bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline characteristics associated with PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).
Authors: Aggarwal Rahul Raj , Heller Glenn , Hillman David W. , Xiao Han , Picus Joel , Taplin Mary-Ellen , Dorff Tanya B. , Appleman Leonard Joseph , Weckstein Douglas Jay , Patnaik Akash , Bryce Alan Haruo , Shevrin Daniel H. , Mohler James , Anderson Daniel M. , Rao Arpit , Tagawa Scott T. , Tan Alan , Eggener Scott E. , Ryan Charles J. , Morris Michael J. 
Published: March 2023

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .
The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer.
Authors: Matsubara Nobuaki , Sakai Shunsuke , Yamashita Riu , Misumi Toshihiro , Shiota Masaki , Eto Masatoshi , Kato Taigo , Osawa Takahiro , Abe Takashige , Shinohara Nobuo , Nishimoto Koshiro , Yasumizu Yota , Tanaka Nobuyuki , Oya Mototsugu , Fujisawa Takao , Horasawa Satoshi , Nakamura Yoshiaki , Yoshino Takayuki , Nonomura Norio 
Published: March 2023

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.
Impact of somatic DNA repair mutations on bone-related efficacy endpoints in patients with metastatic castration-resistant prostate cancer (mCRPC): A retrospective analysis.
Authors: Cursano Maria Concetta , Giunta Emilio Francesco , Scarpi Emanuela , Casadei Chiara , Virga Alessandra , Ulivi Paola , Bleve Sara , Brighi Nicole , Ravaglia Giorgia , Pantano Francesco , Santini Daniele , Conteduca Vincenza , De Giorgi Ugo 
Published: March 2023

214 Background: Up to 80% of mCRPC have bone metastases and about 25% of metastatic prostate cancer harbor mutations in DNA damage repair defects (DDR). DDR gene mutations are a negative prognostic factor, being associated with short metastasis-free survival and cancer-specific survival. We analyzed the impact of somatic mutations in DDR genes on bone-related efficacy endpoints in mCRPC. Methods: We retrospectively analyzed the mutational status of mCRPC patients per FoundationOne analysis in tissue biopsy or, when it was not possible, in liquid biopsy (performed at the onset of mCRPC). We evaluated the impact of DDR gene mutations on bone-related efficacy endpoints at the time of mCRPC diagnoses, by dividing patients in two main groups (mutated DDR, specifically, mutations in at least one of BRCA1/2, ATM, FANCA, ATR, CHEK2, RAD51, PALB2, and CDK12 genes: group A; wild-type DDR: group B). We investigated differences between the two groups in terms of time from bone metastases onset to death, skeletal metastatic tumor burden (sites and number of lesions), skeletal-related events (SRE) incidence, and time to first on-study SRE. Results: Of the 131 patients with mCRPC enrolled, 115 had bone metastases. Clinical data distribution, according to molecular profile, is presented. There is no difference in terms of sites of metastases and time from bone metastases onset to death between the 2 groups. Mutated DDR status was associated with bone metastases volume (p = 0.0325), but did not affect SRE incidence and time to SRE onset. Conclusions: In our analysis, mutated DDR status was associated with higher bone metastases volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. [Table: see text]
Effect of neuroendocrine differentiation on therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.
Authors: Xu Nanwei , Zhao Jinge , Shen Pengfei , Chen Ni , Zeng Hao 
Published: March 2023

216 Background: This study aims to explore the prognostic value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel therapy. Methods: We retrospectively analyzed data of 262 mCRPC patients treated with abiraterone or docetaxel as first-line therapy. NED status was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: In total, NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED<10% and NED≥10%, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5-Mo vs. 10.3-Mo, P<0.001), median rPFS (mrPFS, 15.9-Mo vs. 19.5-Mo, P=0.010), and median OS (mOS, 23.2-Mo vs. 34.3-Mo, P=0.014). Likewise, for mCRPC patients receiving docetaxel-based chemotherapy, the positive detection of NED also predicted shorter mPSA-PFS (3.8-Mo vs. 5.9-Mo, P=0.052), mrPFS (8.4-Mo vs. 20.4-Mo, P=0.016) and mOS (13.6-Mo vs. 29.0-Mo, P=0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients’ survival outcomes deteriorated as the NED proportion grew in both therapies. Both abiraterone and docetaxel exerted similar and unfavorable efficacy on NED-positive mCRPC patients. Conclusions: For mCRPC patients receiving abiraterone or docetaxel treatment, NED and its proportion were critical prognostic factors. NED detection at mCRPC might aid in predicting patients’ outcomes and optimizing treatment decisions.
Androgen receptor (AR) mutations in men with metastatic castration-resistant prostate cancer (mCRPC): Incidence and natural history.
Authors: Bernard-Tessier Alice , Mulier Guillaume , Nay Paula , Baldini Capucine , Albiges Laurence , Colomba Emeline , Flippot Ronan , Lavaud Pernelle , Naoun Natacha , Patrikidou Anna , Loriot Yohann , Massard Christophe , Foulon Stéphanie , Fizazi Karim 
Published: March 2023

