Mortality In Prostate Cancer Patients Research Articles

Impact of Smoking on Overall and Cancer-Specific Mortality in Prostate Cancer: Elevated Risks in Older and Early-Stage Patients—A Population-Based Study

Prostate cancer (PCa) ranks sixth in cancer mortality among Taiwanese men, with smoking rates remaining high despite the 2009 Tobacco Hazards Prevention Act. This study used the Taiwan Cancer Registry to evaluate smoking’s impact on PCa mortality, providing important information for healthcare strategies and patient management. From 2011 to 2017, 23,107 PCa patients were analyzed, with 7164 smokers and 15,943 non-smokers. The baseline characteristics, clinical stages, comorbidities, and treatment modalities were all included to estimate overall and cancer-specific mortality using the Cox regression model and Kaplan–Meier analysis. The stratified analysis of clinical stage and age group was also estimated. Our study found an association between smoking and increased overall and cancer-specific mortality in PCa patients. Although smokers over 60 had higher risks of overall mortality than non-smokers, cancer-specific mortality did not show significant differences in any age group. Smokers had higher overall mortality than non-smokers across all clinical stages, but cancer-specific mortality was significantly raised only in early-stage cases. In conclusion, smoking is associated with higher overall mortality in PCa patients, with a significant increase in cancer-specific mortality in early-stage cases. Therefore, active smoking management is critical for clinical urologists, particularly in the treatment of early-stage patients.

SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. Statement of significanceSLC4A4 is a novel driver of enzalutamide resistance.

Effect of metformin on incidence, recurrence, and mortality in prostate cancer patients: integrating evidence from real-world studies.

Metformin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between metformin use and the risk of occurrence of prostate cancer (PCa). The purpose of this study was to assess the effect of metformin on clinical outcomes in patients with PCa in a meta-analysis and to explore the possible dose-response relationship. A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of metformin on the risk of PCa. Relevant subgroup analyses and sensitivity analyses were performed. The across studies results show that metformin use associated with lower incidence of PCa (RR: 0.82, 95% CI: 0.74-0.91). Metformin use was also found to reduce PCa recurrence, but the results were not statistically significant (RR: 0.97, 95% CI: 0.81-1.15). Metformin use was not associated with PCa mortality (RR: 0.94, 95% CI: 0.81-1.09). The results of subgroup analyses indicated that the type of study was a cohort study and the population came from both Asia and Europe showed that taking metformin reduced the incidence of PCa. A linear correlation was found between the duration of metformin use and its protective effect. This meta-analysis revealed an independent correlation between metformin use and reduced incidence of PCa. Metformin use was not associated with either PCa recurrence rate or mortality. Furthermore, the effect of metformin on PCa incidence was found to be related to duration.

PSA Levels and Mortality in Prostate Cancer Patients

IntroductionProstate cancer (PC) is the second most common cancer among men around the world. Several smaller studies have explored the relationship between elevated PSA and mortality, but results have been conflicting. Additionally, studies have shown that Black men are more likely to be diagnosed with PC at late-stages and may have a twofold increase in mortality risk. This study aims to evaluate the relationship between PSA levels and mortality in patients with PC and differences between Black versus White patients. MethodsIn this retrospective study, the TriNetX database, was used to extract de-identified EMRs of 198,083 patients. Patients were included if they were diagnosed with PC and had obtained a PSA level (measured in ng/mL) within 6 months prior to diagnosis. Cohorts were separated into 7 groups based on intervals of PSA, ranging from < 2 to ≥ 500 and compared to a control cohort with a PSA of 4 to 20 for differing 2-year mortality rates. A subgroup analysis was performed to compare mortality differences between Black and White patients. A posthoc analysis evaluated 5- and 10-year mortality amongst all patients with PC. ResultsAfter propensity matching, mortality risk was significantly lower for patients with PSA < 2 (5.9% vs. 7.5%; RR 0.784; P < .001) when compared to the control cohort. Mortality was significantly higher for all other subsequent PSA intervals > 20, with the lowest risk ratios at PSA 20-100 (24.1% vs. 10.0%; RR 2.419; P < .001) and highest at PSA 200 to 500 (50.4% vs. 10.8%; RR 4.673; P < .001). The sub-group analysis showed that when compared to White patients, Black patients with PSA < 20 had similar mortalities, but had significantly lower 2-year mortality rates at PSA levels ≥ 20. The posthoc analysis of PSA levels and 5- and 10-year mortality of all patients with PC showed similar trends to the 2-year outcomes. ConclusionThis study found that prostate cancer patients with significantly elevated PSA levels have a greater mortality, and Black patients have lower 2-year mortality rates than their White counterparts when matched for PSA levels greater than 20.

