bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzalutamide (E) re-challenge as second-line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with first-line enzalutamide + docetaxel (D): Preliminary results of a post-progression analysis of CHEIRON trial.
Authors: Caffo Orazio , Aieta Michele , Palesandro Erica , Macerelli Marianna , Mucciarini Claudia , Nicodemo Maurizio , De Giorgi Ugo , Sartori Donata , Fratino Lucia , Iacovelli Roberto , Rossetti Sabrina , Scapoli Daniela , Morelli Franco , Carrozza Francesco , Nole Franco , Zagonel Vittorina , Messina Carlo , Gasparro Donatello 
Published: February 2020

123 Background: CHEIRON trial was a phase II study which randomized previously untreated mCRPC pts to receive D 75 mg/m2 IV d1 q3w for 8 courses alone or plus E 160 mg PO daily. As per protocol, E was administered in experimental arm for only 24 wks until D conclusion. The study met its primary endpoint since the rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). The clinicians were asked to consider an E re-challenge as first post-progression treatment for those pts without disease progression at the chemotherapy end in the experimental arm. We presented the preliminary analysis of E activity in post-progression setting of CHEIRON DE arm. Methods: We evaluated all patients enrolled in the experimental arm, focusing on pts who received E as first post-progression treatment. We collected data concerning the treatment duration and disease control and compared the outcomes of pts treated with E re-challenge with those of pts who received other treatments at the time of first progression after experimental therapy. Results: Among the 120 pts who received DE experimental arm, 101 did not show a disease progression and 82 received a second-line active treatment: 54 (66%) were treated with E, the other received abiraterone (10 pts), cabazitaxel (13 pts), and radium 223 (5 pts). The median interval between the end of DE and the start of E re-challenge was 7.6 mos (range 0.9-18.4 mos). At a median follow-up of 15.5 mos, the median duration of E re-challenge was 9.8 mos (range 1.9-30.9) with 22 pts still on treatment. Pts who received E rechallenge showed a median progression free survival of 11.4 mos which was significantly longer compared to 4.5 mos showed in pts who received other treatments (p < 0.0001). The median overall survival was 20.4 mos and 12.3 mos, respectively (p = NS). Conclusions: In pts who received first-line DE in the CHEIRON trial, the reintroduction of E after a per-protocol discontinuation demonstrated to be feasible, with a prolonged disease control compared to the other post-progression therapeutic options. Clinical trial information: NCT02453009.
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Long-term follow up of secondary endpoints.
Authors: Maughan Benjamin Louis , Hahn Andrew W , Nussenzveig Roberto , Hoffman John , Morton Kathryn , Gupta Sumati , Batten Julia Anne , Thorley Jared , Hawks Josiah , Santos Victor Sacristan , Nachaegari Gayatri , Wang Xuechen , Boucher Kenneth M. , Haaland Benjamin , Agarwal Neeraj 
Published: February 2020

125 Background: RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, men with mCRPC and a significant decline in serum bone metabolism markers (BMM) had improved survival with atrasentan, a bone targeting agent (PMID 24565955). We hypothesized that RA+EZ is safe, and decrease bone metabolism markers compared to EZ alone. Here we report the long-term follow up of the secondary clinical endpoints. Methods: In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment; 2) safety. Secondary objectives: changes in 4 other markers of bone resorption or formation, and PSA progression free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results: After a safety lead in phase (n=8), 39 men were randomized (2:1) to RA+EZ vs EZ. Median follow up is 19.3 months (range 3 – 24 months). Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057) and met the primary endpoint (2018 ESMO annual meeting: Annals of Oncology). There was a consistent trend regarding PSA-PFS, rPFS and OS favoring RA+EZ over EZ. . . (Table). Notably, no bone fractures have occurred in either group with extended follow up. Conclusions: The use of RA+EZ was safe with a longer follow up with no increase in skeletal related events including fractures. All secondary endpoints, numerically favored RA+EZ vs EZ. Clinical trial information: NCT02614859.
Non-rising PSA disease progression on C-11 choline PET/CT imaging in patients receiving second generation hormone therapies (2nd-HT).
Authors: Ahmed Mohamed E. , Andrews Jack R. , Dundar Ayca , Jimbo Masaya , Joshi Vidhu B. , Motterle Giovanni , Karnes Jeffrey , Kwon Eugene D. , Bryce Alan Haruo , Kendi Ayse T. , Bold Michael S. 
Published: February 2020

