bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment outcomes of patients with metastatic prostate cancer and co-morbid diabetes mellitus.
Authors: Govindan Srinivas , Luo Suhong , Cheranda Nina , Riekhof Forest , Schoen Martin W. 
Published: February 2022

113 Background: In metastatic castrate resistant prostate cancer (mCRPC) there is a lack of studies that explore the interaction of comorbidities on treatment outcomes, which presents a challenge in choosing the right drug. In patients with diabetes mellitus, two common therapies, enzalutamide (ENZ) and abiraterone (ABI) have different effectiveness due to different mechanisms of action and because ABI requires co-administration of prednisone. Thus, in this study, we aim to assess the survival of patients with comorbid diabetes treated with ENZ and ABI. Methods: Patients treated with AA or ENZ for mCRPC from September 10, 2014, to June 2, 2017 were identified within the Veterans Health Administration. For these patients, presence of diabetes or complicated diabetes was determined using the Charlson method from the International Classification of Diseases (ICD) 9/10 codes. A Kaplan–Meier time to event analysis and the cox proportional hazards modeling was used to analyze the data with the latter including covariates such as age, Charlson Comorbidity Index, body-mass index, treatment with bone-directed therapy, black race, and baseline PSA at start of treatment with ENZ or ABI. Results: We identified 5822 patients treated for mCRPC, of which 2202 had diabetes and were treated using either ENZ (n = 1041) or ABI (n = 1161). Median survival of patients with diabetes treated with ENZ was 3 months longer than in patients treated with ABI (23.8 vs. 20.8, p = 0.002 by log-rank). In 3620 patients without diabetes, no significant difference in median survival (24.7 vs. 22.7 months, p = 0.065) was seen between ENZ (n = 1463) and ABI (n = 2157). In a multivariable model, ENZ was associated with improved survival in patients with diabetes (adjusted HR 0.87, 95% CI 0.79-0.97) and in patients without diabetes (adjusted HR 0.90, 95% CI 0.83-0.98). Conclusions: ENZ was associated with improved 3-month median survival in patients with diabetes compared to ABI in unadjusted analyses. Additionally, in adjusted analyses the cox proportional model also showed significantly better survival in mCRPC patients treated with ENZ both with and without diabetes, although the findings are more robust for patients with diabetes. The cause of these differences is unknown, so there may be differences in efficacy and adverse events between the two agents in real-world use. Further assessment of patient outcomes with comorbid disease is appropriate to improve care of patients with advanced prostate cancer.
Community oncologists’ perceptions of and barriers to access for 177LU-PSMA-617 in metastatic castration-resistant prostate cancer.
Authors: Gajra Ajeet , Estupinian Ricardo , Fortier Stephanie , Jeune-Smith Yolaine , Feinberg Bruce A. , Vaishampayan Ulka N. 
Published: February 2022

120 Background: Metastatic castration-resistant prostate cancer (mCRPC) is a difficult-to-treat cancer with poor patient outcomes. In June 2021, 177Lu-PSMA-617 was granted U.S. FDA breakthrough designation for the treatment of mCRPC based on results from the phase III VISION trial showing a 4-month increased median overall survival (15.3 v 11.3 m; HR 0.62 [0.52-0.74], P < 0.001) and a 5.3-month increased radiographic progression-free survival (8.7 v 3.4 m; HR 0.40 [0.29-0.57] for 177Lu-PSMA-617 versus standard of care (SOC). If approved, 177Lu-PSMA-617 has the potential to improve patient outcomes, but its impact will depend significantly on how community-based medical oncologists (cbMO) plan to integrate it into patient management. The present study surveyed cbMO regarding their perceptions of the VISION trial data and potential barriers to 177Lu-PSMA-617 use in mCRPC. Methods: Between June and October 2021, practicing U.S.-based cbMO were invited to attend a virtual meeting and were presented with the VISION trial data. Their reactions to the data and preferences were collected using audience response technology. Results are presented using descriptive statistics. Results: Among the 287 participating cbMO, median years in practice was 17 (1-45), and median time spent in direct patient care was 90% (20-100%). In the past year, 46% of cbMO managed 6-15 patients with mCRPC, and 27% managed 16 or more. CbMO reported that at the time of referral, their patients with mCRPC had commonly been treated with androgen deprivation therapy (77%) and one (49%) or two plus (20%) novel hormonal agents. After reviewing the recent data from the VISION trial showing improved survival outcomes in mCRPC, 51% of cbMO reported that both the safety and efficacy data were compelling, and they were very likely to prescribe 177Lu-PSMA-617 if approved; 33% indicated that the efficacy data alone was compelling and were likely to prescribe 177Lu-PSMA-617. The top 2 limitations of the VISION trial were identified as PSMA gallium positivity for eligibility (54%) and the disallowance of radium-223 on the SOC arm (48%). Regarding perceived barriers to future use of 177Lu-PSMA-617, 68% and 64% of cbMO reported availability of a PSMA-gallium scan and availability/access of the therapy itself, respectively, would be the greatest barriers. Additional barriers included cost (42%) and difficulty with reimbursement (30%), highlighting the importance of addressing access and financial considerations associated with 177Lu-PSMA-617. Conclusions: Most cbMO found the VISION trial data of 177Lu-PSMA-617 in mCRPC compelling and indicated that they are likely to incorporate it into their patient management, if approved. However, major barriers such as the incorporation of PSMA-gallium scans, 177Lu-PSMA-617 availability, and cost will need to be addressed to encourage widespread adoption of this new therapy.
Overall survival (OS) after progression on first novel hormonal therapy (NHT) in patients (pts) with metastatic castration-sensitive versus castration-resistant prostate cancer (mCSPC versus mCRPC).
Authors: Sayegh Nicolas , Tripathi Nishita , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Chigarira Beverly , Li Haoran , Tandar Clara , Goel Divyam , Nordblad Blake , Cheney Jackson , Sahu Kamal Kant , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: February 2022

