bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic characterization of primary and metastatic prostate cancer (PC) using a targeted next-generation sequencing assay.
Authors: Abida Wassim , Brennan Ryan , Armenia Joshua , Curtis Kristen Rebecca , Gopalan Anuradha , Arcila Maria E. , Danila Daniel Costin , Rathkopf Dana E. , Morris Michael J. , Slovin Susan F. , Solit David B. , Hyman David Michael , Durack Jeremy C. , Solomon Stephen Barnett , Reuter Victor E. , Taylor Barry S. , Berger Michael F. , Schultz Nikolaus , Scher Howard I.
Published: February 2017

254

Background: Genomic alterations in PC have been described across the disease continuum, creating opportunities for selective clinical trial enrollment of patients (pts) with high-risk or metastatic disease based on their tumor profile. MSK-IMPACT is an exon capture-based sequencing assay performed in a CLIA-certified laboratory that targets 410 cancer-associated genes, many of which are potential drug targets. We assessed mutations and copy number alterations (CNAs) in primary and metastatic samples from untreated, hormone-treated and castration resistant pts. Methods: PC pts were enrolled on an IRB-approved protocol for tumor genomic profiling. Fixed tumor and matched germline samples were subjected to DNA sequencing analysis using MSK-IMPACT for the identification of somatic mutations and CNAs. Results: 315 samples from 271 pts were successfully sequenced (Table). Overall success rate was 80% (67% for bone). 14 tumors were pathologically classified as neuroendocrine or had neuroendocrine features. 23% of patients had tumor somatic alterations in DNA repair genes (BRCA2, BRCA1, ATM, FANCA and CDK12). Additional alterations were observed in PI3K, MAPK and Wnt-βCatenin pathway genes. Common alterations in the metastatic tumors include TP53 deletion/mutation (42%), AR amplification/mutation (38%), PTEN deletion/mutation (27%), RB1 deletion/mutation (20%), BRCA2 deletion/mutation (11%), FOXA1 mutation (11%) and SPOP mutation (4%). Among metastatic samples, tumors from pts with castration-resistant disease had higher CNA burden when compared to tumors from non-castration-resistant pts (0.31 vs. 0.19 fraction genome altered, p < 0.05, unpaired t-test), as well as higher rates of AR amplification/mutation (49% vs. 3%, p < 0.01, Fisher’s exact test). Conclusions: Genomic profiling of primary and metastatic prostate tumors is feasible with the clinical MSK-IMPACT sequencing assay and has identified actionable alterations in > 40% of patients. This is allowing for selective trial enrollment and further investigation of PC genomics. [Table: see text]
Effect of anti-GRP78 autoantibodies on prostate cancer progression through tissue factor procoagulant activity.
Authors: Al-Hashimi Ali , Shayegan Bobby , Austin Richard
Published: February 2017

258

Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increase PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumour growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titres were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca2+ stores. This very effect on ER Ca2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumour growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.
Prognostic impact of clinical and pathologic criteria in neuroendocrine and aggressive variant prostate cancer.
Authors: Karir Beerinder S. , Vlachostergios Panagiotis J. , Christos Paul J. , Febles Victor RA , Pinto-Chengot Kavya , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T.
Published: February 2017

268

Background: Various clinical and pathologic criteria have been proposed to identify neuroendocrine (NE) or aggressive variant (AV) prostate cancer (PC). We assessed the prognostic value of clinical parameters in a single-institution cohort. Methods: An IRB-approved database was screened for clinical and/or pathologic criteria (Table 1) for NE/AV PC. Patients with advanced CRPC not meeting any of the criteria served as contemporary controls. Overall survival (OS) for each group was assessed using Kaplan-Meier method and comparisons with log-rank test. Results: 249 men were identified, median age 71.5 (45.1-90.8 years). 145 patients met at least 1 criterion suggestive of NE/AV PC, whereas 104 were CRPC only. Median OS for each subgroup, the combined NE/AV PC group, and the CRPC cohort are provided in Table 1. OS for NE/AV PC vs. CRPC cohort was 25.4 vs 33 months (p = 0.26). Patients with parenchymal brain metastasis had the worst survival of 5.2 mo [95%CI 2.1, 8.3]. On multivariate analysis, bulky high-grade disease in prostate/pelvis carried the highest risk of death (HR 1.71 [1.07, 2.74; p = 0.02]). Conclusions: A number of clinical and pathologic criteria have been used to define NE/AV PC for clinical practice or trial enrollment. Some criteria are associated with a shorter survival than others. Additional studies are warranted to further define both prognostic and molecularly defined subgroups. [Table: see text]
Impact of prior definitive therapy on survival outcomes in men with new hormone sensitive metastatic prostate cancer (mHSPC).
Authors: Alex Anitha , Stenehjem David D. , Twardowski Przemyslaw , Cheng Heather H. , Buckley Tyler Howard , Gill David , Patel Shiven B. , Vaishampayan Ulka N. , Agarwal Neeraj
Published: February 2017

