bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of AKR1C3 on the switch from prednisone to dexamethasone in metastatic castration-resistant prostate cancer patients receiving abiraterone.
Authors: Ni Yuchao , Zhao Jinge , Chen Junru , Sun Guangxi , Zhu Sha , Zhang Xingming , Dai Jindong , Wang Zhipeng , Zhang Haoran , Zhu Xudong , Chen Ni , Shen Pengfei , Zeng Hao 
Published: February 2020

133 Background: Abiraterone is the first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) and is recommended to be used with prednisone. Previous studies had demonstrated that the switch from prednisone to dexamethasone in some mCRPC patients can reverse abiraterone-resistance. However, it remains uncertain which group of patients will benefit from such switching. AKR1C3 is a critical enzyme contributing to the drug-resistance of abiraterone. Here, we aim to explore the significance of AKR1C3 in predicting the therapeutic efficacy of the corticosteroid switching in mCRPC patients receiving abiraterone. Methods: In total, 43 PCa patients treated with abiraterone after mCRPC between 2016 and 2018 in our institution were included. After biochemical progression in abiraterone plus prednisone, all cases received a corticosteroid switch to abiraterone plus dexamethasone. The expression of AKR1C3 was detected by immunohistochemical staining from re-biopsy (re‐Bx) of primary prostate lesions at the time of mCRPC. Kaplan‐Meier curves were used to analyze the association between AKR1C3 and treatment outcomes. Results: Totally, AKR1C3 was positive in 19 of 43 (44.19%) cases. In the corticosteroid switch treatment, 30% PSA decline was confirmed in 18/43 (41.86%) patients, while the median PSA progression‐free survival (PSA-PFS) and overall survival (OS) was 4.93 Mo and 31.57 Mo, respectively in the whole cohort. AKR1C3 expression was associated with statistically shorter median PSA-PFS (4.50 Mo vs 7.73 Mo; p =0.010) and numerically lower median OS (25.43 Mo vs 39.37 Mo, p =0.274). While the 30% PSA decline rate was numerically comparable between those with and without AKR1C3 expression (31.6% vs 50.0%, p =0.224). Conclusions: This study showed AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with poor PSA-PFS in the corticosteroid switch from abiraterone plus prednisone to abiraterone plus dexamethasone. These results would be helpful in making optimal personalized treatment decisions for patients with mCRPC, facilitating physicians predicting the effectiveness of corticosteroid switch treatment.
Clinical investigation of neuroendocrine differentiation in prostate cancer.
Authors: Shimomura Tatsuya , Kurauchi Takashi , Sakanaka Keigo , Kimura Takahiro , Egawa Shin 
Published: February 2020

138 Background: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection. The treatment strategy against NEPC is not yet established and some clinical trials are ongoing now. Recently, clinical trial (RADIIANT4) showed that treatment with everolimus was associated with significant improvement in survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. In this study we evaluated the neuroendocrine differentiation of prostate cancer and we tried to introduce everolimus against pathologically proven NEPC and investigated the clinical outcomes of this agent. Methods: Total of 193 prostate cancer cases were included in this study. We tested serum neuroendocrine markers, including (NSE and pro-GRP). And we evaluated positive rate of these markers. Eleven cases were pathologically proven neuroendocrine prostate cancer (NEPC) in this cohort. Seven out of eleven NEPC cases were introduced everolimus 10mg daily. We investigated the change of serum neuroendocrine markers (NSE and pro-GRP), radiologic examination and survival. Results: The positive rate of serum neuroendocrine markers (at least one of the markers increasing above normal limit) were 23.5% in hormone sensitive prostate cancer (HSPC), 59.5% in castration resistant prostate cancer (CRPC), and 100% in neuroendocrine prostate cancer (NEPC). There were significant differences in each other (HSPC vs. CRPC: p=0.0001, CRPC vs. NEPC: p=0.0109). We introduced everolimus in seven cases out of eleven NEPC cases. The median follow up period was 18 months. Neuroendocrine markers decreased in five of seven (71.4%) cases after introduction of everolimus. Median decreasing rate were 67.1% in NSE and 65.5% in pro GRP. 24M progression free survival rate was 57.1% and 24M overall survival rate was 57.1%. Conclusions: There is a possibility that the incidence of NEPC is higher than expected, and treatment against prostate adenocarcinoma accelerate neuroendocrine differentiation. Everolimus showed efficacy against NEPC. Although this study was retrospective and number of cases was limited, everolimus would be a one of the treatment options against NEPC.
IND candidate EPI-7386 as an N-terminal domain androgen receptor inhibitor in development for the treatment of prostate cancer.
Authors: Le Moigne Ronan , Banuelos C. Adriana , Mawji Nasrin R. , Tam Teresa , Wang Jun , Jian Kunzhong , Andersen Raymond J. , Cesano Alessandra , Sadar Marianne , Zhou Han-Jie , Virsik Peter 
Published: February 2020

