Untargeted urine metabolite profiling by mass spectrometry aided by multivariate statistical analysis to predict prostate cancer treatment outcome.

Deciphering metabolomic networks has been demonstrated to provide valuable information for diagnosing and monitoring diseases. Herein, we report a technique to monitor untargeted urine metabolites to evaluate prostate cancer aggressiveness and treatment outcome. Direct chemical profiling of urine was achieved by a combined procedure of hyphenating laser diode thermal desorption with atmospheric pressure chemical ionization mass spectrometry (LDTD-APCI-MS). We describe a conceptually new approach to monitoring preoperative urinary metabolic alterations associated with prostate cancer recurrence. By evaluating mass/charge (m/z) ratios and peak intensities of ions detected by mass spectroscopy of urine samples, we revealed that intensities at m/z 313.2740 (±0.0003) and 341.3054 (±0.0006) attributable to monoacylglycerol backbone fragments from glycerides can be statistically correlated to disease progression.

Changes in prostate cancer survival among insured patients in relation to USPSTF screening recommendations.

BACKGROUND: To investigate the effects of the U.S. Preventive Services Task Force's (USPSTF) 2012 recommendation against prostate-specific antigen (PSA)-based screening for prostate cancer on survival disparities based on insurance status. Prior to the USPSTF's 2012 screening recommendation, previous studies found that insured patients with prostate cancer had better outcomes than uninsured patients. METHODS: Using the SEER 18 database, we examined prostate cancer-specific survival (PCSS) based on diagnostic time period and insurance status. Patients were designated as belonging to the pre-USPSTF era if diagnosed in 2010-2012 or post-USPSTF era if diagnosed in 2014-2016. PCSS was measured with the Kaplan-Meier method, while disparities were measured with the Cox proportional hazards model. RESULTS: During the pre-USPSTF era, uninsured patients experienced worse PCSS compared to insured patients (adjusted HR 1.256, 95% CI 1.037-1.520, p = 0.020). This survival disparity was no longer observed during the post-USPSTF era as a result of decreased PCSS among insured patients combined with unchanged PCSS among uninsured patients (adjusted HR 0.946, 95% CI 0.642-1.394, p = 0.780). CONCLUSIONS: Although the underlying reasons are not clear, the USPSTF's 2012 PSA screening recommendation may have hindered insured patients from being regularly screened for prostate cancer and selectively led to worse outcomes for insured patients without affecting the survival of uninsured patients.

Comparison of perioperative complications for extended vs standard pelvic lymph node dissection in patients undergoing radical prostatectomy for prostate cancer: a meta-analysis.

INTRODUCTION: Pelvic lymph node dissection (PLND) is widely performed for staging in men undergoing radical prostatectomy (RP) for prostate cancer. Our goal was to synthesize all available evidence and data to evaluate perioperative complications for two templates of PLND, standard (sPLND) vs extended (ePLND), at the time of RP in patients with prostate cancer. METHODS: A meta-analysis was performed on relevant literature about complications during PLND. Pubmed, Scopus, WebofScience, and Cochrane Library were systematically searched through July 2021. Meta-analysis was conducted with both fixed-effects and random-effects models to estimate risk ratios (RRs) between treatments. A subgroup analysis was also conducted based on surgery type - open vs robotic. RESULTS: 13 (1 randomized clinical trial and 12 observational studies) studies published between 1997 and 2019 with a total of 7,036 patients were analyzed. Pooled data showed complications in a random-effects model was lower in the sPLND group than the ePLND group (RR, 0.62; 95% CI 0.40-0.97). In a subgroup analysis, neither the open surgery subgroup nor the robotic surgery subgroup showed significant differences in complication rate between sPLND and ePLND. CONCLUSION: ePLND is associated with a significantly greater risk of perioperative complication compared to sPLND, but not when comparing these templates performed via a robotic approach. Additional studies comparing the complication rates of sPLND and ePLND when utilizing a robotic approach should be conducted.

Genomic analysis and long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy.

Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. Materials and methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study. Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group. Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa.

RNA-seq profile of African American men with a clinically localized prostate cancer.

BACKGROUND: Prostate cancer in African American (AA) men has a poor prognosis. This study aimed to identify potential genetic risk factors for prostate cancer in AA men. METHODS: We used prostate cancer tissue from 61 patients who underwent radical prostatectomy. We compared somatic gene expression in Caucasian (CA) and AA men using RNA sequencing. RESULTS: By comparing the RNA-seq data obtained from prostate cancer tissue between AA and CA men, this study showed a significant difference in expression levels of 45 genes. Pathway analysis of 45 genes using Kyoto Encyclopedia of Genes and Genomesenrichment analysis revealed a neuroactive ligand-receptor interaction signal. In addition, the results of the Ingenuity Pathway Analysis showed pathways involved sphingosine-1-phosphate signaling. Furthermore, validating 45 genes in the The Cancer Genome Atlas (TCGA) Provisional cohort, cholinergic receptor muscarinic 3 expression level was significantly lower in AA than in CA men, and the results showed a significantly higher rate of biochemical recurrence in patients with low expression. CONCLUSIONS: We identified genetic differences of clinically localized prostate cancer in AAs and CAs by RNA sequencing.

