bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic characterization of pulmonary-metastatic prostate cancer: A unique molecular subtype.
Authors: Shenderov Eugene , Velho Pedro Isaacsson , Awan Anas Hamid , Mirkheshti Nooshin , Eisenberger Mario A. , Pardoll Drew M. , Antonarakis Emmanuel S. 
Published: March 2019

210 Background: Metastatic prostate cancer (mPC) rarely spreads to the lungs and lung-only metastatic disease has not been clearly defined. This study investigated the clinical and molecular features of lung-only mPC. Methods: This is a retrospective single-institution study. Medical records of 40 metastatic prostate patients with lung-only (N=25) or lung-predominant (N=15) disease were analyzed. Germline and/or somatic DNA sequencing results, when available, were recorded. Results: 25 lung-only mPC patients were identified, of which 14 underwent germline/somatic DNA analysis. Nine (64%) had a driver mutation in either: the WNT pathway (29%), PI3K/PTEN pathway (21%), homologous recombination DNA repair (HRD) (36%) or mismatch repair (MMR) (29%). 15 lung-predominant mPC patients were also analyzed, of which 10 underwent genomic analysis. Seven (70%) had a driver mutation in either: WNT (10%), PI3K/PTEN (40%), HRD (40%), or MMR (21%). Representative driver mutations for both cohorts summarized in Table. In comparison, in our genomic database, 52.1% had a driver mutation (in WNT 15%, PI3K/PTEN 33%, HRD 22% or MMR 4%). The lung-only and lung-predominant cohorts did not differ by age (p=0.41), race, PSA (p=0.16), Gleason sum (p=0.77), intraductal/ductal histology (p=0.71), lymphovascular invasion (p=0.64), perineural invasion (p=0.73), or having relatives with cancer (p=0.22). Our results are limited by the small sample size and retrospective nature of the analysis. Conclusions: In this exploratory study, the overall prevalence of DNA repair gene alterations was higher than anticipated (35%), suggesting a potential enrichment (esp. in MMR mutations) in men with lung-only or lung-predominant mPC. This finding may have important therapeutic implications. These results require prospective validation of the hypothesis that pulmonary-tropic mPC biology may be fundamentally different from non-pulmonary mPC, and that these patients may benefit from PARP inhibitor or anti–PD-1 treatments. Clinical outcomes data will also be presented. [Table: see text]
Quality-of-life (QoL) assessment and reporting in prostate cancer: A systematic review of phase III trials published between 2012 and 2016.
Authors: Marandino Laura , La Salvia Anna , Sonetto Cristina , De Luca Emmanuele , Pignataro Daniele , Zichi Clizia , Di Stefano Rosario F , Ghisoni Eleonora , Lombardi Pasquale , Mariniello Annapaola , Reale Maria Lucia , Trevisi Elena , Leone Gianmarco , Muratori Leonardo , ButtIgliero Consuelo , Tucci Marcello , Aglietta Massimo , Scagliotti Giorgio V. , Perrone Francesco , Di Maio Massimo 
Published: March 2019

219 Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.
The role of enzalutamide-induced hyperactive Jak2-Stat5 feed-forward signaling loop on enzalutamide-resistant prostate cancer growth and as a therapeutic target for second-line treatment.
Authors: Udhane Vindhya , Maranto Cristina , Hoang David , Erickson Andrew , Devi Savita , Jacobsohn Kenneth , Iczkowski Kenneth , See William , Kilari Deepak , Mirtti Tuomas , Nevalainen Marja 
Published: March 2019

221 Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.
Plasma cell-free DNA-based prognosis in metastatic hormone sensitive prostate cancer.
Authors: Kohli Manish , Yadav Siddhartha , Tan Winston , Riaz Irbaz Bin , Zheng Tiantian , Wang Amy , Montesinos Carlos , Wong Calvin , Du Peter , Jia Shidong , Yu Jianjun 
Published: March 2019

