Prostate Cancer-specific Mortality Research Articles

Neighborhood deprivation and risk of mortality among men with prostate cancer: Findings from a long-term follow-up study.

BackgroundThe overall survival rate of prostate cancer (PCa) has improved over the past decades. However, huge socioeconomic and racial disparities in overall and prostate cancer‐specific mortality exist. The neighborhood‐level factors including socioeconomic disadvantage and lack of access to care may contribute to disparities in cancer mortality. This study examines the impact of neighborhood deprivation on mortality among PCa survivors.MethodsNorth Carolina–Louisiana Prostate Cancer Project (PCaP) data were used. A total of 2113 men, 1046 AA and 1067 EA, with PCa were included in the analysis. Neighborhood deprivation was measured by the Area Deprivation Index (ADI) at the census block group level using data from the US Census Bureau. Quintiles of ADI were created. Cox proportional hazards and competing risk models with mixed effects were performed to estimate the effect of neighborhood deprivation on all‐cause and PCa‐specific mortality adjusted for age, race, study site, insurance status, and comorbidities.ResultsParticipants living in the most deprived neighborhoods had an increased risk for all‐cause mortality (quintiles 4 + 5: adjusted hazard ratio [aHR] = 1.51, 95% confidence interval [CI] = 1.16–1.96) compared to those in the least deprived (quintile 1) neighborhoods. The risk of prostate cancer‐specific mortality was also higher among those living in the deprived neighborhoods (quintiles 4 + 5: aHR = 1.90, 95% CI = 1.10–3.50) than those in the least deprived neighborhood.ConclusionsThe findings suggest neighborhood‐level resources or health interventions are essential to improve survival among men with PCa. Additional research should focus on the mechanisms of how the neighborhood environment affects mortality.

Ambient air exposures to arsenic and cadmium and overall and prostate cancer-specific survival among prostate cancer cases in Pennsylvania, 2004 to 2014.

Exposures to arsenic (As) and cadmium (Cd) have been associated with higher prostate cancer (PC) mortality; however, these associations have been inconsistent. The authors investigated whether higher ambient air concentrations of As and Cd are associated with lower overall and PC-specific survival among PC cases in Pennsylvania. Incident PC cases of patients, aged 40 years or older, with a clinical diagnosis and nonmetastatic disease were identified in the 2004 to 2014 Pennsylvania Cancer Registry. Demographic, clinical, and pathologic information were extracted from the Pennsylvania Cancer Registry. The 3- and 5-year average and cumulative air concentrations of As and Cd were extracted from the Environmental Protection Agency's Toxics Release Inventory database. Spatial-temporal hierarchical accelerated failure time models were used to examine the associations between air concentrations of As and Cd and overall and PC-specific survival for the total population and stratified by geographical region defined by rurality and Appalachia status, after adjusting for confounders. There were 78,914 PC cases included. Increasing 3- and 5-year average and cumulative air concentrations of As and Cd were significantly associated with lower overall and PC-specific survival among cases, after adjusting for confounders, for the total population, and stratified by geographical region for most of the estimates. Data suggest that increasing ambient air exposures to As and Cd may play a role in overall and PC-specific mortality risk among PC cases. Exposures to As and Cd are modifiable and may provide insight into potential strategies to improve PC health outcomes. Arsenic and cadmium exposures linked to increased prostate cancer deaths remain unclear. We investigated whether air levels of arsenic and cadmium reported to be released from industries decrease overall and prostate cancer-specific survival among prostate cancer cases identified in the 2004 to 2014 Pennsylvania Cancer Registry. Among the 78,914 prostate cancer cases, increasing air levels of arsenic and cadmium are found to be associated with lower overall and prostate cancer-specific survival for the total population and within rural and urban Appalachia and urban non-Appalachia counties in Pennsylvania. Reducing exposures to arsenic and cadmium have the potential to decrease prostate cancer deaths.

Association between health-care system and prostate cancer mortality for African American men with localized and metastatic prostate cancer.

