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Current Oncology Reports Feb 2024Prostate cancer is the most frequently diagnosed non-cutaneous malignancy of men in the USA; notably, the incidence is higher among men of African, followed by European... (Review)
Review
PURPOSE OF REVIEW
Prostate cancer is the most frequently diagnosed non-cutaneous malignancy of men in the USA; notably, the incidence is higher among men of African, followed by European and Asian ancestry. Germline mutations and, in particular, mutations in DNA damage repair genes (DDRGs) have been implicated in the pathogenesis of prostate cancer. This review intends to discuss the implication of ancestry on prostate cancer, specifically in regard to lack of diversity in genomic and genetic databases and the ability of providers to properly counsel patients on the significance of cancer genetic results.
RECENT FINDINGS
Ancestral differences in prostate cancer-associated DDRG germline mutations are increasingly recognized. Guidelines for treatment by the National Comprehensive Cancer Network® (NCCN®) support germline testing in certain patients, and a myriad of genetic testing panels for DDRG mutations are now available in clinical practice. However, the consensus among providers on what genes and mutations to include in the genetic tests has evolved from experience from men of European ancestry (EA). Gaps in ancestry-informed clinical practice exist in genetic risk assessment, implementation of screening, counseling, guiding recommendations, treatment, and clinical trial enrollment. The lack of diversity in tumor genomic and genetic databases may hinder ancestry-specific disease-predisposing alterations from being discovered and targeted in prostate cancer and, therefore, impede the ability of providers to accurately counsel patients on the significance of cancer genetic test results.
Topics: Male; Humans; Germ-Line Mutation; Prostatic Neoplasms; Mutation; Genetic Testing; Genetic Predisposition to Disease
PubMed: 38265515
DOI: 10.1007/s11912-024-01493-x -
Journal of Translational Medicine Oct 2023Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict...
PURPOSE
Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk.
METHODS
Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC).
RESULTS
In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS.
CONCLUSION
This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.
Topics: Humans; Male; Biopsy; Neoplasm Grading; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Early Detection of Cancer; Urinalysis; Metabolome; Urine
PubMed: 37821919
DOI: 10.1186/s12967-023-04424-9 -
Abdominal Radiology (New York) Dec 2023Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Imaging techniques such as CT, MRI, and bone scans have traditionally... (Review)
Review
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Imaging techniques such as CT, MRI, and bone scans have traditionally been used for diagnosis and staging. Molecular imaging modalities targeting the prostate-specific membrane antigen (PSMA) have recently gained attention due to their high affinity and accuracy. PSMA PET has been combined with other modalities such as multiparametric MRI for better diagnostic and prognostic performance. PSMA imaging has been studied at different clinical settings with a wide range of disease aggressiveness. In this review we will explore the role of PSMA PET in high-risk prostate cancer staging, biochemical recurrence, and castration-resistant prostate cancer. The primary focus of this review article is to examine the latest developments in the use of PSMA imaging and emphasize the clinical situations where its effectiveness has been demonstrated to significantly impact the treatment of prostate cancer. In addition, we will touch upon the potential future advancements of PSMA PET imaging and its evolving significance in the management of prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms; Prostate-Specific Antigen; Positron Emission Tomography Computed Tomography; Choline; Neoplasm Staging; Recurrence; Molecular Targeted Therapy
PubMed: 37493837
DOI: 10.1007/s00261-023-04002-z -
International Journal of Molecular... Feb 2024Prostate cancer (PCa) is the second most common cancer and the fifth highest cause of cancer-related death among men in the world [...].
Prostate cancer (PCa) is the second most common cancer and the fifth highest cause of cancer-related death among men in the world [...].
Topics: Male; Humans; Prostatic Neoplasms; Disease Progression
PubMed: 38473699
DOI: 10.3390/ijms25052451 -
Biochimica Et Biophysica Acta. Reviews... Mar 2024Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis.... (Review)
Review
Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis. Each malignant focus has distinct somatic mutations and gene expression patterns, which represents a challenge for the development of prognostic tests for localized prostate cancer. Additionally, the molecular heterogeneity of advanced prostate cancer has important implications for management, particularly for patients with metastatic and locally recurrent cancer. Studies have shown that prostate cancers with mutations in DNA damage response genes are more sensitive to drugs inhibiting the poly ADP-ribose polymerase (PARP) enzyme. However, testing for such mutations should consider both spatial and temporal heterogeneity. Here, we summarize studies where multiregional genomics and transcriptomics analyses have been performed for primary prostate cancer. We further discuss the vast interfocal heterogeneity and how prognostic biomarkers and a molecular definition of the index tumor should be developed. The concept of focal treatments in prostate cancer has been evolving as a demand from patients and clinicians and is one example where there is a need for defining an index tumor. Here, biomarkers must have proven value for individual malignant foci. The potential discovery and implementation of biomarkers that are agnostic to heterogeneity are also explored as an alternative to multisample testing. Thus, deciding upon whole-organ treatment, such as radical prostatectomy, should depend on information from biomarkers which are informative for the whole organ.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Mutation; Prostatectomy; Biomarkers
PubMed: 38272101
DOI: 10.1016/j.bbcan.2024.189080 -
British Journal of Cancer Aug 2023Striking geographic variations in prostate cancer incidence suggest an aetiological role for spatially-distributed factors. We assessed whether neighbourhood social...