142 Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively active AR splice variants lacking the LBD (e.g. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. In a phase I trial, the first-generation AR NTD inhibitor (aniten) EPI-002, demonstrated minor PSA declines in mCRPC patients. The efficacy and safety profile of second generation aniten IND-candidate EPI-7386 will be presented. Methods: Novel aniten chemical structures were developed to increase molecule potency using a wide variety of CRPC models. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. IND-enabling studies further support the compounds’ safety profile. Results: EPI-7386 demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human hepatocytes and across animal species. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to induce tumor regression in CRPC xenografts and show superiority to enzalutamide (ENZ) in ENZ resistant models. In addition, the combination of ENZ with EPI-7386 demonstrated a more robust antitumor response. IND-enabling studies demonstrate a safe and well-tolerated profile supporting an IND filing in 1Q 2020. Pharmacodynamic markers specific to anitens will be presented, in addition to early clinical development plans. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-002. It demonstrated potential as a single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of aniten will be discussed.
Role of metastases-directed therapy (MDT) in the management of solitary metastatic prostate cancer.
Authors: Ahmed Mohamed E. , Jimbo Masaya , Haloi Rimki , Andrews Jack R. , Motterle Giovanni , Joshi Vidhu B. , Kendi Ayse T. , Stish Brad J. , Park Sean Sunghun , Karnes Jeffrey , Kwon Eugene D. 
Published: February 2020

143 Background: Systemic treatment in the management of metastatic prostate cancer is inevitable. However, there is a growing interest in metastases-directed therapy (MDT). We sought to investigate the efficacy of MDT in treating patients with solitary metastatic prostate cancer and hence, delaying initiation of systemic treatment (i.e., Androgen deprivation therapy or chemotherapy). Methods: We retrospectively identified 61 patients treated with targeted therapy in the form of surgery (n = 30), stereotactic body radiation therapy (SBRT) (n = 25), or cryotherapy (n = 7) for their solitary metastases prostate cancer. Complete response was defined by achieving a PSA value of ≤0.2 ng/ml plus resolution of the solitary metastatic lesion on C-11 choline PET choline scan, while incomplete response was defined by a residual PSA of > 0.2 ng/ml and/or radiographic evidence of disease following metastases-targeted therapy. Results: Mean (±SD) age was 68.4 (±7.8) yrs., median (IQR) primary Gleason Score was 7 (7-9) and median (IQR) pre-MDT PSA was 2 (1.3-3.8) ng/ml. Median (IQR) time from primary treatment of the prostate to MDT was 5.1 (2.7-10.1) years. None of the patients were on hormone therapy at the time of presentation with solitary metastases prostate cancer. 30 patients had bone metastases, 29 patients had lymph node metastases, 1 patient had soft tissue metastasis (pelvic metastatic mass), and another patient had visceral metastasis (to the lung). 42% of the patients (n = 26) achieved complete response to targeted therapy. Median time to initiation of 2nd line systemic treatment following MDT was 17.8 months for the complete responders versus 9.3 months for incomplete responders. 11% of the patients (n = 7) did not require 2nd line therapy after their MDT for a mean (±SD) time of 56.9 (±22.5) months. Conclusions: The use of targeted therapy in the management of patients with solitary metastatic disease or low-volume metastatic disease can provide comparable outcomes to those of systemic treatment. Further studies are warranted.
A prospective study of the relationship between clinical outcomes of enzalutamide and serum androgen levels measured by LC-MS/MS in patients with CRPC.
Authors: Miyazawa Yoshiyuki , Miyao Takeshi , Nakamura Toshiyuki , Takezawa Yutaka , Shimizu Nobuaki , Matsuo Yasushige , Ogura Haruyuki , Takei Tomoyuki , Oka Daisuke , Arai Seiji , Sekine Yoshitaka , Koike Hidekazu , Matsui Hiroshi , Shibata Yasuhiro , Suzuki Kazuhiro 
Published: February 2020