27 Background: African American (AA) men with prostate cancer (PC) present with more advanced disease and have worse survival than comparable non-Hispanic White (White) men. Recent studies suggest that receiving care within an equal access setting may attenuate these disparities. We hypothesize that AA men receiving care within the Veterans Health Administration (VHA) will have improved outcomes compared to AA men receiving care in the general population as assessed by the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We identified AA men diagnosed with PC between 2004 and 2015 in the VHA and SEER. For comparisons of covariate distributions across subgroups, we used the chi-squared test with continuity correction. We analyzed the cumulative incidence (with 95% confidence intervals (CIs)) of PC specific mortality (PCSM) in the VHA and SEER. Additionally, multivariable Cox proportional hazards models controlling for demographic information were performed. Results: The cohort included 85,409 AA men (VHA: 27,415, SEER: 57,994). Median follow-up was 4.79 years in the VHA and 5.16 years in SEER. In the VHA, AA men were more likely to present with localized disease (VHA 94.7% vs SEER 86.4%, p < 0.001) and less likely to have metastatic disease (3.2% vs 4.3%, p < 0.001). The 5-year cumulative incidence of PCSM was lower for patients in the VHA (VHA: 3.8% [CI: 3.5-4.1%] vs. SEER: 5.0% [CI: 4.8-5.2%], p < 0.001). The PCSM difference was largest in men with metastatic disease. In metastatic patients, cumulative incidence of PCSM at five years was significantly lower in the VHA (VHA 52.5% [CI: 48.0-56.5%] vs. SEER 64.8% [CI: 62.3-67.1%], p < 0.001). In contrast, AA men with localized disease had similar PCSM in the VHA and SEER (VHA 2.4% [CI: 2.2-2.6%] vs. SEER 2.6% [CI: 2.4-2.7%], p = 0.09 at five years). On multivariable analysis, VHA system was associated with lower PCSM [Hazard Ratio (HR): 0.91, p < 0.001]. There was a significant interaction between VHA system and distant metastases at diagnosis [p < 0.001] indicating larger differences in PCSM by healthcare system in metastatic patients as compared to localized patients. VHA system was associated with reduced PCSM in metastatic patients [HR 0.84, p < 0.001] but not in localized patients [HR 0.96, p = 0.13]. Conclusions: AA men in the VHA had a significantly lower incidence of PCSM than those in the SEER database, especially for those who presented with distant metastases at diagnosis. Future work should examine how cost and access to care affect disparities in outcomes for AA men.

Impact of U.S. Preventative Services Task Force grade D recommendation against prostate-specific antigen screening on prostate cancer mortality.

51 Background: The U. S. Preventative Services Task Force (USPSTF) recommendation regarding prostate-specific antigen (PSA) transitioned to a grade D recommendation against PSA screening for adult males in 2012. The impact of this recommendation against PSA screening on prostate cancer-specific mortality (PCSM) in contemporary cohorts is unknown. Our study evaluated PCSM between 1999-2019, comparing mortality rates before and after this change to screening guidelines. Methods: Age-adjusted PCSM rates per 100,000 men were obtained from the National Center for Health Statistics from 1999 – 2019. Trends in PCSM rates from 1999 – 2012 and 2014 – 2019 were estimated using linear regression with year and binary indicator of pre-2013/post-2013 status as interaction terms. Age-adjusted rates of PCSM were calculated for men ≥50 years and by race, ethnicity, urbanization and census region. Similarly, age-adjusted rates of overall cancer mortality (exclusive of PCSM) were calculated. Behavioral Risk Factor Surveillance System was used to establish trends in PSA screening from 2001 – 2018. North American Association of Central Cancer Registries was used to determine age-adjusted incidence of localized and metastatic PC at the time of diagnosis from 1999 – 2017. Results: The age-adjusted PCSM rate in the U.S. decreased linearly at a rate of (-)0.28 per 100,000/year from 1999 – 2012 and subsequently stalled at a rate of no change from 2014 – 2019 (p < 0.001). This effect was particularly striking for men aged 60 – 69, men > 80 years, and Black men. Men aged 60 – 64 had a decreasing rate of (-)0.009 per 100,000/year prior to 2013, followed by a rise of (+)0.001 per 100,000/year (p < 0.001). Among Black men, PCSM rate was decreasing linearly at (-)0.700/100,000/year from 1999-2012 and flattened at a rate of (-)0.091/100,000/year from 2014-2019 (p < 0.001). These changes were seen across races, urbanization and census regions (p < 0.001) and were accompanied by decreases in PSA screening (p = 0.02) together with increases in diagnosis of metastatic disease. These trends were inconsistent with mortality trends observed across all malignancies. Conclusions: Using comprehensive data on PCSM through 2019, this study illustrates decreasing PCSM over time which flattened or increased following the 2012 change in USPSTF guideline, along with a decrease in PSA screening. The change in PCSM was seen in all ages, races, ethnicities, urbanization and census regions, but particularly in men from 60 – 69 and > 80 years old, and Black men. These changes were accompanied by increased diagnosis of metastatic PC and are discordant from trends across other malignancies. These findings suggest that the change in PSA screening guideline may have contributed to the stagnancy of PCSM rates in recent years. The updated 2018 USPSTF guideline supporting shared-decision making may reverse these trends over time.