269

Background: In mHSPC, treating the primary tumor may have a biologic effect on the metastatic sites, and definitive therapy in this setting has been hypothesized to delay disease progression and even death. Outcomes with prior definitive therapy in this setting have not been reported. Methods: In this multicenter study, men with new mHSPC, starting androgen deprivation therapy (ADT) were included. Index date was the day of starting ADT. Kaplan-Meier and Cox proportional hazard methods assessed time to castrate resistance (CRPC) and overall survival (OS) in those with or without prior definitive therapy. Variables significant at P < 0.05 were included in the final models. Results: A total of 235 men with mHSPC were included (median age ~ 67 yrs). Prior definitive therapy was performed in 64 men (27%). Results are presented in the table. Conclusions: Definitive treatment was associated with improved time to CRPC and OS in univariate analysis; however, when combined with other prognostic factors the significance was not maintained. Analysis of a larger data set is warranted to fully assess the role of prior definitive therapy in mHSPC. [Table: see text]
Patient reported outcomes in NRG Oncology/RTOG 0938, evaluating two ultrahypofractionated regimens (UHR) for prostate cancer (CaP).
Authors: Lukka Himanshu , Pugh Stephanie L. , Bruner Deborah , Bahary Jean-Paul , Lawton Colleen Anne , Efstathiou Jason A. , Kudchadker Rajat , Ponsky Lee Evan , Seaward Samantha A. , Dayes Ian S. , Gopaul Darindra , Michalski Jeff M. , Delouya Guila , Kaplan Irving D. , Horwitz Eric M. , Roach Mack , Pinover Wayne , Beyer David , Sandler Howard M. , Kachnic Lisa A.
Published: February 2017

27

Background: The considerable interest in short UHR 5-12 fractions(fr) in management of CaP is based on potential radiobiological advantages, patient convenience & resource allocation benefits. Prior to comparison with standard RT regimens (SRTR), a study was undertaken whose primary objective was to demonstrate that 1-year health-related quality of life (HRQOL) for at least one UHR arm was not significantly lower than baseline as measured by the Bowel & Urinary domains EPIC instrument(EPIC B&U). Secondary objectives included acute & late GI & GU toxicity. Methods: RTOG 0938 is a randomized phase II study of CaP patients(pts), (Gleason score 2-6, stage T1-2a & PSA < 10 ng/mL) receiving 36.25 Gy (5 fr of 7.25 Gy in 2 wks), or 51.6 Gy (12 fr of 4.3 Gy in 2.5 wks). Pts were stratified according to RT technique – Cyberknife vs IMRT/VMAT or protons. A change in EPIC bowel domain score (baseline to 1-year) > 5 points & in EPIC urinary domain score > 2 points were felt to be clinically significant. The frequency for > 5 point change in bowel score (FREQE-B) in ≤ 35% of pts was considered acceptable, with the frequency ≥ 55% unacceptable. Similarly, the frequency for > 2 point change in urinary score (FREQE-U) in ≤ 40% was considered acceptable, with the frequency ≥ 60% unacceptable. A sample size of 156 pts was needed for 95% power with one-sided significance level of 0.025 to preserve an overall level of 0.05. Results: 240 pts were enrolled to ensure adequacy of data for analysis. The compliance for HRQOL completion was good ( > 80%). The 1 year FREQE-B for 5 fr was 23.5% (p < 0.001) & 12 fr was 23.1% (p < 0.001). The 1 year FREQE-U for 5 fr was 35.3% (p < 0.001) & 12 fr was 34.7% (p < 0.001). Conclusions: This study confirms that based on changes in EPIC B&U (baseline to 1-year), acute & late toxicity, both the 5 & 12 fr regimens are well tolerated. These UHR need to be compared to current SRTR in the context of a RCT with efficacy & toxicity endpoints. Supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, UG1CA189867 from the National Cancer Institute (NCI). Clinical trial information: NCT01434290. [Table: see text]
Clinical differences between African-Americans (AA) and Caucasians (CA) with and without family history (FH) of prostate cancer.
Authors: Garvey Cathryn E. , Cotogno Patrick , Ernst Emma M. , Ledet Elisa M. , Sartor A. Oliver
Published: February 2017

279

Background: Prostate cancer is one of the most common adult malignancies. Two well characterized risk factors for prostate cancer (PCa) are family history (FH) and race. The goal of this study was to distinguish the influence of family history and race with regards to clinically relevant covariates. Methods: In this single-institution study, 497 PCa patients from Tulane Hospital were clinically annotated and FH was evaluated. FH was defined as having ≥ 1 first degree relative affected with PCa and/or ≥ 2 affected second or third degree relatives. There were 147 AA and 350 CA patients; 66 AA and 120 CA reported PCa FH. The following clinical factors were documented: age and PSA at diagnosis (dx), Gleason score (biopsy or radical prostatectomy), and presence of metastasis (at any time). Chi-square, ANOVA, and odds ratio tests were performed to identify potential clinical correlates with regard to FH and race. Results: Results indicate that race and FH are not independent (p = 0.0266), where AAs were 1.5 times more likely to have a FH of PCa than CAs (95% CI 1.0543-2.3133). On average, men with a FH of PCa were younger at dx (p = 0.0063). FH significantly impacted age at dx for AAs (p = 0.036) but not CAs. No difference in age of dx was detected between race. FH of PCa did not influence PSA at dx in either CA (6.5, 1.2-681) or AA (19.2, 1.7-500) men, however race did (p = 0.004). CAs with FH of PCa were more likely to be diagnosed with low or intermediate risk PCa (Gleason score ≤ 7, p = 0.03). Gleason scores were not significantly different between races. Overall, FH did not influence metastasis. Although, AAs (n = 19) were 1.61 times more likely to develop metastatic disease compared to CA men. Conclusions: For AAs, FH lowered age at dx but did not have influence on development of metastatic disease, Gleason score or PSA. For CAs, Gleason score was lower in men with a FH. Overall AAs, as compared to CAs had more metastatic disease and higher PSAs at dx. Continuing to track clinical differences between AAs and CAs with a FH of PCa may provide additional insights into underlying racial and clinical disparities.
The role of adjuvant radiotherapy in pathologically node positive prostate cancer.
Authors: Jegadeesh Naresh , Liu Yuan , Zhang Chao , Zhong Jim , Gillespie Theresa Wicklin , Kucuk Omer , Rossi Peter John , Master Viraj A. , Alemozaffar Mehrdad , Jani Ashesh B.
Published: February 2017

