bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and genomic characterization of invasive circulating tumor cells (iCTCs) from men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Friedlander Terence W. , Premasekharan Gayatri , Ngo Vy , Doty Shaun , Harris Anna , Winter Michael , Gilbert Elizabeth , Craik Charles , Paris Pamela
Published: February 2017

120

Background: Identification, enumeration, and genomic analysis of circulating tumor cells (CTCs) may allow for a better understanding of the mechanisms of resistance to therapies in metastatic castration-resistant prostate cancer (mCRPC). The Vitatex VitaAssay platform captures invasive CTCs (iCTCs) in a cell surface marker-independent fashion based on their ability to invade a fluorescently-labeled cell-adhesion matrix (CAM), allowing for the analysis of multiple CTC subpopulations. Here we sought to estimate epithelial, mesenchymal, and stem-like iCTC subpopulation diversity in men with CRPC starting abiraterone acetate therapy, to compare the genomic profiles of iCTCs to matched metastatic biopsies, and to explore the potential for 2D and 3D CTC culture. Methods: iCTCs were isolated from men with mCRPC using the CAM platform, and paired metastatic biopsies were performed. iCTCs were defined as CAM+/CD45-/CD14-/DAPI+, mesenchymal iCTCs as vimentin+/CAM+/CD45-/CD14-/DAPI+, and stem-like iCTCs as CD44+/CAM+/CD45-/CD14-/DAPI+. iCTCs were enumerated and purified using FACS. Agilent array comparative genomic hybridization (aCGH) of iCTCs and paired biopsies was performed, and to explore the potential for ex-vivo cell expansion and spheroid formation, iCTCs were cultured separately in CAM and in matrigel for up to 10 days. Results: iCTCs were isolated using the CAM platform from 29 men, of whom seven have undergone paired metastatic biopsy. The median pre-FACS purity was 1.06% (range 0.11%-10.16%). Post-FACS purity was increased to greater than 90%, and a median of 60 (range 2 to 1,314) iCTCs/7.5ml were detected by FACS. Both vimentin+ and CD44+ iCTCs are detectable, and compromise between 10 to 50% of total iCTCs. iCTC aCGH profiles resemble paired soft tissue biopsy, in vitro iCTCs culture is feasible, and iCTC spheroids were observed. Conclusions: Multiple CRPC iCTC subpopulations are identifiable from men starting abiraterone therapy, and cell sorting techniques increase iCTC purity. iCTCs resemble metastatic CRPC tissue and can be expanded in culture. Further enumeration, genomic profiling, and clinical correlation of paired iCTCs taken from men with abiraterone-resistant CRPC is underway, and may shed light on mechanisms of abiraterone resistance.
Clinical implications of bone scan underuse for patients with high-risk prostate cancer (CaP).
Authors: Falchook Aaron David , Hendrix Laura H. , Chen Ronald C.
Published: February 2017

124

Background: National practice guidelines recommend bone scans during workup of high-risk CaP patients. Omission of bone scans may lead to aggressive and futile treatments in patients with undiagnosed metastatic disease. We hypothesized that patients who did not vs. did have a bone scan have inferior survival after treatment. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed from 2004-07 were included. Prevalence of bone scan use in patients with apparent high-risk CaP (N=19,885) was calculated, without consideration of M-stage which is a downstream result of the scan. Then, we excluded patients with M1 disease and compared prostate cancer specific mortality (PCSM) among 17,450 patients with apparent M0 cancer who received vs. did not receive a staging bone scan. Kaplan-Meier estimates and Cox multivariate models were used. Results: Only 60% of high-risk patients received a bone scan. In patients with apparent M0 disease, 58% of those who did not receive a bone scan received curative-intent treatment – either surgery or radiation (Table). With median follow-up of 3.3 years, PCSM was higher in patients who did not receive a bone scan (4-year 22% vs. 18%, p<.001). When stratified by treatment, a significant PCSM difference was seen among radiation patients (4-year PCSM 19% no bone scan vs. 14% bone scan, p=.006), but not in surgical or no treatment/hormone only patients. On multivariate analysis controlling for age, race, marital status, comorbidity, diagnosis year, regional socioeconomic status, geographic region, and population density, PCSM difference in radiation patients remained significant (hazard ratio 1.36 for no bone scan, p=.04). Conclusions: 40% of high risk CaP patients did not receive recommended bone scan during workup. Patients with apparent non-metastatic CaP but did not receive a staging bone scan often received curative-intent treatments. A worse survival among patients without bone scan suggests a potential overtreatment in patients with undiagnosed metastatic disease. [Table: see text]
Predicting radical prostatectomy outcome: Cell cycle progression (CCP) score compared with primary Gleason grade among men with clinical Gleason less than 7 who are upgraded to Gleason 7.
Authors: Cooperberg Matthew R. , Freedland Stephen J. , Schlomm Thorsten , Reid Julia E. , Stone Steven , Brawer Michael K.
Published: February 2017

