Cumulative Incidence Of Prostate Cancer-specific Mortality Research Articles

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.

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 percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.

78 Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen > 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with < 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P< 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P< 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( Pinteraction= 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes.

Extremely Dose Escalated Radiation Therapy Improves Cancer-Specific Survival Compared With Radical Prostatectomy or Conventionally Dose-Escalated Radiation Therapy in Gleason Score 9-10 Prostate Adenocarcinoma: A Multi-institutional Analysis of 1403 Patie

Purpose/Objective(s): To compare the outcomes of a modern cohort of patients with Gleason Score (GS) 9-10 prostate adenocarcinoma (PCa) following treatment with external beam radiotherapy (EBRT), extremely dose-escalated radiotherapy (exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP). Materials/Methods: One thousand four hundred three patients with biopsy GS 9-10 PCa who received definitive treatment between 2000 and 2013 were included (506 treated with EBRT, 392 with EBRT+BT, and 505 with RP). Distant metastasis-free survival (DMFS) and prostate cancer-specific mortality (PCSM) were compared across the three cohorts with four cause-specific Cox regression models: (a) unadjusted, (b) covariate-adjusted for age, ln(iPSA), cT stage, and GS, (c) propensity score adjusted for the same covariates, and (d) in a doubly robust analysis (i.e., propensity score and covariate adjusted). Four analogous Fine and Gray competing risk models were developed to compare cumulative PCSM incidence. Results: The median follow-up period was 5.1 years (5.1, 6.4, and 4.3 years in the EBRT, EBRT + BT, and RP cohorts, respectively). The median doses among EBRT and EBRT+BT patients were isoeffective to 81 Gy and 96 Gy in 1.8 Gy fractions, respectively. Over 90% of patients treated with EBRT or EBRT+BT received ADT (median durations of 23 months and 12 months, respectively). Nearly 40% of RP patients received postoperative RT; 78% of postoperative RT was delivered in the salvage setting. PCSM was significantly lower among EBRT+BT patients than among either EBRT or RP patients in all cause-specific hazard models and Fine and Gray competing risk models, including unadjusted models (P<0.05 in unadjusted models and P<0.01 in all other models). PCSM was not significantly different between EBRT and RP patients in any model. DMFS was also significantly higher among patients treated with EBRT+BT in all cause-specific hazard models. In all adjusted models, DMFS was significantly superior among EBRT patients than RP patients (P<0.05). Five- and 10-year cumulative incidences of PCSM were 3% and 12% with EBRT+BT, 10% and 20% with EBRT, and 9% and 19% with RP, respectively (P<0.001). Overall survival was not significantly different between cohorts. Conclusion: In this multi-institutional consortium comprising over 1400 patients with GS 9-10 PCa, extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP in multiple models. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT cohort. This is hypothesis generating and suggests that improved local control via dose-escalation may have systemic control and survival implications even for patients with very high risk disease.

Radical prostatectomy in Denmark: Survival analysis and temporal trends in clinicopathological parameters with up to 20 years of follow-up

ObjectivesTo describe mortality, cause of death, and temporal trends in clinicopathological parameters with up to 20 years of follow-up in a nationwide cohort of prostate cancer (PCa) patients who underwent radical prostatectomy (RP). Materials and methodsA total of 6857 patients with PCa treated with RP at six different hospitals in Denmark between 1995 and 2011. Data were extracted from the nationwide DaPCa database. Histopathology reports from the RP specimens were manually reviewed. Date and cause of death were obtained from national registries and cross-checked in patient files.The cumulative incidence of PCa specific mortality (PCSM) was analysed with the Aalen-Johansen method for competing risks with non-PCa death as a competing event. Risk of PCSM was analysed in a multivariate Cox regression model using age, preoperative PSA level, surgical margin status, RP Gleason score (GS), pathological T-category, and N-category as explanatory variables. ResultsThe median follow-up was 6.4 years. Significant temporal changes in clinicopathological parameters were observed. During the study period, median age at surgery increased from 61.4 to 64.8 years and median preoperative PSA declined from 12.0 to 8.0 ng/ml. The proportion of men with pT2 PCa increased from 65% to 75% whereas the proportion of pT3 cancers decreased from 28% to 25%. The percentage of men with positive surgical margins decreased from 37% to 20%. During follow-up, 644 patients died, whereof 189 (29.3%) died from PCa. The cumulative incidence of PCSM and other-cause mortality after 15 years was 10.3% (95% CI 8.0–12.7) and 18.2% (95% CI 15.4–20.9), respectively. In a multivariate analysis, RP GS (P ≤ 0.001) and pT-category (P ≤ 0.001) were significantly associated with the risk of PCSM. Compared with GS ≤6, both GS +4 (HR 1.47), GS 4 + 3 (HR 2.32), GS 8 (HR 4.8) and GS 9 or 10 (HR 5.26) significantly increased the risk of PCa death. T3a PCa and T3b/T4 was also a significant predictor of PCSM with an increased risk of PCa death compared with pT2 of 2.24 and 4.5, respectively. ConclusionsIn a complete national cohort of men treated with RP during a 17-year period, we described the incidence of mortality after RP and predictors of PCSM. We demonstrated that RP GS and pT-category are the most significant predictors of PCa mortality. We found that an increasing proportion of men undergo RP for low-risk PCa suggesting that early detection of PCa is indeed undergoing in Denmark despite national recommendations. The Danish national results seem to concur with findings from international single- and multi-institutional reports.

