with non-metastatic, locally advanced CRPC, RC/PEx to resect symptomatic disease is feasible and appears clinically beneficial. In addition to local control, it may confer significant disease free intervals and relief of symptoms. Even after relapse, performance status was sufficient to undergo systemic therapy.
Biomarker development trial of satraplatin in patients with metastatic castrate-resistant prostate cancer.
Authors: Liaw Bobby Chi-Hung , Seng Sonia Maria , Galsky Matt D. , Tsao Che-Kai , Febbo Phillip G. , Oh William K.
Published: February 2017

170

Background: While satraplatin, a fourth generation oral platinum analogue, failed to improve overall survival (OS) in an unselected metastatic castrate-resistant prostate cancer (mCRPC) population (Sternberg, JCO 2009), anti-tumor activity was demonstrated, suggesting a “platinum-sensitive” subset of patients. Predictive biomarkers may not only select patients most likely to benefit from novel “targeted” therapies but also from standard (even discarded) cytotoxic agents. Development of predictive biomarkers in mCRPC is hampered by the fact that PC is associated with a long natural history and evolving genetic changes, highlighting the need for immediate pre-treatment metastatic tissue samples for biomarker development. In this trial, we sought to determine the feasibility of obtaining metastatic biopsies in patients with mCRPC treated with satraplatin. Methods: Docetaxel-refractory mCRPC patients underwent image-guided biopsy of metastatic lesions prior to treatment with satraplatin 80 mg/m2 PO on days 1 to 5 of a 35-day cycle and prednisone 5 mg PO twice daily. Biopsy samples are analyzed by whole exome and RNA sequencing, and peripheral blood samples are undergoing transcriptional profiling, to facilitate biomarker development. Results: Thirteen patients were enrolled with a median age of 71 (range: 55 to 80), prostate-specific antigen (PSA) of 82 ng/ml (0.04-3057), and Gleason score 8 (7 to 9). All patients received prior docetaxel, four (31%) had more than or eqaul to two prior chemotherapies, and two (15%) received abiraterone. Drug-related grade 3/4 toxicities included leukopenia (23%), neutropenia (8%), thrombocytopenia (8%), fatigue (8%), renal failure (8%), dysphagia (17%), and diarrhea (8%). A median of four cycles of satraplatin were completed, with declines of serum PSA of greater than or equal to 30% achieved in 4 of 13 patients (31%; 95% CI, 57.3 to 85.4%). Median time to PSA progression was 12.4 weeks (95% CI, 7.2 to 29.7+ weeks). Metastatic pre-treatment biopsies were collected in all study patients; genomic analysis is ongoing. Conclusions: This study confirms that satraplatin has anti-cancer activity in a subset of patients with mCRPC. Trials that require pre-treatment metastatic tumor biopsies are feasible. Analysis of the correlation between molecular signatures and treatment response will be presented at the meeting. Clinical trial information: NCT01289067.
The effect of [-2]proPSA and prostate health index (phi) on the accuracy of the prediction of initial and repeat prostate biopsies compared to tPSA and percent fPSA in young men (age 65 or younger).
Authors: Boegemann Martin , Vincendeau Sébastien , Stephan Carsten , Houlgatte Alain , Krabbe Laura-Maria , Blanchet Jean-Sebastien , Semjonow Axel
Published: February 2017