13

Background: Improved prognostic markers for prostate cancer are an important part of addressing the issue of over- and under-treatment in prostate cancer. Gleason score (GS), prostate-specific antigen and clinical stage work well for population risk assessment but lack precision for individual patients. Concern over undergrading on biopsy is felt to be a major barrier to increasing use of active surveillance. Molecular analysis can further refine risk assessment as demonstrated by the cell cycle progression (CCP) score (Prolaris) which has been shown to predict prostate cancer aggressiveness in eight separate cohorts. In these studies, CCP scores typically ranged from −2 to +3 with each one−unit increase in CCP score corresponding to approximately a doubling of the risk of the studied event (recurrence or death from prostate cancer). In the present investigation, we sought to assess how upgrading compared with CCP in predicting failure after radical prostatectomy (RP). Methods: In this study, we examined men from three cohorts (UCSF, Martini Clinic, and Durham VAMC) with clinical GS (cGS) less than 7 who had pathologic GS (pGS) 3+4 or 4+3. The CCP assay was performed using RP specimen from UCSF and biopsy material from the other cohorts. We compared the rates of biochemical recurrence (BCR) as predicted by pGS, CAPRA, or CCP score alone versus CAPRA combined with CCP score using a Cox proportional hazards model stratified by cohort. Results: Among the 230 men with cGS less than 7 and pGS equal to 7 included in this analysis, 207 had pGS 3+4 and 57 had BCR; 23 had pGS 4+3; and eight had BCR. There was no difference in BCR based on GS (p=0.8) or CAPRA (p=0.4). In contrast, CCP score alone and a pre-defined score combining the CCP score and CAPRA were prognostic of BCR (HR=1.82 [95 % CI 1.32-2.52; p<0.001]; HR=1.84 [95 % CI 1.10-3.05; p=0.021] respectively). Conclusions: These data indicate that the risk of BCR is indistinguishable in men with cGS less than 7 who have pGS 3+4 or 4+3. However, the CCP assay does provide stratification of this risk. Tests that can predict BCR on biopsy will aid in initial therapeutic decision making.
The impact of pelvic magnetic resonance imaging on risk stratification in patients with localized prostate cancer.
Authors: Marcus David Mitchell , Rossi Peter John , Nour Sherif , Jani Ashesh B.
Published: February 2017

130

Background: We aimed to determine the impact of multiparametric magnetic resonance imaging (MRI) of the prostate on established risk stratification criteria in patients with clinically localized adenocarcinoma of the prostate (ACP). Methods: We included patients who had undergone multiparametric prostate MRI at our institution as part of their initial workup for ACP. Traditional risk stratification criteria (prostate specific antigen, clinical T stage, biopsy Gleason score) were recorded, and the initial National Comprehensive Cancer Network (NCCN) risk group was calculated. The NCCN risk group was then recalculated incorporating MRI findings. The impact of MRI findings on changes in risk group classification was evaluated using the Stuart-Maxwell test for marginal homogeneity. Results: Of 71 patients analyzed, 11 (15.5%), 39 (54.9%), and 21 (29.6%) had low, intermediate, and high risk disease, respectively. MRI findings led to risk group upstaging in 12 cases (16.9%). The highest yield was demonstrated in patients with intermediate-risk disease, in whom MRI led to upstaging in 25.6% of patients. The Stuart-Maxwell test demonstrated a significant difference between pre-MRI and post-MRI risk group classifications (p <0.01) for the entire cohort. Pre-MRI and post-MRI risk groups for all patients are shown in the table, with off-diagonal elements representing risk group changes. MRI findings resulted in clearly documented changes in the treatment strategy for 5 patients (7.0%), including addition of androgen deprivation therapy in 2 patients, elimination of definitive therapy in 2 patients determined to have metastatic disease, and elimination of a brachytherapy boost in one patient. Conclusions: In our cohort of patients with clinically localized ACP, MRI findings often led to significant changes in risk stratification and treatment. Our findings support the routine use of MRI in the workup of patients with clinically localized ACP, particularly those with intermediate risk disease . [Table: see text]
Preliminary results of a telomerase-based circulating tumor cell assay in prostate cancer patients undergoing definitive radiotherapy.
Authors: MacArthur Kelly M. , Kao Gary D. , Hahn Stephen M. , Christodouleas John Paul , Bekelman Justin E. , Dorsey Jay Fitzgerald
Published: February 2017

139

Background: Circulating tumor cell (CTC) analysis provides a minimally invasive tool to serially assess a primary tumor and its response to treatment, which may assist management. We conducted a pilot study among patients with localized prostate cancer to examine the potential effectiveness of a novel telomerase-based CTC assay for tracking the response to definitive radiotherapy (RT). Methods: The assay relies on processing and exposure of peripheral blood samples to an adenoviral vector, utilizing the human telomerase promoter to drive the expression of a fluorescent reporter. Such a system results in high specificity and sensitivity for prostate cancer cell detection since telomerase is elevated in almost all malignancies, but not in normal cells. Peripheral blood samples from patients with localized prostate cancer were obtained up to one month prior to initiating RT (pre-RT), one-half to two-thirds through completion of the RT course (mid-RT), and after completion of RT (post-RT, 3 to 6 months following completion of treatment). Fifty seven subjects were enrolled on this study, with a mean age of 67 (SD 6.7 years). Fifteen had low-risk, 25 had intermediate risk, and 17 had high risk disease at the time of diagnosis. Twenty subjects received androgen suppression. Results: We successfully detected CTCs in the majority of patients undergoing definitive radiotherapy for localized prostate cancer of varying Gleason scores (GS), risk status, and disease stages. The mean CTC counts per ml of blood were: Pre-RT 20.2 (standard error (SE) 8.5), mid-RT 11.0 (SE 2.5), and post-RT 1.0 (SE 0.4). The difference in CTC counts from pre-RT to post-RT was statistically significant (p<0.03). Conclusions: We have successfully detected CTCs in patients undergoing definitive RT for localized prostate cancer with a novel CTC assay. CTC counts appear to decline after definitive radiotherapy. While these promising results may further aid research of CTCs in prostate cancer, the ultimate implications for subsequent patient decisions and management remain to be studied.
The role of IL-23 in regulating metastatic prostate cancer through STAT-3/ROR-gamma signaling.
Authors: Yousif Nasser Ghaly , Alhasani Salam , Slimani H , Doug Jim , Mohammad Bassim I , Machil Suzan , Deb Abdallah Ali , Romalid Niky
Published: February 2017