Significant association of brachytherapy boost with reduced prostate cancer-specific mortality in contemporary patients with localized, unfavorable-risk prostate cancer.

A randomized trial recently found that adding brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical recurrence-free survival but not prostate cancer-specific mortality (PCSM). We investigated the relationship between BT boost and PCSM in a modern cohort from a large population-based database. We conducted an analysis of patients in Surveillance, Epidemiology, and End Results diagnosed with intermediate- or high-risk prostate cancer in 2004-2011, treated with EBRT only or EBRT + BT. The cumulative incidence of PCSM was evaluated in the presence of other-cause mortality as a competing risk. Propensity score matching and multivariable Fine and Gray proportional hazard models were used to evaluate the association of combined modality RT on PCSM. A total of 52,535 patients were identified, of which 19.6% were treated with EBRT + BT. One-third of cases were high-risk. On multivariable analysis, the adjusted hazard ratio (AHR) of PCSM for EBRT + BT vs. EBRT alone was 0.69 (95% confidence interval [CI], 0.55-0.87, p = 0.002), and the adjusted incidence of PCSM was 1.8% vs. 2.7% at 8 years, respectively. In subgroup analyses, the AHR for PCSM was also significantly reduced with EBRT + BT for high-risk disease (AHR 0.70; 95% CI, 0.52-0.94, p = 0.02; adjusted incidence of PCSM at 8 years, 5.4% vs. 7.6%), but not for intermediate-risk disease. BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease.

Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma

To describe mortality, cause of death, and temporal trends in clinicopathological parameters with up to 20 years of follow-up in a nationwide cohort of prostate cancer (PCa) patients who underwent radical prostatectomy (RP).A total of 6857 patients with PCa treated with RP at six different hospitals in Denmark between 1995 and 2011. Data were extracted from the nationwide DaPCa database. Histopathology reports from the RP specimens were manually reviewed. Date and cause of death were obtained from national registries and cross-checked in patient files.The cumulative incidence of PCa specific mortality (PCSM) was analysed with the Aalen-Johansen method for competing risks with non-PCa death as a competing event. Risk of PCSM was analysed in a multivariate Cox regression model using age, preoperative PSA level, surgical margin status, RP Gleason score (GS), pathological T-category, and N-category as explanatory variables.The median follow-up was 6.4 years. Significant temporal changes in clinicopathological parameters were observed. During the study period, median age at surgery increased from 61.4 to 64.8 years and median preoperative PSA declined from 12.0 to 8.0 ng/ml. The proportion of men with pT2 PCa increased from 65% to 75% whereas the proportion of pT3 cancers decreased from 28% to 25%. The percentage of men with positive surgical margins decreased from 37% to 20%. During follow-up, 644 patients died, whereof 189 (29.3%) died from PCa. The cumulative incidence of PCSM and other-cause mortality after 15 years was 10.3% (95% CI 8.0–12.7) and 18.2% (95% CI 15.4–20.9), respectively. In a multivariate analysis, RP GS (P ≤ 0.001) and pT-category (P ≤ 0.001) were significantly associated with the risk of PCSM. Compared with GS ≤6, both GS +4 (HR 1.47), GS 4 + 3 (HR 2.32), GS 8 (HR 4.8) and GS 9 or 10 (HR 5.26) significantly increased the risk of PCa death. T3a PCa and T3b/T4 was also a significant predictor of PCSM with an increased risk of PCa death compared with pT2 of 2.24 and 4.5, respectively.In a complete national cohort of men treated with RP during a 17-year period, we described the incidence of mortality after RP and predictors of PCSM. We demonstrated that RP GS and pT-category are the most significant predictors of PCa mortality. We found that an increasing proportion of men undergo RP for low-risk PCa suggesting that early detection of PCa is indeed undergoing in Denmark despite national recommendations. The Danish national results seem to concur with findings from international single- and multi-institutional reports.