144 Background: Despite having well-recognized limitations, urologists often rely on serial PSA testing as a marker for treatment response or disease progression. To determine if PSA was indeed a reliable marker for treatment response or disease progression, we compared PSA levels against C-11 choline PET/CT in the evaluation of patients with advanced prostate cancer treated with second generation hormonal therapy (2nd-HT). Methods: We retrospectively identified 239 patients who were undergoing treatment with 2nd-HT (enzalutamide or abiraterone) for advanced prostate cancer. While on treatment, patients underwent serial PSA testing and C-11 choline PET/ CTs every 3 – 6 months. Paradoxical response was defined as increasing blood pool-corrected SUVmax of known choline-avid lesions and/or identification of new choline-avid lesions, despite stable or down-trending PSA. Results: Median (IQR) age was 70.4(64.3 – 75.7) years and median (IQR) primary Gleason Score was 8 (7 – 9). In our study, 19% of patients (n = 46/239) who were receiving 2nd-HT exhibited paradoxical response. Median (IQR) PSA and corrected SUVmax at baseline evaluation were 1.3 ng/mL (0.3 – 12.8 ng/mL) and 3.5 (1.8 – 5.8), respectively. Median (IQR) PSA and corrected SUVmax at the time of paradoxical response were 0.4 ng/mL (0.1 – 5.4 ng/mL) and 4.5 (2.8 – 6.8), respectively. The median duration of 2nd-HT treatment prior to detection of paradoxical response was 4.8 months (2.9 – 10.1 months). No significant difference was noted between patients receiving enzalutamide versus abiraterone (p = 0.35). Independent predictors of paradoxical response were prior primary systemic treatment (i.e. hormonal/chemo-hormonal therapy versus local therapy) and patient’s age at time of 2nd-HT initiation on univariate and multivariate analysis. Conclusions: Our retrospective review demonstrated prostate cancer disease progression discordant with PSA down-trending in 19% of patients receiving 2nd-HT. We conclude that in this subset of patients with advanced prostate cancer, PSA may not be a reliable marker of treatment response of disease progression, and routine radiographic evaluation in these patients is warranted.
New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.
Authors: Lawrence Mitchell , Clouston David , Frydenberg Mark , Murphy Declan G. , Pezaro Carmel Jo , Pook David William , Thorne Heather , Sandhu Shahneen Kaur , Toivanen Roxanne , Taylor Renea , Risbridger Gail ,   kConFab, CASCADE, MURAL
Published: February 2020

151 Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.
Plasma circulating tumor DNA (ctDNA) based clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Tan Winston , Zheng Tiantian , Wang Amy , Huo Yelia , Montesinos Carlos , Wong Calvin , Du Pan , Jia Shidong , Yu Jianjun 
Published: February 2020

160 Background: mCRPC is a heterogeneous disease state with variable survival and molecular markers that define survival continue to be determined. We applied a 120 gene panel based targeted next-gen sequencing (NGS) approach to probe plasma ctDNA based outcomes for survival. Methods: mCRPC chemo-naive patients (pts) were enrolled in a prospective study and plasma cell free DNA (cfDNA) extracted. ctDNA fractions estimated based on somatic variants. NGS of plasma cfDNA was performed using HiSeq X Ten on a panel of 120 genes (PredicineLDT). Clinical and molecular prognostic factors were determined for overall survival (OS). Cox proportional hazard regression was used to estimate hazard ratios (HR) at the univariate level and only significant associations included in multivariate analysis (significance at P<0.05). Results: 96 mCRPC pts were enrolled. 17/96 pts failed NGS QC. Median cfDNA, ctDNA yields for 79/96 pts are provided in Table. Median follow up for study cohort was 92.5 months (mon) (Range:62.3-109.6); median survival time was 25.9 mon (95% CI:19.9, 31.4) and 72/79 pts had died. TMPRSS2-ERG fusion was detected in 18/79 pts. Significant alterations associated with OS are listed in Table. 49/59 pts underwent subsequent docetaxel chemo. In chemo treated pts significant copy number alterations predictive of survival included AR amplification (p=0.01, HR=2.0, 95% CI[1.2, 3.5], RB1 loss (p=3.20E-06, HR=5.0, 95% CI[2.4, 10.6], PTEN(p=0.009, HR=2.6, 95% CI[1.2, 5.4]), CDH1(p=0.001, HR=4.3, 95% CI[1.6, 11.4]). Conclusions: ctDNA yield in mCRPC state was the most significant prognostic factor for survival, Several specific plasma genomic perturbations were observed topredict docetaxel efficacy and need further evaluation.[Table: see text]
Association of high plasma glutamine levels with outcome in metastatic castration-resistant prostate (mCRPC) patients treated with taxanes.
Authors: Pereira Diaz Veronica , Marin Mercedes , Jiménez Natalia , Reig Oscar , Victoria Iván , Esposito Francis , Prat Aleix , Mellado Begona 
Published: February 2020

