Prostate Cancer-specific Mortality Research Articles

Race has no impact on prostate cancer-specific mortality, when comparing patients with similar risk of other-cause mortality: An analysis of a population-based cohort.

Other-cause mortality (OCM) can serve as a surrogate for access-to-care. The authors sought to compare prostate cancer-specific mortality (PCSM) in Black versus White men matched based on their calculated OCM risk. The Surveillance, Epidemiology, and End Results (SEER) database was queried for Black and White men diagnosed with prostate cancer between 2004 to 2009, to collect long-term follow-up. A Cox regression was used to calculate the OCM risk using all available covariates. This calculated OCM risk was used to construct a 1:1 propensity score matched (PSM) cohort. Then, a competing-risks multivariable tested the impact of race on PCSM. A total of 94,363 patients were identified, with 19,398 Black men and 74,965 White men. The median (IQR) follow-up was 11.3 years (9.8-12.8). In the unmatched-cohort at 10-years, PCSM and OCM were 5.5% versus 3.5% and 13.8% versus 8.4% in non-Hispanic Black (NHB) versus non-Hispanic White (NHW) patients (all p<.0001). The standardized mean difference was <0.15 for all covariates, indicating a good match. In the matched cohort at 10-years, OCM was 13.6% and 10.0% in NHB versus NHW (p<.0001), whereas the PCSM was 5.3% versus 4.7% (p<.01). On competing-risks multivariable analysis on PCSM, Black men had a hazard ratio of 1.08 (95% confidence interval, 0.98-1.20) compared to White men with a p=.13. The results of this study showed similar PCSM in Black and White patients, when matched with their calculated OCM risk. This report is the first to indicate at a population-based level that race has no impact on PCSM. Prostate cancer is a very common cancer among men and it is associated with health disparities that disproportionately impact Black men compared to White men. There is an on-going discussion of whether disparities between these two groups stem from genetic or environmental factors. This study sought to examine if matching based on overall health status, a proxy for the impact of social determinants of health, mitigated significant differences in outcomes. When matched using risk of death from any cause other than prostate cancer, Black and White men had no significant differences in prostate cancer death.

Impact of comorbidities on prostate cancer-specific mortality: A population-based cohort study.

To assess the impact of comorbidities on prostate cancer mortality. We studied 15,695 South Australian men diagnosed with prostate cancer between 2003 and 2019 from state-wide administrative linked data sets. Comorbidity was measured 1-year before prostate cancer diagnosis using Rx-Risk, a medication-based comorbidity index. Flexible parametric competing risk regression was used to estimate the independent association between comorbidities and prostate cancer-specific mortality. Specific common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and pain) were also assessed to determine their association with mortality. All models were adjusted for sociodemographic variables, tumor characteristics, and treatment type. Prostate cancer-specific mortality was higher for patients with a Rx-Risk score ≥3 versus 0 (adjusted sub-hazard ratio (sHR) 1.34, 95% CI: 1.15-1.56). Lower comorbidity scores (Rx-Risk score 2 vs. 0 and Rx-Risk score 1 vs. 0) were not significantly associated with prostate cancer-specific mortality. Men who were using medications for cardiac disorders (sHR 1.31, 95% CI: 1.13-1.52), chronic airway disease (sHR 1.20, 95% CI: 1.01-1.44), depression and anxiety (sHR 1.17, 95% CI: 1.02-1.35), and thrombosis (sHR 1.21, 95% CI: 1.04-1.42) were at increased risk of dying from prostate cancer compared with men not on those medications. Use of medications for diabetes and chronic pain were not associated with prostate cancer-specific mortality. All Rx-Risk score categories and the specific comorbidities were also associated with increased risk of all-cause mortality. The findings showed that ≥3 comorbid conditions and specific comorbidities including cardiac disease, chronic airway disease, depression and anxiety, and thrombosis were associated with poor prostate cancer-specific survival. Appropriate management of these comorbidities may help to improve survival in prostate cancer patients.

Molecular diagnostics of prostate cancer: impact of molecular tests.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men. Prostate-specific antigen (PSA) testing is used in screening programs for early detection with a consequent reduction of PCa-specific mortality at the cost of overdiagnosis and overtreatment of the nonaggressive PCa. Recently, several assays have been commercially developed to implement PCa diagnosis, but they have not been included in both screening and diagnosis of PCa. This review aims to describe the actual and novel commercially available molecular biomarkers that can be used in PCa management to implement and tailor the screening and diagnosis of PCa.

Plant-Based Diets and Disease Progression in Men With Prostate Cancer.