221 Background: AR ligand binding domain (LBD) activating somatic point mutation is a known mechanism of resistance to androgen-receptor signaling inhibitor (ARSI) treatment in mCRPC, leading to a persistent addiction to steroid hormones. Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation. In CYPIDES Part 1, AR LBD mutations (ARm) strongly predicted for PSA decline with ODM-208 (Fizazi, ASCO GU 2021). Here, we evaluated clinical and genomic data associated with ARm in patients with mCRPC. Methods: We reviewed clinical and molecular data from patients with mCRPC who progressed after ≥1 ARSI and ≥1 line of taxane-based chemotherapy or were ineligible to chemotherapy, pre-screened in CYPIDES and STESIDES trials at our center. Circulating tumor DNA (ctDNA) was tested for AR LBD mutation (Guardant360 CDx and Sysmex OncoBEAM) and for genomic analysis (FoundationOne Liquid CDx, STING trial, NCT04932525) to screen for actionable targets. Results: From March 2020 to January 2022, 272 men were screened. Median age was 62y. Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively. Median PSA at screening was 59 ng/mL (IQR 11; 246). ARm was found in 69 patients (25%). The most frequent mutations were L702H (15%), T878A (12%), H875Y (7%), V716M (2%), F877L (2%), W742C (1%), globally consistent with previous reports. Associations of ARm with relevant baseline characteristics of patients are summarized. Duration of enzalutamide exposure was correlated with the number of AR mutations per patient (p = 0.006) whereas no correlation was found for abiraterone exposure duration (p=0.71). In 173 (64%) patients with available genomic testing, no alterations were found to be mutually exclusive with ARm, including in DNA repair alteration. Conclusions: AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. [Table: see text]
Role of epigenetic regulator KMT2C mutation detected by liquid biopsy in survival in patients with prostate cancer.
Authors: Xu Nanwei , Zhu Sha , Shen Pengfei , Zeng Hao 
Published: March 2023

222 Background: KMT2 (lysine methyltransferase) family enzymes exert epigenetic regulation to active gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1 and is also the top mutated gene in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. Methods: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cfDNA-based liquid biopsy test results in this study. We explored the association of KMT2C mutations with other mutations and investigates the prognostic significance of KMT2C mutation measured by overall survival (OS) and castration-resistance free survival (CFS). In addition, we explored the prognostic value of KMT2C mutation in different patient subgroups. Results: The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS (CFS: mutated 9.9 vs. WT 22.0 months, p=0.015; OS: mutated 71.9 vs. WT 137.4 months, p=0.012). KMT2C mutation was also an independent risk factor in OS [HR: 3.815 (1.461, 9.96), P=0.006] in multivariate analyses. Besides, we also explored the association of KMT2C mutations and other genes, and the results showed that KMT2C mutation was related to Serine/Threonine-Protein Kinase 11 ( STK11, p=0.004) and Catenin Beta 1 ( CTNNB1, p=0.008) mutations. For OS, KMT2C mutation was significantly associated with survival in patient subgroups with PI3K pathway mutation (HR: 6.64, p=0.009) or WNT pathway mutation (HR: 2.44, p=0.043). Conclusions: KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS, and KMT2C mutation was associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutation was significantly associated with survival in certain patient subgroups, such as patients with PI3K and WNT pathway mutation, etc.
Inherited mutations in DNA damage gene repair (gDDR) in Italian men with metastatic prostate cancer.
Authors: De Giorgi Ugo , Casadei Chiara , Conteduca Vincenza , Gurioli Giorgia , Scarpi Emanuela , Cursano Maria Concetta , Brighi Nicole , Lolli Cristian , Schepisi Giuseppe , Basso Umberto , Fornarini Giuseppe , Bleve Sara , Farolfi Alberto , Altavilla Amelia , Olmos David , Castro Elena 
Published: March 2023