28

Background: The postoperative management of prostate cancer with regional lymph nodal involvement (LNI) is controversial. Prospective evidence to guide the role of radiotherapy (RT) in this setting does not exist. Randomized studies demonstrate an improvement in disease-related outcomes with adjuvant RT in high-risk patients without LNI following prostatectomy (RP). Retrospective evidence supports the selective use of RT with LNI following extended pelvic lymph node dissection. It is unclear if this experience is generalizable to practice in the United States where extended dissection is uncommon. We sought to identify patients with LNI who may derive a survival benefit following adjuvant RT. Methods: The National Cancer Data Base was queried for M0 patients with prostate adenocarcinoma who underwent RP with pathologic LNI. Adjvuant RT was defined as delivered within 6 months following RP. Kaplan-Meier, log-rank test, and multivariable Cox proportional hazards regression were performed with overall survival (OS) as the primary outcome. Propensity score matching (PSM) was employed to further reduce treatment selection bias. Results: 7,902 patients diagnosed between 2003-2011 were eligible for analysis; 1,439 (18.2%) received RT. RT was more frequently employed in patients with lower Charlson-Deyo Comorbidity Score, higher T stage, <5 nodes examined, ≥50% nodal positivity ratio, Gleason 8-10, ≥20 PSA, positive surgical margin, and <65 years of age (all p < 0.05). Five year OS was 87.6% vs. 85% in those receiving RT vs. not (p = 0.075). With androgen deprivation (ADT) (n = 3,265), 5-year OS was 87.2% vs. 82.7% in those receiving RT vs. not (p = 0.004). In multivariable analysis, the use of RT was independently associated with improved OS (HR 0.73, 95% CI 0.59-0.89, p = 0.002). 894 remained in each cohort following PSM. In this analysis, RT remained associated with OS (HR 0.66, 95% CI 0.51-0.85, p = 0.002). Conclusions: Adjuvant RT was associated with improved OS following RP in patients with LNI in this large generalizable retrospective analysis. This effect appears stronger in those receiving ADT. This series is the largest describing adjuvant RT in this population. In the absence of prospective evidence, these results may help guide therapy in this setting.
Copy number variations in AR-associated and DNA repair genes from plasma cell-free DNA of metastatic CRPC patients.
Authors: Gambhira Ratish , Ledet Elisa M. , Dotiwala Aryeneesh , Mandal Diptasri , Sartor A. Oliver
Published: February 2017

281

Background: Cell-free DNA (cfDNA) present in the plasma of advanced cancer patients can reflect tumor related genetic alterations. Recent data suggests copy number variations (CNVs) in AR-associated and DNA repair pathway genes play a potential role in prostate cancer progression. Here, we performed sequencing of cfDNA from 13 mCRPC patients to evaluate its potential in elucidating tumor related genetic variations. The long-term goal of our project is to correlate cfDNA derived genetic alterations with prostate cancer progression and/or therapeutic resistance/responses. Methods: cfDNA was isolated from 13 advanced mCRPC patient plasma samples using the Qiagen circulating nucleic acid kit. 100ng of cfDNA was utilized for library construction; and the libraries were paired-end sequenced on the Illumina HiSeq 2000. The resulting data was analyzed using the GATK best practices bioinformatics pipeline and the visualized using the SNP & Variation Suite v8.x. Results: The bioanalyzer profiles of cfDNA derived from mCRPC patients is highly fragmented with an average fragment size of 306-605bp. Although, several CNVs were found across the genome, we focused analysis on CNVs related to AR associated and DNA repair genes. Our preliminary analysis of cfDNA, despite low sequencing depth, shows full or partial amplifications in AR (13/13), and other genes including FOXA1, NCOR1, NCOR2 and/or PIK3CA (7/13) and NCOR2 (10/13). For DNA repair genes partial/full amplifications were present in BRAC1, BRAC2, ATM, CDK12, MLH1 and/or MSH2 (7/13). Deletions are less reliably detected in the highly fragmented cfDNA. The majority of these CNVs have been reported in the WGS studies from metastatic CRPC tissue derived genomic DNA (cBioPortal). We are currently validating cfDNA genomic alterations by comparing it to germ line DNA derived via qPCR. Conclusions: Our preliminary study indicates that AR and DNA repair related genetic alterations could be found in the cfDNA derived from metastatic CRPC patients. This warrants more detailed examination of these cfDNA genetic alterations for identifying clinically relevant issues in mCRPC patients.
Association of changing prostate-specific antigen (PSA) levels on repeat testing with lower risk for Gleason Score (GS) ≥ 7 prostate cancer.
Authors: Nordström Tobias , Adolfsson Jan , Gronberg Henrik , Eklund Martin
Published: February 2017