BACKGROUND
Striking geographic variations in prostate cancer incidence suggest an aetiological role for spatially-distributed factors. We assessed whether neighbourhood social deprivation, which can reflect limited social contacts, unfavourable lifestyle and environmental exposures, is associated with prostate cancer risk.
METHODS
In 2005-2012, we recruited 1931 incident prostate cancer cases and 1994 controls in a case-control study in Montreal, Canada. Lifetime residential addresses were linked to an area-based social deprivation index around recruitment (2006) and about 10 years earlier (1996). Logistic regression estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS
Men residing in areas characterised by greater social deprivation had elevated prostate cancer risks (ORs of 1.54 and 1.60 for recent and past exposures, respectively; highest vs lowest quintiles), independently from area- and individual-level confounders and screening patterns. The increase in risk with recent high social deprivation was particularly elevated for high-grade prostate cancer at diagnosis (OR 1.87, 95% CI 1.32-2.64). Associations were more pronounced for neighbourhoods with higher proportions of separated/divorced or widowed individuals in the past, and with higher percentages of residents living alone recently.
CONCLUSIONS
These novel findings, suggesting that neighbourhood-level social deprivation increases the risk of prostate cancer, point out to potential targeted public health interventions.
Topics: Male; Humans; Case-Control Studies; Canada; Environmental Exposure; Social Deprivation; Prostatic Neoplasms; Residence Characteristics; Socioeconomic Factors
PubMed: 37188877
DOI: 10.1038/s41416-023-02299-7 -
Oncogene Jul 2023Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or...
Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.
Topics: Male; Mice; Humans; Animals; Prostate; Protein Serine-Threonine Kinases; Signal Transduction; Prostatic Neoplasms; Epithelial Cells; Tumor Microenvironment; Doublecortin-Like Kinases
PubMed: 37386128
DOI: 10.1038/s41388-023-02743-1 -
Oncotarget Jun 2024Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies,... (Review)
Review
Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. This research perspective defines an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. Overall, in this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.
Topics: Humans; DNA Damage; Immunotherapy; Prostatic Neoplasms; Reactive Oxygen Species; Male; Oxidative Stress; DNA Repair; Animals; Cysteine
PubMed: 38900609
DOI: 10.18632/oncotarget.28595 -
Journal of Translational Medicine Sep 2023Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation...
BACKGROUND
Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients.
METHODS
In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed.
RESULTS
The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance.
CONCLUSION
Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.
Topics: Humans; Male; Androgen Antagonists; Androgens; Clonal Evolution; Prostatic Neoplasms; Tumor Microenvironment; East Asian People; Prostatic Neoplasms, Castration-Resistant
PubMed: 37726835
DOI: 10.1186/s12967-023-04320-2 -
Biomedicine & Pharmacotherapy =... Dec 2023Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage... (Review)
Review
Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage advanced prostate cancer. However, most individuals with metastatic hormone-sensitive prostate cancer (mHSPC) administered ADT alone are at risk of developing metastatic castration-resistant prostate cancer (mCRPC) in less than two years. New approaches employing novel AR inhibitors (ARi) as intensified upfront systemic treatment in mHSPC have recently demonstrated substantial benefits in delaying disease progression and prolonging overall survival. Administration of novel ARi has become the new standard of care in mHSPC. The new landscape simultaneously makes treatment choice more challenging. This review provides comprehensive data on molecular structure, pharmaceutical properties, and efficacy and safety profiles reported by pivotal clinical trials. We also discuss future directions with ongoing Phase III trials of novel ARi in mHSPC. Considering these biological and clinical insights, this review aimed to provide a comprehensive understanding of differences in the development and applications of novel ARi for mHSPC, which may be helpful in designing strategies for first-line treatment choices.
Topics: Humans; Male; Androgen Receptor Antagonists; Hormones; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Treatment Outcome
PubMed: 37925933
DOI: 10.1016/j.biopha.2023.115806