242 Background: We evaluated plasma cell free based genomic aberrations for prognosticating survival of newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patients (pts). Methods: Plasma was collected from mHSPC pts enrolled between 2009-2014. Platelet poor plasma (PPP) fractions were processed uniformly and cell free DNA (cfDNA) extracted using Qiagen kits. Pts were followed after initiating hormonal therapy until death. Next Gen Sequencing (NGS) of cfDNA was performed using Illumina HiSeq X for a preselected panel of 128 genes (PredicineDDR-77 cancer driver genes; 29 genes in BRCA-FA homologous recombination deficiency (HRD) pathway; 22 DNA damage repair pathway genes). Statistical analyses of plasma genome based aberrations with overall survival (OS) were performed in R 3.5.1. Cox proportional-hazard models were used for survival analysis. Results: An average of 2.5 ml PPP from 99 pts yielded a median of 10.5 ng (range: 2.8-702) cfDNA per sample. 15/99 pt samples with a yield < 5 ng were excluded from sequencing; 9/99 samples failed NGS. Median follow-up time was 80.2 months (mths) (Range: 74.7, 87]); median OS was 69.1 mths (range: 54,NR). 29 pts with full NGS data had high volume metastatic disease. cfDNA yield correlated with metastatic volume (P = 0.01). Univariate analysis revealed both variables prognostic for OS (Metastatic volume: log-rank P=0.01, HR=2.1, 95% CI: 1.1-3.8; cfDNA yield: P =0.04, HR = 1.3, 95% CI: 1.03-1.7). Multivariate regression showed prognostic value of cfDNA yield remained independent of metastatic volume (P = 0.03, HR = 1.34, 95% CI: 1.02-1.76). 54/67 samples with NGS data had at least one mutation/copy number variation detected. Top mutated genes included TP53 (N=18), ATM (N=9), CHEK2 (N=7), FANCM (N=6), RB1 (N=6), BRCA2 (N=5), PIK3CA (N=4) and 37/67 pts harbored 1≥ variant in HDR pathways. These pts had a shorter survival (median: 58.6 mths) (P=0.04, HR= 2.28, 95% CI: 1.01-5.18) and pts with ATM mutations did significantly worse (median survival: 47.4 mths) (HR=4.03, P=0.0005, 95% CI: 1.73-9.37). Conclusions: Plasma cfDNA yield is prognostic for survival in newly diagnosed mHSPC state and presence of HRD pathway genomic aberrations in plasma cfDNA are associated with poor survival.
DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.
Authors: Vu James , Moses Marcus Marie , Ranasinghe Lahiru , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver , Ledet Elisa 
Published: March 2019

245 Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients with a DNA repair pathogenic mutation were more likely to have > 2 family members affected by cancer, regardless of cancer type or degree of relationship (p = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.
Safety of high dose rate prostate brachytherapy in patients with high baseline international prostate symptom scores.
Authors: Morgan Tiffany , Rossi Peter John , Cutrell Patrick , Zhang Chao , Press Robert H. , Rahnema Sara , Sanda Martin George , Pattaras John , Cimmino Cara B. , Jani Ashesh B. , Patel Pretesh R. 
Published: March 2019

25 Background: Though a high baseline international prostate symptom score (IPSS) is considered a relative contraindication for low dose rate (LDR) brachytherapy, use of high dose rate (HDR) technique has several theoretical advantages including increased ability to sculpt dose and spare normal tissue via post-implant dosimetry. We report our institutional QOL data for those undergoing HDR with an IPSS score ≥15 compared to those with an IPSS score <15. Methods: The charts of 95 patients with localized adenocarcinoma of the prostate treated with HDR as monotherapy or as a boost after external beam radiation (EBRT) at a single institution between 2012 and 2015 were reviewed. All patients completed the IPSS and Expanded Prostate Index for Prostate Cancer–Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and at least one follow-up survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time. Results: Median follow-up in the IPSS <15 group (n=79) was 23 months and 16 months in the IPSS ≥15 group (n=16). Median IPSS score was 6 (range 0-14) and 19 (range 15-30), respectively. A majority of patients in both groups were diagnosed with National Comprehensive Cancer Network (NCCN) intermediate risk disease. Median prostate volume was 45.4cc in the IPSS ≥15 group and 46.3cc in the IPSS <15 group (p=0.901). IPSS, incontinence, and urinary irritation/obstruction scores were significantly higher in the IPSS ≥15 group compared to the IPSS <15 group at baseline (all p≤0.05). By the >24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS score <15 (all p>0.1). 12.5% in the IPSS ≥15 group developed a new grade 2 GU toxicity requiring an alpha-blocker compared to 26.5% in the IPSS <15 group (p=0.34). No patients required emergency placement of a foley catheter within 30 days of treatment. Conclusions: Given the low rates of GU toxicity, including a low risk of urinary obstruction requiring catheterization after HDR brachytherapy for those with a baseline IPSS score ≥15, this technique appears appropriate even for those with high baseline urinary symptoms.
Clinical characteristics of men with prostate cancer and evaluation of NCCN prostate cancer guidelines on germline genetic testing outcomes.
Authors: Greenberg Samantha , O'Neil Brock , Cooney Kathleen A. , Pappas Lisa M. , Tward Jonathan David 
Published: March 2019