284

Background: PSA levels are often verified before recommending a prostate biopsy because of the variability of PSA, We used data from the STHLM3 trial to assess the value of a second PSA test taken prior to biopsy. Methods: STHLM3 is a prospective and population-based prostate cancer diagnostic study performed in Stockholm, Sweden, 2013-2015. 1686 men in STHLM3 with a PSA value 3-10 ng/ml performed a second PSA test within 8 weeks of the first test and then underwent prostate biopsy. We compared proportions of cancer detected in men with stable PSA levels (2nd PSA within +/-10% of 1stPSA) to men whose PSA levels increased or decreased at least 10%, respectively. Results: Men with GS ≥ 7 cancer in the biopsy had more stable PSA than men with benign biopsies; the median change was 13.7% (inter-quartile range (IQR) 6.1-26.9) in men with benign biopsies, 13.0% (IQR 6.1-25.6) in men with GS ≤ 6 tumors and 8.2% (IQR 4.5-16.7) in men with GS ≥ 7 tumors. The average risk of having GS ≥ 7 cancer was 15.4% (95% CI 13.7 – 17.1) after the first test (i.e. the entire cohort), 21.6% (95% CI 18.6 – 24.6) in men with stable PSA levels compared with 13.5% (95% CI 10.2 – 16.7) and 9.0% (95% CI 6.6 – 11.4) if PSA levels increased or decreased at least 10%, respectively. There were no significant differences in risk of GS ≤ 6 tumor for men with stable PSA compared to men with increasing/decreasing PSA. Conclusions: As previously shown, the risk of prostate cancer decreases if a repeat PSA test shows decreasing levels. We show that this effect mainly affect GS ≥ 7 tumors, and that the risk of prostate cancer also decreases with increasing PSA values. Our findings need validation, but suggest that PSA is more stable in men with GS ≥ 7 cancer, whereas elevated but fluctuating PSA levels to a higher degree are caused by other processes (e.g. inflammation). Use of decision tools could aid incorporation of complex information such as repeat PSA values in diagnostics.
Evaluation of response to enzalutamide (E) consecutively after disease progression on abiraterone/prednisone (AP) and potential predictors of response.
Authors: Emamekhoo Hamid , Elson Paul , Grivas Petros , Shomali William , Edwin Natasha Catherine , Rini Brian I. , Garcia Jorge A.
Published: February 2017

294

Background: Efficacy data of E immediately after AP failure in castrate resistant prostate cancer (CRPC) is limited. Although clinical cross-resistant has been observed, the optimal sequence of these agents is not defined. Specific patient pt) characteristics on AP could be useful in selecting appropriate pts for subsequent therapy with E. Methods: We retrospectively reviewed records of 40 pts with CRPC treated at the Cleveland Clinic with E immediately after disease progression on AP. We evaluated clinical / pathological features that could predict subsequent response or lack thereof to E. For this exploratory analysis, best % change in PSA (%Ch-PSA) was used as indicator of treatment response. Results: Median age at E initiation was 69 (58-81), median time from diagnosis to AP initiation was 6.1 years (0.9-16.3). Median PSA was 30.9ng/mL (1.5-1680) at the time of AP initiation and 66.9ng/mL (2.52-3130) at E initiation. 30/40 and 35/40 pts had bone metastasis at AP and E initiation, respectively. Prior treatments to AP included Ketoconazole (45%), Docetaxel (35%). Median time to PSA progression on AP was 9.6 m (0.5-49.6) and 2.3 m (1.8-3.1) on subsequent E. 26/39 pts on AP achieved PSA decline >25%; among these 20 had >50% PSA decline. Similarly, 13 and 8 pts receiving subsequent E achieved >25% and >50% PSA decline, respectively. 10/40 pts did not have PSA response with either agent. 4 pts had PSA decline > 50% on both agents. There was no significant correlation between %Ch-PSA on E and %Ch-PSA on AP, pre-E PSA, time to PSA progression on AP, or time from diagnosis to AP. Longer interval between AP and E initiation was associated with better outcome on E (p=.03). Prior treatment to AP did not predict subsequent response to E. Conclusions: Except for the association between longer interval between AP and E initiation with PSA response on subsequent E, other clinicopathological factors did not predict response to consecutive E in this cohort of pts. Identifying clinical and/or molecular factors predictive of response to AP and E in this setting is of critical importance. Ongoing randomized prospective studies will help determine the optimal treatment sequencing in men with CRPC.
Interrogating metastatic prostate cancer treatment switch decisions.
Authors: Lorente David , Ravi Praful , Mehra Niven , Pezaro Carmel Jo , Omlin Aurelius Gabriel , Miranda Miguel , Payne Heather , Hall Emma , Terstappen Leon W M M , Ijzerman Maarten J , De Bono Johann S.
Published: February 2017