Association between prostate-specific antigen screening and prostate cancer mortality in a racially diverse cohort of United States veterans.

225 Background: African American (AA) men are known to develop more aggressive forms of prostate cancer at a younger age compared to their Non-Hispanic White (NHW) counterparts. However, few AA men were included in the major randomized trials assessing the efficacy of Prostate-Specific Antigen (PSA) screening. It is thus unknown whether PSA screening may be more beneficial in the AA population. Methods: We conducted a retrospective analysis of men diagnosed with prostate cancer in the United States (US) Veterans Affairs Health System (VA) using the VA Informatics and Computing Infrastructure. Inclusion criteria were AA or NHW men aged 55-69 diagnosed with intermediate or high-risk prostate cancer between 2004 and 2017. Patients were classified as never screened with PSA prior to diagnosis, screened at least once prior to diagnosis (some screening), or screened in 5 consecutive years prior to diagnosis (annual screening). A lead-time bias adjusted multivariate regression model was implemented to assess the effect of screening on prostate cancer specific mortality (PCSM), with covariates including age, comorbidities, BMI, smoking history, marital status and primary care utilization. Results: A total of 45,825 men met the inclusion criteria and were included in the analysis, including 14,294 (31.1%) AA men and 31,151 (68.9%) NHW men. When compared to no screening, any prior PSA screening was associated with improved PCSM for both AA (subdistribution hazard ratio (SHR) 0.64, p < 0.001) and NHW (SHR 0.62, p < 0.001) patients. Annual PSA screening (vs no or some screening) was associated with improved PCSM for AA men (SHR 0.68, p = 0.013) but not NHW men (SHR 0.90, p = 0.240). Other significant predictors of worse PCSM in both AA and NHW men included older age, earlier year of diagnosis, greater comorbidity burden, and cigarette smoking. Conclusions: In a diverse population of US veterans, at least one prior screening PSA was associated with improved PCSM in both AA and NHW patients. Annual PSA screening was associated with reduced PCSM in AA but not NHW men, suggesting that more intensive screening protocols may be beneficial for AA patients.

Disease progression and competing mortality for men undergoing active surveillance for low-risk prostate cancer.

282 Background: Active surveillance is a common management strategy for men with low-risk prostate cancer. However, there is some concern that delaying definitive therapy could lead to progressive disease and a missed opportunity to cure the cancer. We sought to study the impact of Gleason grade progression on the risk of metastases and prostate cancer-specific mortality (PCSM). We then sought to compare the risks of PCSM with the risk of competing mortality in this real-world cohort of men on active surveillance. Methods: This was a retrospective population-based cohort study using patient records from the Veterans Heath Administration Informatics and Computing Infrastructure of patients with a diagnosis of low-risk prostate cancer from January 1, 2001, to December 31, 2015, who were managed with active surveillance. Follow-up extended through March 31, 2020. Low-risk prostate cancer was defined as International Society of Urologic Pathology grade group (GG) 1, clinical tumor stage 2A or lower, PSA level of 10 ng/dL or lower. Active surveillance was defined as no definitive treatment within the first year after diagnosis with at least 1 additional re-staging biopsy after diagnostic biopsy. We identified men with pathologic upgrading to ≥GG2 and ≥GG3. We calculated the cumulative incidence of metastases, PCSM, and non-cancer mortality for men with and without pathologic upgrading. Results: The cohort included 8562 men with low-risk PC. Pathologic upgrading to ≥GG2 and ≥GG3 occurred in 3227 and 1200 men, respectively. For all patients, the 8-year cumulative incidence of metastases and PCSM was 0.8% (95% CI: 0.6-1.0%) and 0.4% (CI:0.3-0.6%), respectively. Pathologic upgrading to ≥GG2 was associated with an increased risk of metastases at 8 years (1.2% vs 0.5%, p < 0.001). Pathologic upgrading to ≥GG3 was also associated with an increased risk of metastases at 8 years (2.7% vs 0.5%, p < 0.001). In contrast, pathologic upgrading to ≥GG2 was not associated with an increased risk of PCSM at 8 years (0.5% vs 0.4%, p = 0.793). Similarly, pathologic upgrading to ≥GG3 was not associated with an increased risk of PCSM at 8 years (0.7% vs 0.4%, p = 0.82). The 8-year cumulative incidence of non-cancer mortality for all patients was 6.5% (95% CI:5.9-7.1%). Overall, the risk of non-cancer mortality was 16.25 (6.5/0.4) times higher than the risk of PCSM, regardless of upgrading status. Conclusions: For men with low-risk PC on active surveillance, pathologic upgrading was associated with a small increased risk of metastases but no increased risk of death from prostate cancer. Regardless of upgrading status, the risk of non-cancer mortality was substantially higher than the risk of PCSM. Future work is required to better tailor the intensity of follow up for surveillance protocols for men at risk of competing mortality.