121 Background: Novel hormonal therapy (NHT) i.e. novel androgen receptor or androgen synthesis inhibitors have been approved for treatment of pts with mCSPC and mCRPC based on improved OS. However, OS of patients after progression on first-line NHT for mCSPC is not well characterized. It is currently unknown whether the OS in pts “after” progression on first-line NHT in mCSPC versus mCRPC is significantly different. Herein, our objective was to assess OS after disease progression on NHT given as the first-line therapy in the mCSPC vs first-line therapy in mCRPC setting. Methods: In this IRB-approved study, patient-level data were collected retrospectively, only those treated with NHT as first-line therapy for mCSPC or mCRPC were included. For patients receiving NHT in the mCRPC setting, no prior NHT was allowed in the mCSPC setting. Median overall survival and hazard ratios were determined by Kaplan-Meier analysis. Results: A total of 173 pts (45 mCSPC and 128 mCRPC) were eligible and included in the analysis. Median OS in the mCSPC versus mCRPC were similar: 23 vs. 17 months, hazard ratio: 0.9855, (95% CI: 0.6225 – 1.560, P=0.951). See the table. Conclusions: These results suggest median OS is similar after progression on one NHT whether given in the first-line mCSPC or first-line mCRPC setting. These data have implications on patient counseling and prognostication as well as the design of clinical trials in patients experiencing disease progression on an NHT. These hypothesis generating data need external validation.[Table: see text]
BXCL701: First-in-class oral activator of systemic innate immunity combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small-cell neuroendocrine carcinoma (SCNC) phenotype—Phase 2a interim results.
Authors: Tagawa Scott T. , Zhang Jingsong , Monk Paul , Zhu Xinhua , Jones Robert , Linch Mark David , Costin Dan , De Bono Johann S. , Karsh Lawrence Ivan , Petrylak Daniel P. , Borderies Pascal , Deshpande Rashmi Majali , O'Neill Vincent , Aggarwal Rahul Raj 
Published: February 2022

126 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a phase 1b/2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype (and in adenocarcinoma). SCNC is highly proliferative and aggressive and does not express androgen receptor or PSA. Here are reported the interim results of the phase 2a after enrollment of 16 patients for the SCNC cohort. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor). Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response defined as RECIST 1.1 ± PSA50 ± CTC count conversion. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 9/27/21, 16 patients with SCNC were enrolled (10 evaluable, 6 in active treatment): at the 7/08/21 data extract, 9 of the evaluable patients had prior chemotherapy and a median of 2 prior lines of therapy (range 1-4); 33% have bone only disease. Median follow-up duration is 9 weeks (range 1-27)/ 3 cycles. Although follow-up was short, anti-tumor activity was observed. 3/ 10 evaluable patients showed responses—1 RECIST-defined confirmed PR + 1 unconfirmed PR (both 18 weeks/ 6 cycles) + 1 CTC conversion—amounting to a 30% Composite Response rate, meeting protocol-defined expansion criteria from stage 1 to stage 2. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Additional interim phase 2a study results will be presented. Clinical trial information: NCT03910660.
Progression-free survival, PFS, depending on the site of lymph-node metastases in patients after salvage lymph node dissection, sLAD, in lymph node only recurrent prostate cancer.
Authors: Pfister David , Nestler Tim , Haidl Friederike , Paffenholz Pia , Hartmann Florian , Heidenreich Axel 
Published: February 2022