296

Background: Increased availability of treatment options in CRPC requires improved biomarkers to optimize decision making for therapeutic sequencing. Despite evidence for the value of CTCs in assessing prognosis and response to treatment, their use in clinical practice is not widely implemented. Clinicians rely on PCWG2 criteria based on PSA, clinical and radiological criteria although these are only inconsistently used in clinical practice. We evaluated the trends for clinical decision-making by physicians treating CRPC. Methods: An online questionnaire was distributed to physicians treating PC from the UK, Switzerland and Australia. Questions on clinical practice, familiarity with progression criteria, use of CTCs and clinical-decision making were formulated. Results: 111 participants replied. Most (84.7%) were oncologists treating ≥ 50 patients per year (65.3%). Although only 39.6% usually used PCWG2 in clinical practice, 74.5% considered PSA, bone scans and CT to be useful for monitoring disease. 55.6% considered PSA to be an important biomarker. A minority were able to identify PSA (41.4%) and bone scan (39.4%) progression criteria by PCWG2. On average, more physicians discontinued cabazitaxel (28%) than docetaxel (10.4%) before cycle 4. Similar number of cycles were given to bone only disease compared to RECIST evaluable patients. Clinical progression was most important for switching treatment for most physicians (90.5%), followed by RECIST (71.6%), bone scan (47.7%), CTC (23.2%) and PSA (21.1%). The main challenge associated with the use of CTCs was the access to technology (84.7%). Most respondents (92%) would not stop therapy with rising PSA but falling CTC counts; most (88.8%) would not stop with declining PSA but rising CTCs. Although 50% acknowledged the prognostic value of CTCs, only 33% would use them to guide decision-making. Conclusions: A significant number of physicians discontinue treatment before 12 weeks. Most physicians rely on clinical progression for decision-making. Knowledge of PCWG2 response and progression criteria is generally suboptimal. Greater physician awareness, access to technology and further evidence and will be required for the implementation of CTCs as a routine biomarker in CRPC.
Regular aspirin use and the risk of lethal prostate cancer in the Physicians' Health Study.
Authors: Allard Christopher Brian , Downer Mary K , Preston Mark A , Gaziano J. Michael , Stampfer Meir J. , Mucci Lorelei A. , Batista Julie
Published: February 2017

306

Background: Aspirin exerts chemopreventive effects against several malignancies. An inverse association between regular aspirin intake and advanced prostate cancer is suggested by previous reports, but potential effects on lethal prostate cancer have not been characterized. Methods: The study population comprised 22,071 male physicians enrolled in the prospective Physicians' Health Study followed from 1982-2009. We evaluated the relationship between regular aspirin intake ( > 3 tablets per week) and lethal prostate cancer (metastases or prostate cancer death). Secondary outcomes included the incidence of total, high-grade (Gleason 8-10), and advanced (T3b-T4 or N1 or M1) cancers. Cox proportional hazards models estimated age- and multivariate-adjusted hazard ratios (HR) for the incidence of primary and secondary outcomes and survival among participants with prostate cancer. Results: Over 27 years of follow-up (533,261 person-years), 3,183 men were diagnosed with prostate cancer, of whom 402 developed lethal disease. Decreased multivariate-adjusted risks of lethal prostate cancer were observed for regular aspirin users (HR: 0.67, 95%CI: 0.55-0.82). Recent regular use (within 12 months) was protective, with effects diminishing with time since last regular use (p for trend = 0.007). Among men with prostate cancer, regular aspirin use after diagnosis was associated with decreased prostate cancer mortality (HR: 0.79, 95%CI: 0.64-0.98), whereas pre-diagnostic use did not confer a measurable benefit. Regular aspirin use was not significantly associated with the incidence of total, high-grade, or advanced cancers. Conclusions: Regular aspirin use was associated with a decreased risk of lethal prostate cancer in this cohort of American physicians. An inhibitory effect of regular aspirin use on prostate cancer progression is suggested.
Ex vivo propagation and characterization of circulating tumor cell clusters from late stage prostate cancer patients.
Authors: Lim James , Ryan Charles J. , Adams Bruce , Hough Jeff , Chow Tianna
Published: February 2017

314

Background: Cells shed by a tumor into the bloodstream upon metastasis present an opportunity to study the properties of these cells for biomarker discovery, drug development, and personalized therapy. Enrichment and expansion of circulating tumor cells (CTCs) in culture enables molecular characterization not readily available for rare cells. Here, we demonstrate the successful identification and culture of rare circulating tumor cell clusters from peripheral blood of metastatic castration resistant prostate cancer patients (mCRPC). Methods: The approach to isolate CTC clusters relies on nucleated cell enrichment via Ficoll-based centrifugation from 15 mL of peripheral blood. A collagen-based cell-binding substrate was used to capture cell clusters with preferential affinity for collagen (i.e. epithelial-like cells). Hypoxic and pressurized culturing conditions were used to maintain and propagate adhered CTC clusters. After 7 days in culture, immunofluorescence imaging, qPCR and/or mRNAseq were performed on CTC clusters that had formed colonies. Results: Blood samples processed within 3 hours from time of draw yielded a 25% success rate (4/16) for identifying PSMA+/EpCAM+/CD45- CTC colonies. Morphologically distinct CTC colonies cultivated at 1% oxygen and increased hydrostatic pressure (2 PSI) were positive for PSMA and EpCAM staining as observed via confocal microscopy, with individual colonies ranging from approximately 50 to 1000 in cell number. Colonies consistently revealed white blood cell contaminants (T-cells and dendritic cells, 10 to 30% of colony) that did not appear to perturb colony growth. CTC colonies were collected for qPCR analysis and mRNAseq via laser-capture microdissection and/or micropipetting. Genomic analysis revealed differential gene expression patterns between CTC colonies cultured from the same patient sample, with a subset expressing neuroendocrine like signatures (AURKA), stem cell markers (SOX2, OCT4), and immuno-oncology relevant markers (PD-L1, CTLA4). Conclusions: In conclusion, we show that viable CTCs are amenable to ex vivo culture, providing both functional and molecular insights into a sub-population of CTCs with propagating potential. The presence of T-cells and dendritic cells on CTC colonies warrants further investigation, and may provide unique insights into immune-tumor interactions. The culturing platform is currently being evaluated as a research tool for biomarker discovery and as a clinical tool for disease monitoring and treatment decision-making.
Treatment outcome of enzalutamide against castration resistant prostate cancer in Japanese cohort.
Authors: Shimomura Tatsuya
Published: February 2017

