bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of ARV7 expression with molecular and clinical characteristics in prostate cancer.
Authors: Joshi Himanshu , Pinski Jacek K.
Published: February 2017

109

Background: Prostate cancer (PC) is the most common cancer in men over the age of 60 and the second leading cause of cancer mortality in the United States. Clinicopathological parameters such as Gleason score, tumor volume, surgical margins, prostate-specific antigen (PSA), Ki-67 index and clinical stage are used as prognostic markers for clinical outcomes. Identification of novel molecular markers could improve our understanding of the clinical behavior of this disease. Androgen receptor isoforms, in particular variant 7 (ARV7 or AR3) have been recently studied for elucidating their potential role in PC progression, associated with epithelial-mesenchymal transition (EMT), disease aggressiveness, increased proliferation and therapeutic resistance. Our study is analyzing the association of ARV7 mRNA expression to clinical characteristics and is analyzing the genomic data to identify differentially altered genes by ARV expression status, summarized as a potential functional network. Methods: We obtained the TCGA public dataset of prostate adenocarcinoma tumors (N=499) that included the clinical data, gene and isoform expression and mutation data. Cases were categorized into ARV7 over-expressing (ARV+) and normal or low expression (ARV –/N) by using a cut-off of upper 25th percentile of the background genomic expression. Analysis was performed in R and Perl by using custom-made scripts. Differentially altered genes and pathways were identified and were summarized as potential functional networks. Results: We categorized 30 out of the 499 tumors as ARV+. ARV7 over-expression was found to be significantly associated with older age at diagnosis (>70), advanced clinical stage, nodal involvement, high Gleason score and a poor therapeutic response. We also observed a trend towards shorter disease-free survival among ARV+ tumors. In addition, ARV+ tumors showed significantly higher number of mutations in 20 key regulatory pathways including Jak-STAT signaling, homologous recombination, ErbB and Wnt signaling pathways. Conclusions: ARV7 overexpression is associated with genomic alterations in key regulatory pathways and poorer clinical outcome in PC patients.
Dosimetric predictors of sexual function decline following LDR brachytherapy for prostate cancer (PCa).
Authors: Mian Omar Y , Robertson Scott P. , Narang Amol , Aggarwal Sameer , Bae Hee Joon , Gergis Carol , McNutt Todd R. , Tran Phuoc T. , DeWeese Theodore L. , Song Danny
Published: February 2017

113

Background: Conventional dosimetric standards for implant quality do not adequately predict patient reported QoL measures following prostate brachytherapy. We used a dynamic learning knowledgebase (Oncospace) to explore relationships between dose and patient-reported outcomes. Methods: Patient reported quality of life outcomes were prospectively collected for 366 patients with stage cT1-T2 PCa over a 10 year interval. Patients received Pd-103 seed implantation under real-time ultrasound guidance, and completed a QoL instrument (IIEF-5) prior to treatment and at follow-up. Multivariate risk models were used to evaluate dose/toxicity relationships and the Oncospace learning environment generated prediction models using granular dose volume relationships. Results: Median follow-up was 36 months (SD 28.5). In the cohort, 23.7% (n = 87) received combined brachytherapy and EBRT; 14.7% (n = 54) had received prior androgen suppression therapy. Sexual QoL data at minimum of 2 years was available in 141 men. The mean decrement in sexual function per the IIEF-5 instrument was 3.76 points (SD 10.3), with 17.0% of men reporting a decrement of 10 points or greater. There was no significant association with prior androgen suppression (p = 0.20) or combined EBRT use (p = 0.69). DVH curves were queried and dichotomized according to stable sexual function vs significant decline ( > 10) at 2 years post-implant. A logistic regression model was used to generate probability surface maps of volumetric dose effects on outcomes. Logistic regression revealed a correlation between dose to the cavernosal nerves and total SHIM score throughout the high dose region of the DVH curve (p < 0.05). No similar dose/volume correlation with sexual function emerged for structures. Conclusions: Granular dose/volume and toxicity correlation using the Oncospace learning environment exposed a statistically significant relationship between volumetric dose to the cavernosal nerves and sexual function decline in patients undergoing LDR brachytheramarpy. Minimization of dose to the cavernosal nerves may preserve sexual function after permanent prostate seed brachytherapy.
Does prostate inflammation on a negative prostate biopsy vary by race? Results from the REDUCE study.
Authors: Vidal Adriana , Howard Lauren , Moreira Daniel , Castro Ramiro , Andriole Gerald L. , Taioli Emanuela , Freedland Stephen J.
Published: February 2017