Statin use and survival in men receiving androgen-ablative therapies for advanced prostate cancer: A systematic review and meta-analysis of cohort studies.

83 Background: Mounting evidence support a role for statins in improving survival in advanced prostate cancer (PC), particularly among men on androgen-ablative therapies. This study aimed to systemically review and meta-analyze the relationship between statin use and survival among men with PC on androgen deprivation therapy (ADT) or androgen receptor-axis-targeted therapies (ARATs). Methods: This review was conducted in accordance with the Cochrane Handbook for Systematic Reviews and reported in compliance with the MOOSE guidelines. Medline, Embase, Epub Ahead of Print, Cochrane CT, Cochrane SR, and Web of Science were searched from inception to May 18, 2021, for observational studies reporting associations of postdiagnostic statin use and survival outcomes (hazard ratios [HRs]). Two authors independently abstracted all data. Study quality was assessed using the Newcastle-Ottawa Scale. The primary outcomes included overall mortality (OM) and Prostate cancer-specific mortality (PCSM). Summary estimates pooled multivariable HRs with 95% confidence intervals (CIs) using the generic inverse variance method with random-effects modelling. Heterogeneity was assessed and quantified. A priori subgroup and sensitivity analyses were undertaken, and publication bias was evaluated. Confidence in the evidence was assessed using GRADE. Results: Twenty-five cohorts of 119,878 men (64,717 statin users [54%]) with over 74,416 mortality events were included. Postdiagnostic statin use was associated with a 27% reduction in the risk of OM (19 cohorts, HR 0.73 [95%CI: 0.66 to 0.82], I2= 83%) and a 35% reduction in the risk of PCSM (14 cohorts, HR 0.65 [95%CI: 0.58 to 0.73], I2= 74%), with significant heterogeneity in both estimates. Subgroup analyses identified a PCSM-advantage of statins for men on ARATs compared to ADT (HR 0.40 [95%CI: 0.30 to 0.55] vs HR 0.68 [95%CI: 0.60 to 0.76], p-difference < 0.01). Confidence in the overall evidence was “low” for both outcomes. Conclusions: Postdiagnostic statin use reduced both overall and prostate cancer-specific mortality in men on androgen-ablative therapies for advanced PC. Randomized controlled trials are warranted to validate these findings.

Validation of the performance of the Decipher biopsy genomic classifier in intermediate-risk prostate cancer on the phase III randomized trial NRG Oncology/RTOG 0126.