318

Background: Enzalutamide (ENZ) is next generation anti androgen agent and prolonged survival both of before chemotherapy and after chemotherapy setting. In japan, it was approved to use against castration resistant prostate cancer (CRPC) from June 2014 and there is few report of treatment outcome of this agent in Asian countries. Prostate cancer is well known with the racial difference and then we investigated the outcome of enzalutamide in Japanese cohort. Methods: Total of 120 CRPC cases were introduced enzalutamide from June 2014 to July 2015 in our department and were investigated (before chemotherapy in 57 cases (group 1) and after chemotherapy in 62 cases (group 2) (One case was unknown)). We compared treatment outcome of these two groups and compared with AFFIRM and PREVAIL. Results: Comparing group 1, group 2 was younger in age, higher PSA, lower hemoglobin, higher ALP, higher LDH and higher CRP at starting ENZ. In terms of survival, OS of group 1 was better than group 2 (12 month survival rate were 0.95 and 0.58, respectively. p = 0.0088). However there was no significant difference in PSA response between Group 1 and 2 (Mean PSA decline was 51.7% and 50.1%, respectively. p = 7764). PSA response rate (PSARR) ≥ a50% was 57.8 % (group 1) and 58.1% (group 2)( p = 0.985). And PSARR ≥ a50% did not affect survival in both groups. (p = 0.1152 and 0.1288, respectively). When comparing group 1 with PREVAIL trial, survival rate was similar but PSA response was poorer. And when comparing group 2 with AFFIRM trial, survival rate was worse but PSA response was similar. Conclusions: Although this study was retrospective and follow up period was not long, we concluded that docetaxel treatment before enzalutamide affected survival rate, however that did not affect PSA response. And there were differences in outcome between this Japanese study and major randomized clinical trials (PREVAIL and AFFIRM).
High dose rate brachytherapy and external beam radiotherapy for local and locally advanced prostate cancer: Uni-institutional long term results.
Authors: Pellizzon Antonio Cassio Assis , Fogaroli Ricardo César , Silva Maria Leticia GOBO , Guedes Douglas , .Chen Michael , Gondim Guilhreme , Ramos Henderson
Published: February 2017

319

Background: Dose-escalation is a determining factor that influences biochemical control (BC) of prostate cancer. High-dose rate brachytherapy (HDR) is one method for providing BC. Methods: Patients with histological diagnosis Gleason scored (GS), clinical stage T1 to T3a, no evidence of metastatic disease, prostate volume > 20cc < 60cc and initial PSA (PSAi) < 60 mg/ml treated from 1997 to 2005 with an Institutional Policy of treatment were evaluated. Results: There were 273 patients treated with this treatment combination at AC Camargo Cancer Center, Sao Paulo, Brazil. The median age and FU time were 64.7 and 10.3 years, respectively. Two hundred thirteen (78.0%) patients had FU longer than 5 years. Actuarial 10-year OS, CSS and BC were 89.8%, 63.6% and 71.8%, respectively. On univariate analyses GS < 7, clinical stage < T2b, low risk group (LR), absence adjuvant androgen deprivation (ADT), age > 65, PSAi < 10, localized EBRT and three dimensional HDR planning were associated with improved CSS and BC. PSAi and age were not favorable associated to BC. Multivariate Cox regression analyses confirmed LR, GS < 7, PSAi < 10, absence of ADT, age < 65 years as predictors of improved CSS and BC. For OS only LR was confirmed as predictive factor. Conclusions: The present data represents a unique single institution study at long FU for the given technique and the comparison with the current literature data confirms the excellent results achieved with this treatment combination.
Clinicians’ attitudes and preferences in choosing the first line drug for metastatic castration resistant prostate cancer (mCRPC): Preliminary results from a multicenter Italian study after the introduction of abiraterone acetate (AA) in the clinical practice.
Authors: Caffo Orazio , Ortega Cinzia , Sava Teodoro , Sacco Cosimo , Barni Sandro , Ermacora Paola , La Russa Francesca , Maines Francesca , Prati Veronica , Ruatta Fiorella , Veccia Antonello , Galligioni Enzo
Published: February 2017