116

Background: Prostateinflammation is linked with prostate cancer. However, whether prostate inflammation varies by race is unclear. Methods: We analyzed baseline acute and chronic prostate inflammation by race in REDUCE. REDUCE was a 4-year, multicenter, placebo-controlled study where all men received a single, negative prostate biopsy within 6 months prior to enrollment. Among 8,046 men who met the inclusion criteria, we included those with data on baseline biopsy prostate inflammation, acute/chronic or none, determined by central pathology. Logistic regression was used to compare prostate inflammation by race, and models were adjusted for demographic and clinical features. Results: Of the 8,046 men, 7,326 were white (91.1%), 184 (2.3%) black, 132 (1.6%) Asian, 323 (4.0%) Hispanic, and 81(1%) unknown. Seventy eight percent of men had chronic and 15% had acute prostate inflammation. Men with chronic inflammation were older (p<0.001), while men with acute inflammation were younger (p<0.001) compared to men with none prostate inflammation. Both acute and chronic inflammation was associated with lower PSA (all p≤0.0001), smaller prostate volume (all p≤0.0001) and geographic region (all p≤0.006). On crude analysis, compared to whites, Asian men were two times more likely to have acute prostate inflammation (OR=1.92, 95%CI: 1.29-2.85, p=0.001), whereas the associations with Hispanic and black race were not significant (all p≥0.39). However, on multivariable analysis, black men were 36% less likely to have acute prostate inflammation (OR=0.64, 95%CI: 0.41-0.99, p=0.04), whereas the likelihood of having acute prostate inflammation remained high in Asians (OR=1.85, 95%CI: 1.25-2.85, p=0.004). No associations by race were found with chronic prostate inflammation. Conclusions: Given that at the population level, black race is a high risk factor for PC and Asian men have lower risk of PC, these data indicate that the presence of acute inflammation in a negative prostate biopsy could be an indication of future PC risk. Further studies to confirm these findings are needed. Clinical trial information: NCT00056407.
Utility of PCA3 and TMPRSS2:ERG urinary biomarkers in African American men undergoing prostate biopsy.
Authors: Feibus Allison H. , Sartor A. Oliver , Moparty Krishnarao , Kattan Michael W. , Chagin Kevin M. , Ledet Elisa M. , Levy Justin , Lee Benjamin , Thomas Raju , Silberstein Jonathan L.
Published: February 2017

126

Background: To determine the performance characteristics of urinary PCA3 andTMPRSS2:ERG (T2:ERG) in a racially diverse group of men. Methods: Following IRB approval, from 2013-2015, post digital rectal exam (DRE) urine was prospectively collected in patients without known prostate cancer (PCa), prior to biopsy. PCA3 and T2:ERG RNA copies were quantified and normalized to PSA mRNA copies using Progensa assay (Hologic, San Diego, CA). Prediction models for PCa and high-grade PCa were created using standard of care (SOC) variables (age, race, family history of PCa, prior prostate biopsy and abnormal DRE) plus PSA. Decision Curve Analysis was performed to compare the net benefit of using SOC, plus PSA, with the addition of PCA3 and T2:ERG. Results: Of 304 patients, 182 (60%) were AA; 139(46%) were diagnosed with PCa (69% AA). PCA3 and T2:ERG scores were greater in men with PCa, ≥ 3 cores, ≥ 33.3% cores, > 50% involvement of greatest biopsy core and Epstein significant PCa (p-values < 0.04). PCA3 added to the SOC plus PSA model for the detection of any PCa in the overall cohort (0.747 vs 0.677; p < 0.0001), in AA only (0.711 vs 0.638; p = 0.0002) and non-AA (0.781 vs 0.732; p = 0.0016). PCA3 added to the model for the prediction of high-grade PCa for the overall cohort (0.804 vs 0.78; p = 0.0002) and AA only (0.759 vs 0.717; p = 0.0003) but not non-AA. Decision curve analysis demonstrated significant net benefit with the addition of PCA3 compared with SOC plus PSA. For AA, T2:ERG did not improve concordance statistics for the detection any or high-grade PCa. Conclusions: For AA, urinary PCA3 improves the ability to predict the presence of any and high-grade PCa. However for this population, T2:ERG urinary assay does not add significantly to standard detection and risk stratification tools.
Ability of an epigenetic assay to identify anterior prostate tumors based on a negative 12-core biopsy.
Authors: Morgan Todd Matthew , Salami Simpa Samuel , Wei John Thomas , Palapattu Ganesh S. , Gursky Amy , Van Criekinge Wim , Van Neste Leander , Mehra Rohit
Published: February 2017

131

Background: There is increasing awareness that anterior-predominant prostate cancers (PCa) are poorly sampled by 12-core transrectal ultrasound-guided (TRUS) prostate biopsies. Approximately one-fifth of all prostate tumors occur in this area, and many are high grade and extend beyond the prostatic capsule. An epigenetic assay, detecting PCa-specific DNA-methylation of GSTP1, RASSF1 and APC has shown to be a significant predictor for the presence of PCa in histopathologically cancer-negative biopsies through a cancer-associated field effect. It is currently unknown whether the field effect from an anterior-predominant cancer may be detected in standard posteriorly-directed sextant biopsy specimens. Methods: Seven patients with at least one prior negative TRUS biopsy were subsequently diagnosed with anterior-only PCa based on a transperineal mapping template prostate biopsy (MTPB). Three patients were diagnosed with low-grade Gleason score (GS) 6 tumors and four patients with GS ≥7 tumors. The outcome of the MTPB was compared with the result of the epigenetic test performed on the prior cancer-negative TRUS biopsy. Results: MTPB included a median of 68 cores (IQR 53-76). A total of 6 patients (86%) were methylation-positive at initial biopsy, suggesting that the field effect from these anterior-predominant cancers extends to the region of TRUS biopsy sampling. No methylation was found for one patient with only one GS6 positive core at MTPB and a tumor volume of 4%. Methylation intensities were higher for patients with GS ≥7 compared to those with GS6. A logistic regression model combining these intensities with traditional risk factors (PSA, age, TRUS-biopsy pathology and DRE) indicated higher risk scores for high-grade tumors. Conclusions: Aberrant DNA-methylation patterns are present in normal-appearing tissue from TRUS biopsy of patients with anteriorly located tumors. Although a small study, this is a unique cohort that underwent extensive sampling at re-biopsy demonstrating the presence of an anterior-predominant tumor. These results indicate that an epigenetic assay may be valuable even in patients with negative posteriorly-directed TRUS biopsies to detected anterior-predominant PCa.
Evaluation of MRI/TRUS fusion targeted biopsy versus 12-Core standard biopsy with pre-biopsy 1.5 Tesla multi-parametric MRI for diagnosis of prostate cancer in a community cancer center.
Authors: Bandyk Mark Gregory
Published: February 2017

