scholarly journals Comparison of metastatic castration-resistant prostate cancer in bone with other sites: clinical characteristics, molecular features and immune status

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11133
Author(s):  
Zhengquan Xu ◽  
Yanhong Ding ◽  
Wei Lu ◽  
Ke Zhang ◽  
Fei Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Characteristics ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Specific Antigen ◽  
Functional Enrichment ◽  
Castration Resistant Prostate Cancer ◽  
Hub Genes ◽  
Molecular Features ◽  
Castration Resistant

Metastatic castration-resistant prostate cancer (mCRPC) is the lethal stage and the leading cause of death in prostate cancer patients, among which bone metastasis is the most common site. Here in this article, we downloaded the gene expression data and clinical information from online dataset. We found that prostate cancer metastasis in bone is prone to have higher prostate-specific antigen (PSA) and longer time on first-line androgen receptor signaling inhibitors (ARSI). A total of 1,263 differentially expressed genes (DEGs) were identified and results of functional enrichment analysis indicated the enrichment in categories related to cell migration, cancer related pathways and metabolism. We identified the top 20 hub genes from the PPI network and analyzed the clinical characteristics correlated with these hub genes. Finally, we analyzed the immune cell abundance ratio of each sample in different groups. Our results reveal the different clinical characteristics, the immune cell infiltration pattern in different sites of mCRPC, and identify multiple critical related genes and pathways, which provides basis for individualized treatment.

Characterization of PSA at death in patients with metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 184-184
Author(s):  
Krishna Bikkasani ◽  
Qian Qin ◽  
Justin Lin ◽  
Matt D. Galsky ◽  
Bobby Chi-Hung Liaw ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Characteristics ◽  
Descriptive Analysis ◽  
Specific Antigen ◽  
Predictive Biomarker ◽  
Mount Sinai Hospital ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant ◽  
Mount Sinai

184 Background: Prostate Specific Antigen (PSA) is a valuable prognostic and predictive biomarker in prostate cancer (PC). Currently, the significance of PSA at death is undefined. In this single institution retrospective study, we aim to characterize the significance of PSA at death in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer patients seen between 2010-2018, we stratified patients into the following cohorts based on their PSA at death: < 10, 10-100, 100-1000, and > 1000 ng/ml. We excluded data of patients who had less than 3 visits to the Mount Sinai Hospital. A descriptive analysis was performed to assess clinical characteristics of disease, treatment response, and outcomes. Results: We identified 1097 PC patients, and 101 were found to be deceased following a diagnosis of mCRPC. Cohorts of higher PSA level at death were associated with: a lower Gleason score at diagnosis, a longer time to castration resistance, higher burden of metastatic disease at death (non-visceral and visceral), and longer OS in patients with mCRPC (see table). Conclusions: In this study, PSA at death is associated with several important clinical characteristics and outcome, including overall survival. These differences may be attributed to their underlying biologic behavior. These results are hypothesis generating, and larger studies will be needed to further assess the significance of these findings. [Table: see text]

The association of ATM alterations with clinical and molecular features in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17019-e17019
Author(s):  
Guo Xi ◽  
Qing WANG ◽  
Qin Zhang ◽  
Qianqian Duan ◽  
Yaqin Liu
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Specific Antigen ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoints ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Features ◽  
Castration Resistant ◽  
Homozygous Deletions

