bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus who do not achieve an optimal PSA response to intensiﬁed androgen deprivation therapy (i-ADT).
Authors: Mathew Thomas Vinay , Sayegh Nicolas , Chigarira Beverly , Gebrael Georges , Jo Yeonjung , Tripathi Nishita , Nussenzveig Roberto , Li Haoran , Sahu Kamal Kant Kant , Tandar Clara , Goel Divyam , Iyer Puja , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: March 2023

234 Background: Pts with mCSPC receiving i-ADT and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) demonstrate significantly better overall survival (OS) as compared to those with a PSA nadir > 0.2 ng/mL (PSA-H) (Chi AUA 2021, Saad ASCO 2022). We hypothesized that tumor gene expression proﬁle would differ between PSA-L and PSA-H. Methods: In this IRB-approved retrospective study, eligibility criteria included conﬁrmed mCSPC receiving i-ADT with androgen receptor-axis-targeted therapy (ARAT) and availability of RNAseq proﬁling performed by a CLIA-certiﬁed lab of primary prostate biopsies collected before treatment. Pts were divided into 2 groups: PSA-L and PSA-H based on achieving a PSA nadir ≤0.2 ng/mL at any time during treatment course. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p values (q values) for each differentially expressed gene. These results were subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R studio v4.2. Results: 78 pts were eligible: 55 were PSA-L, and 23 were PSA-H. The most significantly upregulated pathways in PSA-L were the TNFA signaling, androgen response (AR), estrogen response, and interferon-alpha response pathways. The most upregulated pathways in PSA-H were epithelial-mesenchymal transition, coagulation, and bile acid metabolism pathways. Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show that mCSPC pts on i-ADT with PSA-L have distinct baseline tumor gene expression profiles, such as upregulation of AR signaling, compared to pts with PSA-H. After external validation, these findings may help personalize medicine prior to initiation of therapy in pts not expected to achieve PSA-L. [Table: see text]
Correlation of tumor gene expression profile and gleason score (GS) in patients (pts) with metastatic prostate cancer.
Authors: Sayegh Nicolas , Tripathi Nishita , Chigarira Beverly , Jo Yeonjung , Mathew Thomas Vinay , Nussenzveig Roberto , Sahu Kamal Kant Kant , Li Haoran , Gebrael Georges , Tandar Clara , Goel Divyam , Rathi Nityam , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: March 2023

235 Background: GS is the most powerful prognostic predictor in prostate adenocarcinoma. However, the underlying reasons of disease aggressiveness as a function of GS are currently unknown. Herein we sought to investigate the corresponding differences in gene expression profiles of pts with prostate adenocarcinoma with respect to GS. Methods: In this IRB approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA certified lab. Pts were categorized into two cohorts: low GS (GS <8) and high GS (GS ≥ 8). The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analyses were undertaken using R v4.2. Results: Fifty-seven pts were eligible, of which 13 had a GS <8 and 44 had a GS ≥8. Tumor tissues with high GS had a significantly higher expression of genes involved in the immune pathways (e.g., inflammatory response, interferon-γ, allograft rejection, and interferon-α), epithelial-mesenchymal transition, KRAS signaling, E2F targets and G2M checkpoint (q for all <0.01). The genes involved in the androgen response pathway were significantly more expressed in biopsies with a low GS (q<0.01). Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with prostatic adenocarcinoma with a GS ≥8 demonstrated a different transcriptomic profile than those with a GS <8. Higher GS tumor tissues had upregulated of inflammatory, proliferation, and KRAS signaling. Lower GS tumor tissues had upregulated androgen signaling pathway. These hypothesis-generating results upon external validation may provide the rationale for personalized therapy in men with prostatic cancer. [Table: see text]
Use of prostate cancer subtyping by gene expression to predict response to radiation and chemohormonal therapies.
Authors: Weiner Adam B , Liu Yang , Hakansson Alexander K. , Zhao Xin , Proudfoot James Alexander , Zhang JJ Haijing , Karnes R. Jeffrey , Den Robert Benjamin , Kishan Amar Upadhyaya , Reiter Robert Evan , Hamid Anis , Ross Ashley , Tran Phuoc T. , Chua Melvin L.K. Lee Kiang , Spratt Daniel Eidelberg , Attard Gerhardt , Lotan Tamara L. , Sweeney Christopher J , Davicioni Elai , Schaeffer Edward M. 
Published: March 2023