171

Background: Prostate-specific antigen (tPSA) based screening reduces mortality. But recent recommendations do not endorse PSA-screening due to possible over-diagnosis and over-treatment and the resulting harm afflicted to patients. Screening studies showed the maximum benefit in young men age 65 or younger. tPSA and percent free PSA (%fPSA) lack specificity in the diagnosis of PCa. [-2]proPSA and the "prostate health index" (phi) improve this diagnostic specifity in a non-age adjusted population. Markers to diagnose clinicaly relevant cancers in young men are needed. Methods: The clinical performance of [-2]proPSA and phi were evaluated in a multicenter study. A total of 1,362 patients (769 age 65 or younger) scheduled for initial or repeated prostate biopsy (668 with, 694 without PCa, each 10 or more core biopsies) were recruited in four different sites based on PSA level 1.6 to 8.0 ng/mL WHO-calibrated (2-10 ng/mL classically calibrated). Serum samples taken prior to digital rectal examination (DRE) were measured for the concentration of tPSA, fPSA and [-2]proPSA with Beckman Coulter immunoassays on Access 2 or DxI800 instruments. Phi was calculated as: [-2]proPSA/fPSA x √tPSA. Results: In univariate analysis [-2]proPSA/fPSA (%[-2]proPSA) and phi were the best predictors of PCa detection in patients at initial biopsy (AUC: 0,72 and 0,73) and repeated biopsy (AUC: 0,74 and 0,74). Analysis of the data for men age 65 and younger (n=593) showed that %[-2]proPSA and phi significantly improved PCa dectection (AUC: 0,72 and 0,73) as compared with tPSA (AUC: 0,53) or %fPSA (AUC: 0,62). In the detection of significant PCa (based on PRIAS criteria) %[-2]proPSA and phi demonstrated the best performance in the whole cohort and in young men (65 and younger) years as well (AUC 0,68 and 0,73). Conclusions: This multicenter study showed that [-2]proPSA and phi have a superior clinical performance in detecting PCa in the PSA range of 2 to 10 ng/mL compared to tPSA and %fPSA at initial and repeat biopsies. This superiority is maintained for the detection of PCa in young men (age 65 or younger).
Focal nodular prostatic peripheral zone enhancement on CT to predict clinically significant (Gleason 4+3 and higher) prostate cancer.
Authors: Glazer Daniel I. , Davenport Matthew S. , Cohan Richard H. , Ellis James H. , Caoili Elaine M. , Stein Erica B. , Childress John C. , Masch William R. , Brown Jordan M. , Mollard Brett J. , Montgomery Jeffrey S. , Palapattu Ganesh S. , Francis Isaac R.
Published: February 2017

173

Background: CTs are insensitive for prostate cancer and inaccurate for local prostate cancer staging. However, enhancing peripheral zone nodules can be seen on a CT, and their significance is uncertain. The purpose of this study was to determine whether focal nodular enhancement within the prostatic peripheral zone on a CT is predictive of clinically significant prostate cancer. Methods: Institutional review board approval was obtained and informed consent waived for this Health Insurance Portability and Accountability Act-compliant retrospective study. Forty-three patients with high-grade prostate cancer (Gleason 4+3 [n=14], 3+5 [n=1], 4+4 [n=1], 4+5 [n=19], 5+4 [n=8]) and 96 with cystoprostatectomy-confirmed low-grade (Gleason 3+4 [n=24], 3+3 [n=23]) or absent (n=49) prostate cancer imaged with contrast-enhanced CT within nine months of histology (median: 18 days) comprised the study population. CT images were reviewed by 10 blinded radiologists (five attendings, five residents) who scored peripheral zone enhancement on a scale of 1 (benign) to 5 (malignant). Focal nodular enhancement was considered malignant. Likelihood ratios (LR) and specificities were calculated. Results: Scores of ‘5’ were strongly predictive of clinically significant prostate cancer (pooled LR+: 9.6 [95% CI: 5.8-15.8]) with rare false positives (pooled specificity: 0.98 [942/960, 95% CI: 0.98-0.99]). Attendings outperformed residents (LR+: 14.7 [95% CI: 5.8-37.2] vs. 7.6 [95% CI: 4.2-13.7]) with similar specificity (0.99 [475/480, 95% CI: 0.98-1.00] vs. 0.97 [467/480, 95% CI: 0.96-0.99]). Conclusions: Focal nodular peripheral zone enhancement on a CT is specific and predictive of clinically significant prostate cancer.
Biochemical response to ketoconazole therapy in post-chemotherapy mCRPC patients.
Authors: Roeder M. Andreas , Berg Kasper Drimer , Hunde Daniel , Nerstroem Camilla , Thomsen Frederik Birkebæk , Brasso Klaus , Iversen Peter
Published: February 2017

