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Cancer Reports (Hoboken, N.J.) Sep 2023Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM), who are at increased risk for prostate... (Review)
Review
BACKGROUND
Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM), who are at increased risk for prostate cancer, and European American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome-wide association studies, several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility.
RECENT FINDINGS
Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM, samples from AAM remain to be unrepresented in different studies.
CONCLUSION
This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications and may lead to the widening of the existing disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity.
Topics: Male; Humans; Genome-Wide Association Study; Precision Medicine; Prostatic Neoplasms; Genomics; White
PubMed: 37565547
DOI: 10.1002/cnr2.1867 -
BMC Urology Sep 2023Treatment decisions for localized prostate cancer must balance patient preferences, oncologic risk, and preservation of sexual, urinary and bowel function. While Active... (Review)
Review
BACKGROUND
Treatment decisions for localized prostate cancer must balance patient preferences, oncologic risk, and preservation of sexual, urinary and bowel function. While Active Surveillance (AS) is the recommended option for men with Grade Group 1 (Gleason Score 3 + 3 = 6) prostate cancer without other intermediate-risk features, men with Grade Group 2 (Gleason Score 3 + 4 = 7) are typically recommended active treatment. For select patients, AS can be a possible initial management strategy for men with Grade Group 2. Herein, we review current urology guidelines and the urologic literature regarding recommendations and evidence for AS for this patient group.
MAIN BODY
AS benefits men with prostate cancer by maintaining their current quality of life and avoiding treatment side effects. AS protocols with close follow up always allow for an option to change course and pursue curative treatment. All the major guideline organizations now include Grade Group 2 disease with slightly differing definitions of eligibility based on risk using prostate-specific antigen (PSA) level, Gleason score, clinical stage, and other factors. Selected men with Grade Group 2 on AS have similar rates of deferred treatment and metastasis to men with Grade Group 1 on AS. There is a growing body of evidence from randomized controlled trials, large observational (prospective and retrospective) cohorts that confirm the oncologic safety of AS for these men. While some men will inevitably conclude AS at some point due to clinical reclassification with biopsy or imaging, some men may be able to stay on AS until transition to watchful waiting (WW). Magnetic resonance imaging is an important tool to confirm AS eligibility, to monitor progression and guide prostate biopsy.
CONCLUSION
AS is a viable initial management option for well-informed and select men with Grade Group 2 prostate cancer, low volume of pattern 4, and no other adverse clinicopathologic findings following a well-defined monitoring protocol. In the modern era of AS, urologists have tools at their disposal to better stage patients at initial diagnosis, risk stratify patients, and gain information on the biologic potential of a patient's prostate cancer.
Topics: Male; Humans; Watchful Waiting; Neoplasm Grading; Quality of Life; Prospective Studies; Retrospective Studies; Prostatic Neoplasms; Prostate-Specific Antigen
PubMed: 37777716
DOI: 10.1186/s12894-023-01314-6 -
Nature Communications Oct 2023While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel...
While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.
Topics: Humans; Male; Carrier Proteins; CD47 Antigen; Macrophages; Phagocytosis; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Signal Transduction; Tumor Escape; Neoplasm Metastasis; Tumor Cells, Cultured
PubMed: 37848444
DOI: 10.1038/s41467-023-42303-5 -
Journal of Experimental & Clinical... Aug 2023Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic...
BACKGROUND
Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10-17% CRPC patients. The detailed mechanisms remain unclear..
METHODS
The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting.
RESULTS
The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists.
CONCLUSIONS
TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.
Topics: Humans; Male; Autophagy; Cell Line, Tumor; Drug Resistance, Neoplasm; Mitochondrial Precursor Protein Import Complex Proteins; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms, Castration-Resistant; Reactive Oxygen Species; Receptors, Androgen; Androgen Receptor Antagonists; Animals
PubMed: 37563661
DOI: 10.1186/s13046-023-02776-0 -
International Journal of Surgery... Dec 2023The early detection of high-grade prostate cancer (HGPCa) is of great importance. However, the current detection strategies result in a high rate of negative biopsies...
BACKGROUND
The early detection of high-grade prostate cancer (HGPCa) is of great importance. However, the current detection strategies result in a high rate of negative biopsies and high medical costs. In this study, the authors aimed to establish an Asian Prostate Cancer Artificial intelligence (APCA) score with no extra cost other than routine health check-ups to predict the risk of HGPCa.