Abstract A002: Cardiovascular diseases predominate inflammaging causes of death among patients with prostate cancer: A population-based analysis using the SEER database

Abstract Inflammaging, characterized by chronic low-grade systemic inflammation, is a hallmark of physiological aging. It has been postulated as a unifying risk factor for various age-related conditions encompassing cardiovascular, pulmonary, hepatic, renal, articular, and neurological diseases, giving rise to the concept of 'age-related diseases of inflammation.' Recent research has unveiled a significantly increased prevalence of antecedent age-related diseases of inflammation in patients with hematologic malignancies. Consequently, we posit that the risk of mortality due to cardiovascular diseases in patients with solid cancers such as prostate cancer surpasses that attributed to other causes. We conducted a population-based analysis utilizing the Surveillance, Epidemiology, and End Results (SEER 17) data spanning from 2000 to 2019. A total of 70,715 prostate cancer patients meeting our selection criteria were included in the analysis. We calculated standardized mortality ratios (SMRs) and utilized competing risk analysis. Within this cohort, 3,217 (4.5%) died of cardiovascular causes as compared to 67,498 (95.5%) due to non-cardiovascular causes. Among patients over 50 years of age, the proportion of deaths due to cardiovascular diseases (CVD) was significantly larger than that of other causes (99.41% versus 97.58%, p &amp;lt;0.0001). Most of the prostate cancer patients who died due to CVD were above 50 years of age (99.41%), white (76.75%), diagnosed with adenocarcinoma (99.96%), of intermediate (44.26%) and high-grade disease (30.56%), diagnosed with localized disease (91.97%), had radiotherapy (98.57%), no surgery (93.94%), no chemotherapy (98.38%), and no metastasis at diagnosis (96.05%). Prostate cancer cases above 50 years of age were 33% less likely to die from CVD after a diagnosis of prostate cancer in comparison to a reference US population of the same age and racial distribution (SMR= 0.67, 95% CI= 0.65-0.69, absolute excess ratio (AER)= -35.96 per 10,000 PYR), most probably reflecting a decline in the incidence of CVD-related deaths with time. However, the cumulative incidence of CVD deaths was higher in cases above 50 years of age as compared to cases at or below 50. Finally, taking prostate cancer-specific deaths, other cause deaths, and other cancer-specific deaths as competing risk factors to CVD deaths, and after adjustment for potential confounders, we found that cases of prostate cancer above 50 years of age were nearly 3.5 times more likely to die from CVD as compared to cases at or below the age of 50 (Subdistribution hazard ratio (SDHR)= 3.65, 95%CI= 2.32-5.73). In conclusion, despite a declining trend, CVDs are predominant contributors to mortality in prostate cancer patients. Consequently, there is a compelling need to investigate similar mortality patterns across other cancer types and to explore potential associations with genetic and treatment-related factors. Citation Format: Amr Ebied, Abdelrahman Ali, Chighaf Bakour. Cardiovascular diseases predominate inflammaging causes of death among patients with prostate cancer: A population-based analysis using the SEER database [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A002.

Higher insoluble fiber intake is associated with a lower risk of prostate cancer: results from the PLCO cohort