241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.
Differences in the tumor transcriptomic profile of patients (pts) with advanced prostate cancer (PCa) with and without diabetes mellitus (DM).
Authors: Tripathi Nishita , Li Haoran , Chigarira Beverly , Kumar Shruti Adidam , JongTaek Kim , Sayegh Nicolas , Gebrael Georges , Jo Yeonjung , Sahu Kamal Kant Kant , Mathew Thomas Vinay , Nussenzveig Roberto , Goel Divyam , Tandar Clara , Rathi Nityam , Swami Umang , Agarwal Neeraj , Maughan Benjamin L. 
Published: March 2023

244 Background: Pre-existing DM is associated with increased PCa specific and all-cause mortality in men with prostate cancer (PMID: 27652121). However, the underlying reasons are unclear. We hypothesized that transcriptomic profile of metastatic PCa pts with diagnosis of DM prior to the diagnosis of metastatic disease and start of systemic therapy will be different from those without DM. Methods: In this IRB-approved retrospective study, advanced PCa pts with available RNA profiling of treatment naïve tumor tissue through a CLIA-certified laboratory were included. Based on pre-existing DM prior to onset of metastatic disease, pts was grouped into DM and non-DM. Differential gene expression analysis between the two groups was performed using DeSeq2. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. Gene ontology analysis using TopGO software was done to identify the biological process occurring at the molecular level of these differentially expressed genes. All bioinformatic analysis was conducted in R studio, version 4.1.1. Results: 75 pts were eligible and included: 20 DM vs 55 non-DM. Baseline characteristics (DM vs non-DM): median age 63.5 vs 64 years; median PSA at diagnosis 20 vs 18.85ng/mL; de novo disease: 55% vs 43.6%; Gleason score ≥8: 60% vs 74.5%. DM pts had upregulation of the following pathways: TNF alpha signaling, inflammatory response, IL-6 JAK STAT3 signaling, heme metabolism, and the p53 pathway vs non-DM pts. Gene ontology analysis and individual differential gene expression profiles will be reported at the meeting. Conclusions: Our study found that pre-existing DM is associated with upregulation of inflammatory pathways in pts with PCa These hypothesis-generating results need external validation. Identification of transcriptomic biomarkers in these subsets of pts may help with further drug development. [Table: see text]
Social determinants of health (SDOH) and survival among patients with metastatic prostate cancer (mPC): A systematic literature review (SLR).
Authors: Freedland Stephen J. , Niyazov Alexander , Nazari Jonathan , Worthington Evelyn , Lansing Austin , Rosta Emily , Samjoo Imtiaz 
Published: March 2023