Plant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about postdiagnostic plant-based diet patterns in individuals with prostate cancer. To examine whether postdiagnostic plant-based dietary patterns are associated with risk of prostate cancer progression and prostate cancer-specific mortality. This longitudinal observational cohort study included men with biopsy-proven nonmetastatic prostate cancer (stage ≤T3a) from the diet and lifestyle substudy within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) enrolled at 43 urology practices across the US from 1999 to 2018. Participants completed a comprehensive diet and lifestyle questionnaire (including a validated food frequency questionnaire [FFQ]) between 2004 and 2016. Data were analyzed from August 2022 to April 2023. Overall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) scores were calculated from the FFQ. The primary outcome was prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer-specific mortality). The secondary outcome was prostate cancer-specific mortality. Among 2062 participants (median [IQR] age, 65.0 [59.0-70.0] years), 61 (3%) identified as African American, 3 (<1%) identified as American Indian or Alaska Native, 9 (<1%) identified as Asian or Pacific Islander, 15 (1%) identified as Latino, and 1959 (95%) identified as White. Median (IQR) time from prostate cancer diagnosis to FFQ was 31.3 (15.9-62.0) months after diagnosis. During a median (IQR) follow-up of 6.5 (1.3-12.8) years after the FFQ, 190 progression events and 61 prostate cancer-specific mortality events were observed. Men scoring in the highest vs lowest quintile of PDI had a 47% lower risk of progression (HR, 0.53; 95% CI, 0.37-0.74; P for trend = .003). The hPDI was not associated with risk of progression overall. However, among 680 individuals with Gleason grade 7 or higher at diagnosis, the highest hPDI quintile was associated with a 55% lower risk of progression compared with the lowest hPDI quintile (HR 0.45; 95% CI, 0.25-0.81; P for trend = .01); no association was observed in individuals with Gleason grade less than 7. In this cohort study of 2062 men with prostate cancer, higher intake of plant foods after prostate cancer diagnosis was associated with lower risk of cancer progression. These findings suggest nutritional assessment and counseling may be recommended to patients with prostate cancer to help establish healthy dietary practices and support well-being and overall health.

Disparities in treatment patterns and mortality in prostate cancer: Interaction between Black race and end-stage kidney disease.

Black men and men with end-stage kidney disease have lower rates of treatment and higher mortality for prostate cancer. We studied the interaction of end-stage kidney disease (ESKD) with Black race for treatment rates and mortality for men with prostate cancer. We included 516 Black and 551 White men with ESKD before prostate cancer 22,299 Black men, and 141,821 White men without ESKD who were 40 years or older from the Surveillance, Epidemiology, and End-Results-Medicare data (2004-2016). All Black men with or without ESKD and White men with ESKD had higher prostate-specific antigen levels at diagnosis than White men without ESKD. Black men with ESKD had the lowest rates for treatment in both local and advanced stages of prostate cancer (age-adjusted risk ratio: 0.76, 95% Confidence Interval (CI): 0.71-0.82 for local stage and age-adjusted risk ratio: 0.82, 95% CI: 0.76-0.9 for advanced stages) compared to White men without ESKD. Compared to White men without ESKD, prostate cancer-specific mortality was higher in White men with ESKD for both local and advanced stages (age-adjusted hazard ratio: 1.8, 95% CI: 1.2-2.8 and HR: 1.6, 95% CI: 1.2-2.2) and it was higher for ESKD Black men only in advanced stage prostate cancer (age-adjusted hazard ratio: 2.4, 95% CI: 1.5-3.6). Our findings suggest that having a comorbidity such as ESKD makes Black men more vulnerable to racial disparities in prostate cancer treatment and mortality.

Elective Pelvic Lymph Node Radiation Therapy and the Risk of Death in Patients With Unfavorable-Risk Prostate Cancer: A Postrandomization Analysis.

Although a contemporary randomized clinical trial has led to the use of whole-pelvic radiation therapy (WPRT), long-term data evaluating a potential reduction in mortality are lacking and are addressed in the current study. From 2005 to 2015, 350 men with localized, unfavorable-risk prostate cancer (PC) were randomly assigned to receive androgen deprivation therapy (ADT) and RT plus docetaxel versus ADT and RT. Treatment of the pelvic lymph nodes was at the discretion of the treating physician. Multivariable Cox and Fine and Grays regression analyses were performed to assess whether a significant association existed between radiation treatment volume and all-cause mortality (ACM) and PC-specific mortality (PCSM), respectively, adjusting for known PC prognostic factors and comorbidity. An interaction term between age (categorized by dichotomization at 65 years to enable clinical interpretation and applicability of the results and which approximates the median (66 years [IQR, 61-70]) and radiation treatment volume was included in the analysis. After a median follow-up of 10.20 years (IQR, 7.96-11.41), 89 men died (25.43%); of these, 42 died of PC (47.19%). Of the 350 randomly assigned patients, 88 (25.14%) received WPRT. In men younger than 65 years, WPRT was associated with a significantly lower ACM risk (adjusted hazard ratio [AHR], 0.33 [95% CI, 0.11 to 0.97]; P = .04) and lower PCSM risk (AHR, 0.17 [95% CI, 0.02 to 1.35]; P = .09) after adjusting for covariates, whereas this was not the case for men 65 years or older. WPRT has the potential to reduce mortality in younger men with unfavorable-risk PC.