131 Background: To analyze the influence of anatomic site in patients with lymph node only recurrent disease in 68Ga-PSMA-PET. Methods: We retrospectively analyzed PFS after salvage lymph node dissection in 98 patients. Patients were stratified to Group 1 advanced (retroperitoneal) (=9), Group 2 atypical (pararectal, presacral)(n=5), Group 3 typical (A iliaca externa, interna, Fossa obturator, A iliaca communis) (n=74) and Group 4 multifocal (combination of all groups)(n=10) recurrence. There were no statistically significant differences in the four patient groups in preoperative clinical parameters. Results: The most obvious PSA reduction after sLAD could have been demonstrated in patients with atypically located lymph node metastases (3.6ng/ml to 0.25ng/ml) although this did not reach statistic significance. Patients in the advanced group showed stable PSA values (3,55ng/ml to 3.26ng/ml). Significant results are seen in Group3 (2,52ng/ml to 1,7ng/ml)(p=0.01). Even patients with multifocal disease had a significant decrease in PSA (3.24ng/ml to 1.41ng/ml). 6- and 12 months PFS for Group 1-4 was 41.7% and 13.9%, 60% and 40%, 52.7% and 25.7% and 60% and 40% respectively. Conclusions: SLAD is an individual treatment approach for patients with lymph node only recurrent disease after radical prostatectomy and or radiotherapy. In our preliminary results we could not demonstrate a significant difference in early oncologic results in the four patient groups. Nevertheless, there might be an influence by patient numbers in the different groups so that a validation in a larger cohort is recommended.
A microRNA-based classifier for identification of neuroendocrine differentiation in metastatic castration-resistant prostate cancer.
Authors: Saini Sharanjot , Bhagirath Divya , Patel Nikhil , Sharma Ashok , Lee Tae Jin 
Published: February 2022

149 Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an extremely aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as enzalutamide (ENZ) and abiraterone. This aggressive variant arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein cells undergo a lineage switch and exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Currently, histopathological assessment combined with immunohistochemical detection in PCa tissues/serum levels of neuronal markers including SYP, NSE, CHGA and CD56 is currently used to monitor NED in CRPC patients. However, these markers are not sufficiently specific, highlighting the urgent need of novel molecular markers to assess emergence of NED in CRPC patients. Recently, we demonstrated that progression of advanced CRPC with adenocarcinoma characteristics to CRPC-NE is associated with a characteristic set of miRNA alterations that promote plasticity of advanced PCa to NEPC (Bhagirath et al., Oncogene, 2020). Importantly, we could develop a ‘novel miRNA classifier’ to robustly stratify CRPC-NE tumors from CRPC-Adenocarcinomas. Here we further validate the classifier in independent clinical cohorts and deduce the optimal miRNA genes required for NEPC diagnosis. Methods: Human clinical samples with corresponding clinical information were procured from two independent sites of Prostate Cancer Biorepository Network (PCBN). FFPE sections from clinical samples were microdissected, RNA were extracted and small RNA sequencing was performed using an Illumina NextSeq 500 platform. Sequencing data were analyzed and machine learning algorithms were applied. The performance of classifier was measured using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the primary evaluation metric. Results: Unsupervised analysis of sequencing data by principal component analyses (PCA) revealed distinct clustering of the CRPC-NE tumors from CRPC-Adenocarcinomas based on miRNA profiles suggesting that miRNA profiles can be used to stratify these tumor types. We applied the ‘43-miRNA classifier data’ we deduced earlier to these validation cohorts. Our analyses showed that a set of 5 miRNAs of the classifier are important in distinguishing between CRPC-Adeno vs CRPC-NE with an AUC=0.8318. Conclusions: A ‘5- miRNA’ classifier was validated to be of significance in two independent validation cohorts. We propose this miRNA classifier as an important tool for diagnosing NED in CRPC patients.
Interrelation of functional homologous recombination deficiency and hrr pathway alterations in prostate cancer.
Authors: Zhu Jason , El-Refai Sherif Mohamed , Mauer Elizabeth , Leibowitz Benjamin D. , Brown Landon Carter , Grigg Claud , Kearns James T , Matulay Justin T. , Clark Peter E , Raghavan Derek , Burgess Earle F 
Published: February 2022

151 Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer. Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 ( BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm. Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. < 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. > 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non- BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p < 0.001) and PALB2-/- (3/4, p = 0.082). Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.[Table: see text]
Prognostic and predictive utility of DNA damage response (DDR) aberrations detected in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fettke Heidi , Hauser Christine , Kwan Edmond Michael , Dai Chao , Zheng Tiantian , Wang Amy , Tan Winston , Du Pan , Ng Nicole , Bukczynska Patricia , Foroughi Siavash , Graham Lisa-Jane K. , Horvath Lisa , Mahon Kate Lynette , Jia Shidong , Kohli Manish , Azad Arun 
Published: February 2022