Observation with or without late radiotherapy is equivalent to early radiotherapy in high-risk prostate cancer after radical prostatectomy: A SEER-Medicare analysis on trends, survival outcomes, and complications.

BACKGROUND: We aimed to illustrate national trends of post-radical prostatectomy (RP) radiotherapy (RT) and compare outcomes and toxicities in patients receiving eRT versus observation with or without late radiotherapy (lRT). METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2001 to 2011, we identified 7557 patients with high-risk pathologic features after RP (≥pT3N0 and/or positive surgical margins). Our study cohort consisted of patients receiving RT within 6 months of surgery (eRT), those receiving RT after 6 months (lRT), and those never receiving RT (observation). Another subcohort, delayed RT (dRT), encompassed both lRT and observation. Trends of post-RP RT were compared using the Cochran-Armitage trend test. Cox regression models identified factors predictive of worse survival outcomes. Kaplan-Meier analyses compared the eRT and the dRT groups. RESULTS: Among those with pathologically confirmed high-risk prostate cancer (PCa) after RP, 12.7% (n = 959), 13.2% (n = 1710), and 74.1% (n = 4888) underwent eRT, lRT, and observation without RT, respectively. Of these strategies, the proportion of men on observation without RT increased significantly over time (p = 0.004). The multivariable Cox regression model demonstrated similar outcomes between the eRT and the dRT groups. At a median follow-up of 5.9 years, five-year overall and cancer-specific survival outcomes were more favorable in the dRT group, when compared to the eRT group. CONCLUSIONS: A blanket adoption of the eRT in high-risk PCa based on clinical trials with limited follow-up may result in overtreatment of a significant number of men and expose them to unnecessary radiation toxicity.

Transcription factor 4 expression in circulating tumor cells from castration-resistant prostate cancer.

INTRODUCTION: Neuroendocrine differentiation is partly caused by antiandrogen therapy and exhibits an androgen receptor-independent growth mechanism. We hypothesized that the expression of transcription factor 4, an inducer of neuroendocrine differentiation, in circulating tumor cells is related to drug resistance in castration-resistant prostate cancer. CASE PRESENTATION: We evaluate the messenger ribonucleic acid expression of transcription factor 4 in circulating tumor cells from 17 patients with castration-resistant prostate cancer and compared these levels between patients receiving antiandrogen therapies and those who were resistant to antiandrogen therapies and receiving chemotherapies. The expression of transcription factor 4 in circulating tumor cells was significantly higher among patients receiving chemotherapies. CONCLUSION: This study shows that transcription factor 4 is higher in the group of patients who were judged by their physicians to need chemotherapy treatment.

Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy.

Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 µmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.

Therapeutic prognosis of prostate cancer using surface-enhanced Raman scattering of patient urine and multivariate statistical analysis.

Surface-enhanced Raman scattering (SERS) is highly sensitive and label-free analytical technique based on Raman spectroscopy aided by field-multiplying plasmonic nanostructures. We report the use of SERS measurements of patient urine in conjunction with biostatistical algorithms to assess the treatment response of prostate cancer (PCa) in 12 recurrent (Re) and 63 nonrecurrent (NRe) patient cohorts. Multiple Raman spectra are collected from each urine sample using monodisperse silver nanoparticles (AgNPs) for Raman signal enhancement. Genetic algorithms-partial least squares-linear discriminant analysis (GA-PLS-LDA) was employed to analyze the Raman spectra. Comprehensive GA-PLS-LDA analyses of these Raman spectral features (p = 3.50 × 10-16 ) yield an accuracy of 86.6%, sensitivity of 86.0%, and specificity 87.1% in differentiating the Re and NRe cohorts. Our study suggests that SERS combined with multivariate GA-PLS-LDA algorithm can potentially be used to detect and monitor the risk of PCa relapse and to aid with decision-making for optimal intermediate secondary therapy to recurred patients.

Fourteen-Core Systematic Biopsy That Includes Two Anterior Cores in Men With PI-RADS Lesion ≥ 3 is Comparable With Magnetic Resonance Imaging-ultrasound Fusion Biopsy in Detecting Clinically Significant Prostate Cancer: A Single-institution Experience.