142

Background: Interleukin-23 (IL-23) plays an important role in expanding the Th17 cell population and induce signal transducer and activator of transcription 3 (STAT-3) to up-regulates the expression of Retinoic Acid Receptor-Related Orphan Receptor Gamma-T (ROR-gamma). STAT-3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Furthermore, recent studies identified a critical role for ROR-gamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. The goal of this study is to evaluate prospectively the prognostic importance of circulating IL-23 in patients with metastatic prostate cancer through downstream signaling. Methods: The study involved 140 men diagnosed with stages I to IV prostate cancer and 120 healthy controls. IL-23 serum concentration measure by a quantitative enzyme immunoassay technique associated with clinical-pathological variables. Blocking IL-23 with anti-p19 Ab in mice inoculation with two types of metastatic prostate cancer cell lines (LNCaP and DU-145) to study the pathway of IL-23 in vivo by using western blot and real-time RT-PCR. Results: We found a statistically significant higher systemic IL-23 level in the metastatic group in comparison with non-metastatic group (19.32±5.35 pg/ml vs. 7.25±3.42 pg/ml, p<0.05). Patients with shorter overall survival presented higher IL-23 levels, suggesting a negative prognostic correlation. Furthermore, systemic delivery of blocking Abs directed against IL-23 completely inhibited STAT3/ROR-gamma levels in mice. Conclusions: These results demonstrate that STAT3/ROR-gamma, is a downstream mediator for IL-23–induced prostate metastasis in murine mice. IL-23 may represent an attractive therapeutic target or a biomarker in metastatic prostate cancer by blocking downstream effects. However, further studies are needed in larger samples to better investigate the implications of IL-23 in prostate cancer.
Prevalence of fractures among men with stage IV prostate cancer (S4PC).
Authors: Abdulhalim Abdulla M. , Onukwugha Ebere , Woods Corinne , Qian Yi , Arellano Jorge , Balakumaran Arun , Mullins C. Daniel , Hussain Arif
Published: February 2017

143

Background: Fractures (fx) are common in men with stage 4 prostate cancer (S4PC), resulting in significant clinical consequences, such as increased pain and decreased quality of life. The aim of this study was to estimate the prevalence of fx among men diagnosed with non-metastatic (M0) or metastatic (M1) S4PC and evaluate risk factors associated with fx. Methods: We estimated the prevalence of fx among men age 66 or older diagnosed with M0 or M1 S4PC using data from the U.S. SEER-Medicare datasets between 2000 to 2007. Men were followed through December 2009 or until they were lost to follow up. Codes indicating “pathologic fracture” or “fracture,” excluding codes suggesting accidents/falls in the 14 days prior to the fx, were used to identify fx. Results: Among 9,826 men with S4PC (M1 = 7301; M0 = 2525), 12.9% experienced a post-diagnosis fx based on the codes used. The prevalence of fx was nearly twice as high in men with M1 versus M0 S4PC (M1 = 14.7%; M0 = 7.5%). The median time from diagnosis of S4PC to first fx was five months for men with M1 S4PC versus 34 months for men with M0 S4PC. Compared to men with no fx, men who experienced fx were more likely to be older (20.3% vs. 17.8%), of white/non-Hispanic race (81.1% vs. 75.3%), have well (cancer grade 1) or moderately (cancer grade 2) differentiated tumors (48.7% vs. 41.7%), have a claim of osteoporosis (2.4% vs. 0.6%) or osteoarthritis (9.3% vs. 6.5%) in the year prior to S4PC diagnosis, and to have taken a bone mineral density (BMD) test (13.5% vs. 8.1%). All differences were significant at p<0.05 level. Overall, 92% of men did not receive BMD testing at any time post diagnosis despite the fact that 67% of the men received ADT. Conclusions: In men with M1 S4PC at diagnosis, the prevalence of fx is higher and the time to fx is substantially shorter than in men with M0 S4PC at diagnosis. Furthermore, most men with S4PC do not receive BMD testing. A significant need remains to monitor bone health and treat fx, particularly among M1 S4PC patients.
Optimal testosterone suppression on medical ADT should strive to suppress free testosterone levels to levels similar to orchiectomy: What is that value?
Authors: Yu Evan Y. , Getzenberg Robert H. , Smith Jordan , Hancock Michael L. , Smith Matthew Raymond , Malkowicz S. Bruce , Sieber Paul , Dalton James T. , Steiner Mitchell S.
Published: February 2017