332

Background: For one decade, docetaxel (DOC) represented the only therapeutic option for mCRPC pts. Recently, AA and enzalutamide demonstrated a survival gain in first line setting. Lacking direct comparison with DOC and considering some differences in selection criteria of the pivotal trials, the choice between DOC and these hormonal agents, which have a quite different toxicity profile, is often driven by pts’ characteristics and feelings and by clinicians’ attitudes and preferences as well. To date, only AA is available in Italy, from September 2014, for the first line setting and the present study explores the attitudes and preferences of clinicians in choosing between DOC and AA. Methods: We retrospectively reviewed the clinical records of all mCRPC pts who received a first-line treatment in 5 Italian hospitals after the introduction of AA in the clinical practice. All pts were treated with AA 1,000 mg po + prednisone (PDN) 10 mg po daily or with DOC at the dose of 75 mg/sqm i.v. every three wks. For each pt we have recorded the pre-first line clinical history and the baseline characteristics. Results: From September 2014 to August 2015, we collected a consecutive series of 70 mCRPC pts: 49 received AA, 21 DOC. The median age was 74 yrs (range 46-90), 6% had visceral mets; 8% had a performance status 2; 47% had pain. Pts treated with AA were significantly older (75.8 vs 69.7 yrs; p = 0.002); received more previous hormone therapies (2.19 vs 1.76; p = 0.03), had a longer interval between first hormone therapy and the start of mCRPC first line (47.6 vs 21.2 mos; p = 0.01) and finally, were less frequently symptomatic (27% vs 67%; p = 0.02%). Conclusions: The present study is the first to explore the clinicians’ attitudes and preferences, in the routine clinical practice, in choosing the first line drug for mCRPC pts. From our preliminary data, it appears that some pts characteristics are important in driving the choice of the clinicians between AA and DOC. Data collection is ongoing in other Italian hospitals.
Management of metastatic prostate cancer patients in first line: Audit of real-life practices.
Authors: Turpin Anthony , Lemoine Laetitia , Berdah Jean François , Massard Christophe , Culine Stephane , Bauvin Eric , Penel Nicolas
Published: February 2017

333

Background: Docetaxel and new hormonal therapies (NHT, abiraterone and enzalutamide) are both appropriate options in management of castration resistant prostate cancer (CRPCa) patients in first line therapy. There is no reliable guidance for choosing the best option. We have carried out an audit of real life practice among French physicians. Methods: We used an online software and built a questionnaire with 22 closed questions. With the help of French regional networks in Oncology and GETUG (Groupe d’étude des tumeurs urogénitales), this questionnaire has been sent to 481 physicians treating patients with CRPCa. All the answers were declarative, individual and, anonymized. The descriptive analysis was based on percentages and their 95% confidence intervals in the case of categorical variables, and the median and extreme values in the case of continuous variables. Results: From March to July 2015, 101 physicians (20,9%) completed the questionnaire: 49 medical oncologists, 29 radiation-oncologists, 21 urological surgeons and two other specialists from 22 French regions. The selection criteria for choosing docetaxel first were: presence of visceral metastases (78.2%), heavy tumour burden (68.3%), aggressive tumour disease (67.3%), short-term efficacy of the castration (65.4%). The selection criteria for the NHT were: long-term efficacy of castration (67.3%), higher age (67.3%), low tumour grade (56.4%) and absence of symptoms (53.5%). Under Docetaxel, 1st tumour re-assessment was done mainly after 3 (1-6) cycles, this assessment included PSA, thoraco-abdominopelvic CT and bone scintigraphy in respectively 96%, 68% and 58% of cases. Physicians assessed PSA level every cycle in 40.8% of cases and every 3 cycles in 41.8%. Under NHT, tumour reassessment was done mainly after 3 months of treatment (1-6) and included PSA, thoraco-abdominopelvic CT and bone scintigraphy, in respectively, 90%, 58%, and 62% of cases. Physicians assessed PSA level every 3 months in 50.5% of cases and monthly in 29.3%. Conclusions: This is the first descriptive study depicting real-life practice in French physicians treating CRPCa. Practices are heterogeneous. Guidelines for management of CRPCa are needed.
Prevalence of glucocorticoid use in prostate cancer patients.
Authors: Ellis Lorie , Behl Ajay , Xiao Yongling , Pilon Dominic , Lefebvre Patrick
Published: February 2017

336

Background: The prevalence of glucocorticoid (GC) use increases with age consistent with age-acquired diseases such as chronic obstructive pulmonary and inflammatory conditions for which GCs are indicated. GCs are commonly used alone or in combination with other therapies for prostate cancer (PC), but studies of GC treatment patterns in treated and untreated PC patients (pts) have not been widely reported. This study aimed to describe the prevalence of GC use in PC. Methods: Patients with ≥ 2 PC diagnoses or ≥1 claim for a PC therapy and ≥ 12 months continuous eligibility between 1/2005 and 7/2014 were identified in Truven Health MarketScan databases. The index date for the treated cohort (i.e., pts receiving LHRH agonist, adrenal blocker, anti-androgen, chemotherapy, oral mCRPC therapy, surgery or radiation) was defined as the date of the most recent PC treatment. The index date for the untreated cohort (i.e., with PC diagnosis but without PC treatment) was defined as the most recent PC diagnosis date. GC use was summarized post-index, for treated and untreated PC pts using descriptive statistics. Baseline demographics and comorbidities were also reported. Results: A total of 321,113 eligible PC pts were identified. Of these, 223,953 (70%) were untreated and 97,160 (30%) pts were treated with a PC therapy. Untreated pts had a mean age of 68 years and a mean Quan-Charlson comorbidity index (CCI) of 1.7 and treated pts had a mean age of 71 years and a mean CCI of 1.8. Approximately 30% of untreated pts and 40% of treated pts received GCs during the observation period. Among treated pts, 70% of pts receiving chemotherapy and 88% of pts receiving oral mCRPC therapies (abiraterone and enzalutamide) had evidence of GC use. Median daily GC dose was 24 mg in untreated and 20 mg in treated PC pts. Median daily GC dose was 14mg in chemotherapy-treated pts and 10 mg in pts treated with oral mCRPC therapies. Conclusions: GC use is common in pts with PC, including in those not receiving PC therapies. Median daily GC dosages tended to be lower in pts treated with PC therapies than in those without PC therapies. GC use in PC pts may be related to non-PC comorbidities which should be made known to PC physicians.
Abiraterone acetate in metastatic castration-resistant prostate cancer after chemotherapy: A “real life” retrospective analysis of progression-free (PFS) and overall survival (OS) according to duration of androgen deprivation therapy.
Authors: Fabbri Maria Agnese , Marchetti Paolo , Cortesi Enrico , Santini Daniele , Gamucci Teresa , Angelini Francesco , Sperduti Isabella , Longo Flavia , Pellegrino Arianna , Milano Annalisa , Quadrini Silvia , Mancini ML , Primi Francesca , Nelli Fabrizio , Ratta Raffaele , Ruggeri Enzo
Published: February 2017