Prognosis of Gleason score 8 prostatic adenocarcinoma in needle biopsies: a nationwide population-based study.

A 5-tier grouping of Gleason scores has recently been proposed. Studies have indicated prognostic heterogeneity within these groups. We assessed prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) for men diagnosed with Gleason score 3 + 5 = 8, 4 + 4 = 8 and 5 + 3 = 8 acinar adenocarcinoma on needle biopsy in a population-based national cohort. The Prostate Cancer data Base Sweden 5.0 was used for survival analysis with PCSM and ACM at 5 and 10years as endpoints. Multivariable Cox regression models controlling for socioeconomic factors, stage and primary treatment type were used for PCSM and ACM. Among 199,620 men reported with prostate cancer in 2000-2020, 172,112 were diagnosed on needle biopsy. In 18,281 (11%), there was a Gleason score of 8 in needle biopsies, including a Gleason score of 3 + 5, 4 + 4 and 5 + 3 in 11%, 86% and 2.3%, respectively. The primary treatment was androgen deprivation therapy (55%), deferred treatment (8%), radical prostatectomy (16%) or radical radiotherapy (21%). PCSM in men with Gleason scores of 3 + 5, 4 + 4 and 5 + 3 at 5years of follow-up was 0.10 (95% CI 0.09-0.12), 0.22 (0.22-0.23) and 0.32 (0.27-0.36), respectively, and at 10years 0.19 (0.17-0.22), 0.34 (0.33-0.35) and 0.44 (0.39-0.49), respectively. There was a significantly higher PCSM after 5 and 10years in men with Gleason score 5 + 3 cancers than in those with 4 + 4 and in Gleason score 4 + 4 cancers than in those with 3 + 5. Grouping of Gleason scores will eliminate the prognostic granularity of Gleason scoring, thus diminishing the prognostic significance of this proposed grading system.

Assessing the Efficacy and Long-Term Outcomes of Surgical Intervention Versus Radiotherapy: A Comprehensive Systematic Review and Meta-Analysis of Prostate Cancer Treatment Modalities.

There is controversy regarding the most effective primary treatment of choice for prostate cancer (PCa) in terms of patient outcomes, such as surgery or radiotherapy (RT). This study evaluated the comparative efficacy and long-term outcomes of radical prostatectomy (RP) and RT for PCa treatment. A thorough literature review of relevant databases was conducted, focusing on academic and clinical studies published from 2019 onwards. The inclusion criteria included randomized controlled trials (RCTs) and other observational studies comparing survival outcomes in patients treated with surgery and RT. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines to provide an overview of the data. We selected 19 studies based on the inclusion criteria. Of the total 19 studies, 12 advocated RP as the preferred treatment to improve survival outcomes in patients with PCa. The results of our synthesis showed that prostate cancer-specific mortality (PCSM) was lower in patients treated with RT. The total effect size for the analysis was calculated as Z=1.19 (p-value=0.23). The heterogeneity in the studies was as follows: Tau2=0.09, Chi2=20.25, df=4, I2=80%. Moreover, overall survival (OS) was shown to be higher in patients who underwent prostatectomy. The combined effect for the analysis was found to be: HR=0.97 (0.93, 1.01). The total effect was calculated as Z=1.33 (p-value= 0.18). The heterogeneity was found to be Tau2=0.00, Chi2=1.33, df=2, and I2=0%. However, overall mortality (OM) was shown to be independent of the treatment modality. RT is the preferred strategy for PCa treatment, as it balances efficacy and long-term outcomes. Clinical decision-making should consider individual patient characteristicsand future research should delve into specific subpopulations and long-term outcomes to further refine the treatment guidelines.

Excess weight, weight gain, and prostate cancer risk and prognosis: the PROCA-life study.

