bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of PSA progression in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated in the COU-AA-302 trial.
Authors: Lorente David , Lozano Rebeca , de Velasco Guillermo , De Julian Maria , Rodrigo Miguel , Sanchez Angel L , Di Capua Carlos , Castro Elena , Sanchez Hernandez Alfredo , Olmos David 
Published: May 2019

e16541 Background: PSA is a widely used biomarker for monitoring outcome in mCRPC. Current treatment guidelines do not consider PSA progression before at least 12 weeks of treatment, and recommend treatment continuation in pts experiencing progression by PSA only, without radiographic or clinicall progression. We aimed to evaluate the prognostic value of a PSA progression in mCRPC pts treated with first-line therapy. Methods: We analyzed the value of a PSA progression (PSAProg) at cycle 5 in pts treated in the COU-AA-302 trial. PSAProg was defined as an increase ≥ 25% and ≥ 2 ng/mL from baseline, confirmed by a second reading. Radiographic progression (RadProg) was defined as per PCWG2 criteria for bone scan or RECIST progression. Survival and radiographic progression-free survival (rPFS) from the time of PSAProg was calculated using Kaplan-Meier estimates. Cox-regression models were used to evaluate the impact of PSAProg and treatment arm on survival. Results: 1088 pts were randomized in the COU-AA-302 trial. 908 pts (83.5%) had valid baseline and cycle 5 PSA values. Of these, 222 (24.4%) pts experienced PSAProg, which was confirmed in 195 (21.5%) pts; 45/479 (9.4%) of abiraterone and 150/429 (35%) of placebo-treated pts. A confirmed PSAProg was associated with shorter survival (37.8 vs 26m; HR: 1.8; p < 0.001) and rPFS (13.9 vs 5.6m; HR:2.1; p < 0.001). Median survival from the time of PSAProg was 22.2m (95%CI:18.9-25.4). Abiraterone-treated pts had a significantly longer survival from the time of PSAProg (23.1 vs 17.4m; HR: 0.64; p = 0.018). 111 pts (56,9%) experienced PSAprog without RadProg; in pts with PSAprog only, median time to RadProg was 7.4m (95%CI:7.1-12.9). No differences in rPFS from the time of PSAprog were observed in abiraterone vs placebo-treated pts (HR: 0.99; p = 0.963). Conclusions: 9.4% of abiraterone-treated pts in the COU-AA-302 trial experienced PSAProg at 12 weeks (cycle 5 day 1). PSAProg was associated with significantly worse survival. Abiraterone increased survival from the time of PSAProg, which supports its continued use in pts with PSA progression only at 12 weeks. This study was carried out under YODA Project #2018-3011.
Targeting checkpoint kinases in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Atiq Mohammad Omar , Chakraborty Goutam , Nandakumar Subhiksha , Mazzu Ying Zhang , Stopsack Konrad Hermann , Jehane Lina E. , Yoshikawa Yuki , Khan Nabeela , Lee Gwo-Shu Mary , Kantoff Philip W. 
Published: May 2019

e16543 Background: The identification of DNA damage response (DDR) gene abnormalities in various cancers has provided potential therapeutic targets including the poly ADP-ribose polymerase enzyme (PARP). PARP inhibitors are now approved for use in ovarian, breast, and prostate cancer (PC). Olaparib and rucaparib have been given Breakthrough Therapy designation by the FDA for use in patients with metastatic castration-resistant prostate cancer and germline BRCA1/2 or ATM mutations. However, drug resistance limits the efficacy of PARPi. Somatic reversion mutations of BRCA1/2 have been described as one potential mechanism of resistance to PARPi in patients with germline BRCA1/2 mutations. However, in PC, the BRCA2 gene is frequently deleted, in contrast to other cancers, where it is mutated. Thus, we hypothesize that resistance to PARPi in PC may involve alternative molecular mechanisms. Methods: We performed cell viability assays to determine the inhibitory growth (IG) concentrations of olaparib and talazoparib on human castration-resistant PC cell lines (PC-3 and LNCaP-Abl) that have heterozygous genomic deletions of BRCA2. Parental PC-3 cells were cultured in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media for approximately 2 months to develop talazoparib-resistant cells. We then performed an analysis of phosphorylation status in untreated and treated parental PC-3 and talazoparib-resistant clones with a phosphokinase array. We confirmed this with Western blot. Results: Talazoparib-resistant PC-3 clones showed significantly enhanced cell growth compared to parental cells when cultured in media supplemented with the IG 90% concentration of talazoparib or olaparib. The phosphokinase array revealed a significant increase in the phosphorylation of CHEK2 in talazoparib-resistant clones compared to parental PC-3 cells. Interestingly, a similar increase was seen after 72 hours of treatment with talazoparib, indicating an early connection between PARP inhibition and CHEK2 phosphorylation in PC cells. Moreover, a pan-CHEK inhibitor, prexasertib, led to significant cell growth inhibition in talazoparib-resistant PC-3 clones and a significantly lower IG 50% concentration compared to parental PC-3 cells. Conclusions: We speculate that early activation of CHEK2 may be a primary mechanism of resistance to PARPi in PC cells with deletion of BRCA2. Furthermore, our preliminary data showed that CHEK inhibition can overcome PARPi resistance, indicating a potential for CHEK inhibitor-based therapy for PC patients.
Pilot study to enhance FDG-PET imaging of prostate cancers with the metabolic inhibitor ranolazine.
Authors: Schlaepfer Isabel R. , Kessler Elizabeth R , Kwak Jennifer J , Liebman Lauren , Maroni Paul , Karki Ramesh , Lopez Paniagua Dan , Koo Phillip , La Rosa Francisco G. , Gao Dexiang , Glode L. Michael , Flaig Thomas W. , Lam Elaine Tat 
Published: May 2019