139

Background: Academic centers report the magnetic resonance imaging (MRI)/ transrectal ultrasound (TRUS) fusion biopsy increases detection of high−risk and high Gleason score (GS) prostate cancer (CaP) as compared to standard 12−core biopsy among men for suspected CaP. This prospective trial evaluated the utility and benefits of performing MRI/TRUS fusion biopsy in a community cancer center. Methods: Men suspected of CaP underwent prostate multi−parametric magnetic resonance imaging (mpMRI) using a 1.5 tesla GE 450W GEMS magnet with a 32 channel phased anterior array coil to identify suspicious regions for prostate cancer. Regions were graded with Prostate Imaging Reporting and Data System (PI−RADS V2.0) by a single radiologist (5 years of experience). Men underwent concurrent MRI/TRUS fusion targeted and 12−core standard biopsies using an image guided fusion system. This prospective trial evaluated 79 men for number of positive biopsies by GS, biopsy technique and cohort (biopsy naïve, prior negative biopsy and CaP under surveillance). McNemar test was used for statistical analysis. Results: Study group included 79 men (mean age 66 years) with mean PSA 8.25 ng/mL. Cancer detection rate (CDR) and GS for the entire cohort by biopsy technique were determined. Overall, target biopsy (TB) diagnosed more GS ≥ 7 versus the 12−core standard biopsy (SB) (26 vs 18) and less GS6 (13 vs 21) (p = 0.057). Exact agreement was demonstrated in 66% of cases between TB and SB for GS ≥ 7, GS6 and no cancer. SB found cancers in 11 men missed by the TB, but 73% of these cancers were low grade GS6. TB of higher PI−RADS category lesions found more and higher grade cancers: 73% PI−RAD 5, GS ≥ 7; 80% PI−RAD 4, GS > 6; and 73% PI−RAD 3 were benign. In the biopsy naïve group (32 men), TB detected more GS ≥ 7 than SB (19 vs 13) (p = 0.11). Conclusions: Utilizing a mpMRI with a 1.5 tesla magnet and no endorectal coil, these encouraging preliminary results suggest MRI/TRUS fusion biopsy can be validated in the community for CaP detection. Results support a new paradigm in CaP detection utilizing pre−biopsy mpMRI and targeting higher PI−RADS lesions possibly eliminating SB.
Imaging characteristics of patients with prostate cancer with favorable 17-gene genomic prostate score on 3T multiparametric prostate MRI.
Authors: Katz Aaron , Liu Corinne , Kosinski Kaitlin E.
Published: February 2017

14

Background: Our practice utilizes a biopsy-based 17 gene test that is clinically validated as a predictor of favorable pathology and used to guide use of active surveillance for men with very low, low, and intermediate risk prostate cancer. The purpose of this study was to evaluate the imaging characteristics and PIRADS score of prostate cancer patients with a Genomic Prostate Score (GPS) indicating favorable pathology. Methods: 300 consecutive 3T Multiparametric Prostate MRI (MP-MRI) were identified from March 26, 2012, to June 29, 2015. Thirty patients (age 44-84 years) with GPS scores indicating favorable pathology were included in the study. Prostate Imaging Reporting and Data System (PIRADS) scores were assigned to each MP-MRI. MRI index lesions were defined as discrete hypointense T2 signal with at least one anatomically corresponding abnormal functional MRI parameter (diffusion weighted and dynamic contrast-enhanced images). The MRI examinations were evaluated for number and laterality of MRI index lesions and in relation to biopsy pathology findings after the MP-MRI was performed. Results: Out of 30 MP-MRI, 7 (23.3%) PIRADS 5, 10 (33.3%) PIRADS 4, 10 (33.3%) PIRADS 3, 1 (3.3%) PIRADS 2, and 2 (6.7%) PIRADS 1. Thirteen (43%) had bilateral MRI index lesions. Twenty-six (87%) MP-MRI had 1-3 MRI index lesions, 2 (7%) had 4-6 MRI index lesions and 2 (7%) had no index lesions. Six (20%) patients underwent curative treatment. Four (13.3%) patients underwent a transrectal ultrasound guided targeted biopsy and one underwent a prostatectomy after the MP-MRI. One harbored Gleason 7 with a PIRADS 1, 2 harbored Gleason 7 with PIRADS 5, and two were benign with PIRADS scores of 3 and 4. Conclusions: Patients with prostate cancer with a GPS score indicating favorable pathology had PIRADS scores ranging from 5 to 1, with the majority indicating either high or very high likelihood of harboring clinically significant cancer. This may imply that MP-MRI should continue to play an important role in stratifying patients with prostate cancer, even in those with favorable pathology. A study with a larger sample size and biopsy results after the initial MP-MRI to look for tumor upgrading is needed.
Prediction of postoperative histology in patients with prostate cancer using preoperative Ga-68-PSMA-PET/CT.
Authors: Boegemann Martin , Semjonow Axel , Breyholz Hans-Joerg , Schrader Andres Jan , Krabbe Laura-Maria , Weckesser Matthias , Schaefers Michael , Barth Peter J. , Huss Sebastian , Rahbar Kambiz
Published: February 2017