Studies of excess weight and weight changes throughout adult life for prostate cancer (PCa) risk and prognosis have shown inconsistent results. In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), 16,960 healthy men from the prospective cohort Tromsø Study (1994-2016) were included. Body mass index (BMI) and weight were measured at all four attendings, and weight change was calculated as the difference between the first and last of either Tromsø4, Tromsø5 or Tromsø6. Overall, 904 men developed PCa during 16 years of follow-up, and Poisson regression with fractional polynomials was used to investigate trends in incidence. Cox proportional hazard and logistic regression models were used to study associations between measurements of BMI and weight change and PCa risk, severity, and mortality. At study entry, 46% of the participants (median age 44 years) were overweight, and 14% were obese (BMI > 30 kg/m2). We observed a 127% increase in overall age adjusted PCa incidence in the cohort during 1995 through 2019. No overall associations between BMI or weight change and PCa risk were observed. However, in sub-group analysis, weight gain among obese men was associated with a three-fold higher PCa risk (HR 3.03, 95% CI 1.39-6.58) compared with obese men with stable weight. Overweight was associated with lower risk of metastatic cancer (OR 0.48, 95% CI 0.30-0.75) at diagnosis. Men with obesity had higher risk of PCa-specific death (HR 1.72, 95% CI 1.03-2.88), while nonsmoking obese PCa cases had two times higher PCa-specific mortality compared with normal weighted PCa cases (HR 2.10, 95% CI 1.11-3.70). In our cohort, weight gain among obese men was associated with higher risk of PCa, and obesity was associated with higher PCa-specific mortality, especially among nonsmokers. The relationship between weight and risk for PCa remains complicated, and future studies are needed to determine clinical implications.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality

The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. isrctn.org Identifier: ISRCTN92187251.

A body shape index (ABSI) but not body mass index (BMI) is associated with prostate cancer-specific mortality: Evidence from the US NHANES database.

Prostate cancer (PCa) is a common malignancy in males and obesity may play a role in its development and progression. Associations between visceral obesity measured by a body shape index (ABSI) and PCa mortality have not been thoroughly investigated. This study assessed the associations between ABSI, body mass index (BMI), and long-term PCa-specific mortality using a nationally representative US database. This population-based longitudinal study collected data of males aged ≥40 years diagnosed with PCa and who underwent surgery and/or radiation from the National Health and Nutrition Examination Survey database 2001-2010. All included participants were followed through the end of 2019 using the National Center for Health Statistics Linked Mortality File. Associations between PCa-specific mortality, BMI, and ABSI were determined using Cox proportional hazards regression and receiver operating characteristic (ROC) curve analysis. Data of 294 men (representing 1,393,857 US nationals) were analyzed. After adjusting for confounders, no significant associations were found between BMI (adjusted hazard ratio [aHR] = 1.06, 95% confidence interval [CI]: 0.97-1.16, p = 0.222), continuous ABSI (aHR = 1.29, 95% CI: 0.83-2.02, p = 0.253), or ABSI in category (Q4 vs. Q1-Q3: aHR = 1.52, 95% CI: 0.72-3.24, p = 0.265), and greater risk of PCa-specific mortality. However, among participants who had been diagnosed within 4 years, the highest ABSI quartile but not in BMI was significantly associated with greater risk for PCa-specific mortality (Q4 vs. Q1-Q3: aHR = 5.34, 95% CI: 2.26-12.62, p = 0.001). In ROC analysis for this subgroup, the area under the curve of ABSI alone for predicting PCa-specific mortality was 0.638 (95% CI: 0.448-0.828), reaching 0.729 (95% CI: 0.490-0.968 when combined with other covariates. In US males with PCa diagnosed within 4 years, high ABSI but not BMI is independently associated with increased PCa-specific mortality.

Mortality Risks Associated with Depression in Men with Prostate Cancer

BackgroundMen diagnosed with prostate cancer (PC) have an increased risk of depression; however, it is unclear to what extent depression affects long-term survival. A better understanding of such effects is needed to improve long-term care and outcomes for men with PC. ObjectiveTo determine the associations between major depression and mortality in a national cohort of men with PC. Design, setting, and participantsA national cohort study was conducted of all 180 189 men diagnosed with PC in Sweden during 1998–2017. Subsequent diagnoses of major depression were ascertained from nationwide outpatient and inpatient records through 2018. Outcome measurements and statistical analysisDeaths were identified from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) for all-cause mortality associated with major depression, adjusting for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005–2017. PC-specific mortality was examined using competing risks models. Results and limitationsIn 1.3 million person-years of follow-up, 16 134 (9%) men with PC were diagnosed with major depression and 65 643 (36%) men died. After adjusting for sociodemographic factors and comorbidities, major depression was associated with significantly higher all-cause mortality in men with high-risk PC (HR, 1.50; 95% confidence interval [CI], 1.44–1.55) or low- or intermediate-risk PC (1.64; 1.56–1.71). These risks were elevated regardless of PC treatment or age at PC diagnosis, except for youngest men (<55 yr) in whom the risks were nonsignificant. Major depression was also associated with increased PC-specific mortality in men with either high-risk PC (HR, 1.35; 95% CI, 1.28–1.43) or low- or intermediate-risk PC (1.42; 1.27–1.59). This study was limited to Sweden and will need replication in other countries when feasible. ConclusionsIn this national cohort of men with PC, major depression was associated with ∼50% higher all-cause mortality. Men with PC need timely detection and treatment of depression to support their long-term outcomes and survival. Patient summaryIn this report, we examined the effects of depression on survival in men with prostate cancer. We found that among all men with prostate cancer, those who developed depression had a 50% higher risk of dying than those without depression. Men with prostate cancer need close monitoring for the detection and treatment of depression to improve their long-term health outcomes.