e16551 Background: 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) is a widely-used imaging modality for many cancers; however, its utility in prostate cancer is limited. Fatty acid oxidation (FAO) is a primary source of energy for early prostate cancer. We previously demonstrated that FAO inhibition in prostate cancer mouse models resulted in increased glucose metabolism and enhanced tumor FDG uptake, with peak uptake at 24 hours. To validate these preclinical findings, we conducted a pilot study to evaluate whether a partial FAO inhibitor, ranolazine, increases tumor FDG uptake on PET imaging for prostate cancer. Methods: Prostate cancer patients with untreated localized cancer (arm 1) and with metastatic disease on hormonal or other therapy (arm 2) were enrolled and underwent baseline and post-treatment FDG-PET/CT scans (standard dose of 10 mCi FDG). Ranolazine 1000mg PO BID x 2 doses was given within 24-48 hours of the second scan. The primary objective was to evaluate the rate of successful enhancement of FDG uptake on PET imaging, based on one or more of the following criteria: 30% increase in maximum SUV with an absolute change of 2 units; 30% increase in mean SUV with an absolute change of 0.75 units; or 20% increase in mean SUV with an absolute change of 1 unit. Results: Eleven patients (four in arm 1, seven in arm 2) were enrolled. Ranolazine was well tolerated by all participants, with no adverse effects observed. Both increases and decreases in SUV uptake were observed on the post-ranolazine scans. No patient met the predefined criteria for successful enhancement of FDG uptake. There was an incidental finding of thyroid cancer seen in one patient that was discovered on PET imaging. The study was closed early due to the emerging clinical availability of alternative and effective PET imaging modalities such as [11C] choline, [18F] fluciclovine, [68Ga] PSMA, and [18F] sodium fluoride. Conclusions: Given the small sample size, we were not able to make any firm conclusions. In this limited study, ranolazine treatment did not result in enhanced FDG-PET-tumor detection. ClinicalTrials.gov identifier: NCT01992016. Supported by the William Meyn Foundation; NIH/NCI P30CA46934, 5K12CA086913, CA168934; ACS RSG-16-256-01-TBE; Colorado Translational Research Imaging Center Pilot Award; Paul Sandoval Cancer Research Summer Fellowship. Clinical trial information: NCT01992016.
IMPACT of putative chemopreventative agents on prostate cancer diagnosis.
Authors: Goldberg Hanan , Moshin Faizan , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher J.D. , Herrera Cáceres Jaime Omar , Ahmed Ardalan , Alibhai Shabbir M.H. , Berlin Alejandro , Saskin Refik , Hamilton Robert James , Fleshner Neil Eric 
Published: May 2019