252 Background: Growing evidence suggests up to 12% of men with metastatic prostate cancer (PC) harbor a pathogenic variant (PV) in genes associated with hereditary cancer risk. Updated NCCN PC guidelines include consideration for germline testing (GT) in men with high risk, very high risk, regional, or metastatic PC. As a result, we expanded our criteria for GT in men with PC to include these groups and men with a strong family history for PC beginning in January 2018. This study reports the clinical characteristics and germline findings before and after this expansion. Methods: Men with PC underwent multi-gene genetic testing (GT) for PVs from June 2016-June 2018 with genetic counselors. Clinical information and germline GT results were analyzed. Results: Of 285 eligible men who met with a genetic counselor, there were 201 evaluable GT results. One PV was excluded for suspicion of clonal hematopoiesis of indeterminate potential. Twenty-seven PVs were identified in 24 men (12.4%). Three men had two PVs identified (1.5%), at least one PV of which was in ATM or BRCA2. The most common PVs were ATM (n = 6, 3.0%), BRCA2 (n = 7, 3.5%), MYH (n = 4, 2.0%), and HOXB13 (n = 4, 2.0%). Rate of PVs were not statistically different across the two timeframes of GT, (2016-17, 14%; 2018, 11.2%; p = 0.60). PVs were not statistically associated with a higher ISUP group (1-3: 10.1%, 4-5: 13.6%; p = 0.49) and were distributed across multiple NCCN risk groups. Almost all men tested reported a family history of cancer, with the most frequent cancers reported including PC (n = 79, 39.3%), breast (n = 55, 27.4%), and colon cancer (n = 23, 11.4%). Family history of PC was not statistically associated with genetic test results (PV: 54%, no PV: 37%; p = 0.11). Conclusions: Expanding germline GT criteria will substantially increase patient volume without significant changes to the PV rate. Higher PC risk defined by ISUP or NCCN was not associated with the rate of PVs. Given this finding, further broadening the criteria for GT in PC may be warranted.
Treatment patterns and outcomes for metastatic castration-resistant prostate cancer (mCRPC) in a real-world setting: A retrospective study of greater than 2500 patients.
Authors: Higano Celestia S. , Sternberg Cora N. , Saad Fred , TOMBAL Bertrand F. , Miller Kurt , Kalinovsky Jan , Jiao XiaoLong , Tangirala Krishna , Sartor A. Oliver 
Published: March 2019

256 Background: In the era of expanding therapeutic options for mCRPC, there is a growing need to develop an optimal treatment sequence. This real-world study evaluated treatment patterns and outcomes in mCRPC patients. Methods: This retrospective cohort study used the Flatiron prostate cancer core registry (Jan 2013 to Sep 2017) to assess real-world treatment patterns (lines of therapy and transitions to subsequent lines) and outcomes (overall survival, OS) in patients with mCRPC. Descriptive analysis was performed for treatment patterns, and the Kaplan–Meier method was used to analyze OS. Results: This study comprised 2559 patients with mCRPC who received up to three lines of therapy. 23% of patients did not receive a life-prolonging therapy after the initial diagnosis of mCRPC. In the first-line (1L) setting, abiraterone (Abi, 37%) was the most-prescribed therapy, followed by enzalutamide (Enza, 28%) and docetaxel (15%). In the second line (2L), combination therapies were frequent (17%), with rates similar to taxane-based chemotherapy (docetaxel or cabazitaxel). Enza was the most-common 2L therapy used after Abi, and vice versa. Radium-223 (Ra-223) was prescribed as 1L therapy in 5% and 2L therapy in 9% of patients, either as monotherapy or part of a combination regimen. When Ra-223 was used in the 1L setting, similar proportions of patients received subsequent therapy with Enza (14%), Abi (13%), or chemotherapy (11%). Ra-223 was commonly used in the third line (14%), but less frequently than chemotherapy (36%). After each line, ~50% of patients did not receive a subsequent life-prolonging agent. Overall, 66% of patients used bone health agents at any time (denosumab, 48%; zoledronic acid, 24%). The median OS from the diagnosis of mCRPC was 21 months. Conclusions: This real-world study shows that not all patients with mCRPC received a life-prolonging therapy. Among patients who received an anti-cancer therapy, approximately half did not receive a subsequent life-prolonging therapy. Abi and Enza were the most-common 1L therapies, and their back-to-back use was common despite reported cross-resistance and limited benefit.
Radiation-related lymphopenia after pelvic nodal irradiation for prostate cancer.
Authors: Dutta Sunil W , Schad Michael D , Muller Donald A , Wijesooriya Krishni , Showalter Timothy N 
Published: March 2019