Abstract 2220: Associations between post-diagnostic lifestyle and dietary patterns with prostate cancer survival in the Multiethnic Cohort

Abstract Background: Prostate cancer (PCa) remains a leading cause of cancer-related death among men despite high 5-year survival rates for localized and regional diseases. This study evaluated healthy lifestyle and dietary patterns in relation to PCa survival in a multiethnic population. Methods: We prospectively followed 2,603 men with non-metastatic PCa in the Multiethnic Cohort (MEC) for a median duration of 10.9 years (497 African American, 754 Japanese American, 577 Latino, 129 Native Hawaiian, and 646 White men) starting in 1993. We documented 1,321 deaths, including 196 from PCa. Lifestyle pattern was assessed after diagnosis by a previously reported PCa Behavior Score, which includes BMI, physical activity, and smoking, and a modified version including diet (based on the sum of saturated fat, whole milk, alcohol, and processed meat intake). We also evaluated six indices of inflammatory and insulinemic potential of diet and lifestyle patterns (E-DII, EDIP, EDIH, ELIH, EDIR, and ELIR); and three indices of plant-based diets: an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI). We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between each index with PCa-specific and all-cause mortality. We adjusted for education, race/ethnicity, smoking, BMI, physical activity (if not part of the score), family history of PCa, and first course of treatment. Results: Across the five racial/ethnic groups, Japanese American men exhibited healthier lifestyle and dietary patterns post-diagnosis, while African American and Native Hawaiian men tended to have less healthy behaviors. The PCa Behavior Score was statistically significantly associated with a reduced risk of all-cause mortality (HR per point=0.71, 95% CI 0.63-0.80), and a similar trend persisted when incorporating diet into the score. The PDI was statistically significantly inversely associated with all-cause mortality (HR per SD=0.90, 95% CI 0.83-0.97), while the uPDI showed a positive association (HR=1.10, 95% CI 1.12-1.18). None of the lifestyle or dietary patterns were associated with PCa mortality (p-values&amp;gt;0.05). No clear trends were observed for inflammatory and insulinemic dietary patterns after PCa diagnosis with all-cause or PCa-specific mortality. Conclusion: Adopting a healthy lifestyle and diet was associated with longer overall survival among men with PCa. We did not find these practices to be associated with a lower risk of PCa-specific mortality among men diagnosed with non-metastatic disease. However, 85% of the observed deaths during follow-up were due to other causes; this underscores the importance of counseling all men, including those with non-metastatic prostate cancer on health behaviors to manage comorbidities. Citation Format: Anqi Wang, Erin L. Van Blarigan, Iona Cheng, June M. Chan, Peggy Wan, Song-Yi Park, Fei Chen, Loic Le Marchand, Lynne Wilkens, Stacey A. Kenfield, Christopher A. Haiman. Associations between post-diagnostic lifestyle and dietary patterns with prostate cancer survival in the Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2220.

Abstract 3813: Relationship between race/ethnicity and oncologic outcomes in patients with biochemical recurrence after primary treatment for prostate cancer