INTRODUCTION: Magnetic resonance imaging (MRI)-ultrasound fusion targeted prostate biopsy (FB) has been advocated by many experts as a replacement for the standard template biopsy. Herein, we compared pathology results and cancer detection rates of FB with our standard 14-core systematic prostate biopsy (SB) that includes 2 anterior cores. MATERIALS AND METHODS: One hundred two men with elevated prostate-specific antigen and suspicious lesions on multiparametric MRI, Prostate Imaging Reporting And Data System (PI-RADS) v2 score ≥ 3, underwent FB. Each target lesion was biopsied 3 times; our SB was performed concurrently. Biopsy results were compared for overall and clinically significant (cs), defined as Gleason score ≥ 7, cancer detection. RESULTS: Fifty-two percent of patients had positive biopsy results, and of those, 44 had cs prostate cancer (PCa). The overall detection rates for FB and SB were 39% and 50%, respectively, and there was no statistical difference in the detection rate of csPCa detection rate (P = .42). Of 17 patients diagnosed with a high-risk PCa, defined as Gleason score ≥ 8, SB identified 15, whereas FB identified 10. Within the SB group, 21 had positive anterior core biopsies, of which 11 were cs. CONCLUSION: Expanding the standard template prostate biopsies to include 2 anterior horn sampling may be just as effective as FB in men with PI-RADS lesion ≥ 3, thereby mitigating the increased cost associated with FB.

CXC Chemokine/Receptor Axis Profile and Metastasis in Prostate Cancer.

In this study, the effects of the CXC chemokine/receptor axis on lymph node and distant metastases of prostate cancer (PC) were analyzed. Further, mRNA expression data of metastatic PC were extracted from the Stand Up To Cancer-Prostate Cancer Foundation Dream Team database and differences between metastatic sites were comprehensively analyzed. CXC chemokine/receptor mRNA expression data of primary PC included in the Cancer Genome Atlas were used to analyze the relationships of CXC chemokine/receptor expression with lymph node metastasis and cancer progression. In metastatic PC, significantly higher expression of ELR+ CXC chemokines/receptors and significantly lower expression of ELR- CXC chemokines/receptors were observed in bone metastases relative to lymph node metastases. In primary PC, significantly higher ELR- CXC chemokine/receptor expression and significantly lower ELR+ CXC chemokine/receptor expression were observed in patients with lymph node metastasis relative to those without. Multivariate logistic regression analysis identified CXCL10 expression as an independent predictor of lymph node metastasis. Furthermore, the log-rank test results revealed that co-expression of CXCL10/CXCR3 was associated with postoperative recurrence. These findings demonstrate heterogeneous expression of CXC chemokine/receptor genes in primary PC as well as differences in expression patterns according to the metastatic site.

Abrogation of survival disparity between Black and White individuals after the USPSTF's 2012 prostate-specific antigen-based prostate cancer screening recommendation.

BACKGROUND: In May 2012, the US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA)-based screening for prostate cancer (PCa), assigning it a grade D. This decision then was modified in 2018 to a grade C for men aged 55 to 69 years. The authors hypothesized that changes in screening practices would reduce survival outcomes for both Black and White men but maintain racial discrepancies in outcomes. METHODS: Using the Surveillance, Epidemiology, and End Results database, the authors examined PCa-specific survival based on race and year of diagnosis. The period between January 2010 and December 2012 was categorized as the pre-USPSTF era, whereas the period between January 2014 and December 2016 was classified as the post-USPSTF era. The year 2013 was considered the transition year and was excluded from the analysis. RESULTS: A total of 49,388 men were identified in the pre-USPSTF era who were diagnosed with PCa, approximately 83.7% of whom were White and 16.3% of whom were Black. In the post-USPSTF era, a total of 41,829 men were diagnosed with PCa, approximately 82.7% of whom were White and 17.3% of whom were Black. When compared with the pre-USPSTF era, men diagnosed in the post-USPSTF era were found to have more adverse clinical features. In the pre-USPSTF era, White men were less likely to die of PCa than Black men. This survival disparity between White and Black men was no longer observed in the post-USPSTF era. CONCLUSIONS: In men diagnosed with PCa between 2014 and 2016, a survival disparity between White and Black men was not observed due to a decrease in survival among White men while the survival of Black men remained steady.

The cytoreductive prostatectomy in metastatic prostate cancer: what the individual trials are hoping to answer.