144

Background: The goal of medical androgen deprivation therapy (ADT) for advanced prostate cancer is to provide an equivalency to orchiectomy based upon older assays for serum testosterone (T). Literature shows that based on more modern assays, medical ADT does not always provide optimal total T suppression equivalent to orchiectomy. With the understanding that free, or unbound, T is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free T to levels similar to orchiectomy. Free T has not been well studied in a substantial number of orchiectomized men. The purpose of this study was to examine a subpopulation of orchiectomized men in a clinical trial to determine the level of serum-free T in advanced prostate cancer. Methods: Baseline data was utilized from a double blind, randomized, placebo controlled trial (G300203) to determine the capacity of toremifene 80 mg to prevent bone fractures in men on ADT. This study included 1,389 men from 150 sites in the U.S. and Mexico. Baseline characteristics, including whether men were on medical ADT or status post orchiectomy, were available. Free T levels were assayed at baseline by radioimmunoassay (RIA) (Diagnostic Products Corporation) and are reported for men who underwent orchiectomy. Results: A subpopulation of 114 men underwent orchiectomy. Median age was 76 (range 51 to 90). Median serum free T level was 0.92 pg/ml (min. 0.35 pg/ml and max. 33.95 pg/ml) with a mean level of 1.71 pg/ml ± 2.77. Conclusions: This study is believed to be the largest cohort in which free T levels have been reported in men who underwent orchiectomy. In this cohort, median serum free T is approximately 0.9 pg/ml. This value could be considered to be the optimal testosterone suppression of free T with orchiectomy and represents the goal of medical ADT. At the time this study was performed, RIA was considered to be the standard but has since been shown to underestimate free T levels by 20 to 60%. Currently, equilibrium dialysis coupled with LC-MS/MS is the gold standard, but the results from this analysis provide us with increased understanding of the optimal level of free T in treating advanced prostate cancer. Clinical trial information: NCT00129142.
The effects of anticoagulant use in high-risk prostate cancer treated with radiotherapy on overall survival and biochemical control.
Authors: Chun Stephen G. , Jacobs Corbin D , Yan Jingsheng , Xie Xian-Jin , Choe Kevin S , Hannan Raquibul , Pistenmaa David A. , Lotan Yair , Roehrborn Claus G , Kim Dong W.
Published: February 2017

146

Background: High-risk localized prostate cancer (PC) has suboptimal treatment outcomes due to therapeutic resistance to radiation and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in high-risk PC. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit in patients treated with concurrent radiotherapy in patients with high-risk prostate cancer defined as Gleason Score (GS) 8 or higher, Stage T3a or higher, or prostate-specific antigen (PSA) of 20 or more. Methods: Analysis was performed of 74 patients identified who were treated with definitive external beam radiotherapy with National Comprehensive Cancer Network defined high-risk PC from 2005 to 2008 at The University of Texas Southwestern Medical Center. Of these patients, 43 took concurrent AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were explored. A minimum of 5 years of follow-up were available for all patients. Results: For patients taking any AC compared to no AC, there was improved FFBF compared to of 84.4% versus 62.1% (P = 0.0003), and for aspirin the FFBF was 83.7% versus 64% (P = 0.0008). Aspirin was also associated with reduced rates of distant metastasis of 12.2% versus 26.7% in patients who did not take aspirin (P = 0.039). On multivariate analysis, patients taking aspirin with PSA of 20 or more had 5 year OS 95.8% versus 70% (P = 0.031), and GS 9-10 had 5 year OS 88.2% versus 37.5% (P = 0.013). Conclusions: AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with PSA of 20 or more or GS 9 to 10 who are most likely to experience prostate cancer specific mortality. This hypothesis generating data suggests AC use may represent an opportunity to improve patient outcomes by overcoming therapeutic resistance.
Increasing use of radical prostatectomy for lower-risk prostate cancer in Denmark.
Authors: Roeder M. Andreas , Brasso Klaus , Christensen Ib Jarle , Johansen Jorgen , Langkilde Niels Christian , Hvarness Helle , Jakobsen Henrik , Carlsson Steen , Borre Michael , Iversen Peter
Published: February 2017

149

Background: Denmark introduced radical prostatectomy (RP) as the last Nordic country in 1995. Since then, a rapid increment in the Danish incidence of prostate cancer (PCa) is indicative of increasing opportunistic prostate-specific antigen (PSA) testing. We hypothesized that an increasing proportion of men undergo RP for lower-risk PCa. Methods: All patients undergoing RP in Denmark between 1995 and 2011 were included. Changes over time in age at surgery, preoperative PSA, clinical T-category, biopsy Gleason score (GS) are described. Tests for statistically significant changes in trends were performed using linear regression and Cochran-Armitage trend test. Results: Median age at surgery increased from 61.4 to 64.8 (p<0.0001) during the 16 year period. Median preoperative PSA declined from 11.5 to 7.9 ng/ml (p<0.0001). Distribution of biopsy GS changed significantly, especially after 2005. Biopsy GS=7 was found in 20.2% of the patients in 2005 compared to 57.1% in 2011. The proportion of T1 disease increased from 32% to 56%. The proportion of patients above age 65 increased from 26.8% to 48.3% in the 16 year period studied. To adjust for grade, PSA, and age migration, we analyzed changes in the proportion of men age over age 65, with PSA less than or equal to 10 ng/ml, biopsy GS≤3+4, and clinical T1 disease over time. In the 16 year period, this proportion increased from 2% to 16% (p<0-001) of the cohort undergoing RP in Denmark. Conclusions: Significant preoperative age, stage, and Gleason grade migration was found in this complete Danish nation-wide cohort of patients undergoing RP during the past 16 years. This has occurred in the absence of any major changes to the national Danish guidelines for diagnosis and treatment of localized PCa. This effect is likely attributed to an increasing use of PSA although national guidelines recommend against PSA screening. Further, new guidelines from the International Society of Urological Pathology have had a major impact on risk classification. According to recently published randomized trials, the risk of overtreatment of localized PCa with RP is an increasing problem in Denmark.
Long-term oncologic outcomes of neoadjuvant chemohormonal therapy followed by radical prostatectomy for patients with clinically localized, high-risk prostate cancer.
Authors: Silberstein Jonathan L , Poon Stephen A , Sjoberg Daniel , Vickers Andrew J. , Bernie Aaron , Konety Badrinath R. , Kelly William Kevin , Eastham James Andrew
Published: February 2017