Abstract Background: Prostate cancer (PC) is the most common form of cancer in men and accounts for ~35% and 24% of all new cancer diagnoses in Black and Hispanic men, respectively. Incidence rates of PC are higher and cancer is diagnosed at a younger age in Black compared to White men. The most frequently utilized primary treatment options are radical prostatectomy (with or without adjuvant radiotherapy) or radiotherapy. Despite the success of primary treatments for localized PC, many patients (pts) will eventually develop biochemical recurrence (BCR), defined as rising prostate-specific antigen (PSA) levels. Pts with BCR are at a higher risk of developing distant metastases and ultimately dying from PC. This targeted literature review aimed to assess the real-world (RW) relationship between race/ethnicity and BCR, and further identify any differences in oncologic outcomes (risk of metastases, PC-specific mortality, and overall survival). Methods: A targeted literature search was performed using Embase, PubMed, and the past 2 years of American Society of Clinical Oncology conference proceedings. Selected studies were limited to English-language articles focusing on BCR and race or ethnicity among US populations, published between 1/2010 and 7/2023. Results: Ten studies were selected after title and abstract review. Most studies had a White pt majority (83%-92%). Six studies reported no differences in BCR or oncologic outcomes when pts were stratified by race/ethnicity. Four studies reported a higher BCR risk for Black pts with low-risk PC after radical prostatectomy, but not for pts with high-risk PC. PSA and PSA doubling time (PSADT) were found to be strong predictors of oncologic outcomes. Conclusions: The FDA draft guidance on diversity plans recommends that clinical trials enroll an adequate number of participants from underrepresented racial and ethnic populations. This requires an understanding of the diversity of the population that will eventually use the treatment and of which race/ethnicity differences in outcomes should be expected and investigated. Based on this targeted review among pts with localized PC, most RW studies had a White pt majority, and the race distribution in these studies aligned with published census and epidemiology data. In addition, findings suggest that race/ethnicity differences were not pronounced among high-risk PC pts in the US when given equal access to care or treatment, and that oncologic outcomes and BCR risk were similar across Black, White, and Hispanic pt populations. Conversely, PSA and PSADT may be stronger prognostic markers for BCR and oncologic outcomes. Future clinical trials are needed to support these RW findings and should aim to actively enroll racial/ethnic minorities to identify potential differences in efficacy and safety, and to help advance the evidence base for pt PC management. Citation Format: Nasreen Khan, Vanessa Quintero, Clara Beck, Miryana Dimova-Dobreva, Binita Patel. Relationship between race/ethnicity and oncologic outcomes in patients with biochemical recurrence after primary treatment for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3813.

Abstract 7007: 5hmc-sequencing identifies candidate genes in Puerto Rican Hispanic/Latino men with aggressive prostate cancer

Abstract Introduction: Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population which has the highest prostate cancer (PCa) specific mortality when compared with other Hispanic populations. According to the recent PR Cancer Registry data, PCa is the leading cancer type in terms of incidence (38% of all cancer cases) and mortality (16% of all cancer deaths) in PR H/L men. PR H/L men also have significantly higher PCa-specific mortality than non-Hispanic Whites (NHW) and non-Hispanic Blacks (NHB). So far, little is known about higher mortality in PR H/L men. It is believed that epigenetic changes of key genes play a critical role in aggressive tumors. Therefore, our study was aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. Methods: We prepared sequencing libraries using the enriched 5hmC DNA from 42 prostate tumor and 44 adjacent normal FFPE samples. We performed sequencing on an Illumina NextSeq 500 with 75bp single end. We used DESeq2 package to identify differentially methylated genes (DMGs). We also downloaded additional 5hmC data (Database: EGAS00001004942) of 51 localized PCa and 7 adjacent normal for confirmation analysis. We used Gleason score (GS) as a cut-off to identify DMGs in aggressive PCa patients (GS- 7 (3+4) or less, Non-aggressive; GS- 7 (4+3) and above, Aggressive). Results: We identified 808 DMGs in tumors compared to adjacent normal tissues (FDR&amp;lt;0.05, log2FC&amp;gt;|0.4|). Pathway analysis of DMGs demonstrated that cell-cycle, cell division, and DNA repair related pathways were most upregulated in tumors. Since 5hmC abundance is highly correlated with gene expression levels, we further investigated 808 DMGs with TCGA prostate cancer gene expression data. This analysis identified 59/73 DMGs (80.1%, (FDR&amp;lt;0.05, delta&amp;gt;|1|) with significant 5hmC and gene expression changes in the same direction. We also performed differential methylation analysis in another dataset and observed that 129 DMGs were common with our results. Finally, we demonstrated 111 DMGs (p&amp;lt;0.05) in aggressive tumors (n=7) compared to non-aggressive tumors (n=15). These 111 DMGs include important 5hmC hypomethylated genes (BCCIP and KLK10) and hypermethylated genes (COX6C, ARMC2, PVT1) in aggressive PCa patients. Conclusions: Our study identifies 59 genes having coordinated epigenetic and transcriptomic changes in PR H/L men and 111 DMGs in aggressive tumors. The coordinated 59 genes include tumor suppressor genes such as DKK3 and PRDM8 with downregulated 5hmC and gene expression levels. Also, previous studies reported downregulation of BCCIP and KLK10 and upregulation of COX6C, ARMC2, PVT1 expression in PCa. The coordinated changes in 5hmC could be critical in aggressive PCa biology, hence in future, these genes will be validated as candidate biomarkers and targets for aggressive PCa among PR H/L men. Citation Format: Manishkumar S. Patel, Muosa Almubarak, Jaime Matta, Carmen Ortiz-Sánchez, Jarline Encarnacion, Gilberto Ruiz-Deya, Julie Dutil, Jasreman Dhillon, Kosj Yamoah, Anders Berglund, Hyun Park, Liang Wang, Jong Y. Park. 5hmc-sequencing identifies candidate genes in Puerto Rican Hispanic/Latino men with aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7007.