153 Background: The prognostic significance of DDR alterations in mCRPC remains unclear, with conflicting data from prior reports. Whether DDR alterations are predictive of outcomes with therapeutic agents other than PARP inhibitors in mCRPC is also poorly understood. With increasing use of molecular profiling in mCRPC, understanding the full prognostic and predictive utility of plasma DDR alterations is paramount. Methods: A next-generation sequencing Predicine liquid biopsy assay was used to profile cfDNA and germline DNA in 407 mCRPC patients (pts) from two independent international cohorts (n=162 Australia, n=245 US). DDR genes profiled were BRCA2, ATM, BRCA1, MLH1 and MSH2. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between DDR alterations and clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: Median age was 74 (IQR 67-79), with median follow up 74 months and median OS 23 months. 65/407 (16%) harboured pathogenic DDR alterations, including 21 patients with ³1 alteration. Frequency of genomic aberrations are shown in the table. BRCA2 alterations were further classified as heterozygous loss (66%), homozygous loss (14%), monoallelic mutation (11%) and biallelic mutation/loss of heterozygosity (9%). Aberrations in any DDR gene, ATM, MLH1 + MSH2 or BRCA2 were associated with shorter OS on univariable analysis, but only any DDR or BRCA2 aberration remained significant upon adjusting for clinical prognosticators and ctDNA fraction (Table). Pre-treatment BRCA2 aberration was associated with significantly shorter OS and lower PSA RR compared to BRCA2 wt for pts receiving an AR pathway inhibitor (ARPI) (18 vs 32 months, p=0.006; 36 vs 60%, p=0.04 respectively) but not for taxane chemotherapy (17 vs 20 months, p=0.3; 45 vs 66, p=0.1 respectively). Conclusions: Detection of an aberration in any DDR gene or BRCA2 was an independent poor prognostic factor across 2 large independent cohorts of mCRPC patients. Intriguingly, patients with a BRCA2 alteration appeared to have worse outcomes with ARPI but not chemotherapy, suggesting predictive utility of DDR profiling. Our data collectively speak to the potential role of DDR alterations, in particular BRCA2, as prognostic and/ or predictive biomarkers in mCRPC.[Table: see text]
Effect of androgen receptor directed therapy in prostate cancer patients with COVID-19.
Authors: Unlu Serhan , Shin Junghee Jenny , Par-Young Jennefer , Vinetz Joseph , Petrylak Daniel P. , Kang Insoo , Kim Joseph W. 
Published: February 2022

161 Background: TMPRSS2 is one of the two key enzymes that SARS-CoV-2 requires for its entry to the cell. TMPRSS2 is regulated by androgen receptor. It is well described Androgen Receptor Directed Therapy (ARDT) downregulates the expression of TMPRSS2. We hypothesized that the ARDT has a protective role in patients with prostate cancer (PCa) from poor outcome of COVID-19. Methods: A retrospective chart review of PCa patients with COVID-19 between March to October 2020 in the Yale-New Haven Health System was performed. Demographics, comorbidities, home medications, laboratory data, treatment, and clinical outcomes of COVID-19 were collected. ARDT was defined as the use of GnRH agonist, GnRH antagonist, or androgen receptor antagonist. This study was reviewed and approved by the Institutional Review Boards of Yale University. Results: A total of 146 (1.1%) prostate cancer cases were identified from the 13,642 cases of COVID-19. The clinical characteristics are summarized in the table. Twenty-five (17%) were on active ARDT and 121 (83%) not on ARDT (non-ARDT). The rates of hospitalization were the same: 52%, between the ARDT and non-ARDT group. Of those admitted, mean duration of hospitalization were 9.2 days (Range 1-25) and 14.9 days (Range: 2-47) in ARDT and non-ARDT groups, respectively (p=0.14). Rates of hospital stay >30 days were 0% versus 14.3% (9/63) in ARDT and non-ARDT groups, respectively (p=0.15). Intubation rates were 0% versus 11% (7/63) for ARDT and non-ARDT groups, respectively (p=0.21). Mortality rates were 8% and 13.2%, in ARDT and non-ARDT groups, respectively (p=0.47). Conclusions: The prevalence of PCa was infrequent. Despite advanced stage of the cancer in ARDT group, there was a trend toward decreased severity of COVID-19 and mortality rates compared to non-ARDT group. Our data support further investigation on a protective role of hormone therapy in PCa patients with COVID-19.[Table: see text]