e17019 Background: Ataxia telangiectasia-mutated（ATM）is a serine/threonine kinase involved in DNA-damage repair (DDR) system and regulating cell cycle checkpoints, senescence, and apoptosis. Several clinical studies provide evidence about the DDR-mutated metastatic castration-resistant prostate cancer (mCRPC) benefit from PARP inhibitors (PARPi). However. the efficacy of PARPi was limited for mCRPC patients harboring ATM aberrations. We aimed to determine the association of ATM mutations with clinical and molecular features in patients with mCRPC. Methods: A total of three independent prostate cancer cohorts (MCTP, N = 61; SU2C-PCF, N = 429; MSKCC, N = 451) were used for analysis. We selected patients with characteristics “mCRPC” and “histology type: prostate adenocarcinoma”. Both the somatic and germline pathogenic alterations were analyzed, including single nucleotide variations (SNVs), in-frame insertions or deletions (Indels), frameshifts, homozygous deletions and fusions. The statistical analysis was conducted by R software (v.3.6.2). Results: We merged the three mCRPC cohorts, generating a new cohort consisting of 507 mCRPC patients. The median age was 62 (range, 38.6-89). The number of biopsies was 1-3 per patient. Of the 527 sequenced specimens, 39% were lymph node, 27% were bone, and 14% were liver. Forty percent of the patients had exposed to or on-treatment with next-generation androgen receptor signaling inhibitor (ARSI). A total of 44 patients (8.7%) harbored deleterious variations in ATM, including 10 homozygous deletions. The coexistence mutations were most commonly located in androgen receptor ( AR), followed by TTN/KMT2C/MUC16/TP53. Furthermore, we explored the association of pathogenic ATM alterations with clinical features. Compared with noncarriers of ATM mutations , carriers were diagnosed at a younger age (median: 59 vs 62.4, P = 0.022). In the subgroup from SU2C-PCF cohort, prostate specific antigen (PSA) at diagnosis and the proportion of Gleason score between 8-10 were analyzed, both showed no significant differences between the two groups. Notably, we observed a statistically significant higher TMB in ATM-altered group than ATM wildtype group (median, 2.04 vs 1.61, P = 0.013). Overall survival (OS) was not compared because of the limited clinical outcomes in ATM-mutated population. Conclusions: This study involving 3 cohorts identified the prevalence of pathogenic somatic or germline ATM mutations and explored the association of ATM alterations with both clinical and molecular features. Patients with ATM mutations tended to diagnose prostate cancer at an earlier age. Meanwhile, significantly higher TMB might imply potential immunotherapy opportunities in ATM-altered mCRPC without standard-of-care approaches.

Identification of immune cell infiltration pattern and related critical genes in metastatic castration-resistant prostate cancer by bioinformatics analysis

2021 ◽  
pp. 1-15
Author(s):  
Caibin Fan ◽  
Wei Lu ◽  
Kai Li ◽  
Chunchun Zhao ◽  
Fei Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Protein Interaction ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Cell Infiltration ◽  
Castration Resistant Prostate Cancer ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Castration Resistant

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal stage of prostate cancer and the main cause of morbidity and mortality, which is also a potential target for immunotherapy. METHOD: In this study, using the Approximate Relative Subset of RNA Transcripts (CIBERSORT) online method, we analysed the immune cell abundance ratio of each sample in the mCRPC dataset. The EdgeR (an R package) was used to classify differentially expressed genes (DEGs). Using the Database for annotation, visualisation and interactive exploration (DAVID) online method, we performed functional enrichment analyses. STRING online database and Cytoscape tools have been used to analyse protein-protein interaction (PPI) and classify hub genes. RESULTS: The profiles of immune infiltration in mCRPC showed that Macrophages M2, Macrophages M0, T cells CD4 memory resting, T cells CD8 and Plasma cells were the main infiltration cell types in mCRPC samples. Macrophage M0 and T cell CD4 memory resting abundance ratios were correlated with clinical outcomes. We identified 1102 differentially expressed genes (DEGs) associated with the above two immune cells to further explore the underlying mechanisms. Enrichment analysis found that DEGs were substantially enriched in immune response, cell metastasis, and metabolism related categories. We identified 20 hub genes by the protein-protein interaction network analysis. Further analysis showed that three critical hub genes, CCR5, COL1A1 and CXCR3, were significantly associated with prostate cancer prognosis. CONCLUSION: Our findings revealed the pattern of immune cell infiltration in mCRPC, and identified the types and genes of immune cells correlated with clinical outcomes. A new theoretical basis for immunotherapy may be given by our results.

scholarly journals Clinical characteristics and outcomes for patients with non‑metastatic castration-resistant prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Arnold ◽  
Maria Cristina Penaloza-Ramos ◽  
Lola Adedokun ◽  
Sarah Rees ◽  
Mohamed Lockhat ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Characteristics ◽  
Doubling Time ◽  
Specific Antigen ◽  
Proportional Hazard ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Cox Proportional Hazard ◽  
Psa Doubling Time ◽  
Cox Proportional Hazard Models