26 Background: Given uncertainty regarding the effectiveness of pelvic nodal irradiation (PNI) for prostate cancer, we aimed to determine whether prostate cancer patients treated with PNI are at a higher risk of developing radiation-related lymphopenia (RRL) and whether RRL is predictive for worse treatment outcomes. Methods: The electronic charts of 886 consecutive patients treated with radiation therapy (RT) for prostate cancer from 2006 to 2018 at our institution were retrospectively analyzed. Qualifying patients were those with total lymphocyte counts (TLCs) within one year prior to and 3–24 months after the start of RT. Lymphopenia was the primary outcome; overall survival (OS) and biochemical progression-free survival (bPFS) were secondary outcomes. Results: Thirty-six patients with PNI and ninety-five patients without PNI qualified. In the PNI cohort, 61.1% of patients developed RRL (median follow-up TLC < 1000 cells/µL), versus 26.3% of non-PNI patients. On univariate analysis, initial prostate specific antigen (iPSA), baseline lymphopenia, treatment modality, PNI status, increased planned target volume, and androgen deprivation therapy administration were all significant predictors of RRL ( p < 0.05). On multivariate analysis, PNI status was a significant predictor of RRL ( p < 0.001; HR 3.42; 95% CI 1.22–9.61) as well as iPSA ( p = 0.006; HR 1.05; 95% CI 1.00–1.11) and baseline lymphopenia ( p = 0.007; HR 8.32; 95% CI 2.19–31.6). RRL was not predictive for bPFS, distant metastasis, or OS on multivariate analysis, though the numbers of events were likely insufficient for these analyses. Conclusions: The higher risk of RRL among PNI patients comports with other papers that show increased treatment volumes are associated with higher rates of RRL. Mounting evidence for the adverse effects of RRL on clinical outcomes supports the significance of our findings and suggests further studies are needed on RRL as a potential harm of PNI that may affect interpretation of results from clinical trials of PNI.
The effect of the timing of biochemical failure after external beam radiotherapy or low-dose-rate brachytherapy for definitive prostate cancer treatment.
Authors: Ciezki Jay P. , Reddy Chandana A. , Mian Omar Y. , Tendulkar Rahul D. , Ulchaker James , Angermeier Kenneth , Campbell Steven , Stephenson Andrew J. , Stovsky Mark , Klein Eric A. 
Published: March 2019

28 Background: To assess the effect of the timing of biochemical failure (bF) after definitive radiotherapy with external beam (EBRT) or low dose-rate brachytherapy (LDR) on clinical failure (cF) and prostate cancer-specific mortality (PCSM). Methods: From 1996 to 2009, 4478 patients were treated and by 2010, 456 patients were noted to have a bF. They were categorized as early (< 5 years post-therapy) or late (≥ 5 years post-therapy) failures. Factors thought to influence cF and PCSM were scored. Cox regression was used to assess the timing of bF on cF and Fine and Gray regression was used to assess the timing of bF on PCSM. Results: There were 330 (72.4 %) patients categorized as early and 126 (27.6 %) as late failures. The median PSA follow-up post-radiotherapy for the early bF group is 82 months vs. 155 months for the late bF group, and the median PSA follow-up post-bF is 54 months for the early bF group vs. 69 months for the late bF group. The early failures were more likely to be high-risk (p = 0.0080), have a higher Gleason score (p = 0.0008), and use ADT (p = 0.0325). The five-year rate of cF post early bF is 61% vs 43% post late bF (p <0.0001). The five-year rate of PCSM post early bF is 27% vs 9% post late bF (p <0.0001). The multivariable analyses assessing the cF and PCSM are shown in Table. Conclusions: Early bF is associated with higher rates of cF and PCSM. Patients treated with LDR have a lower risk of PCSM. [Table: see text]