174

Background: Ketoconazole for the treatment of metastatic castration resistant prostate cancer (mCRPC) has never been investigated in randomized trials. In fact, although ketoconazole is a less potent inhibitor of the CYP-17 enzyme systems compared to abiraterone, there is no head-to-head evidence demonstrating that this translates into improved survival. We analyzed biochemical response rates in post-chemotherapy mCRPC patients who were treated with ketoconazole 200 mg TID plus prednisone 5 mg BID at a single center in Denmark. Methods: Between 2008 and 2012, where neither abiraterone nor enzalutamide was available in Denmark, a total of 30 post-chemotherapy mCRPC patients were managed with ketoconazole. Percent change in prostate-specific antigen (PSA) and alkaline phosphatase (ALP) from baseline were registered. Overall survival was calculated from the initiation of ketoconazole. Results: At initiation of ketoconazole, median age was 66 (range: 58 to 76). Median PSA was 547 ng/ml (65 to 4,241). Median ALP was 159 U/L (51 to 750). The median number of prior cancer therapies was five (three to nine). The median time on ketoconazole treatment was 150 days (14 to 648). A total of 44% patients had any decline in PSA, whereof 31% experienced a decline of >=50%. At three months, a total of 19 patients still received ketoconazole, whereof 26% sustained a PSA decline of >=50% from baseline. A total of 71% experienced any decline in ALP, whereof 36% experienced a maximum decline of >=50%. At three months, 7 of 19 patients (36%) sustained an ALP decline of >=50% from baseline. At follow-up, 28 of 30 patients had died. The median overall survival was 10.5 months (95%CI: 8.3-12.6). Conclusions: Compared to the post-chemotherapy phase II study of abiraterone (58 patients) our cohort most likely had a larger tumor burden (e.g. higher PSA, more therapies prior to start of ketoconazole). Nonetheless, we demonstrated a reasonably comparable maximum >=50% PSA response-rate (43% in phase II) and three-months response-rate >=50% (36% in phase II). Also a significant decline in ALP was demonstrated here which has not been reported in abiraterone trials. Given the large difference in expenditure, a head-to-head comparison of abiraterone and ketoconazole in mCRPC patients still seem justified.
Leveraging the DNA damage and transcriptional-regulatory roles of PARP-1 as a means to improve prostate cancer therapy.
Authors: Schiewer Matthew Joseph , Steffen Jamin , Tholey Renee , Brody Jonathan Robert , Pascal John , Lin Jianqing , Den Robert , Feng Felix Yi-Chung , Gomella Leonard G. , Dicker Adam , Kelly William Kevin , Knudsen Karen E.
Published: February 2017

179

Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function in models of prostatic adenocarcinoma (PCa), and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression (more than 50%), and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. These data, in part, served as critical rationale for current clinical trials combining PARP inhibition and abiraterone for patients with metastatic CRPC NCT01576172 . Given the clinical importance of targeting AR function in PCa, preclinical studies were performed to assess the impact of leveraging the dual roles of PARP-1 as a means to improve therapy for advanced disease. Methods: In vitro and in vivo model systems were utilized to assess impact on AR and tumor growth. Multiple PARP inhibitors were used for additional studies. The impact of PARP-1 on gene expression was also assessed using unbiased analyses. PARP-1 mutants were also utilized to segregate the DNA damage and transcriptional regulatory roles of PARP-1. Results: Critically, PARP-1 inhibitors cooperated with castration to elicit an enhanced therapeutic response, and PARP-1 inhibitors were effective at suppressing CRPC growth in vivo. Multiple PARP inhibitors diminished AR chromatin occupancy, altered AR transcriptional output and reduction in PCa and CRPC cell growth. Conclusions: These data identify PARP-1 as a feasible therapeutic target for advanced prostate cancer. Multiple PARP inhibitors show pre-clinical efficacy in models of PCa and CRPC and merit consideration for clinical trial, and a concept will be presented.
Impact of prior radiation treatment (tx) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).
Authors: Finkelstein Steven E. , Nordquist Luke T. , Dakhil Shaker R. , Green Nathan B. , Heath Elisabeth I. , Tutrone Ronald , Vogelzang Nicholas J. , Armstrong Andrew J. , Cooperberg Matthew R. , Tyler Robert Claude , Sims Robert Brownell , Whitmore James Boyd , Higano Celestia S.
Published: February 2017

183

Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Approval of sip-T was based primarily on the randomized, controlled, phase 3 study (IMPACT) that demonstrated a 22% reduction in the risk of death. Since radiation tx could suppress bone marrow function and therefore immune function, IMPACT excluded patients (pts) who received radiation more than or equal to 28 days prior to registration. PROCEED is an ongoing phase 4 registry enrolling pts tx with commercial sip-T in the real-world setting. Palliative radiation (PR) tx for bone pain prior to sip-T is not restricted in PROCEED, so the effects of prior radiation on sip-T manufacturing parameters can be evaluated. Methods: Pts treated with sip-T at or before six months were eligible. Baseline pt demographics and disease characteristics were collected. Sip-T product parameters that were assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (large CD54+cells), and APC activation (upregulation of CD54; a measure of product potency). Results: Data were available for 1,244 pts enrolled by May 2013, who completed tx; of those, 112 (9.0%) pts received PR to bone metastases prior to sip-T and 517 (41.6%) pts had no prior radiation of any kind (NRT). To ensure that groups (grp) were homogeneous and to limit the comparison of NRT pts with those who had PR only for bone metastases, pts with radical prostatectomy were isolated from each grp for further study, resulting in 44 pts in the PR grp and 159 pts in the NRT grp. Median cumulative APC counts were similar between grp, however TNC counts (PR: 9.89 vs. NRT: 12.09 x 109; P=0.002) and APC activation (PR: 34.2 vs. NRT: 38.5; P=0.048) were lower in the PR grp. However, the percentage of pts receiving all three infusions in each group was comparable (PR: 93.2% vs NRT: 95.0%; P=0.71). Conclusions: In the real-world setting, there is no evidence that prior radiation inhibits successful production of sip-T. Although TNC counts and APC activation were lower, APC counts were comparable in radiation treated pts. Effects on in vivo post treatment immune measures are being collected prospectively in a companion trial called PRIME. Clinical trial information: NCT01306890.
Accuracy of NaF PET/CT scan to detect bone metastases in CRPC.
Authors: Alom Modar , Aleksic Ilija , Ruhle Brian , Iannotta Peter , Okeefe Colin , Mouraviev Vladimir , Albala David , Pieczonka Christopher Michael
Published: February 2017