144

Background: Recently developed 68Ga labeled prostate specific membrane antigen (PSMA) ligands were introduced as diagnostic tools to detect prostate cancer (PCa), PCa relapse and metastases with high accuracy. In this study we assessed the usability of preoperative PSMA-PET/CT information on congruency of spread of PCA compared with postoperative PCa-maps derived from radical prostatectomy (RPE) specimens. Methods: We referred 6 patients with biopsy proven high risk PCa to PSMA-PET/CT prior to RPE. Whole body PET/CT (Biograph mCT with 128 slice CT, Siemens) was performed 62±8 minutes after injection of 160±31 MBq [68Ga]-PSMA-HBED-CC (DKFZ-Ga-PSMA-11) as described by routine acquisition protocol. After RPE, prostate specimens were processed in the local pathology department. Topographical analysis of extension of PCa was reconstructed from representative slides on a schematic diagram resulting in a PCa-map of the prostate. After aligning the cutting planes of the PSMA-PET/CT to the PCa-map we defined 20 segments of the prostate and the seminal vesicles. We measured the maximum standard uptake value (SUV) of PSMA activity of the respective segments and compared the concordance of PSMA-positive and -negative areas with those of PCa and no PCa on the PCa-maps. We calculated sensitivity, specificity, positive and negative likelihood ratios (LR) taking available segments into account. Results: 106/112 segments were analyzed. 8 segments were excluded due to spillover of PSMA-activity in bladder urine. All but 3 segments with no PCa on the PCa-maps showed no uptake in PSMA-PET/CT (Specificity = 92%). The sensitivity of PSMA-PET/CT for showing PCa areas was equally 92%. The positive and negative LR for PSMA-PET/CT detecting or ruling out PCa was 11.5 and 0.09, respectively. Conclusions: This preliminary proof of concept study shows that prediction of later pathologic results in RPE-specimens could be estimated by preoperative PSMA-PET/CT. With optimized acquisition protocols it may be possible to improve our preliminary results. Perspectively PSMA-PET/CT may be helpful for identifying PCa suspicious lesions prior to prostate biopsy and support decision making prior to RPE or radiation therapy.
Evaluation of the clinical advantage of endo-rectal balloons (ERBs) for prostate treatments.
Authors: Barton Sarah J , Stratford Julia , Brand Douglas , Thompson Catherine , Taylor Cathy , Logue John P. , Wylie James , Coyle Catherine , McWilliam Alan , Choudhury Ananya
Published: February 2017

148

Background: The challenge of prostate and rectal motion during radiotherapy has been firmly established, both these problems are exacerbated by rectal instability. A number of different mechanical methods have been explored to see if the rectum can be stabilised. This study aimed to establish whether there is a clinical advantage in the use of ERB’s for the treatment of prostate patients, assessing inter-fractional prostate stability and dose to the rectum. Methods: This planning study was based on 10 patients with 2 sets of CT and Cone beam CT (CBCT) data with and without an ERB in situ. The ERB was a 100cc air filled RectalPro balloon. CBCT scan with and without the ERB were taken on the same day. The scans were contoured and planned using pinnacle version 9.8 with rotational arc therapy to a dose of 60Gy in 20 fractions, for an Elekta Agility treatment unit. An assumption was made that the prostate stability was directly related to the rectal stability. Based on this assumption, comparisons of the rectal position and dose on the CBCT verses the respective CBCT were made. The rectal DVH on the plans for the ERB verses no ERB were compared and a two-tailed T-test was used for statistical analysis of all comparisons. Results: Positional analysis demonstrated 12% improvement in the dice coefficient similarity score of the rectum for the ERB (P=0.0003). This only correlated to a significant improvement in the AP movement at mid prostate for the ERBs (P=0.031). The ERB position was seen to be influenced by the angle of insertion. Removal of the CBCT data from the 4 ERBs with largest deviations in insertion angle significantly reduced the inter-fractional movement seen with the ERBs. The lower rectal doses showed an improvement of around 8% for the ERB group, although for the 57Gy dose was 2.5% better with no-ERB as shown in the Table. Conclusions: There is a clinical and statistical benefit in the dose reduction for the rectal wall in the use of ERB’s for prostate radiotherapy. Although the ERB position needs to be confirmed with IGRT to remove the potential for inter-fractional positional error. [Table: see text]
Effect of caloric restriction on the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers.
Authors: Schiewer Matthew Joseph , Gitman Robert Scott , Trabulsi Edouard John , DeAngelis Taziana , Kelly William Kevin , Gomella Leonard G. , Knudsen Karen E. , Dicker Adam , Simone Nicole Lynn
Published: February 2017

16

Background: Locally advanced prostate cancers (LAPC) are aggressive, have poor prognosis, and are associated with high recurrence rates and conversion to castrate resistance. The molecular underpinnings of LAPC are being investigated to identify novel therapeutics. Animal models have shown that caloric restriction (CR) can potentially prevent the initiation of prostate cancer. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors. Methods: To assess the effect of CR with radiation in vivo, 6 week old male nude mice were injected with LNCaP (hormone sensitive, N = 60) or PC3 (hormone refractory, N = 60) tumor cells. Once tumors were palpable, mice were randomized to be treated with one of 4 conditions: ad libitum (AL) diet, 8Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. Results: After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (p < 0.01) and an 80% reduction with CR+RT (p < 0.01). After LNCaP tumor injection, compared with ad libitum, the mice had a 49% reduction in tumor size with CR and a 55% reduction with CR+RT (p < 0.01). Tissue evaluation of mice treated with CR or CR+RT from both the LNCaP and PC3 models revealed decreased proliferation via Ki-67 and increased apoptosis with cleaved caspase-3 levels. Furthermore we establish significant changes of the pro-inflammatory IGF-1R pathway hypothesized to play in intricate roll in prostate cancer; down regulation of serum IGF-1R, IRS-1, PI3K, pAKT, and IGF-1:IGF-BP3. Conclusions: For the first time, we have shown that the efficacy of radiation can be increased by decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models. Future clinical trials should consider the innovative use of CR to augment standard cancer therapy as it has the potential to change the biology of tumors and enhance the opportunity for clinical benefit.
Do patients and physicians perceive PSA screening discussions the same?
Authors: Talcott James Austin , Aharonoff Gina , Bezuhly Maureen , Osborne Michael P.
Published: February 2017