269 Background: The 22-gene Decipher genomic classifier (GC) is a prognostic biomarker that has been validated in phase III trials in high-risk localized, post-prostatectomy, and metastatic and non-metastatic castration-resistant prostate cancer. Herein, we report the first validation of the biopsy GC in intermediate-risk prostate cancer from the phase III randomized trial NRG/RTOG 0126. Methods: After National Cancer Institute approval, biopsy slides were collected from the NRG biobank from RTOG 0126, a phase III randomized trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiotherapy without the use of concomitant hormone therapy. RNA was extracted from the highest grade tumor foci and processed through a quality control (QC) pipeline prior to generation of the previously locked 22-gene GC model. After GC data was generated it was linked with clinical outcomes to assess prognostic performance. The primary endpoint for this ancillary project was disease progression, defined as biochemical failure, local failure, distant metastasis or prostate cancer-specific mortality, as well as use of salvage therapy. Secondary endpoints included the previous individual endpoints, metastasis-free survival, and overall survival. Independent GC prognostic performance was assessed using cause-specific Cox or competing risk adjusted Fine-Gray multivariable models that included randomization arm and prognostic stratification factors. Death without events were treated as competing risks. Results: A total of 215 patient samples passed QC of the 449 that had suitable cDNA for expression analysis. The median follow-up was 12.8 years (range 2.4-17.7), and 61% had Gleason 3+4, 24% had Gleason 4+3, and the median PSA was 7.2 ng/mL (IQR 5.0-10.2). On multivariable analysis the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR] 1.13, 95%CI (1.01-1.26), p = 0.03), biochemical failure (sHR 1.23, 95%CI 1.10-1.37, p < 0.001), distant metastasis (sHR 1.28, 95%CI 1.06-1.54, p = 0.01), and PCSM (sHR 1.45, 95%CI 1.20-1.76, p < 0.001). In patients with lower GC scores the 10-year distant metastasis rate difference between the 70.2 Gy and 79.2 Gy was 5%, as compared with 26% for higher GC patients. Conclusions: This study represents the first validation of any biopsy-based gene expression classifier in intermediate-risk prostate cancer. Decipher is independently prognostic and can identify patients that have low rates of metastatic events despite not receiving concurrent hormone therapy, and can be used to help personalize therapy in this setting. Clinical trial information: NCT00033631.

CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.

TPS198 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 & 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.

Prognostic Analysis for Patients With Parathyroid Carcinoma: A Population-Based Study.

BackgroundParathyroid carcinoma (PC) is a rare but often lethal malignancy for which staging system, prognostic indicators, and treatment guidelines are still not established. We aimed to explore the prognostic parameters and construct a nomogram for cancer-specific survival (CSS) of PC.MethodsA retrospective analysis of 604 PC patients in the SEER database from 2001 through 2018 was performed. All the cases were randomly assigned to the training cohort (n = 424) or the validation cohort (n = 180) at a ratio of 7:3. The Kaplan–Meier method and Cox regression model were applied to estimate the CSS and risk factors, and a nomogram was constructed. The predictive accuracy and discriminative ability of the nomogram in CSS were assessed by concordance index (C-index), the area under the curve (AUC) of receiver operating characteristics (ROC), and the calibration curve.ResultsAge at diagnosis > 70 years [hazard ratio (HR): 3.55, 95% CI: 1.07–11.78, p = 0.039] and tumor size > 35 mm (HR 4.22, 95% CI: 1.67–10.68, p = 0.002) were associated with worse CSS. Compared with distant metastasis, localized (HR 0.17, 95% CI: 0.06–0.47, p = 0.001) and regional lesions (HR 0.22, 95% CI: 0.07–0.66, p = 0.007) showed an improved CSS rate. Parathyroidectomy was the recommended treatment (p = 0.02). The C-index of the nomogram was 0.826, and the AUC for 5-, 10-, and 15-year CSS was 83.7%, 79.7%, and 80.7%, respectively. The calibration curve presented good agreement between prediction by nomogram and actual observation.ConclusionAge at diagnosis > 70 years, tumor size > 35 mm, and distant metastasis were independent risk factors for PC-specific mortality. Parathyroidectomy was currently the most recommended treatment for PC. This nomogram provided individualized assessment and reliable prognostic prediction for patients with PC.

Red Blood Cell Distribution Width Is Associated with All-cause Mortality but Not Adverse Cancer-specific Outcomes in Men with Clinically Localized Prostate Cancer Treated with Radical Prostatectomy: Findings Based on a Multicenter Shared Equal Access Regional Cancer Hospital Registry

BackgroundRecent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression. ObjectiveTo investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort. Design, setting, and participantsData were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017. Outcome measurements and statistical analysisBiochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer–specific mortality (PCSM) were secondary outcomes. Results and limitationsThe mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46–127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D’Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa. ConclusionsPreoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research. Patient summaryProstate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.