186

Background: The current standard for imaging Castration Resistant Prostate Cancer (CRPC) is aimed at detecting metastatic lesions to the bones. However, discovery, validation, and implementation of new imaging modalities have fallen considerably behind that of new therapies for this population. Recent studies have shown the NaF PET/CT Scans are significantly more sensitive and accurate in detecting bone lesions than conventionally used Bone Scintigraphy with Technetium-99 (Tc-99). This study conducted retrospective analysis to compare the competence of these two methods for identifying bone metastases. Methods: We conducted a charts review of 613 patients being currently treated with androgen deprivation therapy (ADT) and identified 55 patients who obtained a Na18F PET/CT Scan. Results: The median age was 75.5 years with a range of 52-89, for our cohort. Of these 55 patients, 5 (11.9%) were determined to have metastasis with Tc-99 Bone Scintigraphy alone while 27 (49.1%) were determined to have metastases with NaF Scan (p<0.005). 8 (19%) patients had equivocal findings on Tc-99 Bone Scintigraphy. Therefore, for all of them we performed NaF scan to define a bone metastatic disease that demonstrated in 5 (62.5%) cases of these as having no bone involvement and 3(37.5%) as positive for bone lesions (Table). However, data of NaF scan also indicated 5(9%) patients as having equivocal findings for metastatic disease. Conclusions: According to our data, NaF is more sensitive for detecting bone lesions (11.9 vs. 49.1%). It was also able to delineating equivocal TC-99 Bone Scintigraphy findings, where it deemed 62.5% as negative and 37.5% as positive for bone lesions. NaF PET scan is a feasible option for CRPC for detecting bone metastases, early in disease progression. With coverage of this procedure by Medicare patients have more sensitive and specific tool for early diagnosis and monitoring of treatment of CRPC. [Table: see text]
Heterogeneity of prostate-specific membrane antigen (PSMA) expression in classic and apoptotic circulating tumor cells (CTC) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Anand Aseem , Krupa Rachel , Louw Jessica , Arslan Zaina , Dittamore Ryan , Scher Howard I.
Published: February 2017

198

Background: Prostate-specific membrane antigen (PSMA) is a folate hydrolase expressed on the surface of PC cells that has been used as a target to detect disease and selectively deliver cytotoxic agents and radionuclides. The ability to detect PSMA levels on circulating tumor cells (CTCs) may identify patients likely to benefit from such targeted therapy. Technology developed by Epic Sciences utilizes high definition imaging of plated nucleated cells. Methods: Blood samples were obtained from patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Cells were stained for CK, CD45, PSMA and categorized as classic CTC (CK+, CD45-, intact/morphologically distinct nuclei) or apoptotic CTC (CK+, CD45-, morphology suggesting apoptosis). Clinical data including treatment, metastatic sites, Veridex CellSearch CTC enumeration, prostate-specific antigen, and alkaline phosphatase was collected. Results: Fourteen pts with mCRPC, including eight with serial samples were analyzed (33 samples in total). At the first draw (t1), classic CTC were detected in 13 pts (93%), (median two cells/ml, range 0 to 40 cells/ml) and apoptotic CTC in 14 pts (100%) (median four cells/ml, range 1 to 18 cells/ml), including six pts (42%) with no CTC by Veridex CellSearch. PSMA expression was detected in five pts (36%) with classic CTC of which a median of 32% of cells (range 5 to 100%) expressed the antigen. Similar intra-patient heterogeneity was seen for the 10 pts (71.4%) with PSMA+ apoptotic CTCs (median 33.5%, range 11 to 75% cells). During treatment, often with more complete androgen suppression, PSMA was detected in 3 of the 8 (38%) pts with no PSMA+ classic CTCs at t1. The presence of PSMA expression in apoptotic CTCs did not appear to change while on therapy. Conclusions: A larger percentage of PSMA expression was seen in mCRPC pts in apoptotic CTC (10 out of 14) than classic CTC (5 out of 14) at t1, with intra-patient cell heterogeneity of PSMA expression in both CTC populations. Serial measures suggest dynamic changes in PSMA expression over time. The threshold of detectable cells and proportion and degree of PSMA expression that associates with drug sensitivity is unknown. Larger samples of pts at discrete time points on therapy are underway to further elucidate the potential clinical relevance.
PSMA, EpCAM, VEGF, and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy.
Authors: Hoving Hilde , Ananias Hildo J. K. , Rybalov Maxim , Vanderpoel Henk , Rosati Stefano , De Jong Igle
Published: February 2017