164 Background: Cancer cells may metabolize glutamine to fulfill their metabolic needs. In prostate cancer it has been shown that androgen receptor signaling promotes glutamine metabolism by increasing the expression of the glutamine transporters, and that stromal glutamine may promote tumor growth. Methods: We retrospectively tested glutamine levels in frozen plasma samples from mCRPC patients treated with taxanes, which were included in a prospective biomarker study in our institution. Glutamine levels were determined by a bioluminescent assay. Optimal cut-offs for glutamine levels were assessed using maximally selected log-rank statistics to determine low and high level groups. Pre-treatment glutamine level was correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Seventy eight mCRPC patients treated with taxanes were included. Median age was 70.3 (55.8-83.5) years and median follow-up was 13.1 (0.2-53.9) months. Glutamine was tested in 88 plasma samples: 69 from pre-docetaxel and 19 pre-cabazitaxel treatment (10 patients had both samples). High glutamine levels significantly correlated with worst PSA-progression-free survival (PFS) (median 2.8 vs 4.7 months, hazard ratio [HR] 1.8, 95%CI 1.1-2.7, P= 0.012) and overall survival (OS) (median 12.4 vs 20.4, HR 2, 95%CI 1.2-3.3, P= 0.006). In a multivariate analysis, high plasma glutamine levels were independently associated with shorter PSA-PFS (HR 2.3, 95%CI 1.4-3.7, P< 0.001) and OS (HR 2.2, 95%CI 1.3-3.7, P= 0.003). Patients with high glutamine levels were more likely to present PSA progression to taxanes than those with low levels (odds ratio [OR] 3, 95%CI 1.2-7.7, P= 0.016). Moreover, samples from patients treated with abiraterone or enzalutamide before taxanes (51 samples from 43 patients) had significantly higher glutamine levels (T-test, P= 0.014) than those without these prior therapies. Conclusions: Glutamine can be detected in plasma of mCRPC patients and higher levels are associated with adverse clinical outcome, supporting the relevance of metabolism in prostate cancer progression.
Association of neuroendocrine (NE) mRNA expression profiling in hormone-sensitive tumors samples with adverse clinical outcome in castration-resistant prostate cancer (CRPC) patients.
Authors: Orrillo Mayra , Jimenez Natalia , Reig Oscar , Castellano Giancarlo , Font Albert , Domenech Montserrat , Rodriguez-Vida Alejo , Carles Joan , Suarez Cristina , Ferrer Laura , Gonzalez Nuria , Sala Nuria , Rodriguez-Carunchio Leonardo , Diaz Sherley , Prat Aleix , Marin Mercedes , Mellado Begona 
Published: February 2020

165 Background: NE dedifferentiation is associated to clinical aggressiveness and resistance to androgen receptor inhibition in prostate cancer. We investigated impact of a NE expression signature in the clinical outcome of mCRPC patients treated with taxanes. Methods: This is a multicenter retrospective study. A customized panel of 45 NE-related gene signature was tested in total RNA from formalin-fixed paraffin-embedded hormone-sensitive tumor samples, by the nCounter platform (Nanostring Technologies). Patients were grouped according to their molecular profile by unsupervised clustering. Expression levels were correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Eighty seven patients were included in the study, 79 were treated with docetaxel and 8 with cabazitaxel. Median age was 64.8 (44-88.3) years and median follow-up was 20.7 (1.17-74.4) months. High expression of the NE signature was associated with a shorter time of CRPC development (N=60, median 12.8 vs 21.6, HR 2.4, 95%CI 1.3-4.3, P=0.003) and shorter OS from CRPC diagnosis (median 24.1 vs 41.33, HR 2.3, 95%CI 1.4-3.8, P=0.001). Moreover, according to the outcome to taxanes, high NE signature correlated with lower PSA-PFS (median 6.6 vs 10.1 mo P=0.047, HR 1.6, 95%CI 1-2.7, P=0.05) and OS (median 19 vs 22 mo, HR 1.8, 95%CI 1.1-2.8, P=0.014), and it was independently associated to a lower OS (HR 1.9, 95%CI 1.1-3.2, P=0.016). Conclusions: NE-related gene expression in hormone-sensitive tumor samples is associated with adverse clinical outcome and lower taxane benefit in metastatic CRPC patients. Thus, molecular characterization of primary tumors may be useful to guide treatment strategies in metastatic prostate cancer.
Genomic alterations in visceral versus nonvisceral “metastatic” site tumor tissue in metastatic prostate cancer (mPC).
Authors: Esther John , Swami Umang , Chipman Jonathan , McFarland Taylor Ryan , Hahn Andrew W , Sirohi Deepika , Sharma Prayushi , Nussenzveig Roberto , Agarwal Neeraj , Maughan Benjamin Louis 
Published: February 2020