Abstract 3043: MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer

Abstract Prostate cancer kills 30,000 men per year in the U.S. Yet, of all primary prostate cancers, only a relatively small percentage are aggressive and have the potential to become life threatening. In terms of genomic copy number alterations, concurrent amplification of MYC and loss of tumor suppressor PTEN is the strongest predictor of prostate cancer specific mortality. We have previously shown, in a novel mouse model, that combined MYC overexpression and Pten loss results in the development of precursor lesions (PIN) that lead to aggressive metastatic prostatic adenocarcinoma, yet overexpression of MYC alone or Pten loss alone result only in precursor lesion development. Here, we performed genome wide transcriptome analysis using bulk RNA seq to obtain clues regarding the synergy between MYC overexpression and Pten loss. Prostates harboring PIN lesion were dissected from mice engineered to have MYC activation alone, Pten loss alone, and the combination thereof (BMPC mice), as well as invasive primary adenocarcinomas and metastatic lesions from BMPC mice. Principal Components Analysis (PCA) analysis separated the lesions into highly distinct groups. Genes contributing the most to the first principal component were related to inflammation and cell proliferation/cell cycle progression by functional annotation. The proliferation-related genes were increased somewhat by MYC overexpression alone, were not increased Pten loss, and were more consistently increased by combined MYC overexpression and Pten loss in BMPC. Strikingly, mice with combined MYC overexpression and Pten loss showed approximately 2-4 fold higher Ki67 proliferation index than mice with MYC activation alone. PIN lesions driven by MYC overexpression or PTEN loss alone were characterized by Gene Set Enrichment Analysis (GSEA). Among the pathways with the highest negative enrichment scores in PIN samples with PTEN loss were those that generally describe ribosome biogenesis and translation. PIN lesions with Pten loss showed lower hybridization signals for the 45S rRNA, which was increased by MYC alone and somewhat more in BMPC PIN lesions. Our results demonstrate that combined activation of MYC and Pten loss drive increased cell proliferation beyond that seen with either gene alteration alone. These findings suggest that a key part of the molecular mechanisms by which MYC and PTEN alterations may synergize to drive aggressive prostate cancer is related to increased tumor cell proliferation. Surprisingly, we uncovered the novel finding that Pten loss, in the absence of MYC overexpression, is associated with decreased expression of genes coding for proteins that mediate translation, as well as decreased 45S pre-rRNA. Since ribosome biogenesis is a key driver of cell proliferation, it is likely that loss of both copies of PTEN alone, in the absence of MYC overexpression, would be selected against in early lesions in prostate cancer. Citation Format: Michael Rubenstein, Tracy Jones, Jessica Hicks, Apurv Rege, Qizhi Zheng, Carolina Gomes-Alexandre, Gretchen Hubbard, Srinivasan Yegnasubramanian, Charles Bieberich, Angelo DeMarzo. MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3043.