160

Background: Shared decision making is recommended for prostate-specific antigen (PSA) screening. We are performing a prospective randomized trial of educational interventions to improve screening compliance at an urban academic medical center. We hypothesize that patient and provider characteristics providers will affect compliance. We report the first results for PSA screening. Methods: In a cluster-randomized trial of educational supports for providers, we are recruiting an age- and sex-stratified sample of 216 patients aged 30 to 89 years undergoing an annual physical examination, 18 patients of each of 12 primary care physicians at two affiliated hospitals. Screening guideline format (color-coding) and academic detailing were randomly assigned in a 2 x 2 design. Surveys occurred immediately post-encounter to record recollections of screening discussions, recommendations and plans. Results: We report on the first 44 of 108 planned male participants. Most were white (77%), had a college degree (83%), and currently married (59%). When providers reported a PSA discussion, 13% of patients disagreed, while 23% of patients disagreed when their provider reported a PSA discussion. Discrepancies also occurred on additional elements of informed decision-making (data not shown). Reports also disagreed on physician recommendations: 2 of 8 patients (25%) disagreed with the physician’s report of recommending screening and 6 of 12 patients (50%) disagreed with the physician’s report of not recommending it. Half of patients (49%) reported distress at getting PSA results, but only 5% reported “a lot” of distress. Over half (58%) reported that PSA testing protected against prostate cancer “a lot.” No physician reported recommending PSA testing to men under age 50 or over age 70, but 1 of 6 men under 50 and 3 of 3 men over 70 reported that their physician had recommended testing. Conclusions: In a highly educated population of men and physicians surveyed immediately after their encounter, reports of whether PSA screening had occurred, the information that had been discussed and the recommendation had important discrepancies. Important differences may exist between patients and physicians in perceptions of PSA screening discussions. Clinical trial information: NCT02430948.
Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies (AR Tx) in mCRPC patients.
Authors: Scher Howard I. , Graf Ryon , Louw Jessica , Jendrisak Adam , Johnson Ann , Greene Stephanie , Rodriguez Angel , Schreiber Nicole A. , McLaughlin Brigit , Dugan Lyndsey , Fleisher Martin , Lee Jerry , Wang Yipeng , Marrinucci Dena C. , Landers Mark , Dittamore Ryan Vance
Published: February 2017

163

Background: AR directed Tx, including Abiraterone (A) and Enzalutamide (E), prolong survival in patients with mCRPC and are FDA approved. After primary Tx with either A or E, the response to E or A is decreased as is the duration of response. NGS tissue sequencing of mCRPC shows a range of disease phenotypes and genotypes which are associated with increased tumor heterogeneity. Single site biopsy, may not represent the diversity of disease. Our objective is to develop biomarkers of heterogeneity from the analysis of single cells from patients with mCRPC. Methods: 221 blood samples from 179 unique patients (pts) were collected from pts about to begin AR Tx (n = 150) or Taxanes (n = 71). Samples were analyzed with the Epic Sciences platform. Analysis included digital pathology of 20 discrete phenotypic cell features inclusive of AR, CK, size and shape measures. 9225 single CTCs were characterized, data standardized, features clustered and categorized into 15 phenotypically distinct CTC subtypes. Individual pt samples were then analyzed for the frequency and heterogeneity (Shannon Index) of CTC subtypes and monitored for clinical endpoints. A subset of CTCs (n = 350) were individually sequenced and analyzed for clonality and CNV to assess genomic heterogeneity. Results: A diversity of CTC phenotypes were observed at each line of therapy. In AR Tx pts, high heterogeneity predicts 6mo PFS (OR = 2.57, p = 0.01) and shorter OS (HR = 4.5, p < 0.001). Separately, specific CTC phenotypes also predict 6mo PFS (OR = 5, p < 0.001) and shorter OS (HR = 5.8, p < 0.001). Heterogeneity scores were not associated with taxane resistance. NGS analysis identified subclonal drivers of disease progression including multiple private and/or clustered genomic drivers. Conclusions: Single CTC characterization of phenotype and genotype supports the concept of tumor heterogeneity as a driver of disease resistance. The heterogeneity observed supports the potential value of single cell characterization to identify rare somatic sub-clonal alterations and can aid in the development of rational therapeutic trials.
Treatment patterns after abiraterone acetate in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of COU-AA-302.
Authors: Flaig Thomas W. , Smith Matthew R. , Saad Fred , Rathkopf Dana E. , Mulders Peter F.A. , Small Eric Jay , Shore Neal D. , Fizazi Karim , De Porre Peter , Kheoh Thian , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Ryan Charles J. , De Bono Johann S.
Published: February 2017