PATIENTS AND METHODS
A total of 7476 patients with routine health check-up data who underwent prostate biopsies from January 2008 to December 2021 in eight referral centres in Asia were screened. After data pre-processing and cleaning, 5037 patients and 117 features were analyzed. Seven AI-based algorithms were tested for feature selection and seven AI-based algorithms were tested for classification, with the best combination applied for model construction. The APAC score was established in the CH cohort and validated in a multi-centre cohort and in each validation cohort to evaluate its generalizability in different Asian regions. The performance of the models was evaluated using area under the receiver operating characteristic curve (ROC), calibration plot, and decision curve analyses.
RESULTS
Eighteen features were involved in the APCA score predicting HGPCa, with some of these markers not previously used in prostate cancer diagnosis. The area under the curve (AUC) was 0.76 (95% CI:0.74-0.78) in the multi-centre validation cohort and the increment of AUC (APCA vs. PSA) was 0.16 (95% CI:0.13-0.20). The calibration plots yielded a high degree of coherence and the decision curve analysis yielded a higher net clinical benefit. Applying the APCA score could reduce unnecessary biopsies by 20.2% and 38.4%, at the risk of missing 5.0% and 10.0% of HGPCa cases in the multi-centre validation cohort, respectively.
CONCLUSIONS
The APCA score based on routine health check-ups could reduce unnecessary prostate biopsies without additional examinations in Asian populations. Further prospective population-based studies are warranted to confirm these results.
Topics: Male; Humans; Prostate-Specific Antigen; Artificial Intelligence; Neoplasm Grading; Risk Assessment; Prostatic Neoplasms; Biopsy; ROC Curve
PubMed: 37988414
DOI: 10.1097/JS9.0000000000000862 -
Prostate Cancer and Prostatic Diseases Sep 2023Prostate cancer (PC) is the second most diagnosed cancer in men worldwide. While racial and ethnic differences exist in incidence and mortality, increasing data suggest... (Review)
Review
BACKGROUND
Prostate cancer (PC) is the second most diagnosed cancer in men worldwide. While racial and ethnic differences exist in incidence and mortality, increasing data suggest outcomes by race among men with newly diagnosed PC are similar. However, outcomes among races beyond Black/White have been poorly studied. Moreover, whether outcomes differ by race among men who all have metastatic PC (mPC) is unclear. This systematic literature review (SLR) provides a comprehensive synthesis of current evidence relating race to survival in mPC.
METHODS
An SLR was conducted and reported in accordance with PRISMA guidelines. MEDLINE®, Embase, and Cochrane Library using the Ovid® interface were searched for real-world studies published from January 2012 to July 2022 investigating the impact of race on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with mPC. A supplemental search of key congresses was also conducted. Studies were appraised for risk of bias.
RESULTS
Of 3228 unique records identified, 62 records (47 full-text and 15 conference abstracts), corresponding to 54 unique studies (51 United States and 3 ex-United States) reporting on race and survival were included. While most studies showed no difference between Black vs White patients for OS (n = 21/27) or PCSM (n = 8/9), most showed that Black patients demonstrated improved OS on certain mPC treatments (n = 7/10). Most studies found no survival difference between White patients and Hispanic (OS: n = 6/8; PCSM: n = 5/6) or American Indian/Alaskan Native (AI/AN) (OS: n = 2/3; PCSM: n = 5/5). Most studies found Asian patients had improved OS (n = 3/4) and PCSM (n = 6/6) vs White patients.
CONCLUSIONS
Most studies found Black, Hispanic, and AI/AN patients with mPC had similar survival as White patients, while Black patients on certain therapies and Asian patients showed improved survival. Future studies are needed to understand what aspects of race including social determinants of health are driving these findings.
Topics: Humans; Male; American Indian or Alaska Native; Asian People; Black People; Prostate; Prostatic Neoplasms; Neoplasm Metastasis; Hispanic or Latino; Asian; White; United States; Survival Analysis
PubMed: 37592001
DOI: 10.1038/s41391-023-00710-1 -
Urology Journal Feb 2024Prostate cancer (PCa) is the second most commonly diagnosed cancer and the sixth leading cause of cancer death among men worldwide. Biomarkers are an important tool in... (Review)
Review
PURPOSE
Prostate cancer (PCa) is the second most commonly diagnosed cancer and the sixth leading cause of cancer death among men worldwide. Biomarkers are an important tool in the early detection of PCa. Prostate-specific antigen (PSA) is one of the oldest biomarkers for the early detection of PCa. Digital rectal exam (DRE) is another screening test for PCa detection, which is considered as an irritating experience for patients. Biopsy is still the most reliable method for PCa diagnosis; however, patients are prone to complications. Therefore, developing non-invasive and accurate methods for PCa screening seems urgent to avoid unnecessary biopsies. There has been remarkable development in PCa molecular biomarkers discovery, largely through progress in omics technologies. Due to the many benefits of liquid biopsies, a significant set of PCa diagnostic kits have been developed using urine samples. Despite the unique benefits of these kits, there are still many challenges to their widespread use in clinics. Here, we have reviewed the latest developments of PCa biomarkers in liquid biopsies.