25 Background: Population level data show strong associations between race and other SDOH including income, education, and geographic region of residence. The relationship between SDOH and clinical outcomes has become increasingly recognized. This review examines the impact of SDOH on survival in patients with mPC in real-world (RW) settings. Methods: A systematic literature search in accordance with Cochrane guidelines was conducted on July 7, 2022, searching for RW studies published as full-text (Jan 2012-July 2022) and conferences (Jan 2019-July 2022) using Ovid MEDLINE, Embase, and Cochrane. A manual search of key congress websites for conference abstracts was also conducted. Studies which assessed the impact of SDOHs on survival, treatment access, and other clinical outcomes in patients with mPC were included in the overall SLR. Here, we present results from studies which assessed the impact of SDOH on overall survival (OS) and prostate cancer specific mortality (PCSM). Clinical trials were excluded. Results: Of 3,228 records screened, 86 studies were included, with findings reported in 67 full-text publications (60 US and 7 ex-US) and 28 conference abstracts (22 US and 6 ex-US). The impact of race on survival was reported in 54 studies. While most studies showed no difference between Black vs White for both OS (n=22) and PCSM (n=8), for patients on specific mPC treatments, there was an association between Black race and improved OS (n=5). Asian patients had improved OS vs White patients (n=4), and reduced PCSM vs White (n=6) and Black patients (n=1). Higher income was generally associated with improved OS (n=7), but no difference in PCSM (n=3). Although the regions compared differed, most studies found disparities in OS among US geographic regions (n=5). Education level was generally not associated with OS (n=2) or PCSM (n=3). Most studies showed that married patients had improved OS (n=4) and reduced PCSM (n=3) compared to unmarried patients. Conclusions: This SLR demonstrated that various SDOH are associated with disparities in survival among mPC patients. Asian race, which is generally associated with higher frequency of better SDOH risk factors, was linked with better OS. In contrast, Black race, which is generally associated with higher frequency of worse SDOH risk factors, was associated with similar or better OS. Having lower income and being unmarried were both associated with reduced OS, while disparities in OS were reported across geographic regions of the US. More studies are needed to understand why SDOH are linked with poor outcomes, including their connection with access to care.
Evaluation of the aggressive variant prostate cancer molecular profile (AVPCm) in CLIA environments.
Authors: Viscuse Paul Vincent , Zhang Miao , Rohra Prih , Slack Tidwell Rebecca , Pritchard Colin C. , Subudhi Sumit Kumar , Pilié Patrick Glen , Logothetis Christopher , Corn Paul Gettys , Aparicio Ana 
Published: March 2023

250 Background: 20-30% of prostate cancers respond poorly to androgen receptor (AR)-directed therapies and have an atypical, virulent course. The aggressive variant prostate cancers ( AVPC) encompass virulent androgen indifferent tumors and are characterized by combined defects in ≥ 2/3 of TP53, RB1, and PTEN (AVPC-m). Post-hoc analysis in a phase I/II trial indicated a benefit of carboplatin+cabazitaxel in men with AVPCm+ metastatic castrate resistant prostate cancer (mCRPC). We assess the feasibility of detecting the AVPCm in CLIA-certified environments. Methods: Men with progression of mCRPC undergoing biopsies for standard molecular profiling at MD Anderson Cancer Center (MDACC) were eligible. TP53, RB1, and PTEN expression was assessed by immunohistochemistry (IHC) and read by 2 pathologists independently. Next generation sequencing of solid tumor DNA (stDNA) and circulating tumor DNA (ctDNA) was performed on the MDACC Molecular Diagnostics Laboratory and the University of Washington OncoPlex ctDNA platforms respectively . Results: Of 64 eligible patients, 49 (77%), 37 (58%), and 54 (84%) had results reported for IHC, stDNA, and ctDNA respectively. Concordance of IHC reads between pathologists was variable: Kappa 0.78, 0.67, and 0.91 for TP53, RB1, and PTEN respectively. 36 (66.7%) ctDNA samples had low tumor content, such that false negatives could not be excluded. AVPC-m was detected in 14 (29%) of patients by IHC per the original reading pathologist, 2 (5%) by stDNA NGS, and 7 (39%) by ctDNA NGS. Median turnaround times for IHC, stDNA and ctDNA were 12 (2-35), 28 (12-56) and 16 (11-56) days respectively. Conclusions: We show the operational characteristics of the AVPCm detection using CLIA certified assays. IHC detected a greater proportion of patients with AVPCm+ tumors than stDNA, likely due, partly, to the challenges of copy number loss detection. ctDNA detected the greatest proportion of AVPCm+ tumors but was not evaluable in two thirds of patients. These data serve to inform the design of clinical trials using AVPCm as a criterion for patient selection or stratification. [Table: see text]
Long-term taxane exposure and transdifferentiation of prostate cancer in vitro.
Authors: Von Amsberg Gunhild , Dyshlovoy Sergey , Hauschild Jessica , Sailer Verena , Perner Sven , Offermann Anne , Merkens Lina , Krisp Christoph , Werner Stefan , Pantel Klaus , Kaune Moritz , Tilki Derya , Schlüter Hartmut , Graefen Markus , Bokemeyer Carsten 
Published: March 2023