Cancer Control Outcomes Following Focal Therapy Using High-intensity Focused Ultrasound in 1379 Men with Nonmetastatic Prostate Cancer: A Multi-institute 15-year Experience

BackgroundFocal therapy aims to treat areas of cancer to confer oncological control whilst reducing treatment-related functional detriment. ObjectiveTo report oncological outcomes and adverse events following focal high-intensity focused ultrasound (HIFU) for treating nonmetastatic prostate cancer. Design, setting, and participantsAn analysis of 1379 patients with ≥6 mo of follow-up prospectively recorded in the HIFU Evaluation and Assessment of Treatment (HEAT) registry from 13 UK centres (2005–2020) was conducted. Five or more years of follow-up was available for 325 (24%) patients. Focal HIFU therapy used a transrectal ultrasound-guided device (Sonablate; Sonacare Inc., Charlotte, NC, USA). Outcome measurements and statistical analysisFailure-free survival (FFS) was primarily defined as avoidance of no evidence of disease to require salvage whole-gland or systemic treatment, or metastases or prostate cancer–specific mortality. Differences in FFS between D’Amico risk groups were determined using a log-rank analysis. Adverse events were reported using Clavien-Dindo classification. Results and limitationsThe median (interquartile range) age was 66 (60–71) yr and prostate-specific antigen was 6.9 (4.9–9.4) ng/ml with D’Amico intermediate risk in 65% (896/1379) and high risk in 28% (386/1379). The overall median follow-up was 32 (17–58) mo; for those with ≥5 yr of follow-up, it was 82 (72–94). A total of 252 patients had repeat focal treatment due to residual or recurrent cancer; overall 92 patients required salvage whole-gland treatment. Kaplan-Meier 7-yr FFS was 69% (64–74%). Seven-year FFS in intermediate- and high-risk cancers was 68% (95% confidence interval [CI] 62–75%) and 65% (95% CI 56–74%; p = 0.3). Clavien-Dindo >2 adverse events occurred in 0.5% (7/1379). The median 10-yr follow-up is lacking. ConclusionsFocal HIFU in carefully selected patients with clinically significant prostate cancer, with six and three of ten patients having, respectively, intermediate- and high-risk cancer, has good cancer control in the medium term. Patient summaryFocal high-intensity focused ultrasound treatment to areas of prostate with cancer can provide an alternative to treating the whole prostate. This treatment modality has good medium-term cancer control over 7 yr, although 10-yr data are not yet available.

Metastasis and Mortality in Men With Low- and Intermediate-Risk Prostate Cancer on Active Surveillance.

Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001). Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.

Conventional dose versus dose escalated radiotherapy including high-dose-rate brachytherapy boost for patients with Gleason score 9\u201310 clinical localized prostate cancer

As several recent researches focus on the importance of Gleason 9–10, we examine the role of radiotherapy dose escalation in those patients. We analyzed 476 patients with Gleason score 9–10 prostate cancer treated with radiotherapy. Of them, 127 patients were treated with conventional-dose external beam radiotherapy (Conv RT) and 349 patients were treated with high-dose radiotherapy (HDRT; 249 patients received high-dose-rate brachytherapy boost + external beam radiotherapy [HDR boost] and 100 patients received intensity-modulated radiotherapy [IMRT]). We compared these treatment groups using multi-institutional retrospective data. The patients had a median follow-up period of 66.3 months. HDRT showed superior biochemical disease-free survival (bDFS) rate (85.2%; HDR boost 84.7% and IMRT 86.6%) to Conv RT (71.1%, p < 0.0001) at 5 years, with a hazard ratio of 0.448. There were borderline difference in prostate cancer-specific mortality (PCSM; 4.3% and 2.75%, p = 0.0581), and distant metastasis-free survival (DMFS; 94.4% and 89.6%, p = 0.0916) rates at 5-years between Conv RT and HDRT group. Dose escalated radiotherapy showed better bDFS, borderline improvement in PCSM, and equivocal outcome in DMFS in with clinically localized Gleason 9–10 prostate cancer.

Racial Differences in Prostate Cancer Characteristics and Cancer-Specific Mortality: An Overview

Racial differences of prostate cancer incidence and mortality among Asian, Black, and Caucasian men have been known, however, comprehensive update of this topic is not yet reported. In the present review, an overview of the racial differences in prostate cancer characteristics and cancer-specific mortality is collected and reviewed. Regarding racial differences of incidence and mortality, surprising differences in the incidence of prostate cancer are seen among different populations around the world, with some countries having rates that are 60 to 100 times higher than others. African-American men have a higher incidence of prostate cancer, higher prostate cancer mortality, and are diagnosed with prostate cancer at a younger age than Caucasian American men. Furthermore, race is gaining attention as an important factor to consider for planning active surveillance for localized prostate cancer, especially among African-Americans. In addition, the causes of these differences are being elucidated by genomic profiling. Determinants of racial disparities are multifactorial, including socioeconomic and biologic factors. Although race-specific differences in prostate cancer survival estimates appear to be narrowing over time, there is an ongoing need to continue to understand and mitigate racial factors associated with disparities in health care outcomes.