168

Background: Treatment patterns of mCRPC have changed substantially in the last few years. In COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about treatment patterns after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we characterized subsequent therapy after pts discontinued study drug. Methods: In COU-AA-302, 546 pts were randomized and received AA. Treatment patterns of pts receiving ≥ 1 subsequent therapy for mCRPC after progressing on AA were collected retrospectively and source verified. Results: As of March 2014, 8% (44/546) of pts continued on AA; 67% (365/546) received ≥ 1 subsequent therapy for mCRPC. 36% (194/546) and 15% (83/546) of pts had ≥ 2 and ≥ 3 subsequent therapies, respectively. 80% (435/543) of pts in the P arm had ≥ 1 subsequent therapy. Most frequent subsequent therapy in AA pts was taxane chemotherapy (docetaxel [DOC], cabazitaxel [CBZ]), androgen signaling–directed therapy (AA, enzalutamide [ENZ], ketoconazole [KETO]), and immunotherapy (sipuleucel-T [SIP-T]) (Table). Among AA pts who received DOC as first subsequent therapy, median age was 69 years; median duration of DOC post-AA (n = 261) was 3 months (IQR: 0.95-5.7); and PSA progression was the most common reason for discontinuation. Among AA pts with baseline PSA and ≥ 1 post-baseline PSA value, 40% (40/100) had ≥ 50% PSA decline (27/100 confirmed responses) with first subsequent DOC chemotherapy. Conclusions: This post hoc analysis indicates that treatment with subsequent therapy was common (67% and 80%) in pts with chemotherapy-naïve mCRPC who progressed with AA or P, respectively. PSA decline suggests antitumor activity in pts who progressed with AA and received subsequent DOC. Despite limitations of a retrospective analysis, these data support further assessment of subsequent therapy following AA treatment for mCRPC. Clinical trial information: NCT00887198. [Table: see text]
Long-term indwelling double-J stent for malignant ureteric obstruction: Tolerance and complications.
Authors: Irani Jacques , Biscans Clément , Hugues Guillaume , Bernardeau Simon , Delpech Pierre-Olivier
Published: February 2017

170

Background: JJ stent is designed to be placed for short periods. In rare cases, long-term JJ can be considered particularly in malignant ureteric obstruction. The objective of this study was to assess tolerance and complications in patients with indwelling JJ. Methods: Data from consecutive patients who had a JJ stent placed for more than 6 months between 1992 and 2013 were analyzed. Patients were all followed in a single center where JJ stents were changed every 6 months or earlier in case of complications. Results: The study included 36 patients (22 female and 14 male). Mean age was 69.4 yrs. Median ASA 3 (IQ = 1). Mean creatinine before the 1st JJ 204 micromol/L (SD 232). Most frequent causes of obstruction were colorectal (30%), gynecological (25%) and prostate cancer (14%). In 7 cases, a bilateral JJ stent was placed. Median FU was 26.4 months. Median number of JJ changed per patient was 5.5 (IQ 6.0). Median duration for each JJ was 6 months (IQ 2.1). There was one case of broken stent and 5 cases of stent encrustation, all being managed endoscopically in a single procedure.Grade III-IV complications following theClavien-Dindo classification are reported in the table. All 17 deaths (47.2%) were related to cancer progression. Conclusions: Long-term complications related to indwelling JJ stents are not uncommon. However, we found that when changing the stent systematically every 6 months (or earlier in case of complications), and when taking into account the patient's situation (status/disease) that led to the indwelling JJ indication, tolerance and rate of complications were acceptable. [Table: see text]
Dehydroepiandrosterone in metastatic castration-resistant prostate cancer: Preliminary results from the SU2C-PCF West Coast Dream Team (WCDT).
Authors: Kim Won , Ryan Charles J. , Zhang Li , Youngren Jack , Wilton John , Alumkal Joshi J. , Beer Tomasz M. , Baertsch Robert , Stuart Josh , Chi Kim N. , Gleave Martin , Rettig Matthew , Reiter Robert Evan , Lara Primo , Evans Christopher P. , Small Eric Jay
Published: February 2017

179

Background: Aberrant androgen receptor (AR) phenotypes (e.g. splice variants, amplification) are strongly correlated with abiraterone (Abi) and enzalutamide (Enz) resistance. Low serum dehydroepiandrosterone (DHEA) is also associated with poor outcomes to AR-targeted therapy. Here, we investigate the relationship between serum DHEA, AR phenotype, and treatment efficacy in the WCDT. Methods: Patients (pts) with progressive mCRPC enrolled to the WCDT from UCSF, OHSU, UCLA, UBC, and UCD were included in this analysis. Serum DHEA was analyzed via high-pressure liquid chromatography and tandem mass spectrometry. Limit of quantitation (LQ) of DHEA was 0.2ng/mL. Full-length AR (AR-FL) and AR-v7 expression, obtained via RNAseq of metastatic tumor biopsies, was expressed as total reads mapped to gene. PSA response (PSAr) was defined as ≥ 50% PSA decline. Results: 35 pts were included in this analysis: 15 had treatment-naïve mCRPC, and 20 had prior AR-targeted therapy (14 Abi, 6 Enz). All pts were docetaxel-naïve. 11 pts had DHEA < LQ; of these, 10 had received prior AR-targeted therapy. 12 pts received subsequent chemotherapy, and 23 received subsequent Abi/Enz (7 Abi, 16 Enz). In pts with DHEA < LQ, 4/5 (80%) chemotherapy-treated pts had PSAr, while 1/6 (17%) Abi/Enz-treated pts had PSAr. In pts with DHEA ≥ LQ, 2/7 (27%) chemotherapy-treated pts had PSAr, while 9/16 (56%) Abi/Enz-treated pts had PSAr. The relationship between DHEA and PSAr was significantly different between the treatment groups (p = 0.0285). DHEA was higher in patients with PSAr to Abi/Enz versus those without PSAr (median, 0.871 versus 0.275ng/mL, p = 0.006). In an analysis of 27 pts with RNAseq data, the AR-v7/AR-FL ratio was significantly higher in those with DHEA < LQ (median ratio 8.91, versus 3.38 in DHEA ≥ LQ, p = 0.032). Conclusions: In this exploratory analysis, there is a significant difference in the relationship between DHEA and PSAr in chemotherapy- versus Abi/Enz-treated patients. DHEA < LQ was also associated with a higher AR-v7/AR-FL ratio, a potential avenue for further exploration of tumor biology. These results support a larger study to evaluate DHEA as a potential biomarker in mCRPC. Clinical trial information: NCT02432001.
BPS-001, a complex biologic agent extracted from the medicinal leech (Huridinaria manillensis) for treatment of metastatic castration-resistant prostate cancer.
Authors: Stratton M. Suzanne , Ammar Amr , Wang Yuzhuo , Hessein Mohamed , Guns Emma , Kucuk Omer , Merzouk Ahmed , Kwok David
Published: February 2017