Studies regarding the relationship between fiber intake and prostate cancer (PCa) have conflicting results. Therefore, this study examined the relationship between fiber intake and the risk of PCa by using data from Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. A total of 54,336 participants in the United States, consisting of 6,414 patients with PCa, were included in this study. Multivariate Cox regression models were applied to estimate adjusted hazard ratios (aHRs) and corresponding 95% confidence intervals (CIs). Compared with individuals in the lowest quartile, individuals in the highest quartile of insoluble fiber intake had a significantly lower risk of PCa (aHR, 0.87; 95% CI, 0.78–0.98). By contrast, no significant associations were detected between total fiber intake (aHR, 0.90; 95% CI, 0.80–1.01) or soluble fiber intake (aHR, 0.90; 95% CI, 0.80–1.02). Subgroup analyses showed that insoluble fiber was related to a decreased risk of PCa in subjects with the following characteristics: age > 65 years, nonsmoking or former smokers, education level ≤ high school, non-Hispanic white ethnicity, or without a family history of PCa. In addition, significant combined effects of insoluble fiber intake, age and family history of PCa on the risk of PCa were observed, but no combined effects of smoking status and insoluble fiber intake were observed. In addition, total fiber, insoluble fiber, and soluble fiber intake had no influence on the mortality of PCa patients. These results show that all 3 measures of fiber suggest a protective association, but insoluble fiber may have a stronger association with the risk of PCa. Future studies are warranted to further investigate these relationships.

Prevalence of Preexisting Cardiovascular Diseases in Prostate Cancer Patients and Cardiac Risks of Hormonal Therapy.

Cardiovascular diseases (CVDs) are a prominent cause of mortality in prostate cancer patients. However, it has been reported that patients with preexisting CVDs are at greater risk. Literature on the magnitude of this problem in Saudi Arabia is lacking. To measure the prevalence of prostate cancer patients with preexisting CVDs in our population and to elucidate the possible risk factors of new cardiovascular events (CVEs) in patients who received androgen deprivation therapy (ADT). This retrospective study included all patients newly diagnosed with prostate cancer at a tertiary hospital in the Eastern Province of Saudi Arabia from October 2008 to January 2019. The prevalence of preexisting cardiovascular diseases in these patients were determined. In addition, the incidence of new CVEs after initiating ADT was determined along with the risk factors for the same. The prevalence of preexisting CVD in our cohort was 16%. About 6% of the patients who received ADT had CVEs after a median follow-up of 39 months (IQR: 11-49 months). In the univariate analysis, hyperlipidemia (P = 0.002), stroke (P = 0.001), peripheral vascular disease (P = <0.001), cardiac patients with stents (P = <0.001), and cardiac patients without stent (P = <0.001) were significant risk factors of new CVEs after initiating ADT. However, in the multivariate regression analysis, only history of stroke and CVD (with or without stent) were found to be significant risk factors of new CVEs after initiating ADT (P = 0.01). About one-fifth of the prostate cancer patients had preexisting CVDs. This study also found that luteinizing hormone-releasing hormone agonist could be a risk factor for new CVEs.

Abstract 14846: Rurality and Associated Cardiovascular Events and Mortality in Older Men With Prostate Cancer: Longitudinal SEER Medicare Analysis

Introduction: The effect of rurality as a social determinant of health in cardiovascular events (CVE) in patients with prostate cancer (PC) is unknown. Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified males ≥ 66 years old with a new primary diagnosis of PC between 2009 and 2017. We also identified those who were undergoing leuprolide androgen deprivation therapy (ADT). These patients were followed to identify a primary outcome of CVE that included heart failure (HF), atrial fibrillation (AF), acute myocardial infarction (AMI), peripheral artery disease (PAD), coronary artery disease (CAD), ischemic stroke (IS) and cardiovascular death. Adjusted Cox proportional hazards modeling was performed to estimate all-cause mortality in PC patients stratified by rurality as defined by Medicare. Adjusted Fine-Gray modeling with appropriate competing risk (mortality or type of mortality) was utilized for other outcomes as presented. We adjusted for demographic factors, social determinants of health, cancer-specific factors, and other cardiovascular risk factors apart from the primary exposure of rurality. Results: This study included 102,225 PC patients. Among these, 4,945 (4.8%) belonged to areas with a population of less than 2,500 or less than 20,000 not next to a metro (rural). The use of ADT was noted in 9,071 (8.9%) of patients. The incidence of new CVE and mortality risk due to rurality is presented in Table 1. Rural area was noted to be a risk factor for all-cause mortality [adjusted hazards ratio (aHR) = 1.114 (95% CI= 1.070-1.161)]. No statistically significant association between CVE and rurality, however, was observed in the data. Conclusions: PC patients have a high burden of pre-existing cardiovascular disease prior to PC diagnosis, and rurality increases all-cause mortality. This is consistent with those who are treated with ADT as well.