146 Background: Enzalutamide (ENZ) is commonly used to treat patients with castration resistant prostate cancer (CRPC). However, the kinetics of serum androgen levels before and after ENZ treatment are unknown. We elucidated the kinetics of serum androgens and explored the possibility of identifying a useful marker for predicting the effects of ENZ. Methods: We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. 104 CRPC patients treated with ENZ were analyzed. We investigated the PSA reduction rate (50%, 90%), PSA-progression-free survival (PFS), and overall survival (OS) after administration. To measure levels of androgens accurately we measured serum androgen levels using LC-MS/MS. OS and PSA-PFS were assessed according to the PCWG 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1177). Results: The 50% and 90% PSA decline rates were 62.5% and 25.0%, respectively. Median serum testosterone (T), dihydrotestosterone (DHT), androstenedione (A-dione), and dehydroepiandrosterone-sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. Mean serum levels of T, DHT, and A-dione increased significantly 12 and 24 weeks after compared to before treatment (p < 0.05). We performed a multivariate analysis using a Cox regression to predict OS and PSA-PFS. ECOG PS (0 vs. 1–2), hemoglobin (Hb ≥ 12.5 vs. < 12.5 g/dL), albumin (≥ 3.9 vs. < 3.9 g/dL), visceral metastasis (no vs. yes), EOD (0–2 vs. 3–4), docetaxel treatment (no vs. yes), and DHT level (≥11.25 vs. < 11.25 pg/mL, 11.25 was third quartile) were significant predictors of OS (p < 0.05). Hb (≥12.5 vs. < 12.5 g/dL), docetaxel treatment (no vs. yes), and level of DHT (≥ 5.9 vs. < 5.9 pg/mL) were significant predictors of PSA-PFS (p < 0.05). As a result of the binomial logistic analysis of the predictors of fatigue and decreased appetite, the presence of visceral metastasis (yes) and low DHT (<5.9 pg/mL) were significant predictors of expression. Conclusions: These results suggest that serum androgen levels before ENZ treatment may be useful for predicting efficacy, prognosis, and the incidence of adverse events.
Identification of genomic alterations in signaling pathways associated with poor survival in newly diagnosed metastatic prostate cancer (mCSPC) using artificial intelligence (AI).
Authors: Lin Edwin , Wesolowski Sergiusz , Nussenzveig Roberto , McFarland Taylor Ryan , Swami Umang , Maughan Benjamin Louis , Yandell Mark , Agarwal Neeraj 
Published: February 2020

169 Background: Although the survival outcomes for patients with mCSPC has improved over the last 5 years, disease remains universally fatal even with improved therapies. Currently, genomic information from the tumor is not taken into account for treatment selection and prognostication. AI is increasingly being used in clinical cancer genomics research. Probabilistic Graphical Models (PGMs) are AI algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can establish correlation of baseline somatic genomic alteration with poor survival outcomes in mCSPC. Methods: Eligible men had new mCSPC starting systemic therapy and had tumor genomic profiling done through a CLIA certified lab. Gene alterations with known pathogenicity were grouped into canonical pathways. Multilevel associations between survival, clinical variables (including baseline PSA, Gleason ≥ 8, and visceral metastasis), and genomic signatures (PI3K/AKT/mTOR, HRR, G1/S Cell Cycle, SPOP, TP53, WNT, and MYC) were assessed using a Bayesian Network (BN), and confidence intervals were estimated by bootstrapping. A Kaplan-Meier (KM) survival analysis was performed independently to support the results generated by the BN. Results: Among all variables, only genomic alterations in TP53 and the G1/S pathway were significantly associated with poor overall survival by BN analysis. KM analysis showed concordant results for TP53 (median OS, altered 50 mos vswild-type 84 mos; HR=2.79, 95% CI 1.63 – 4.80; P=0.0002) and G1/S (median OS altered 23 mos vswild-type 73 mos; HR=8.21, 95% CI 3.40 – 19.86; P<0.0001). Conclusions: These hypothesis-generating data reveal genomic signatures associated with poor survival in mCSPC patients. Our results, after external validation, may aid with counseling and treatment selection, as well as patient stratification in future trials in mCSPC.
The effect of abiraterone acetate treatment on CREB and the development of abiraterone acetate resistance in prostate cancer cells.
Authors: Pan Wenting , Zhang Zhouwei , Kimball Hannah , Qiu Fangfang , Lee Gwo-Shu Mary , Choueiri Toni K. , Kantoff Philip W. 
Published: February 2020