153

Background: To determine long-term oncologic outcomes of radical prostatectomy (RP) after neoadjuvant chemo-hormonal therapy for clinically localized, high-risk prostate cancer. Methods: In this phase II multicenter trial of patients with high-risk prostate cancer (prostate-specific antigen greater than 20ng/ml, Gleason greater than or equal to 8, or clinical stage greater than or equal to T3), androgen deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered prior to RP. We report the long-term oncologic outcomes of these patients and compared them to a contemporary cohort who met oncologic inclusion criteria but received RP only. Results: Thirty four patients were enrolled in this study and followed for a median of 13.1 years. Within 10 years most patients experienced biochemical recurrence (BCR-free probability= 22%; 95% CI 10%, 37%). However the probability of disease-specific survival at 10 years was 84% (95% CI 66%, 93%) and overall survival was 78% (95% CI 60%, 89%). The chemohormonal therapy group had higher-risk features than the comparison group (N=123 patients) with an almost doubled risk of calculated preoperative 5-year BCR (69% vs 36%, p<0.0001). After adjusting for these imbalances the CHT group had trends toward improvement in BCR (0.76, 95% CI 0.43, 1.34; p=0.3) and metastasis free survival (0.55, 95% CI 0.24, 1.29; p=.2) although these were not significant. Conclusions: Neoadjuvant chemohormonal therapy followed by RP was associated with lower observed rates of BCR and metastasis compared to a prostatectomy only group; however these results were not significant. Because this treatment strategy has known harms and unproven benefit, this strategy should only be instituted in the setting of a clinical trial.
Methylation-guided stratification of patients with high-risk prostate cancer for the prediction of clinical failure.
Authors: Litovkin Kirill , Joniau Steven , Lerut Evelyne , Laenen Annouschka , Gevaert Olivier , Spahn Martin , Kneitz Burkhard , Isebaert Sofie , Haustermans Karin , Beullens Monique , Van Eynde Aleyde , Bollen Mathieu
Published: February 2017

155

Background: To explore differential DNA methylation of APC, CCDN2, GSTP1, PTGS2, and RARBas a tool to predict clinical failure (CF) in surgically treated patients with high-risk prostate cancer (PCa), as defined by a clinical stage T3a or higher, a biopsy Gleason score of 8 to 10 and/or pre-operative prostatic serum antigen levels more than 20 ng/ml. Methods: A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the marker genes. Formalin-fixed, paraffin-embedded radical prostatectomy samples from 218 patients with high-risk PCa, classified in a training and validation cohort, were analyzed. Kaplan-Meier analysis and Cox multivariate models were used. Results: First, high-risk PCa patients were ranked according to their GSTP1 methylation level, which varied from 0 to 80% in both cohorts. Next, we categorizedthe tumors into three groups based upon the GSTP1 methylation level: low methylation (LM, methylation less than 15%), moderate methylation ([MM], methylation 15 to 50%) and high methylation (HM, methylation more than 50%). When all five marker genes were combined, the median methylation values in the LM groups did not exceed 6% in both cohorts. In contrast, the median methylation values for the marker genes in the HM groups reached 45% in the training cohort and 50% in the validation cohort. Finally, the median methylation values in the MM groups amounted to 18% and 28% for the training and validation cohorts, respectively. Remarkably, patients belonging to the LM, HM, and the combined LM+HM groups had a 2- to 11-fold higher risk of CF as compared to those of the MM group, when correcting for established clinico-pathologic prognostic factors. In addition, the combined LM+HM group showed a significant association with cancer-related death in a multivariate analysis (Hazard ratio, 3.59) compared to the MM group, when both cohorts were combined for analysis. Conclusions: We found that differential methylation of GSTP1 allows the stratification of high-risk PCa patients into three molecular episubtypes, i.e. low, moderate and high DNA methylation level groups. Surprisingly, our data revealed that both low and high methylation levels of GSTP1 are independent predictors of CF.
Modeling acute urinary toxicity after radiotherapy for prostate cancer.
Authors: Carillo Viviana , Rancati Tiziana , Cozzarini Cesare , Villa Sergio , Botti Andrea , Casanova Borca Valeria , Cattari Gabriella , Civardi Francesco , Degli Esposti Claudio , Franco Pierfrancesco , Girelli Giuseppe , Maggio Angelo , Muraglia Alessandro , Palombarini Marcella , Pierelli Alessio , Pignoli Emanuele , Vavassori Vittorio , Zeverino Michele , Valdagni Riccardo , Fiorino Claudio
Published: February 2017

156

Background: DUE-01 is a multi-centric observational study aimed at developing predictive models of genito-urinary toxicity and erectile dysfunction for prostate cancer patients treated with conventional (1.8-2Gy/fr, CONV) or moderate hypofractionation (2.5-2.7Gy/fr, HYPO). Current analysis focused on modelling the relationship between the risk of IPSS≥15 (IPSS15end) at the end of radiotherapy and clinincal/dosimetric risk factors. Methods: Planning data and relevant clinical factors were prospectively collected, including DVH/DSH referred to the whole treatment and to the weekly delivered dose (DVHw/DSHw). Best discriminating DVH/DSH parameters were selected by the differences between patients with/without IPSS15end=1 (t-test). Bootstrap variable selection techniques (300 resamples) in the framework of logistic backward feature selection was used to improve model building (El Naqa, IJROBP 2006). Graphical and quantitative analyses of the variable selection process applied to bootstrap data replicates was used to avoid underfitting/overfitting and to assess the final multivariable model. Results: 247 patients were available (CONV:116, HYPO:131). Seventy one out of 247 (28.7%) reported IPSS15end=1. The most predictive dosimetric tools were the absolute weekly delivered dose (DSHw and DVHw). DSHw and DVHw were alternatively inserted in the bootstrap variable selection flow, together with clinical risk factors. Due to the number of events, a logistic model containing six variables was accepted On the basis of observed frequency of variables in the top six positions, a model including basal IPSS (median OR=1.22, p=0.00001), use of anti-hypertensives (median OR=2.7, p=0.01), absolute bladder surface receiving more than 10.5 Gy/week (s10.5w, median OR=1.16, p=0.0001), and s12.5w (median OR=1.07, p=0.005), was choosen. AUC of this model was 0.80. Silmilar results were obtained when using DVHw. Conclusions: Basal IPSS, use of anti-hypertensive drugs, s10.5w/v10.5w and s12.5w/v12.5w are the main predictors of IPSS>=15 at the end of radiotherapy Bootstrap variable selection technique gives the modeler more insight into the importance and stability of the different variables selected and allows development of more robust models
Using a combination of urine and plasma biomarkers for the development of a scoring sytem that can diagnose and predict prognosis of prostate cancer.
Authors: Albitar Maher , Ma Wanlong , Diep Kevin , Albitar Ferras S. , Fritsche Herbert A. , Shore Neal D.
Published: February 2017