209

Background: We established that subcutaneous BPS-001 reduced tumor size and inhibited tumor growth in PC3, LNCaP and 22RV-1 mouse xenografts; and, tumor lHC demonstrated an increase in caspase-3 and decreases in expression of P21, Ki-67 and PCNA. We also showed that BPS-001 reduced PSA expression in both In vitro and in In vivo xenografts (LNCaP and 22RV1). We now demonstrate that BPS-001 inhibits angiogenesis in the xenografts; and, In vitro studies demonstrate that BPS-001 affects expression of adhesion molecules and the androgen receptor. In addition, BPS-001 inhibited tumor growth in a TRAMP allograft model. Methods: CD31 expression was measured using IHC of the previous mouse xenografts. In vitro androgen receptor and adhesion molecule expression were assessed by Western blot. Transplantable TRAMP-C2 mouse prostate cancer in B57CL allografts were grown to 5 mm prior to initiation of treatment. Immune markers in TRAMP allograft tumors were measured by IHC. Results: Mechanistic studies show BPS-001 acts by blocking angiogenesis demonstrated by a > 50% decrease in expression of CD31 in the LNCaP and 22RV-1 xenografts. Furthermore, preliminary toxicology studies show similar efficacy to docetaxel with no weight loss in the longer-term PC3 xenograft study as was observed with docetaxel. Preliminary toxicology studies of BPS-001 also support a favorable toxicity profile, and the therapeutic dose (1-5 mg/Kg, QW or BIW) is well within the margin of safety. Dose limiting toxicity (bleeding) was observed at doses of 20mg/Kg daily. In vitro studies showed BPS-001 decreased expression of both N- and P- cadherins and the androgen receptor. BPS-001 inhibited tumor growth in the TRAMP allograft models. IHC analyses of the TRAMP allograft tumors suggest immunomodulation. Conclusions: BPS-001 exhibits anticancer activity with no observed toxicity in the therapeutic range. Effects of BPS-001 include inhibition of angiogenesis, downregulation of adhesion molecules associated with advanced prostate cancer and inhibition of androgen receptor signaling. Elucidation of the mechanism of action is ongoing.
The prevalence of objectively measurable disease in phase III trials of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Madan Ankit , Baker Mary K , May Jori E , Naik Gurudatta , Bae Sejong , Sonpavde Guru
Published: February 2017

215

Background: Given the historical low prevalence of measurable disease in mCRPC, phase II trials have employed suboptimal endpoints accounting for prostate specific antigen (PSA) and bone scan changes. Changes in bone scan and PSA have not always translated to survival improvement. Improved computerized tomography technology may be increasing the proportion of men with measurable disease, suggesting that measurable changes need to be reconsidered. We analyzed phase III trials of mCRPC to systematically quantitate the proportion of mCRPC with measurable disease. Methods: Data from the both arms of published phase III trials of mCRPC were eligible for analysis. Baseline characteristics were required including the number enrolled, setting (pre-docetaxel [D], D-based, post-D), proportion of patients with measurable disease and the year of completion of trial accrual. General Linear Model was used to evaluate the difference in measurable disease rate based on setting and year of completion of accrual. Results: Seventeen phase III trials totaling 17,609 men with mCRPC were evaluable; 5160 were pre-D, 7573 were D-based and 4876 were post-D. The trials completed accrual between 2002 and 2012. Ten trials used RECIST 1.0, 5 trials used RECIST 1.1 and 2 trials used other criteria. The overall proportion of men with measurable disease was 47.8%. The measurable disease rate (range) in trials in the pre-D setting was 40.5% (30.5-57), in the D-based setting was 51.9% (29.1-87.5), and in the post-D setting was 48.9% (38.8-56.6). There was no statistical difference in the proportion of men with measurable disease based on setting or year of completion of accrual. Conclusions: The proportion of men with measurable disease in phase III trials of mCRPC completing accrual between 2002 and 2012 was 47.8%% with no significant difference based on setting or year of completing accrual. Given these higher measurable disease rates compared to historical rates and recent demonstration of strong association of RECIST changes with OS in mCRPC, RECIST changes need to be considered as a co-primary endpoint in phase II trials to obtain a firm signal of efficacy before launching phase III trials.
How many patients could have a salvage local treatment after radiotherapy/brachytherapy for prostate cancer?
Authors: Hennequin Christophe , Mongiat-Artus Pierre , De Kerviler Eric , Vercellino Laetitia , Ravery Vincent , Meria Paul , Culine Stephane , Desgrandchamps Francois , Quero Laurent
Published: February 2017