337

Background: Abiraterone acetate (AA) is a potent, selective androgen (CYP17) biosynthesis inhibitor, which showed to improve overall survival in mCRPC pts progressing after docetaxel. Few data are available concerning the clinical outcome of AA treatment in mCRPC in terms of the duration of prior androgen deprivation therapy (ADT). In this retrospective analysis we assessed the PFS and OS in patients affected with mCRPC according to the duration of ADT. Methods: We retrospectively reviewed the clinical data of pts affected by mCRCP progressive after chemotherapy who received AA (1000 mg/d) plus prednisone (5 mg/twice daily). A total of 189 pts were included in the analysis, 71 received AA with ADT duration<12 months (Group A) and 118 received AA with ADT duration ≥ 12 months (Group B). Patient characteristics’ in the two treatment groups (A VS B) were: median age: 75 vs 69 years, Gleason score ≥7: 96% vs 92%; median PSA at AA start 47 (range 36-2130) vs 32 (range 85-2100), No of metastatic sites: 1 : 70% vs 75% ;bone only 50% vs 47%, visceral disease alone: 3% vs 5%; symptomatic disease : 58% vs 40% (p 0.02); median number of prior docetaxel courses: 6 in both groups; second-line cabazitaxel:14% in both groups, bisphosphonates concomitant treatment 66% vs 52.5% (p:0.21). No difference in radical prostatectomy or radiation therapy were evidenced Results: At a median follow-up of 8.5 months (range 1-51) the median progression-free survival (PFS) and the median overall survival (OS) were 10 months (95% CI: 7-13) and 26 months (95% CI: 17-35) respectively in all mCRPC. Group B patients had a statistically significant longer PFS (13 vs 7 months, p=0.009) and OS (28 vs 17 months, p=0.03 months). The median decrease in the PSA level > 50% was observed in 50 % of pts in both groups. AA was well tolerated and no relevant toxicity were observed Conclusions: This retrospective analysis showed a benefit in terms of PFS and OS in group B patients, our finding might be related to the best prognostic factors of patients in group B (less symptomatic).
Time to next line therapy after initiation of sipuleucel-T in metastatic castration-resistant prostate cancer patients.
Authors: Luu Dai , Goldstein Leanne , Twardowski Przemyslaw
Published: February 2017

341

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for patients with symptomatic or minimally asymptomatic metastatic castration-resistant prostate cancer based on prolongation of overall survival. We sought to retrospectively analyze the type and time to next-line therapy after the initiation of Sipuleucel-T (Sip-T) in the era of multiple new other therapeutic compounds that became available since approval of Sip-T to better understand the context of utilization of this immunotherapy in the current era. Methods: We performed a retrospective analysis of 53 patients with metastatic prostate cancer (PC) who have been treated with Sip-T at The City of Hope Medical Center between September 2010 and April 2013 and subsequently received another therapy. Variables included age at Sip-T treatment, Karnofsky Performance Score (KPS), Gleason score at diagnosis, extent of metastatic disease (limited or extensive), and white blood cell (WBC) count pre and post (Sip-T). PSA was measured at six time points (3 pre and 3 post Sip-T) and these were analyzed using a mixed linear regression model. A Cox Proportional Hazard model was used to examine predictors of time in days to next therapy as a function of the above variables including mixed model slopes of PSA. Results: Kaplan – Meier estimated median time to next treatment among the 53 patients was 122 days (95% CI, 86-177 days) and was significantly predicted by slope of PSA from the mixed model (HR = 25.883, p < .0001), WBC post therapy (HR = 1.352, p = 0.0017), and age at Sip-T (HR = 1.044 p = 0.0492). KPS, Gleason score, pre Sip-T WBC, and the extent of metastatic disease were not predictive. Most patients had abiraterone acetate for next treatment (n = 32, 58.2%). Other treatments included docetaxel (n = 5, 9.1%), orteronel with prednisone or prednisone alone (n = 12, 21.8%), and others (n = 6, 10.9%). Conclusions: In our experience median time to subsequent therapies was shorter than reported in pivotal Phase III study. Shorter time to post-Sip-T therapy was associated with older age, higher levels of WBC post-Sip-T therapy and more rapid rate of increase in the PSA level.