163

Background: Relying solely on serum prostate-specific antigen (sPSA) to screen for prostate cancer (PCa) can lead to unnecessary biopsies. Biomarkers from urine and plasma were isolated to develop a detection scoring system for the presence of prostate cancer as well as to better predict aggressiveness. Methods: Urine and plasma specimens were analyzed from 141 patients (61 newly diagnosed PCa patients, 60 benign prostate hyperplasia (BPH) patients, and 20 post-prostatectomy patients) using polymerase chain reaction (PCR) for the levels of UAP1, PDLIM5, IMPDH2, HSPD1, PCA3, PSA, TMPRSS2, ERG, GAPDH, and B2M genes. Patient age, sPSA level, and PCR data were entered through multiple algorithms to determine models most useful for detection of cancer and predicting aggressiveness. Results: We developed an algorithm for distinguishing PCa from BPH (area under the receiver operating characteristic curve [AUROC] of 0.78). Another algorithm distinguishes patients with Gleason Score (GS) ≥ 7 from GS < 7 cancer or BPH (AUROC of 0.88). By incorporating the two algorithms into a scoring system, 75% of the analyzed samples showed concordance between the two models (99% specificity and 68% sensitivity for predicting GS ≥ 7), and 25% showed discordance. Conclusions: A scoring system incorporating two algorithms using urine and plasma biomarkers highly predicts the presence of GS ≥ 7 PCa in 75% of patients. In 25% of patients, the system can be used only to distinguish between the presence of cancer and benign pathology. Our algorithms may assist with both biopsy indication as well as patient prognosis. [Table: see text]
Prognostic utility of the cell cycle progression (CCP) score generated from needle biopsy in men treated with prostatectomy.
Authors: Bishoff Jay T. , Freedland Stephen J. , Gerber Leah , Tennstedt Pierre , Welbourn William , Reid Julia E. , Graefen Markus , Sangale Zaina , Tikishvili Eliso , Park Jimmy , Younus Adib , Gutin Alexander , Lanchbury Jerry S. , Sauter Guido , Brawer Michael K. , Stone Steven , Schlomm Thorsten
Published: February 2017

17

Background: We developed a prognostic RNA signature that is strongly associated with prostate cancer outcomes. The cell cycle progression (CCP) score has proven to have prognostic utility in predicting disease progression in various clinical settings utilizing biopsy, transurethral resection of the prostate (TURP) and post-prostatectomy specimens. Previous studies evaluating post-surgical outcomes were conducted using CCP gene expression measured in the prostatectomy specimen. Here, we demonstrate the ability of the CCP score to predict cancer progression, as measured by both biochemical recurrence (BCR) and metastatic disease after radical prostatectomy, using needle biopsy tissue. Methods: We evaluated the CCP score in three patient cohorts. These included men from the Martini Clinic (MC, N=283), the Durham VA Medical Center (DVA, N=176), and Intermountain Healthcare (IHC, N=123). The CCP score was derived from a simulated biopsy (MC) or diagnostic biopsy (DVA and IHC), and evaluated for association with BCR and metastatic disease in univariable analysis and after adjusting for other clinical information. Results: In all three cohorts, the CCP score was associated with BCR and metastatic disease. The association with BCR remained significant after adjusting for other prognostic clinical variables. In a combined analysis of all three cohorts (N=582), the CCP score was a strong predictor of BCR in both univariable (HR per Interquartile Range [IQR] = 1.68 [95% CI: 1.41, 1.99), p value<10−6]) and multivariable analyses (HR per IQR = 1.53 [95%CI: 1.28, 1.84], p value < 10−4). CCP score was the strongest predictor of metastatic disease in both univariable analysis (HR per IQR = 6.32 [95% CI: 3.41, 11.71, p value<10−7]), and after adjusting for clinical variables (HR per IQR = 4.83 [95% CI: 2.40, 9.74, p value<10−5]). Conclusions: The CCP score derived from a needle biopsy sample was strongly associated with adverse outcome after surgery. It was the strongest predictor of eventual metastatic disease of the tested variables including Gleason and PSA. These results indicate that the CCP score can be used at disease diagnosis to better define patient prognosis and appropriate clinical care.
Patterns and trends in management of locoregional prostatic adenocarcinoma with PSA ≥20 ngm/ML.
Authors: Trulson Jerry J , Huynh Danny , Islam Majdee , Rao Abishek , Pokala Naveen
Published: February 2017