Abstract 14915: Role of Diabetes and Diabetic Medication in Cardiovascular Events and Survival Among Older Men With Prostate Cancer on Androgen Deprivation Therapy: Longitudinal SEER Medicare Analysis

Introduction: The effect of diabetes mellitus (DM) and DM therapy on cardiovascular events (CVE) in patients with prostate cancer (PC) undergoing androgen deprivation therapy (ADT) is unclear in the contemporary era. Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified males ≥ 66-year-old with a new primary diagnosis of PC undergoing leuprolide therapy (ADT) between 2009-2017. These patients were followed for two years to identify a primary outcome of CVE that included heart failure (HF), atrial fibrillation (AF), acute myocardial infarction (AMI), peripheral artery disease (PAD), coronary artery disease (CAD), ischemic stroke (IS) and cardiovascular death. DM medications identified using part D data for this analysis were metformin, insulin, and other orals based on FDA approval dates until 2017. Adjusted Cox proportional hazards modeling was performed to estimate all-cause mortality in PC patients stratified by DM and among those with DM and on different therapies. Adjusted Fine-Gray modeling with appropriate competing risk (mortality or type of mortality) was utilized for other outcomes as presented. We adjusted for demographic factors, social determinants of health, cancer-specific factors, and other cardiovascular risk factors apart from the primary exposure of DM. Results: This study included 9,072 PC patients. Among these 2,822 (31.1%) had DM, and 5,105 (56.3%) had cardiovascular disease prior to PC diagnosis. New CVE was diagnosed in 619 (6.8%; HF = 144, AF = 107, AMI = 40, PAD = 132, CAD = 226, IS = 66) patients in a 2-year period after the PC diagnosis. DM was noted to be a risk factor for CVE [adjusted subdistribution hazards ratio (aSHR) = 1.22 (95% CI= 1.07-1.44)]. The effect of DM and DM medication on mortality is presented in Table 1. Conclusion: PC patients on ADT with DM have a higher risk of CVE and all-cause mortality. Metformin use is associated with reduced all-cause mortality.

Effect of aspirin on incidence, recurrence, and mortality in prostate cancer patients: integrating evidence from randomized controlled trials and real-world studies.

Aspirin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between aspirin use and the risk of occurrence of prostate cancer (PCa). The purpose of this study was to assess the effect of aspirin on clinical outcomes in patients with PCa in a meta-analysis and to explore the possible dose-response relationship. A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of aspirin on the risk of PCa. Relevant subgroup analyses and sensitivity analyses were performed. The across studies results show that aspirin use associated with lower incidence of PCa (RR: 0.96, 95% CI: 0.95-0.98), and reduced mortality (RR: 0.88, 95% CI: 0.82-0.95). The results of the subgroup analysis indicated that both cohort and population studies in the Americas showed a reduction in PCa incidence and mortality with aspirin use. A linear correlation was observed between dosage/duration of aspirin use and its protective effect. Additionally, post-diagnosis aspirin use was associated with decreased risk of PCa mortality. This meta-analysis revealed an independent correlation between the use of aspirin and reductions in both the incidence and mortality rates of PCa. However, randomized controlled trials did not find any association between aspirin use and PCa. Furthermore, the impact of aspirin on PCa occurrence was found to be dependent on both dosage and duration.

Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis.

Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.

Risks of prostate cancer and mortality in the city of Sharjah, United Arab Emirates.