AbstractThis study used linked, routinely-collected datasets to explore incidence, clinical characteristics and outcomes of prostate cancer (PC) patients who experience a rise in prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT), without evidence of metastases in their patient record, termed non-metastatic castration-resistant PC (nmCRPC). Routinely collected administrative data in Wales were used to identify patients diagnosed with PC and nmCRPC from 2000–2015. Logrank tests and Cox proportional hazard models were used to compare time-to-events across subgroups defined by PSA doubling time and age. Of 38,021 patients identified with PC, 1,465 met nmCRPC criteria. PC incidence increased over the study period, while nmCRPC categorizations reduced. Median time from PC diagnosis to nmCRPC categorization was 3.07 years (95% confidence interval [CI] 2.91–3.26) and from nmCRPC categorization to metastases/death was 2.86 years (95% CI 2.67–3.09). Shorter PSA doubling time (≤ 10 months, versus > 10 months) was associated with reduced time to metastases or death (2.11 years [95% CI 1.92–2.30] versus 5.22 years [95% CI 4.87–5.51]). Age was not significantly associated with time to metastases/death. Our findings highlight key clinical characteristics and outcomes for patients with nmCRPC prior to the introduction of recently approved treatments.

scholarly journals Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

2021 ◽  
Author(s):  
Fred Saad ◽  
Martin Bögemann ◽  
Kazuhiro Suzuki ◽  
Neal Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Imaging Techniques ◽  
Specific Antigen ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

scholarly journals Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

The Prostate ◽  
2016 ◽  
Vol 76 (9) ◽  
pp. 810-822 ◽  
Author(s):  
Martine P. Roudier ◽  
Brian R. Winters ◽  
Ilsa Coleman ◽  
Hung-Ming Lam ◽  
Xiaotun Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Features ◽  
Castration Resistant

Bone modifying agents in veterans with castration-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6582-6582
Author(s):  
Jordan Bauman ◽  
Kyle Kumbier ◽  
Jennifer A. Burns ◽  
Jordan Sparks ◽  
Phoebe A. Tsao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Specific Antigen ◽  
Veterans Health ◽  
Health Administration ◽  
Castration Resistant Prostate Cancer ◽  
National Guidelines ◽  
Castration Resistant ◽  
Unit Increase

6582 Background: Skeletal related events (SREs) are a known complication for the 80% of men with metastatic prostate cancer who have bone metastases. Previous studies have demonstrated that bone modifying agents (BMAs) such as zoledronic acid and denosumab reduce SREs in men with metastatic castration-resistant prostate cancer who have bone metastases and are now recommended by national guidelines. We sought to investigate factors associated with use of BMAs in Veterans with CRPC across the Veterans Health Administration (VA). Methods: Using the VA Corporate Data Warehouse, consisting of aggregated medical record data from 130 facilities, we used an algorithm previously published to identify men with a diagnosis of castration-resistant prostate cancer (CRPC) based on rising prostate specific antigen (PSA) levels while on androgen deprivation therapy and who received systemic treatment for CRPC with one of the commonly used therapies: abiraterone, enzalutamide, docetaxel, ketoconazole between 2010 and 2017. To account for clustering among facilities, we used a multilevel multivariable logistic regression to determine the association of patient and disease-specific variables on the odds of a patient receiving a BMA after they started treatment for CRPC. Results: Of 4,998 patients with CRPC in our cohort, 2223 (44%) received either zoledronic acid or denosumab at some point after they were initiated on treatment for CRPC. After adjusting for other variables and accounting for a facility, the odds of receiving a BMA decreased by 3% for every additional year of age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.96-0.98), and decreased significantly with increasing comorbid conditions (OR 0.94, 95% CI 0.72-0.98 for Charlson Comorbidity Index [CCI] of 1; OR 0.69, 95% CI 0.59-0.81 for CCI 2+). Patients who were Black had 25% lower odds of receiving a BMA than patients who were White (OR 0.75, 95% CI 0.65-0.87). PSA at time of CRPC treatment start had a small but not significant effect on receipt of a BMA (OR 1.04, 95% CI 1.00-1.08) for every unit increase of PSA on the log scale. PSA doubling time was not associated with receipt of a BMA. The presence of a diagnosis code for bone metastases was far lower than expected in this cohort of patients with CRPC (40.7%), and thus was not included in the model. We did not expect the presence of bone metastases to vary significantly among the other independent variables. Conclusions: Despite most patients with CRPC historically having bone metastases, less than half of patients with CRPC received a BMA. Patients who are older, had more comorbidities, or were Black were less likely to receive a BMA after starting treatment for CRPC. Understanding factors that lead to different patterns of treatment can guide initiatives toward more guideline-concordant care.

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