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Background: Extremely high prostate specific antigen (PSA) at diagnosis has traditionally precluded a surgical approach for prostate cancer. This database study evaluates the national trends in management of patients with high PSA at prostate cancer diagnosis. Methods: Men age 75 or less with a diagnosis of prostatic adenocarcinoma and a PSA of 20ngm/ml and over were identified from the SEER 18 Database (2004 to 2009). Exclusion criteria included patients with metastatic disease at diagnosis, more than one primary cancer, unknown stage, unknown Gleason score, unknown treatment, or diagnosis at autopsy. Patients were analyzed for demographics, stage at presentation, treatment patterns, and survival using appropriate statistics. Results: A total of 15,485 patients with PSA between 20 and 98.8ngm/ml were identified. Mean age at diagnosis was 64±7.3 years. A total of 4,510 (29.1%) patients did not receive any definitive treatment (NDT group), 6,503 (52%) received Radiation, and 4,472 (28.9%) underwent surgery. A total of 531 patients underwent adjuvant radiation after surgery. The mean PSA of patients who underwent surgery (47.3ngm.ml) or RT (44.3 ngm/ml) was lower than the patients who did not have any definitive treatment (50.9 ngm/ml). Increasing age and increasing T and N stage were associated with a trend towards a surgical approach while Gleason score and PSA levels were not associated a trend towards surgery. Increasing age and Gleason score were associated with an increasing trend towards radiation while increasing PSA, T stage, and N stage were associated with a decreasing trend towards radiation. Increasing age and PSA was associated with an increasing trend towards NDT, while an increasing stage was associated with a reduced trend towards NDT. The N stage and Gleason score did not predict a trend for the NDT. Conclusions: The PSA level, even when very high, is not the sole factor that determines whether or not patients with prostate cancer receive surgery. Nationwide trends suggest that while radiation is the most common treatment modality undertaken by patients with PSA over 20 ngm/ml, patients younger than age 50 are more likely to undergo surgery irrespective of the PSA level.
Real-world utilization of the novel AR-targeted therapies in mCRPC management: An electronic medical records retrospective study.
Authors: Sartor A. Oliver , Mehta Jyotsna , Fonseca Eileen , McGuiness Catherine Balderston , Petrilla Allison , Su Zhen
Published: February 2017

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Background: New androgen receptor (AR) targeted therapies, including abiraterone (AA) and enzalutamide (EZ), have recently been approved for mCRPC management. This study examined use of AA in community oncology practices to understand real world practice patterns. Methods: Deidentified EMRs were retrospectively analyzed for cancer staging, tumor histology, metastatic coding, lab results and drug orders from 78 practices (300+ locations; 37 states; >500,000 cancer patients) to identify mCRPC patients initiating AA between May 2011-Jan 2013, provided there was one year of baseline data prior to starting AA and 3 mos of data after initiating AA. Patients were excluded if participating in clinical trials, diagnosed with other primary neoplasms, or from practices inconsistently reporting data. Key outcomes were changes in systemic anti-cancer therapy, discontinuation of AA, and death during the first 3 mos after AA initiation. Results: Of 3,930 mCRPC patients observed with an oncology visit during study period, 356 met criteria for analysis (mean age at AA initiation 73.3 yrs); 37% of patients (n=131) received prior docetaxel (D) and 16% of patients (n=56) received prior cabazitaxel (C) before starting AA. Of these 356 patients, 153 (43%) experienced a change of therapy or death in the 3 mos post-starting AA. Of the total patients, 19% (n=66) discontinued AA, while 17% (n=62) changed systemic therapy. Of those changing therapy, 5 patients started EZ, 20 CBZ, 24 D. A total of 11% of the total patients (n=39) died within 3 mos of starting AA. Conclusions: Real-world treatment data suggests more than 57% of patients were alive and continuing AA while 43% discontinued AA/changed treatments, or died within 3 mos of starting AA. EMR data provide important insights into real world practice; limitations include inconsistency in data entry and difficulty in aligning prescription start dates with actual dispensed medication. [Table: see text]
Evidence for circulating tumor cell (CTC) alkaline phosphatase (AP) expression in men with bone-metastatic castration-resistant prostate cancer (CRPC) during abiraterone acetate treatment.
Authors: Armstrong Andrew J. , Bitting Rhonda Lynn , Kemeny Gabor , George Daniel J.
Published: February 2017

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Background: Serum alkaline phosphatase (AP) changes in men with metastatic prostate cancer have been described since the Nobel Prize winning discovery of the hormonal dependence of PC. High serum AP is independently associated with mortality in men with castration-resistant prostate cancer (CRPC) and reductions in AP with treatment are favorably prognostic. Transient rises in AP may occur during treatment initiation and reflect bone remodeling/healing. The source of serum AP in men with metastatic prostate cancer, however, remains unclear. We hypothesize that cancer cell osteomimicry and epithelial plasticity may contribute to serum AP elevations in these men. Methods: We examined the expression of AP in the circulating tumor cells (CTCs) of men with metastice CRPC on abiraterone acetate who had elevated serum AP to determine if one possible source of serum AP may be tumor-derived rather than host/bone derived. CTCs were isolated using the CellSearch method and EpCAM ferromagnetic capture, and only CD45 negative cells were considered CTCs. AP was evaluated using immunofluorescence and real time positive and negative controls. Liver function was evaluated to ensure lack of confounding with liver-derived AP. Results: We identified AP to be commonly expressed in the CTCs of men with CRPC who had high serum AP, with no expression in patient leukocytes. One patient had a transient rise in serum AP with no change in other liver enzymes during a dramatic response to abiraterone acetate while his prostate-specific antigen and CTC declined. AP expression was evident and common in his CTCs during this serum AP flare. A second patient was found to have common CTC AP expression in both CK+ and CK- CTCs. This patient had evidence of AR amplification, PTEN loss, and TMPRSS2-ERG fusion in his CK- and CK+ CTCs, accompanied by a high number of OB-cadherin + CTCs, indicating likely osteomimicry and plasticity of these clonal epithelial tumor cells. Conclusions: We provide clinical evidence that PC CTCs express AP, supporting the hypothesis that AP expression is associated with osteomimicry as part of the biology of epithelial plasticity in prostate cancer. These findings support the existence of multiple CTC phenotypes, the clinical significance of which is unknown.
Predicting positive bone marrow biopsies (BMBs) in patients (PTS) with advanced prostate cancer (APC).
Authors: Lorente David , Omlin Aurelius Gabriel , Pezaro Carmel Jo , Tunariu Nina , Ferraldeschi Roberta , Riisnaes Ruth , Mateo Joaquin , Sheridan Elizabeth , Perez Lopez Raquel , Nava Rodrigues Daniel , Crespo Mateus , Figueiredo Ines , Zafeirou Zafeiris , Altavilla Amelia , Attard Gerhardt , De Bono Johann Sebastian
Published: February 2017