223 Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.
Effect of Janus kinase (JAK) signaling inhibition on lineage plasticity and drug sensitivity in castrate resistant prostate cancer.
Authors: Zaidi Samir , Chan Joseph Minhow , Love Jillian , Zhao Jimmy , Setty Manu , Lawrence Kayla , Gopalan Anuradha , Goodrich David , Morris Michael J. , Chen Yu , Karthaus Wouter , Pe'er Dana , Sawyers Charles L. 
Published: March 2023

227 Background: Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells alter their identity and transition into aggressive states. In the case of prostate cancer, cells can acquire a neuroendocrine histology. This is often associated with a loss of tumor suppressor genes, such as TP53, RB1, and PTEN. However, while these genomic events initiate plasticity, tumor progression is not always associated with successive genomic alterations. This, in essence, not only poses a clinical challenge, but also confronts us with a wide-open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? Methods: To study the temporal evolution of lineage plasticity and its relationship to androgen receptor signaling inhibitor (ARSI) resistance, we utilized genetically engineered mouse models (GEMMs) and murine organoids that were deleted for Tp53, Rb1, and/or Pten. Single cell RNA analyses were utilized to dissect which genes and pathways were up-regulated and most associated with the progression of plasticity. Plasticity-associated genes and pathways were perturbed using FDA-approved inhibitors or genetic editing tools. The presence of these pathways was confirmed in a subset of metastatic index lesions obtained by radiologically guided biopsies and as visualized by metabolic imaging. Furthermore, relevant findings were functionally validated in human tumor derived organoids (“tumoroids”). Results: Using GEMMs and organoid models, we found the lineage plasticity depended on increased Janus Kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Pharmacologic inhibition using FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafinitib), or through genetic knockdown, demonstrated increased androgen receptor (AR) signaling and restored ARSI sensitivity. These findings were further validated in a subset of ARSI-insensitive human tumoroids. By performing single cell RNA sequencing on mCRPC tumors biopsies, the presence of highly plastic JAK/STAT- and FGFR-high cells were confirmed, with implications for stratifying patients for clinical trials. Conclusions: JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs). FDA-approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity.
Correlation of age and the tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa).
Authors: Sahu Kamal Kant Kant , Jo Yeonjung , Chigarira Beverly , Kim Jong Taek , Sayegh Nicolas , Gebrael Georges , Tripathi Nishita , Kumar Shruti Adidam , Mathew Thomas Vinay , Li Haoran , Nussenzveig Roberto , Kohli Manish , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang 
Published: March 2023

233 Background: In general, older pts are likely to have an advanced stage PCa, hence poor overall survival (PMID: 18660852). Owing to increased awareness and better diagnostics, the incidence of PCa has steadily increased amongst older adolescents and young adult pts (PMID: 31553489). Recent reports suggest that younger pts often are staged less adequately, present with more advanced stages, and could have worse outcomes than older pts (PMID: 33575208). Hence, elucidating the underlying molecular biology of PCa by age may unravel specific biologic features and distinct genomic expressions specific to young-age PCa, and help investigate new therapeutic targets. Methods: In this IRB-approved retrospective study, eligibility criteria included pts diagnosed with advanced PCa with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on the cohort's age cut-off points (< 65 vs. ≥65 years). DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. The statistical significance level was predetermined at 0.05. Results: 80 pts were eligible: < 65 (n=44) vs ≥65 years (n=36). No differences in Gleason score (<8/≥8), baseline PSA levels, and disease volume (high/low) between the cohorts (Table). As compared to pts ≥65 years; in young pts, (1) the three most upregulated significant pathways were oxidative phosphorylation (OXPHOS), bile acid, and fatty acid metabolism pathways, and (2) the three most downregulated significant pathways were tumor necrosis factor-alpha (TNFα) via NF-Κb, transforming growth factor-β (TGF β), and inflammatory response pathways. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show distinct genomic pathways to be upregulated in younger pts vs. older pts with advanced PCa and may guide further drug development, e.g., OXPHOS inhibitors in younger pts vs. drugs targeting inflammatory response in older pts. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with PCa. [Table: see text]