Adrenal-Permissive Germline HSD3B1 Allele and Prostate Cancer Outcomes

The adrenal androgen-metabolizing 3β-hydroxysteroid dehydrogenase-1 enzyme, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary for synthesizing nontesticular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding the 3β-HSD1 protein with decreased susceptibility to degradation resulting in higher extragonadal androgen synthesis. Retrospective studies have suggested an association of the HSD3B1 adrenal-permissive homozygous genotype with androgen deprivation therapy resistance in prostate cancer. To evaluate differences in mortality outcomes by HSD3B1 genetic status among men with prostate cancer. This cohort study of patients with prostate cancer who were enrolled in the Million Veteran Program within the Veterans Health Administration (VHA) system between 2011 and 2023 collected genotyping and phenotyping information. HSD3B1 genotype status was categorized as AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), or CC (homozygous adrenal-permissive). The primary outcome of this study was prostate cancer-specific mortality (PCSM), defined as the time from diagnosis to death from prostate cancer, censored at the date of last VHA follow-up. Secondary outcomes included incidence of metastases and PCSM in predefined subgroups. Of the 5287 participants (median [IQR] age, 69 [64-74] years), 402 (7.6%) had the CC genotype, 1970 (37.3%) had the AC genotype, and 2915 (55.1%) had the AA genotype. Overall, the primary cause of death for 91 patients (1.7%) was prostate cancer. Cumulative incidence of PCSM at 5 years after prostate cancer diagnosis was higher among men with the CC genotype (4.0%; 95% CI, 1.7%-6.2%) compared with the AC genotype (2.1%; 95% CI, 1.3%-2.8%) and AA genotype (1.9%; 95% CI, 1.3%-2.4%) (P = .02). In the 619 patients who developed metastatic disease at any time, the cumulative incidence of PCSM at 5 years was higher among patients with the CC genotype (36.0%; 95% CI, 16.7%-50.8%) compared with the AC genotype (17.9%; 95% CI, 10.5%-24.7%) and AA genotype (18.5%; 95% CI, 12.0%-24.6%) (P = .01). In this cohort study of US veterans undergoing treatment for prostate cancer at the VHA, the HSD3B1 CC genotype was associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis.

Neighborhood Deprivation, Race and Ethnicity, and Prostate Cancer Outcomes Across California Health Care Systems

Non-Hispanic Black (hereafter, Black) individuals experience worse prostate cancer outcomes due to socioeconomic and racial inequities of access to care. Few studies have empirically evaluated these disparities across different health care systems. To describe the racial and ethnic and neighborhood socioeconomic status (nSES) disparities among residents of the same communities who receive prostate cancer care in the US Department of Veterans Affairs (VA) health care system vs other settings. This cohort study obtained data from the VA Central Cancer Registry for veterans with prostate cancer who received care within the VA Greater Los Angeles Healthcare System (VA cohort) and from the California Cancer Registry (CCR) for nonveterans who received care outside the VA setting (CCR cohort). The cohorts consisted of all males with incident prostate cancer who were living within the same US Census tracts. These individuals received care between 2000 and 2018 and were followed up until death from any cause or censoring on December 31, 2018. Data analyses were conducted between September 2022 and December 2023. Health care setting, self-identified race and ethnicity (SIRE), and nSES. The primary outcome was all-cause mortality (ACM). Cox proportional hazards regression models were used to estimate hazard ratios for associations of SIRE and nSES with prostate cancer outcomes in the VA and CCR cohorts. Included in the analysis were 49 461 males with prostate cancer. Of these, 1881 males were in the VA cohort (mean [SD] age, 65.3 [7.7] years; 833 Black individuals [44.3%], 694 non-Hispanic White [hereafter, White] individuals [36.9%], and 354 individuals [18.8%] of other or unknown race). A total of 47 580 individuals were in the CCR cohort (mean [SD] age, 67.0 [9.6] years; 8183 Black individuals [17.2%], 26 206 White individuals [55.1%], and 13 191 individuals [27.8%] of other or unknown race). In the VA cohort, there were no racial disparities observed for metastasis, ACM, or prostate cancer-specific mortality (PCSM). However, in the CCR cohort, the racial disparities were observed for metastasis (adjusted odds ratio [AOR], 1.36; 95% CI, 1.22-1.52), ACM (adjusted hazard ratio [AHR], 1.13; 95% CI, 1.04-1.24), and PCSM (AHR, 1.15; 95% CI, 1.05-1.25). Heterogeneity was observed for the racial disparity in ACM in the VA vs CCR cohorts (AHR, 0.90 [95% CI, 0.76-1.06] vs 1.13 [95% CI, 1.04-1.24]; P = .01). No evidence of nSES disparities was observed for any prostate cancer outcomes in the VA cohort. However, in the CCR cohort, heterogeneity was observed for nSES disparities with ACM (AHR, 0.82; 95% CI, 0.80-0.84; P = .002) and PCSM (AHR, 0.86; 95% CI, 0.82-0.89; P = .007). Results of this study suggest that racial and nSES disparities were wider among patients seeking care outside of the VA health care system. Health systems-related interventions that address access barriers may mitigate racial and socioeconomic disparities in prostate cancer.

Prognostic Impact of Prostate-Specific Antigen at 6 Months After Radiotherapy in Localized Prostate Cancer: An Individual Patient Data Analysis of Randomized Trials.

We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT). Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment. Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL. PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

The effect of human leukocyte antigen genotype on survival in advanced prostate cancer treated with primary androgen deprivation therapy: the KYUCOG-1401-A study.

Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer. KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated. Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54-10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47-9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82-0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts. This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4+ T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4+ T cells is promising for prostate cancer.