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Background: Advanced prostate cancer (APC) is a molecularly heterogeneous disease, with evidence of clonal evolution that could be responsible for resistance to treatment. About 90% of patients (pts) with APC have bone metastases. The acquisition of a bone marrow biopsies (BMBs) is a safe and feasible technique for obtaining tissue, with a low rate of complications. We hypothesized that pre-biopsy clinical variables may increase the success rate of BMBs in APC. Methods: Standard BMBs of the iliac crest were performed in APC pts between October 2011 and June 2013. All pts signed ethics approved consent. In the control cohort (n=10) BMBs were collected in pts with normal CT and bone scan appearance. Minimum, maximum, and mean Hounsfield Units (HU) of the iliac crest on pre-biopsy CTs were determined. Clinical and laboratory variables were collected from the electronic record system. Biopsies were defined as containing 50 or more or 1 to 50 malignant cells or none (negative). Univariate analysis was performed to determine variables associated with biopsy positivity with 50 or more cells. For variables with p value<0.1, the optimal cut-off point was determined by ROC curve analysis. A multivariate analysis with optimal cut-off points was then performed. Results: A total of 71 BMBs were performed in 57 pts. None of the control biopsies in pts with normal CT and bone scan (10 of 10) contained tumor. A total of 46 of 61 BMBs (75.4%) were positive. 38 of 61 (62.3%) contained 50 or more cells. Prior treatments were docetaxel in 57 (79.2%) and abiraterone in 42 (58%) pts. Bisphosphonates had been used in 21 (28.8%) pts. The significant variables on univariate analysis were ALP more than or equal to 200 IU/L (p=0.059), prostate-specific antigen (PSA) more than or equal to 225 ng/mL (p=0.008), lactate dehydrogenase (LDH) more than or equal to 200 IU/L (p=0.09), mean HU more than or equal to 125 (p=0.000) and maximum HU more than or equal to 550 (p=0.001). These factors were tested in multivariate analysis. Only PSA and mean HU were significant in multivariate analysis. The combined PSA and mean HU score had an ROC AUC of 0.79. Conclusions: A combination of PSA and mean HU on CT could assist physicians in selecting APC patients/ iliac crest site more likely to have a positive BMB. Prospective evaluation is ongoing in a validation set.
Comprehensive geriatric assessment (CGA) in men age 70 or over with localized prostate cancer.
Authors: Osborne Georgina E.C. , Gilbert Duncan Charles , Robinson Angus , Nikapota Ashok , McKinna Fiona , Villanueva Michelle , Ring Alistair E.
Published: February 2017

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Background: There has been a four-fold increase in incidence of prostate cancer (PC) in men age 70 or older in England in the last 30 years. Which treatment (surgery, radiotherapy, or surveillance) is right for which patient depends on a number of factors including the risk of death from competing causes and fitness for the proposed treatment. Objective assessments such as those included in a Comprehensive Geriatric Assessment (CGA) might be helpful in this regard. The primary objective of this study is to describe CGA scores of a cohort of older men with PC. The secondary objectives are to examine if a single score (the Vulnerable Elders Survey [VES-13]), is a suitable screening test for a full CGA and to assess whether scores predict radiotherapy toxicity. Methods: Patients age 70 and older with localised PC completed a CGA prior to commencement of radical radiotherapy. The CGA assessed WHO performance status (PS), activities of daily living (ADL), instrumental activities of daily living (IADL), Charlson co-morbidity index, number of medications, mini-nutritional assessment (MNA), social network index (SNI), G8 score, and VES-13. Participants had acute radiotherapy toxicity assessed 12 weeks post-treatment completion. Results: As of September 2013, 100 patients had been recruited. Median age was 74.5 (range 70 to 82). Ninety five percent of patients had a PS less than two. Using the VES-13 tool, 5.2% scored greater than two. 22.6% scored less than 14 on G8 scoring. Additionally, 13.5% were not fully independent on ADLs, 4.2% were not fully independent on IADLs, 32.3% scored greater than one on the Charlson Index, 12.3% had a history of depression or dementia, and 52.9% were on more than three prescription medications. Fourteen percent were at risk of malnutrition and 2.3% were malnourished according to MNA scores, 25.0% had SNI scores less than three and 9.3% of patients had fallen at least once in the preceding three months. Twelve week follow-up data regarding acute radiotherapy toxicity is currently being collected; these will be correlated with the CGA components and presented at the 2014 ASCO Genitourinary Cancers Symposium. Conclusions: These data demonstrate that many older men with localised prostate cancer are vulnerable according to a CGA. Correlations observed between radiotherapy toxicity and CGA scores would have important implications for therapeutic decisions.