23

Background: In our institution, as soon as biochemical relapse (BR; nadir PSA + 2 ng/ml) occurred after external beam radiotherapy (EBRT) or brachytherapy (BT), 18-fluorocholine-PET-CT (18-FCH-PET) with or without multiparametric prostate MRI are performed. The aim is to select patients for a salvage local treatment (SLT) with a curative intent. We presented here the results of this approach. Methods: Records of patients with BR, without clinical evidence of relapsing disease and with at least a18-FCH-PET performed, were retrospectively reviewed. Patients were considered eligible for SLT if the relapse was only local or in case of nodal relapse reasonably encompass in a RT field. Results: Between 2010 and 2014, 89 pts were included, 23 initially treated with BT and 66 with EBRT. Prognostic group at diagnosis were: favourable: 25 (28%), intermediate: 35 (39%), unfavourable: 29 (33%). At the time of relapse, mean age was 72 yrs and mean PSA level: 6.2 ng/ml. After 18-FCH-PET ± MRI, patients were classified as: no target lesion identified: 20 (22.5%); local relapse: 35 (39%); nodal relapse: 22 (25%); distant metastases: 12 (13%.5%). Among 35 pts with a local relapse, 14 had SLT (cryotherapy:13; cyberknife:1). Reasons to not performed SLT were: advanced age or poor performance status: 10; Gleason 8-10: 2; T3 on MRI: 2; Patient refusal (fear of incontinence): 7. Among 22 pts with a nodal relapse, only 3 could have salvage EBRT. Reasons to not performed SLT were: old age or poor PS: 5; extensive nodal relapse: 8; local and nodal relapse: 6. At the end, 57 pts (64%) are potentially eligible for SLT and 17 (19%) could have it. Conclusions: In routine practice, in a population of 89 pts with a BR, 64% are eligible for SLT but 19% could have it. Main reasons for not having SLT were absence of target lesions, extensive disease, or advanced age. This result justified the realisation of an extensive staging at the time of BR after EBRT or brachytherapy.
A Phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castration-resistant prostate cancer (mCRPC), secondary endpoints.
Authors: Sternberg Cora N. , Armstrong Andrew J. , Pili Roberto , Nederman Tore , Carducci Michael Anthony
Published: February 2017

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Background: TASQ is an oral agent with immunomodulatory, anti-angiogenic and anti-metastatic properties that targets the tumor microenvironment. It was recently reported from this study that in chemotherapy-naïve men with mCRPC, single-agent TASQ statistically significantly improved rPFS, by both central (HR (95% CI) 0.64 (0.54-0.75)) and local review, as compared to PBO but no OS benefit was demonstrated (HR (95% CI) 1.10 (0.94-1.28)). In this abstract the results of secondary efficacy endpoint analyses are presented. Methods: Men with asymptomatic to mildly symptomatic chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive TASQ or PBO once daily until progression or toxicity. Randomization was stratified by KPS ( ≥ 90% vs < 90%), presence/absence of visceral disease, and geographic region. The secondary efficacy endpoints discussed here include a panel of radiological, PSA based and symptomatically assessed measures. Results: 1245 pts were randomized (TASQ, n = 832; PBO, n = 413) between 29 Mar 2011 and 7 Dec 2012 at 240 sites in 37 countries. Baseline characteristics were balanced between the 2 groups. In general, all radiology-based and PSA-based secondary endpoints showed statistically significant differences between TASQ and PBO in favor of TASQ. E.g. median time to radiological progression was 8.4 m for TASQ vs. 5.5 m for PBO, p < 0.001, HR (95% CI) 0.628 (0.534-0.739) by central assessment. However, symptomatically assessed endpoints in general showed statistically significant differences in favor of PBO. E.g. median time to symptomatic progression was 9.5 m for TASQ vs. 11.9 m for PBO, p = 0.031, HR (95% CI) 1.171 (1.014-1.353). Grade ≥ 3 TEAEs were more common with TASQ than PBO (42.8 vs 33.6%). Conclusions: Outcome of the radiological and PSA-based endpoints favor TASQ in contrast to the symptomatically assessed endpoints, which favor placebo. Overall survival was not improved, which may be due to limited efficacy of TASQ in the studied population, toxicity, or the differential use of effective life-prolonging agents post-TASQ/placebo. Clinical trial information: NCT01234311.
Incidence of testosterone escape with LHRH agonists in patients receiving radiotherapy for prostate cancer.
Authors: Wilke Derek R , Patil Nikhilesh Gajanan , Hollenhorst Helmut , Bowes David , Rutledge Robert
Published: February 2017

24

Background: LHRH agonists (LHRHa) are commonly combined with radiotherapy in the neoadjuvant, concurrent, and adjuvant setting. Testosterone escape (TTE) (>1.74 nmol/L or >50 ng/dL) during therapy with LHRHa has been described, but the incidence and impact of TTE on outcome in this patient group needs to be characterized further. Methods: We performed a retrospective review of a database used for clinical outcomes and research ethics board approved studies, including chart audit of select patients (pts) where information was missing. To be included in the study, there had to be information on: 1) type of LHRHa, date of initiation, date of cessation, or duration of therapy and 2) radiotherapy information, with at least 6 months of follow-up after radiotherapy, 3) had to have radiotherapy to the prostate or prostate bed, and 4) had to have a least one testosterone- (TT) and prostatic-specific antigen (PSA) measurement. Results: 670 pts had a start date for androgen deprivation therapy (ADT) in the database. 630 pts had received an LHRHa, 560 pts had a start date for radiotherapy. 375 pts had sufficient information on ADT, radiotherapy, TT, and PSA levels, and 361 of these patients had information regarding their LHRHa. Median follow-up of patients still alive is 4.7 years. The median duration of LHRHa was 2.02 years. The median number of testosterone measurements per patient was 6. The incidence of TTE per patient course of treatment was: buserelin 9.3%; goserelin 10.5%; leuprolide IM 11.5%; leuprolide sc 23.9%; triptorelin 6.7% (p=0.02). Biochemical failure was defined as per the "nadir +2" definition, or at a value > 0.2 in those patients having had previous radical prostatectomy. There was no significant difference in either biochemical failure-free survival or overall survival in patients who experienced TTE versus those who did not. The most common PSA level during a TTE was an undetectable PSA. Conclusions: Even though there appears to be no impact of TTE on either biochemical relapse-free survival or overall survival, this study demonstrates that a rising PSA does not rule out TTE. Longer-term follow-up is planned.