OBJECTIVE: To review the ongoing randomised trials of cytoreductive prostatectomy (CRP) in de novo hormone-sensitive metastatic prostate cancer (HSPC) in order to identify their goals and assess their strengths and weaknesses. METHODS: PubMed, MEDLINE and clinical trials websites searches were performed to identify currently ongoing trials of CRP in de novo HSPC. RESULTS: Nine randomised clinical trials in CRP were identified and included: Southwest Oncology Group (SWOG) 1802, Surgery in Metastatic Carcinoma of Prostate (SIMCAP), Adjuvant Treatments to the Local Tumour for Metastatic Prostate Cancer: Assessment of Novel Treatment Algorithms (IP2-ATLANTA), Testing Radical prostatectomy in men with prostate cancer and oligoMetastases to the bone (TRoMbone), Impact of Radical Prostatectomy as Primary Treatment in Patients with Prostate Cancer with Limited Bone Metastases (g-RAMPP), Cytoreductive Prostatectomy vs Cytoreductive Prostate Irradiation as a Local Treatment Option for Metastatic Prostate Cancer: a Multicentric Feasibility Trial (LoMP II), Androgen-Deprivation Therapy or Androgen-Deprivation Therapy Plus Definitive Treatment (Radiation or Surgery) (FUSCC-OMPCa), and the Testing Radical Prostatectomy in Chinese Men with Prostate Cancer and oligoMetastases to the Bone study. Each study was different; assessing various primary outcome measures including overall survival (OS), progression-free survival and feasibility to randomise between standard therapy and CRP or between radiation therapy and CRP in the metastatic setting. In the oligometastatic setting, the trials assess OS, feasibility to randomise and time to castration resistance. Similarly, a number of secondary endpoints ranging from cancer-specific outcomes to quality-of-life outcomes are being investigated. The inclusion criteria in these trials also varied in terms of volume of metastatic disease (oligometastatic to high-volume metastatic disease), diagnosis of metastases (imaging based vs biopsy confirmed), imaging modalities used (conventional to newer modalities), as well as outcomes and follow-up regimes. CONCLUSION: While there are differences in each protocol, each trial aims to address different aspects of CRP in de novo HSPC. Therefore, the specific goals of each study and the limitations have to be taken into consideration when interpreting the results of these trials.

Individual and joint effects of metformin and statins on mortality among patients with high-risk prostate cancer.

BACKGROUND: Pre-clinical studies suggest that metformin and statins may delay prostate cancer (PCa) metastases; however, data in humans are limited. To the best of our knowledge, this is the first human study aimed to quantify the individual and joint effects of statin and metformin use among patients with high-risk PCa. METHODS: This population-based retrospective cohort study identified patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. The association with all-cause and PCa mortality were evaluated using Cox proportional hazard model with competing causes of death, where propensity scores were used to adjusted imbalances in covariates across groups. RESULTS: Based on 12 700 patients with high-risk PCa, statin alone or in combination with metformin was significantly associated with reduced all-cause mortality (Hazard Ratio [HR]: 0.89; 95% Confidence Interval [CI]: 0.83, 0.96; and HR: 0.75; 95% CI, 0.67-0.83, respectively) and PCa mortality (HR, 0.80; 95% CI: 0.69, 0.92) and 0.64; 95% CI, d 0.51-0.81, respectively. The effects were more pronounced in post-diagnostic users: combination use of metformin/statins was associated with a 32% reduction in all-cause mortality (95% CI, 0.57-0.80), and 54% reduction in PCa mortality (95% CI, 0.30-0.69). No significant association of metformin alone was observed with either all-cause mortality or PCa mortality. CONCLUSIONS: Statin use alone or in combination with metformin was associated with lower all-cause and PCa mortality among high-risk patients, particularly in post-diagnostic settings; further studies are warranted.

Correction to: Unintended consequences of decreased PSA-based prostate cancer screening.

In the original publication, part of funding information was missed.

Results of Phase 1 study on cytoreductive radical prostatectomy in men with newly diagnosed metastatic prostate cancer.

BACKGROUND: Preclinical and retrospective data suggest that cytoreductive radical prostatectomy may benefit a subset of men who present with metastatic prostate cancer (mPCa). Herein, we report the results of the first planned Phase 1 study on cytoreductive surgery. METHODS: From four institutions, 36 patients consented to the study. However, four did not complete surgery because of rapid disease progression (n = 3) and another because of an intraoperatively discovered pericolonic abscess. Men with newly diagnosed clinical mPCa to lymph nodes or bones were eligible. The primary endpoint was the rate of major perioperative complications (Clavien-Dindo Grade 3 or higher) occurring within 90 days of surgery. RESULTS: The mean age at surgery was 64.0 years. The 90-day overall complication rate was 31.2% (n = 10), of which two (6.25%) were considered major complications: one acute tubular necrosis requiring temporary dialysis and one death. In men with more than 6 months of follow-up, 67.9% had prostate specific antigen nadir ≤0.2 ng/mL, while one patient experienced a rapid rise in prostate specific antigen and another a widely disseminated disease that resulted in death 5 months after surgery. Altogether, these results demonstrate that cytoreductive radical prostatectomy is safe and surgically feasible in selected patients who present with mPCa . Yet, there may be a small subset of patients in whom surgery may cause a significant harm. CONCLUSION: Therefore, cytoreductive surgery in men with mPCa should be limited to clinical trials until robust data are available.

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer.

In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that Transcription Factor-4 (TCF4), a transcription factor implicated in WNT signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.