METHODS
Literature on biomarkers for diagnosis of PCa was reviewed during the past two decades.
RESULTS
PSA, PHI, PCA3, and 4K score are among the commonly used markers for PCa diagnosis which have been used over a long-moderate length of time with multiple studies on their performance. We performed a review of their performance. Newer markers are among RNA and DNA markers. Multiple non-coding RNAs (mi-RNAs) were reviewed and their performance on Pca diagnosis was reviewed. Long noncoding RNAs (Lnc RNAs) including PlncRNA-1, HOTAIR, SchLAP-1, MALAT1, MEG3, and PRCAT17.3 were summarized. mRNA markers including TMPRSS2:ERG, and HOXC6 were presented. DNA-based markers including PTEN, HOXB13, and BRCA2 were reviewed. Finally, the use of CircRNAs was reviewed for PCa diagnosis.
CONCLUSION
Many reviewed RNA-based biomarkers have promising results in the diagnosis of PCa.
Topics: Male; Humans; Prostate-Specific Antigen; Biomarkers, Tumor; Antigens, Neoplasm; Prostatic Neoplasms; RNA
PubMed: 37818554
DOI: 10.22037/uj.v20i.7687 -
Oncogene May 2024Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance... (Review)
Review
Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to the standard of care treatments for metastatic disease. Recently, alternative splicing has been recognized as a hallmark of CaP aggressiveness. Alternative splicing events cause treatment resistance and aggressive CaP behavior and are determinants of the emergence of the two major types of late-stage treatment-resistant CaP, namely castration-resistant CaP (CRPC) and neuroendocrine CaP (NEPC). Here, we review recent multi-omics data that are uncovering the complicated landscape of alternative splicing events during CaP progression and the impact that different gene transcript isoforms can have on CaP cell biology and behavior. We discuss renewed insights in the molecular machinery by which alternative splicing occurs and contributes to the failure of systemic CaP therapies. The potential for alternative splicing events to serve as diagnostic markers and/or therapeutic targets is explored. We conclude by considering current challenges and promises associated with splicing-modulating therapies, and their potential for clinical translation into CaP patient care.
Topics: Humans; Alternative Splicing; Male; Drug Resistance, Neoplasm; Disease Progression; Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms; Gene Expression Regulation, Neoplastic; Animals
PubMed: 38658776
DOI: 10.1038/s41388-024-03036-x -
Theranostics 2024Radical prostatectomy (RP) combined with pelvic lymph node dissection (PLND) is the first step in multimodal treatment of prostate cancer (PCa) without distant... (Review)
Review
Radical prostatectomy (RP) combined with pelvic lymph node dissection (PLND) is the first step in multimodal treatment of prostate cancer (PCa) without distant metastases. For a long time, the surgical resection range has been highly dependent on the surgeon's visualization and experience with preoperative imaging. With the rapid development of prostate-specific membrane antigen positron emission tomography and single-photon emission computed tomography (PSMA-PET and PSMA-SPECT), PSMA-targeted surgery has been introduced for a more accurate pathological diagnosis and complete resection of positive surgical margins (PSMs) and micro-lymph node metastases (LNMs). We reviewed PSMA-targeted surgeries, including PSMA-PET-guided prostatic biopsy (PSMA-TB), PSMA-targeted radio-guided surgery (PSMA-RGS), PSMA-targeted fluorescence-guided surgery (PSMA-FGS), and multi-modality/multi-targeted PSMA-targeted surgery. We also discuss the strengths and challenges of PSMA-targeted surgery, and propose that PSMA-targeted surgery could be a great addition to existing surgery protocols, thereby improving the accuracy and convenience of surgery for primary and recurrent PCa in the near future.
Topics: Humans; Male; Prostatic Neoplasms; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatectomy; Surgery, Computer-Assisted; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; Lymph Node Excision
PubMed: 38773975
DOI: 10.7150/thno.95039 -
The Journal of Clinical Investigation Sep 2023BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T...
BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.
Topics: Male; Humans; Androgens; Neoplasm Recurrence, Local; Prostatic Neoplasms; Prostatectomy; Testosterone
PubMed: 37655657
DOI: 10.1172/JCI171117