177 Background: The androgen receptor (AR) remains an essential target in castration resistant prostate cancer (CRPC). Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA approved drug for metastatic CRPC. AA can also be converted to the more active metabolite 4-abiraterone in vivo, which blocks multiple steroidogenic enzymes and antagonizes AR. However, not all patients respond to AA and AA resistance ultimately develops in those patients who initially respond. Methods: We established several AA resistant prostate cancer cell lines and performed a comprehensive study of mechanisms involved in the development of AA resistance. The AA-resistant cell lines are phenotypically stable with aggressive invasive features. By RNA-seq and phospho-kinase array screening, we found that the cAMP response element-CRE binding protein 1 (CREB1) is activated in AA resistant cell lines. Results: Over-expression of the wild type CREB1 or treatment with Forskolin desensitizes the cellular response to AA, while over-expressing the mutated CREB1 (S133A, an essential kinase site) did not significantly affect cell sensitivity to AA. Blocking pCREB1 with the CREB inhibitor increased the sensitivity of AA resistant cell lines to AA. The activation of pCREB1 in AA resistant cell lines may potentially activate the CBP/p300 complex. Our data demonstrated that treatment with a low dose of AA strongly synergistic the efficacy of CBP/p300 inhibitors in prostate cancer cell lines. Taken together, we found that AA treatment activates CREB1 and pCREB1 may interact with the CBP/p300 complex, leading to global gene expression alterations, which subsequently result in the development of drug resistance. Conclusions: Our study indicates that AR-targeted treatment potentially fosters de novo genetic and epigenetic alterations associated with progression. A more effective AR-targeted treatment for CRPC may be developed by considering low doses of multiple targets involved in the development of resistance pathways.
Impact of initial treatment selection on clinical outcomes after biochemical failure in radiorecurrent high-risk prostate cancer.
Authors: Levin-Epstein Rebecca , Romero Tahmineh , Wong Jessica Karen , Cook Kiri , Dess Robert Timothy , Spratt Daniel Eidelberg , Moran Brian Joseph , Merrick Gregory Stephen , Tran Phuoc T. , Demanes David Jeffrey , Stish Brad J. , Krauss Daniel J. , Wedde Trude Baastad , Lilleby Wolfgang , Stock Richard , Tward Jonathan David , Steinberg Michael L. , Horwitz Eric M. , Tendulkar Rahul D. , Kishan Amar Upadhyaya 
Published: February 2020