Prostatic hyperplasia (BPH) and prostate cancer (PCa) are common age-related diseases in men. According to World Health Organization (WHO), PCa is the second most common cancer among Emirati men. This study aimed to identify the risk factors associated with PCa and mortality in a cohort diagnosed with PCa between 2012 and 2021 in Sharjah, United Arab Emirates (UAE). The data collected in this retrospective case-control study included patient demographics and comorbidities, as well as PCa markers such as prostate-specific antigen (PSA), prostate volume, prostate-specific antigen density (PSAD), and Gleason scores. Risk factors for PCa were assessed using multivariate logistic regression analysis, and factors associated with all-cause mortality in PCa patients were evaluated using Cox-proportional hazard analysis. Of the 192 cases analyzed in this study, 88 were diagnosed with PCa and 104 were diagnosed with BPH. Regarding risk factors for PCa, a higher risk of PCa was associated with age 65 or older (OR=2.76, 95% confidence interval (CI): 1.04-7.30; P=0.038) and serum PSAD greater than 0.1 ng/mL2 (OR=3.48, 95% CI:1.66-7.32; P=0.001), whereas being of UAE nationals (OR=0.40, 95% CI:0.18-0.88; P=0.029) were associated with lower risk of PCa, after adjusting for patient demographics and comorbidities. Moreover, regarding cancer markers, higher serum PSA level (P=0.003) and smaller prostate volume (P=0.028) were associated with a higher risk of PCa, after adjusting with patients' age and BMI. Additionally, a high-grade Gleason score was associated with an increased risk of all-cause mortality after adjusting for patient's age and BMI (hazard ratio, aHR= 2.3, 95% CI:1.3-4.1; P= 0.016). This study found that age 65 or older and serum PSAD greater than 0.1 ng/mL2 are risk factors for PCa, while UAE nationality is associated with a lower risk. PSAD may be a better screening marker for PCa compared to traditional markers such as PSA and prostate volume.

The association of type and number of high‐risk criteria with cancer specific mortality in prostate cancer patients treated with radiotherapy

To assess the association between of type and number of D'Amico high-risk criteria (DHRCs) with rates of cancer-specific mortality (CSM) in prostate cancer (PCa) patients treated with external beam radiotherapy (RT). In the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 34,908 RT patients with at least one DHRCs, namely prostate-specific antigen (PSA) >20 ng/dL (hrPSA), biopsy Grade Group (hrGG) 4-5, clinical T stage (hrcT) ≥T2c. Multivariable Cox regression models (CRM), as well as competing risks regression (CRR) model, which further adjust for other cause mortality, tested the association between DHRCs and 5-year CSM. Of 34,908 patients, 14,777 (42%) exclusively harbored hrGG, 5641 (16%) hrPSA, 4390 (13%) had hrcT. Only 8238 (23.7%) harbored any combination of two DHRCs and 1862 (5.3%) had all three DHRCs. Five-year CSM rates ranged from 2.4% to 5.0% when any individual DHRC was present (hrcT, hrPSA, hrGG, in that order), versus 5.2% to 10.5% when two DHRCs were present (hrPSA+hrcT, hrcT+hrGG, hrPSA+hrGG, in that order) versus 14.4% when all three DHRCs were identified. In multivariable CRM hazard ratios relative to hrcT ranged from 1.07 to 1.76 for one DHRC, 2.20 to 3.83 for combinations of two DHRCs, and 5.11 for all three DHRCs. Multivariable CRR yielded to virtually the same results. Our study indicates a stimulus-response effect according to the type and number of DHRCs. This indicates potential for risk-stratification within HR PCa patients that could be applied in clinical decision making to increase or reduce treatment intensity.

The association of type and number of high-risk criteria with cancer-specific mortality in prostate cancer patients treated with radical prostatectomy.

This study aimed to test the association between of type and number of D'Amico high-risk criteria (DHRCs) with cancer-specific mortality (CSM) in high-risk prostate cancer patients treated with radical prostatectomy. In the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 31,281 radical prostatectomy patients with at least 1 DHRC, namely, prostate-specific antigen (PSA) >20 ng/mL (hrPSA), biopsy Gleason Grade Group (hrGGG) score of 4 and 5, or clinical tumor stage ≥T3 (hrcT). Multivariable Cox regression models and competing risks regression models (adjusting for other cause mortality) tested the association between DHRCs and 5-year CSM. Of 31,281 patients, 14,394 (67%) exclusively harbored hrGGG, 3189 (15%) harbored hrPSA, and 1781 (8.2%) harbored hrcT. Only 2132 patients (6.8%) harbored a combination of the 2 DHRCs, and 138 (0.6%) had all 3 DHRCs. Five-year CSM rates ranged from 0.9% to 3.0% when any individual DHRC was present (hrcT, hrPSA, and hrGGG, in that order), 1.6% to 5.9% when 2 DHRCs were present (hrPSA-hrcT, hrcT-hrGGG, and hrPSA-hrGGG, in that order), and 8.1% when all 3 DHRCs were present. Cox regression models and competing risks regression confirmed the independent predictor status of DHRCs for 5-year CSM that was observed in univariable analyses, with hazard ratios from 1.00 to 2.83 for 1 DHRC, 2.35 to 5.88 for combinations of 2 DHRCs, and 7.13 for all 3 DHRCs. Within individual DHRCs, hrcT and hrPSA exhibited weaker effects than hrGGG did. Moreover, a dose-response effect was identified according to the number of DHRCs. Accordingly, the type and number of DHRCs allow further risk stratification within the high-risk subgroup.

Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer.

Castration-resistant prostate cancer (CRPC) is the main driving force of mortality in prostate cancer patients. Among the parameters contributing to the progression of CRPC and treatment failure, elevation of the steroidogenic enzyme AKR1C3 and androgen receptor variant 7 (AR-V7) are frequently reported. The AKR1C3/AR-V7 complex has been recognized as a major driver for drug resistance in advanced prostate cancer. Herein we report that the level of AKR1C3 is reciprocally regulated by the full-length androgen receptor (AR-FL) through binding to the distal enhancer region of the AKR1C3 gene. A novel function of PTUPB in AKR1C3 inhibition was discovered and PTUPB showed more effectiveness than indomethacin and celecoxib in suppressing AKR1C3 activity and CRPC cell growth. PTUPB synergizes with enzalutamide treatment in tumor suppression and gene signature regulation. Combination treatments with PTUPB and enzalutamide provide benefits by blocking AR/AR-V7 signaling, which inhibits the growth of castration relapsed VCaP xenograft tumors and patient-derived xenograft organoids. Targeting of the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer.

Influencing factors for mortality in prostate cancer patients with T1 and T2 stage: a retrospective cohort study.

Few reports have focused on the influencing factors of localized prostate cancer (PCa)-specific mortality so far. This study aimed to develop a competitive risk model for identifying the factors influencing the localized PCa mortality rate based on 135,310 subjects in the Surveillance, Epidemiology, and End Results (SEER) database. We included 135,310 localized PCa male patients from SEER database 2004-2016 in this cohort study, and collected the baseline information of all patients, including age of diagnosis, race, marital status, socioeconomic status (SES), American Joint Committee on Cancer (AJCC) stage, prostate-specific antigen (PSA) Gleason score, and so on. The outcome was considered as PCa-specific mortality in this study. The end time of follow-up was November 2018. Independent risk factors were examined by multivariate Fine-Gray analysis. The results are shown by hazard ratio (HR) and 95% confidence interval (CI). All patients were divided into three groups: died from localized PCa (n=1,400), died from other causes (n=16,996), and survived (n=116,914). The diagnostic age of 119,899 patients was ≥55 years. The multivariate Fine-Gray analysis indicated that age of diagnosis (55-70 years: HR =1.473, 95% CI: 1.124-1.930; >70 years: HR =2.528, 95% CI: 1.901-3.362), race (American India/Alaska Native, Asian/Pacific Islander: HR =0.653, 95% CI: 0.490-0.870), marital status (divorced: HR =1.433, 95% CI: 1.197-1.717; single: HR =1.463, 95% CI: 1.244-1.719; widowed: HR =1.485, 95% CI: 1.222-1.804), therapeutic method (radiotherapy: HR =1.500; 95% CI: 1.119-2.011), SES (4-10: HR =0.799, 95% CI: 0.664-0.961; ≥11: HR =0.670; 95% CI: 0.534-0.839), AJCC stage (HR =0.820, 95% CI: 0.715-0.940), level of PSA (HR: 1.002, 95% CI: 1.002-1.002) and Gleason score (HR: 2.226, 95% CI: 2.108-2.350) were associated with the risk of localized PCa mortality. The study determined the influencing factors for mortality in patients with localized PCa through a competitive risk model. This finding may provide a reference for localized PCa patients: localized PCa patients who are older, divorced, widowed, single, have a radiotherapy, have a high PSA level, and Gleason score may be at high risk.