e16553 Background: Prostate cancer (PC) is the most common non-cutaneous cancer in men and the third most common cause of cancer death in males. Several studies have shown that use of commonly prescribed medications, is associated with improved survival in various malignancies, including PC. There has not been any large population-based study, examining the effects of these and other commonly prescribed medications, such as proton pump inhibitors (PPI), on the rate of PC diagnosis, PC advanced disease and PC-specific death. Methods: A retrospective population-based study using data from the institute of clinical evaluative sciences, including all male patients aged 65 and above in Ontario who have had a negative first prostate biopsy between 1994 and 2016. We assessed the impact of commonly prescribed medications on PC outcomes. The analyzed medications included Statins (hydrophilic and hydrophobic), most commonly used diabetes drugs (metformin, insulins, sulfonylureas, and thizolidinedions), PPIs, 5 alpha reductase inhibitors, and alpha blockers. Time dependent Cox regression proportional hazards models were performed to determine predictors of PC diagnosis, PC advanced disease (defined as usage of hormonal therapy), and PC-specific death. Medication exposure was time varying and modelled as “ever” vs. “never” use or as cumulative exposure. Results: A total of 21,562 men were analyzed over a mean (SD) follow-up time of 8.06 (5.44) years. Overall, 5,187 patients (24%) were diagnosed with PC, 7861 (36.5%) had died, and 647 (3%) died of PC. On multivariable analysis usage of hydrophilic statins modelled as “ever vs. never” was associated with a lower diagnosis rate (OR 0.832, 95% CI 0.732-0.946, p = 0.005) and a significantly decreased PC-specific death (OR 0.676, 95% CI 0.528-0.871, p = 0.0024). In contrast, Pantoprazole was associated with a higher rate of advanced PC disease when modelled as cumulative exposure of 6 months (OR 1.03, 95% CI 1.003-1.06, P = 0.031), and PC-specific death, when modeled as “ever vs. never” (OR 1.26, 95% CI 1.02-1.576, p = 0.031). Conclusions: Hydrophilic statins were associated with a clinically and statistically significant lower PC diagnosis and PC-specific death, while pantoprazole was associated with a higher rate of advanced PC disease and PC-specific death.
Survival in men diagnosed with castration resistant prostate cancer: A population-based observational study in Sweden.
Authors: Aly Markus , Schain Frida , Leval Amy , Liwing Johan , Lawson Joe , Vago Emese , Nordström Tobias , Gronberg Henrik , Andersson Therese M-L , Sjöland Erik , Wang Chen , Eloranta Sandra , Akre Olof 
Published: May 2019

e16555 Background: Data focusing on the castration resistant phase of prostate cancer (PC) outside clinical trial settings are scarce. This study aims to investigate PC-specific and overall survival (OS) in men with castration resistant prostate cancer (CRPC) on a population level. Methods: The STHLM-0 cohort (n = 400 000) with data on all prostate specific antigen (PSA) values and prostate biopsies taken in Stockholm, Sweden, from 2003 to 2015 were linked to other population registries. All men with a PC diagnosis and rising PSA after three months consecutive use of gonadotropin-releasing hormone or surgical castration were defined as CRPC (n = 1712). Kaplan-Meier was used to estimate median time-to-event and 95% confidence intervals (CI). Patients were stratified by metastasis status at PC diagnosis and multivariable Cox regression was used to adjust for clinical subgroups, including Gleason, age, T stage and calendar period (2006-2011 vs 2012-2015). Results: Metastasis at PC diagnosis was associated with shorter OS from castration resistance. From CRPC onset the median OS was 22.8 months (95% CI 21.2-25.5) and 13.1 (95% CI 11.5-14.2) months for patients without and with metastasis at PC diagnosis, respectively. The median PC-specific survival from CRPC was 30.7 (95% CI 27.9-34.7) months and 13.5 (95% CI 12.3-16.1) months for patients without and with metastasis at PC diagnosis, respectively. For patients with metastasis at PC diagnosis, factors influencing OS from CRPC were; entering CRPC stage in the later vs earlier calendar period (HR 0.61 95% CI 0.48-0.78, p < 0.001), age > 80 vs < 70 (HR 1.46, 95% CI 1.05-2.02, p < 0.02), T4 vs T1 stage (HR 1.56, 95% CI:1.02-2.37, p < 004). For patients without metastasis at PC diagnosis, developing CRPC in the later vs the earlier calendar period was associated with superior survival from CRPC (HR 0.78 95% CI 0.65-0.92, p < 0.004). Conclusions: Metastasis at PC diagnosis was associated with worse survival outcomes in CRPC patients. Individuals who became castration resistant in the later calendar period survived longer compared to those in the same stage in the earlier calendar period, most likely due to the introduction of novel agents for CRPC patients and more accurate staging methods.
Predictors and rates of adverse events (AEs) among non-metastatic prostate cancer (nmPC) patients (pts) treated with bicalutamide, abiraterone, or enzalutamide following surgical/medical castration.
Authors: Shah Anuj , Hussain Arif , Shah Ruchit , Ikeme Shelly , Mohamed Ateesha F. , Botteman Marc , Waldeck Reg 
Published: May 2019