208 Background: Treatment of high risk prostate cancer (HRPCa) with external beam radiotherapy (EBRT) plus brachytherapy (BT) boost (EBRT+BT) has been prospectively associated with lower rates of BCR, albeit potentially with increased toxicity, and retrospectively linked to decreased distant metastasis (DM) and PCa-specific mortality (PCSM) compared to EBRT alone. However, it is unclear whether patients who develop BCR following either approach have similar downstream oncologic outcomes. Methods: We identified 706 out of 3820 men with HRPCa treated at 13 institutions from 1998-2015 with EBRT (n=468/2134) or EBRT+BT (n=238/1686) who developed BCR. We compared rates of DM, PCSM, and all-cause mortality (ACM) after BCR between treatment groups using Fine-Gray competing risk regression. Models were adjusted for age, Gleason grade group, initial PSA (iPSA), clinical T stage, time-dependent use of systemic salvage, and interval to BCR using inverse probability of treatment weighting. Results: Median follow-up was 9.9 years from RT and 4.8 years from BCR. Groups were similar in age, iPSA, presence of ≥2 HR features, and median interval to BCR (3.3 years). Most men received neoadjuvant/concurrent androgen deprivation therapy (ADT), 92.5% and 91.0% for EBRT and EBRT+BT, respectively, though for a longer duration with EBRT (median 14.7 vs. 9.0 months, p=0.0012). Local and systemic salvage rates were 2.3% and 36.3% after EBRT, and 2.6% and 43.6% after EBRT+BT, respectively. Initial EBRT+BT was associated with significantly lower rates of DM after BCR (HR 0.48, 95% CI 0.36-0.64, p<0.001). Rates of PCSM and ACM did not significantly differ (HR 0.93, 95% CI 0.67-1.30, p=0.93, and HR 0.8, 95% CI 0.6-1.1, p=0.11, respectively). Conclusions: In this large retrospective series of radiorecurrent HRPCa, initial treatment with EBRT+BT was associated with significantly lower rates of DM after BCR compared with EBRT, despite shorter ADT use and a similar median interval to BCR. Local salvage was widely underutilized in both groups. In the absence of salvage for local failure after EBRT, upfront treatment intensification with BT may reduce DM, though not PCSM or ACM, even after development of BCR.
Preliminary outcomes of a prospective observational study of combinatorial abiraterone acetate/enzalutamide (AA/Enz) and radical radiotherapy (RT) in nonmetastatic node-positive (N+M0) prostate cancer (PCa).
Authors: Tan Mark Ting Le , Woo Wai Yee , Tuan Jeffrey , Tan Terence Wee Kiat , Wang Michael Lian Chek , Chua Eu Tiong , Looi Wen Shen , Li Youquan , Nei Wen Long , Wang Hai-Tao , Chimmiri Anusha , Sim Yen Ling Adelene , Ong Enya Hui Wen , Khor Li Yan , Yeong Joe Poh Sheng , Tan Chien sheng , Tay Kae-Jack , Lee Lui Shiong , Kanesvaran Ravindran , Chua Melvin Lee Kiang 
Published: February 2020

227 Background: Treatment paradigm for N+M0 PCa has evolved, with the advent of multiple options for upfront AA/Enz or RT in combination with conventional hormonal therapy (HT). However, the optimal treatment protocol remains undefined. We therefore conducted a prospective observational study of combination AA/Enz+RT in N+M0 PCa patients. Methods: Patients with biopsy-proven adenocarcinoma of the prostate and N+M0 by imaging (68Ga-PSMA-PET or whole body MRI) were included. Exclusion criteria were 1) ECOG ≥2; 2) severe comorbidities; 3) cardiac event of <6 mo interval. Treatment protocol involved 18 mo of AA (1000 mg with 5 mg prednisolone once daily)/Enz (160 mg once daily)+HT (LHRH agonist/antagonist) in combination with RT to pelvis (54 Gy with simultaneous boost of 60-66 Gy in 27 fr) and prostate (78 Gy/39 fr); RT commenced 1-3 mo upon initiation of AA/Enz. Primary endpoint of this analysis was PSA of ≤0.1 ng/ml at 12 mo. Results: From Jun 2017-Sep 2019, 13 men were recruited; median follow-up duration was 14.0 mo (range 3.0-28.0 mo). Median age of the cohort was 67.0 y (IQR 61.0 – 69.0 y); 84.0% of men had GS8-10 disease, and median number of cN+ nodes was 2 (range 1-5 nodes). 11 received AA, and 2 received Enz. 53.8% (N = 7) and 69.2% (N = 9) of patients achieved a PSA nadir of ≤0.1 ng/ml at 6.0 and 12.0 mo, respectively; this contrasts against a propensity-matched cohort (N = 27) treated by HT+RT alone (33.3% and 51.9%, respectively). No biochemical recurrence was recorded at the time of analysis. 3 and 2 acute ≥G2 GU and GI toxicities were reported during RT. Late ≥G2 GU toxicities were observed in 2 men (G2 frequency). 2 patients experienced G2 fatigue and one with G2 transaminitis secondary to AA, with dose reduction. Germline genetic profiling with whole exome sequencing revealed two patients (15.4%) with BRCA2 frameshift mutations; interestingly, GU/GI RT toxicities were not observed in these patients. Conclusions: Our preliminary results suggest that combinatorial AA/Enz and high dose RT is tolerated and can induce a pronounced PSA response in low volume N+M0 PCa.