201

Background: Currently, there is no imaging modality that can accurately discriminate between locally and distant recurrent prostate cancer after treatment with curative intent. Major drawback of the available techniques is that they are not prostate cancer specific. Selecting patients for salvage cryotherapy of the prostate or salvage prostatectomy by excluding distant metastases proves a diagnostic challenge. In this retrospective pilot study expression of prostate-specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM), vascular endothelial growth factor (VEGF) and gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated and their adequacy for targeted imaging was analyzed. Methods: Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Local recurrence was based on rises in PSA and prostate biopsies. Immunohistochemistry was performed on the radical prostatectomy specimens. A pathologist blinded to clinical and pathological data scored the immunoreactivity on a four point scale in prostate cancer and in stroma. Results: Staining for PSMA was seen in 100% (17 out of 17), EpCAM in 82.3% (14 out of 17), VEGF in 82.3% (14 out of 17) and GRPR in 100% (17 out of 17) of prostate cancer specimens. Staining for PSMA, EpCAM, and VEGF was seen in 0% (0 out of 17) and for GRPR in 100% (17 out of 17) of specimens’ stromal compartments. In 11.8% (2 out of 17) of cases GRPR staining intensity of prostate cancer was higher than that of stroma, while in the remaining 88.2% (15 out of 17) of cases GRPR staining in cancer and stroma was equal. Conclusions: Based on the absence of stromal staining PSMA, EpCAM, and VEGF had a high tumor distinctiveness. GRPR had a low tumor distinctiveness as a result of the high stromal expression. Therefore, PSMA, EpCAM, and VEGF can be used for targeted imaging of locally recurrent prostate cancer after radiotherapy.
Validation of differential expression of microRNA profiles in prostate cancer specimens.
Authors: Waingankar Nikhil , Broccoli Nicholas , Rais-Bahrami Soroush , Smith Kevin , Oswald Michaela , Khalili Houman , Lee Annette , Chan Theresa , Yaskiv Oksana , Gregersen Peter , Vira Manish Arvind
Published: February 2017

203

Background: MicroRNAs (miRNA) are small, noncoding nucleic acids that regulate expression of genes. Altered expression of miRNA has been implicated as a factor in carcinogenesis. We previously demonstrated 27 miRNA with differential expression that varied greater than two-fold between areas of benign and cancerous prostate glands in 64 patients. The goal of this study was to validate these findings in a selected group. Methods: RNA was extracted from prostate cancer foci and areas of benign glands from paraffin embedded prostatectomy specimens from 29 selected patients. Five patients each were selected with Gleason 3+3, 3+4, 4+3, and 4+4 or higher. The remaining nine selected patients went on to develop metastatic disease. Expression profiles for 577 miRNA were analyzed using Taqman OpenArray. Data analysis was performed using the mean-centering method for normalizing miRNA across the original and validation cohorts. Results: Significant overlap was found between the original and validation cohorts for miRNA that were upregulated at least two-fold between benign and cancerous glands (p<0.05). There were no differences in miRNA expression between T2 and T3 cases. Comparison of Gleason 6 vs Gleason 8+ showed significant difference in expression of mir-185, mir106b, and mir-181a. Interestingly, among the subset of patients that developed metastatic disease, the benign prostate glands demonstrated significant overexpression of mir-21 as compared to the benign glands of the localized cohort. Mir-21 is a known oncomir shown to be overexpressed in other metastatic tumors. Conclusions: This study validates our findings on differential expression of miRNA between cancerous and benign glands. There was a significant difference in expression of three miRNAs between Gleason 6 and 8 cancers, and no differences were found between T2 and T3. miRNA may represent a unique signature in the benign glands of patients with metastatic disease.