Racial/ethnic disparities in the distribution and effect of type and number of high-risk criteria on mortality in prostate cancer patients treated with radiotherapy

ABSTRACT Objective To assess differences in the distribution of type and number of D’Amico high-risk criteria (DHRCs) according to race/ethnicity (R/E) and their effect on cancer-specific mortality (CSM) in prostate cancer (PCa) patients treated with external beam radiotherapy (RT). Methods In the SEER database (2004–2016), we identified 31,002 PCa patients treated with RT with at least one DHRCs, namely PSA >20 ng/dL, biopsy Gleason Grade Group 4–5, and clinical T stage ≥T2c. Competing risks regression (CRR) model tested the association between DHRCs and 5-year CSM in all R/E subgroups. Results Of 31,002 patients, 20,894 (67%) were Caucasian, 5256 (17%) were African American, 2868 (9.3%) were Hispanic-Latino, and 1984 (6.4%) were Asian. The distributions of individual DHRCs and combinations of two DHRCs differed according to R/E, but not for the combination of three DHRCs. The effect related to the presence of a single DHRC, and combinations of two or three DHRCs on absolute CSM rates was lowest in Asians (1.2–6.8%), followed by in African Americans (2.3–12.2%) and Caucasians (2.3–12.1%), and highest in Hispanic/Latinos (1.7–13.8%). However, the opposite effect was observed in CRR, where hazard ratios were highest in Asians vs. other R/Es: Asians 1.00–2.59 vs. others 0.5–1.83 for one DHRC, Asians 3.4–4.75 vs. others 0.66–3.66 for two DHRCs, and Asians 7.22 vs. others 3.03–4.99 for all three DHRCs. Conclusions: R/E affects the proportions of DHRCs. Moreover, within the four examined R/E groups, the effect of DHRCs on absolute and relative CSM metrics also differed. Therefore, R/E-specific considerations may be warranted in high-risk PCa patients treated with RT.

SC97 - The association of type and number of high-risk criteria with cancer specific mortality in prostate cancer patients treated with radiotherapy

SC97 - The association of type and number of high-risk criteria with cancer specific mortality in prostate cancer patients treated with radiotherapy

Travel vaccines are strongly associated to reduced mortality in prostate cancer patients - a real effect or residual confounding?

Repurposing of existing drugs and vaccines for diseases that they were not originally intended for is a promising research field. Recently there has been evidence that oral cholera vaccine might be used in the treatment of inflammatory disease and some common cancers. Specifically, Ji et al showed that the administration of cholera vaccine after a prostate cancer diagnosis reduced prostate cancer specific mortality rates by almost 50%. In a cohort of men from Stockholm, Sweden, with more detailed cancer data and a higher coverage of exposure to vaccine, we replicated these findings using a marginal structural Cox model. We showed that administration of cholera vaccine after prostate cancer diagnosis is associated with a significant reduction in mortality (HR 0.46, 95% CI 0.31–0.69, p-value 0.0001) even after adjusting for all known confounders. However, the same effect (or even stronger) could be seen for several other traveling vaccines and malaria prophylaxis. Therefore, we conclude that this effect is most likely due to a healthy traveler bias and is an example of residual confounding.

CT-defined low-skeletal muscle mass as a prognostic marker for survival in prostate cancer: A systematic review and meta-analysis.

Low-skeletal muscle mass (LSMM) is defined as progressive skeletal muscle loss, which can be assessed by imaging modalities. It was shown that this parameter is predictive and prognostic of several clinically relevant factors in several tumor entities. Our aim was to establish the effect of LSMM on overall survival (OS) in prostate cancer patients based on a large patient sample. MEDLINE library, EMBASE and SCOPUS databases were screened for the associations between LSMM and mortality in prostate cancer patients up to April 2021. The primary endpoint of the systematic review was the hazard ratio of LSMM on OS. In total, five studies were suitable for the analysis and included into the present study. The included studies comprised over all 1221 patients. The identified frequency of LSMM was 61.02%. The pooled hazard ratio for the effect of LSMM on OS was 1.4 [95% CI 0.7-2.5] in univariate analysis and was 1.6 [95% CI 1.2-2.1] in multivariate analysis. CT-defined LSMM has a frequency of 61% in patients with PC and shows a positive association with the overall survival with a hazard ratio of 1.4. LSMM assessment should therefore be included into clinical routine as a relevant prognostic biomarker.