e16556 Background: The castration-resistant nmPC treatment landscape has evolved following the recent approval of enzalutamide and abiraterone. Skin rash, fractures, and central nervous system (CNS) AEs have been reported among pts treated with these drugs as well as other antiandrogens (eg. bicalutamide). We assessed the rate and predictors of AEs among nmPC pts treated with abiraterone, enzalutamide, or bicalutamide (“study drugs”) in a real-world setting. Methods: nmPC pts initiating one of the study drugs ≥1 year after medical/surgical castration were identified in the MarketScan Commercial database (2012-17). We included pts who had all the following: a claim for a prostate-specific antigen test or an oncologist visit ≤6 months (mos) before study drug initiation (baseline period), no claim for hormonal therapies (except castration) nor metastasis before study drug, and ≥3-mos metastasis-free follow-up while on study drug. Kaplan Meier analyses were used to describe the rates and median time to onset for 18 CNS AEs (including, but not limited to, fatigue, cognitive impairment, or falls) or any AE (i.e., CNS AE, skin rash, or fracture). Baseline period AE predictors were identified using multivariate Cox-proportional hazards models. Results: 532 pts were included (bicalutamide: 89.7%, enzalutamide: 4.3%, abiraterone: 6.0%). The percentages of pts experiencing CNS AEs/any AE were 19%/22% at 3 mos, 28%/35% at 6 mos, and 43%/52% at 12 mos. Median time to AE onset since study drug initiation was 17.9 mos (CNS AE) and 11.0 mos (any AE) respectively. Significant predictors of having any AEs included baseline period AEs (hazard ratio [HR]: 3.07 [2.35-4.02]), Charlson comorbidity index (1 vs 0) (HR: 1.51 [1.04-1.19]), surgical castration (HR: 1.50 [1.07-2.08]), and older age (HR: 1.021 [1.002-1.040]). Similar predictors were found for CNS AE. Conclusions: nmPC pts treated with bicalutamide, enzalutamide or abiraterone experience high AE rates. Balancing the risks/benefits of treatment in this largely asymptomatic population is paramount to maintaining their quality of survival while optimizing survival outcomes.
Cell cycle progression score differentiates indolent from aggressive prostate cancer in men diagnosed by TURP.
Authors: Cuzick Jack M. , Stone Steven , Rajamani Saradha , Møller Henrik , Berney Daniel M. , Cohen Todd , Scardino Peter T. 
Published: May 2019

e16560 Background: Improved selection of men with localized prostate cancer for conservative management remains a clinical need. We previously showed that the Cell Cycle Progression (CCP) score provides a significant amount of independent prognostic information in men with prostate cancer who opt for conservative management. Here, we extend those results by evaluating the performance of the CCP score in a newly analyzed cohort of conservatively managed men and in a large pooled cohort of men who deferred initial curative therapy. Methods: The CCP score (based on 31 CCP genes and 15 housekeepers) was derived from FFPE tumor sections as previously described. For this study, the CCP score was evaluated in several independent cohorts: 1) a newly studied retrospective cohort from the U.K. diagnosed by a transurethral resection of the prostate (TURP1B, N = 192); 2) a previously studied cohort from the U.K. diagnosed by TURP (TURP1A, N = 200); and 3) two previously studied cohorts from the U.K. diagnosed by needle biopsy (TAPG1, N = 180 and TAPG2, N = 585). The combined cohort included 1,157 conservatively managed men with complete clinical data. Median follow-up for all cohorts was 9.8 years. Hazard ratios (HR) are for a one-unit change in score, and the endpoint for this study was disease specific mortality (DSM). Results: The CCP score was a highly significant predictor of DSM in TURP1B. The univariate HR was 2.96 (95% CI 2.32, 4.04, p = 3.6x10-9), and the multivariate HR after adjusting for CAPRA was 2.27 (95% CI 1.59, 3.23, p = 1.3x10-5). These results are very similar to the HRs obtained in TURP1A cohort, and the test for HR heterogeneity was not significant after adjusting for CAPRA (p = 0.30). In the pooled analyses, the interaction between CCP and cohort was not significant after adjusting for clinical variables. Interestingly, sample type (TURP vs. Needle biopsy) was prognostic even after adjusting for clinical variables. Summaries of the pooled analyses are given in Table. Conclusions: The CCP score adds a significant amount of independent prognostic information for outcome in conservatively managed men. As such, it can be used to help select appropriate patients for deferred treatment regimens like AS or watchful waiting. [Table: see text]
The predictive power of free (vs. total) testosterone in aggressive prostate cancer.
Authors: Towe Maxwell M , Huynh Linda My , El Khatib Farouk , Osman Mohamad M , Yafi Faysal A , Ahlering Thomas Edward 
Published: May 2019