254 Background: Development of aggressive variants of metastatic castration-resistant prostate cancer (AVPC) is a major challenge in the course of therapy but the underlying mechanisms of aggressive transdifferentiation are not completely understood and appropriate tumor models are missing. Here, we investigated the consequences of long-term taxane exposure on hormone-independent, BRCA2-mutated, AR-V7-positive 22Rv1 cells. Methods: 22Rv1 cells were treated with stepwise increased taxane concentrations for 10 months. Individual clones were picked and further cultured in media containing either docetaxel (Doce) or cabazitaxel (Caba). Passage-matched cells were maintained in culture without treatment. Further characterization was carried out using proliferation, migration, metabolic, and colony formation assays as well as proteomics, RNAseq analyses and xenotransplantation in immunodeficient mice. Results: In total, three single cell 22Rv1-DR clones (50-100-fold resistance to Doce) and three 22Rv1-CR clones (80-150-fold resistance to Caba) were successfully established. All clones showed cross-resistance to either drug. Expectedly, treatment-induced overexpression of ABCB1 was detected and validated. Moreover, alteration of drug resistance related SLC7A5, SLC3A2, and SLC25A24 genes was observed. Additionally, an enrichment analyses identified, among others, neuroendocrine transdifferentiation (GO-term “Neuroendocrine tumors”, p=4.46e-5) to be stimulated in prostate 22Rv1 cells under long-term treatment with Doce or Caba. In line with this, the neuroendocrine features were validated in vitro as well as in xenotransplanted tumors in vivo with upregulation of synaptophysin, chromogranin and neuron specific enolase accompanied by downregulation of the androgen receptor (AR) and upregulation of AR spice variants. Additionally, neuritic morphology, shift to higher nuclear-plasma ratio, partial loss of adherent properties and growth slowdown, along with higher migratory activity were detected. Conclusions: Long-term taxane exposure of 22Rv1 cells resulted in the development of neuroendocrine traits in individual cell clones that have successfully been translated into stable cell lines. Thus, we provide a new cell line model for secondary therapy-induced neuroendocrine transdifferentiation. Further in-depth analysis to identify individual alterations in the course of therapy is currently ongoing.
Homologous recombination repair (HRR) mutation concordance between liquid biopsy (LB) and tumor tissue by NGS in a real-world prostate cancer (PC) database.
Authors: Shen John , Wang Liang , Khaki Ali Raza , Jimenez Rafael E , Mauer Elizabeth , Stoppler Melissa Conrad , Chao Calvin Y. , Kohli Manish 
Published: March 2023

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]
Cost-effectiveness analysis of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.
Authors: Kohli Manish , Dougherty Maura , Cutshall Zachary , Beckstead Rylee , Kohli Rhea , Haaland Benjamin , Nelson Richard , Yoo Minkyoung 
Published: March 2023

268 Background: Recently several new treatment regimens have been approved for treating mHSPC, building on the previous standard of care using androgen deprivation therapy (ADT) alone. These include docetaxel+ADT (DA), Abiraterone Acetate+Prednisone+ADT (AAP), Apalutamide+ADT (AAT), Enzalutamide+ADT (ET), Darolutamide+Docetaxel+ADT (DAD) and Abiraterone+Prednisone+ADT+Docetaxel (AAD). There are no current predictive biomarkers for choosing any specific regimen. The goal of this study was to determine the cost-effectiveness of these new treatments from the US public sector perspective with a lifetime horizon. Methods: We developed a partitioned survival model in which mHSPC patients transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven clinical trials included 7,208 patients. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens and subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events, and were obtained from the Federal Supply Schedule and published literature. Results: Average lifetime costs ranged from $154,139 (AAP) to $770,848 (DAD) and mean QALYs ranged from 3.33 (ADT) to 5.08 (ET). All treatment strategies other than AAP and ET were eliminated due to dominance. Compared to AAP, the incremental cost-effectiveness ratio for ET was $484,943/QALY. Results from our analysis including all regimens are shown. Conclusions: Our simulation model found that ET in mHSPC state yielded the most QALYs and would be the most cost-effective option with a WTP threshold as high as $500,000/QALY. However, for a WTP threshold of $150,000/QALY, AAP was the most cost-effective treatment strategy. [Table: see text]