Obesity and prostate cancer: A narrative review

Overweight and obese men with prostate cancer are at an increased risk of disease recurrence, exacerbated treatment-related adverse effects, development of obesity-related comorbidities, earlier progression and development of metastatic disease, and higher all-cause and prostate cancer-specific mortality. The physiological mechanisms associating obesity with poor prostate cancer outcomes remain largely unknown; however, an increased inflammatory environment and metabolic irregularities associated with excess fat mass are commonly postulated. Although research is limited, fat loss strategies using exercise and nutrition programmes may slow down prostate cancer progression and improve a patient's prognosis. This review is an overview of: 1) the association between obesity and poor prostate cancer prognosis; 2) potential physiological mechanisms linking obesity and prostate cancer progression; 3) the effect of obesity on treatments for prostate cancer; and 4) the potential for weight loss strategies to improve outcomes in patients with prostate cancer.

Vitamin D Deficiency at Diagnosis Increases All-Cause and Prostate Cancer-specific Mortality in Jamaican Men.

Background25 hydroxyvitamin D [25(OH)D] and serum calcium have been associated with incident prostate cancer (PCa). However, there is limited data on whether these metabolites predict survival in men of African descent, a population disproportionately affected by PCa. We studied the relationship of 25(OH)D at PCa diagnosis with all-cause and cancer-specific mortality among Jamaican men and examined whether serum calcium modified any associations.MethodsSerum 25(OH)D from 152 Jamaican men with incident PCa within the Prostate Cancer Risk Evaluation (PROSCARE) study were re-evaluated approximately 11 years after enrollment. 25(OH)D analyses were stratified using the using Holick criteria. PCa-specific and all-cause mortality were examined in Kaplan–Meier survival curves and Cox regression models adjusted for age, body mass index (BMI), smoking and Gleason score. Restricted cubic splines evaluated nonlinear associations. Serum calcium was assessed as an effect modifier of the association between 25(OH)D and mortality.ResultsOf cases with available 25(OH)D, 64 men with PCa survived, 38 deaths were PCa specific and 36 died of other causes. At baseline, 9.9% of cases were vitamin D deficient and 61.2% were vitamin D sufficient. Compared to 25(OH)D sufficient men, those with 25(OH)D <20.0 ng/mL concentrations were associated with higher PCa-specific mortality (adjusted HR, 4.95; 95% CI, 1.68, 14.63, P = .004) and all-cause mortality (adjusted HR, 2.40; 95%CI, 1.33, 4. 32, P = .003). Serum calcium was not associated with survival and did not modify any associations with 25(OH)D.Conclusions25(OH)D deficiency at PCa diagnosis predicted decreased survival for overall and PCa-specific cancer in Caribbean men of African ancestry.

The risk of death from prostate cancer in men with Gleason score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy.

We evaluated whether intermediate-risk factors, in addition to age, were associated with risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer. We conducted a prospective cohort study of 1,920 men with Gleason 3+4 adenocarcinoma of the prostate who received brachytherapy (BT) or BT and a median of 4 months of androgen deprivation therapy (ADT). Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether percentage of positive biopsies (PPB), cT2b-T2c stage, prostate-specific antigen (PSA) of 10.1-20.0 ng/ml, and age >70 years (median) were associated with risk of PCSM after adjustment for comorbidity. After median follow-up of 7.8 years, 284 men (14.8%) had died (31 from prostate cancer). For BT alone, increasing PPB, PSA of 10.1-20.0 vs. 4.0-10.0 ng/mL, and age >70 vs. ≤70 were significantly associated with increased risk of PCSM (adjusted hazard ratio 1.015, 95% confidence interval 1.000-1.031, P = 0.048; 5.55, 2.01-15.29, P<0.001; and 3.66, 1.16-11.56, P = 0.03, respectively). The respective results for BT and ADT were 1.009, 0.987-1.031, P = 0.44; 4.17, 1.29-13.50, P = 0.02; and 3.74, 0.87-16.05, P = 0.08. Among men with Gleason score 3+4 prostate cancer treated with BT, the risk of PCSM was elevated in those with PSA of 10.1-20.0 ng/mL and possibly age >70 years, despite the addition of ADT. Should these findings be validated in future studies, then advanced imaging and targeted biopsy of suspicious areas should be investigated in an effort to personalize treatment and minimize the risk of PCSM in these men.