e16570 Background: The role of testosterone in prostate growth and the development of prostate cancer is a controversial topic. Most current data suggest that lower testosterone leads to higher grade conversion, whereas higher testosterone may serve a protective role in preventing both development and recurrence. We seek to analyze whether free testosterone (FT) values can predict aggressiveness in prostate cancers. Methods: We retrospectively reviewed 830 patients who presented to a single surgeon for evaluation and management of prostate cancer. Total Testosterone (TT) and FT values were obtained on each patient at initial visit. All patients underwent radical prostatectomy and samples from surgery were sent for grading and staging. Patients were stratified by FT quartile (25th [≤ 4.42 ng/dL], 50th [4.43 – 5.60 ng/dL], 75th [5.61 – 6.95 ng/dL], and 100th [≥ 6.96 ng/dL]). Results: Of 830 patients, 168 (22.2%), 330 (39.8%), 188 (22.7%), 46 (5.5%), and 98 (11.8%) had GS 3+3, 3+4, 4+3, 4+4, and ≥4+5, respectively. Mean FT values for each Gleason grade group (GGG) were significantly different (p = 0.008). Mean FT was also lower in patients with higher stage disease (p = 0.01). In contrast, TT did not differ significantly among GGG (p = 0.489) or stage (p = 0.670). Patients who had a FT level in the lowest quartile (≤ 4.42 ng/dL) had a higher proportion of GGG 5 (15.6%) than patients in the highest quartile (≥ 6.96 ng/dL) (6.2%) (p = 0.002). After adjusting for age, prostate specific antigen (PSA), and body mass index (BMI) in multivariate analysis, lower FT was a significant predictor of high-risk score 9-10 (OR: 0.912, 95% CI: 0.836-0.994, p = 0.036). These trends showed strong correlation in pathologic stage (p = 0.057), but larger numbers are needed to gauge effect size. Conclusions: Based on our data, biochemically low FT may be a risk factor for high grade and high stage cancer. These results have implications for the current recommendations for testosterone therapy, which is contraindicated in men with prostate cancer. [Table: see text]
Impact of comorbidity and age on treatment choice among men with localized prostate cancer.
Authors: Pinsky Paul F , Pierre-Victor Dudith , Martin Iman K. , Miller Eric , McCaskill-Stevens Worta J. , Grubb Robert L. 
Published: May 2019

e16585 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States. A substantial proportion of PCa patients has at least one comorbidity. Comorbidities have a meaningful impact on cancer treatment choice. The objective of this study was to investigate the effect of comorbidity, as well as age, on treatment choice among men with localized PCa. Methods: From the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, men with localized PCa diagnosed from 1994-2014 were selected (N = 10, 281). Comorbidity score was determined based on a modified Charlson index. Treatment was classified as curative, either radical prostatectomy (RP) or radiation therapy with curative intent (RT), or non-curative (all other modalities). We used multivariate logistic regression to assess the association of treatment choice with age and comorbidity score (including their interaction), controlling for D’Amico risk group, demographics and diagnosis year. Results: About half (48.3%) of patients had comorbidity score ≥ 1. Most men received curative treatment (75.2%); RT (55.2%) was more common than RP (44.8%). The likelihood of curative treatment decreased with increasing age; odds ratios (OR) for curative treatment were 0.63 (95%CI: 0.52-0.76), 0.36 (95%CI: 0.30-0.43) and 0.13 (95%CI: 0.11-0.16) for men aged 65-69, 70-74 and 75+, respectively, compared to men aged 55-64. Men with a comorbidity score of 2+ (OR = 0.84; 95%CI: 0.74-0.96) were less likely to receive curative treatment than men with a score of 0. Within curative treatment, older age was strongly associated with RT. Compared to men aged 55-64 years, men aged 65-69 years (OR = 2.0; 95% CI: 1.72-2.3), 70-74 years (OR = 5.3; 95% CI: 4.5-6.3), and 75+ years (OR = 25.0; 95% CI: 17-33) were more likely to receive RT than RP. Men with a comorbidity score of 1 (OR = 1.16; 95%CI: 1.03-1.30) or 2+ (OR = 1.92; 95%CI: 1.6-2.3) were also more likely to receive RT. The interaction between age and comorbidity score was not significant. Conclusions: In this cohort, age was a strong independent predictor of treatment choice for localized PCa. Although comorbidity was not a strong predictor of curative treatment, it was associated with receipt of RT.