167 Background: Men with mPC with visceral metastasis, as compared to non-visceral disease have inferior outcomes regardless of therapy (PMID: 25403629). Herein, we hypothesize that visceral versus non-visceral metastasis sites differ with regards to underlying genomic alterations (GA). These GA possibly drive metastasis to visceral sites and mediate a more aggressive disease. Identifying these GA may guide future trial designs by better stratifying patients and predicting therapy responses. Methods: In this retrospective analysis, inclusion criteria were: diagnosis of mPC and comprehensive genomic profiling of metastatic tissue by CLIA certified lab. Liver and lung were defined as visceral while bone and lymph nodes were defined as non-visceral metastasis. Evaluated GA were p53, RB1, PTEN, AR, TMB, CDK12, SPOP, MYC, MET, BRCA genes, BRAF, ARID1A. Fisher’s Exact Test was used to compare GA in visceral and non-visceral tumor tissue. Results: Overall 54 men with mPC with visceral (n=8) and non-visceral (n=46) metastatic tissue biopsies were evaluated. Visceral biopsies included liver (3) and lung (5). Non-visceral biopsy sites included lymph nodes (33) and bone (13). Men with or without visceral metastasis had similar baseline characteristics (Fisher’s Exact Test and Wilcoxon Rank Test; Table). Visceral tumor tissue had a significantly greater odds of having RB1 mutation [OR = 12.09; 95% CI = (1.12, 178.21); p-value 0.02] as compared to non-visceral tumor tissue. Conclusions: RB1 GA were more common in visceral as compared to non-visceral metastatic sites in mPC. RB1 loss is associated with ineffectiveness to CDK4/6 inhibitors (PMID 26633733). These hypothesis-generating data suggest that men with mPC with visceral metastasis may not optimally benefit by enrollment on CDK4/6 inhibitor trials. BLM, NA: equal contribution.[Table: see text]
Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.
Authors: Dong Baijun , Fan Liancheng , Yang Bin , Chen Wei , Li Yonghong , Wu Kaijie , Zhang Fengbo , Li Lei , Yao Xudong , Xue Wei 
Published: February 2020

173 Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA(ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level(CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of PARPi. However, these patients seemed to benefit from chemotherapy, espeacially platnium-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.
Distinctive landscape of genetic mutation in patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Zhao Jinge , Sun Guangxi , Zhu Sha , Dai Jindong , Zhang Mengni , Chen Junru , Zhang Xingming , Zhu Xudong , Zhang Haoran , Wang Zhipeng , Ni Yuchao , Zhao Xiaochen , Shen Pengfei , Chen Ni , Zeng Hao 
Published: February 2020

192 Background: Intraductal carcinoma of the prostate (IDC-P) is an independent predictor associated with poor prognosis in men with prostate cancer (PCa) of different stages. Yet, little is known concerning the characteristics of IDC-P at genetic level. The object of this study is to determine the mutation characteristics of patients with IDC-P, aiming at identifying new therapeutic targets for the treatment of IDC-P. Methods: Totally, data of 104 and 35 patients histopathological documented with prostatic adenocarcinoma concomitant with and without IDC-P were included into the current study, respectively. cfDNA was extracted from blood samples for the PCa-related mutation testing through a 90-gene NGS panel. The mutation frequency of different genes was compared between IDC-P positive and negative cases. Results: Almost all the pathogenetic germline mutations were detected from patients with IDC-P [15/104 (14.4%) vs. 1/35 (2.9%), p=0.064]. Pathogenetic germline BRCA2 mutations were all found in IDC-P positive patients [10/104 (9.6%) vs.0/35 (0.0%), p=0.057]. Besides, in terms of somatic mutations, men with IDC-P had significantly higher proportion of mutations in EGFR [30/104 (28.9%) vs. 2/35 (5.7%), p=0.005], KMT2C [20/104 (19.2%) vs. 1/35 (2.9%), p=0.019] and NCOR2 [19/104 (18.3%) vs. 0/35 (0.0%), p=0.006]. Three high frequently mutated sites of EGFR were identified in men with IDC-P, i.e. p.L861Q (12/104, 11.5%), p.L858R (11/104, 10.6%) and p.G719A/C (12/104, 11.5%). These mutated sites have been proved to be associated with therapeutic response from EGFR tyrosine kinase inhibitors (TKIs) in the treatment of lung carcinoma. Conclusions: Patients with IDC-P are candidates for germline and somatic mutations testing for the high frequency of mutations. Germline DDRs and somatic EGFR mutations were frequently occurred in IDC-P positive patients. Though further verification is needed, these mutations had great potential to be used as therapeutic targets in treating patients with IDC-P.