The Influence of the Intraductal Carcinoma of the Prostate on the Short-Term Oncological Outcomes.

The presence of intraductal carcinoma of the prostate (IDC-P) in radical prostatectomy (RP) specimens correlates with adverse prognostic factors such as worse biochemical recurrence-free survival, higher grade and stage disease. This study aimed to investigate the effect of IDC-P in radical prostatectomy specimens on short-term oncological outcomes. Patients who underwent RP at our clinic for prostate cancer between May 2016 and November 2019 were included in the study. They were divided into two groups based on the presence of IDC-P in RP specimens. Their clinical, pathological, and oncologic data were evaluated retrospectively. A total of 98 patients underwent RP with a mean age of 65.5 years (50-83) and a mean follow-up time of 31.2 months (6-52). Seventy and 28 patients were evaluated in the group without IDC-P and group with IDC-P, respectively. Surgical margin positivity (p=0.307) and lymph node metastasis (p=0.017) rates were higher in the group with IDC-P. Although there were no statistical differences between the groups, at follow-up biochemical recurrence rate (p=0.052) was higher, and mean time to biochemical recurrence rates were lower (p=0.057) in the group with IDC-P. The group with IDC-P was associated with a 3-fold increase in prostate cancer-specific mortality to the group without IDC-P (p=0.037). Patients with IDC-P at RP specimens have more advanced disease, shorter biochemical recurrence-free, and cancerspecific survival than those without IDC-P. Defining the presence of IDC-P in RP specimens is critical in choosing the appropriate treatment strategy and predicting the prognosis.

Abstract PR-11: Blood levels of TNFRSF9 and PTN predict lethal prostate cancer among African American men

Abstract OBJECTIVE: Differentiating men who have lethal forms of prostate cancer from those with a more slow-growing disease remains a major challenge in clinical oncology. Risk stratification strategies are particularly needed for men of African descent who disproportionately bear the prostate cancer burden. Methods: Using a high throughput proximal extension assay, we simultaneously measured 82 immune-oncological proteins in the blood of 819 prostate cancer patients at diagnosis of whom 394 were African American (AA) and 425 were European American (EA). These patients were followed up for a median of 8.6 years since their diagnosis during which 57 died of prostate cancer while 202 died of all causes. To identify an immune-oncology protein signature predictive of lethal prostate cancer, we applied a cross-validated, regularized Cox regression model. Included in this model were the 82 immune-oncology proteins and 6 covariates of clinical significance (age, education, BMI, smoking history, aspirin use, and diabetes). Results: We did not identify a robust predictive signature of lethal prostate cancer for EA patients. However, for AA patients a signature primarily driven by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and pleiotrophin (PTN) (both positively associated with the risk of lethal disease) and regular aspirin use (negatively associated with risk) were the top predictors (P &amp;lt; 0.05) based on two selection criteria: the feature frequency and the weight of the features' contribution to the prediction. These features combined predicted prostate cancer-specific mortality with an accuracy of 83.7% (SE=3.8%). The two proteins alone, TNFRSF9 and PTN, predicted prostate cancer-specific mortality with an accuracy of 78.2% (SE=4.2%). AA prostate cancer patients with high levels (&amp;gt; median) of both TNFRSF9 and PTN in their blood at diagnosis had the worst prostate cancer-specific survival. By 10 years, 33% of cases with high levels of both TNFRSF9 and PTN died of prostate cancer compared to only 5% of cases with low levels of both or either of these proteins. Conclusions: Our study describes novel blood markers of lethal prostate cancer that can be used for risk stratification of AA patients at the time of diagnosis. AA patients with high levels of both TNFRSF9 and PTN in their sera had the highest risk of dying from prostate cancer. These markers may also be applicable to African prostate cancer patients since the blood-based immunome of Ghanaian and AA men are similar, as shown by our data. Citation Format: Tsion Zewdu Minas, Julián Candia, Tiffany H. Dorsey, Francine Baker, Wei Tang, Maeve Kiely, Cheryl J. Smith, Symone V. Jordan, Obadi M. Obadi, Anuoluwapo Ajao, Christopher A. Loffredo, Clayton Yates, Michael B. Cook, Stefan Ambs. Blood levels of TNFRSF9 and PTN predict lethal prostate cancer among African American men [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-11.