Prostate Cancer-specific Death Research Articles

Ten-years outcome analysis in patients with clinically localized prostate cancer treated by radical prostatectomy or external beam radiation therapy.

PurposeSince there was no consensus on treatment options for localized prostate cancer, we performed a retrospective study to compare the long-term survival benefit of radiotherapy (RT) versus laparoscopic radical prostatectomy (LRP) in Taiwan.Methods218 patients with clinically localized prostate cancer treated between 2008 and 2017 (64 with LRP and 154 with RT) were enrolled in this study. The outcomes of RT and LRP were assessed after patients were stratified according to Gleason score, stage, and risk group. Crude survival, prostate cancer-specific survival, and metastasis-free survival were evaluated using the log-rank test.ResultsThe 5-year crude survival rate was 93.3% in the LRP group and 59.3% in the RT group. A significant survival benefit was found in the LRP group compared with the RT group (p = 0.004). Furthermore, significant differences were found in disease-specific survival (93.3% vs. 64.7%, p = 0.022) and metastasis-free survival (48% vs. 40.2%, p = 0.045) between the LRP and RT groups.ConclusionsMen with localized prostate cancer treated initially with LRP had a lower risk of prostate cancer-specific death and metastases compared with those treated with RT.

MP55-06 FOCAL ABLATIVE SALVAGE THERAPY FOR RADIO-RECURRENT PROSTATE CANCER: 6 YEAR ONCOLOGICAL AND SAFETY OUTCOMES

MP55-06 FOCAL ABLATIVE SALVAGE THERAPY FOR RADIO-RECURRENT PROSTATE CANCER: 6 YEAR ONCOLOGICAL AND SAFETY OUTCOMES

Methylation Subtypes of Primary Prostate Cancer Predict Poor Prognosis.

Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.

5-Alpha Reductase Inhibitors and Prostate Cancer Mortality among Men with Regular Access to Screening and Health Care.

How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality. We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality. Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07). Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259.

Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n=482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p=0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n=332; HR 2.64; p=0.02) and also biochemical recurrence (Canary; n=988; HR 1.51; p=0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

Barriers to Access Palliative Radiotherapy in Prostate Cancer ― A Population-Based Study

<h3>Purpose/Objective(s)</h3> With improvements in systemic therapy, patients with metastatic malignancies are living longer; however, access to adequate palliative radiotherapy remains an issue. In this study, we aim to describe factors important in access to palliative radiotherapy in patients who received novel Androgen receptor-axis-targeted therapies (ARAT) and died of prostate cancer. The main objective of this investigation was to identify and describe the factors important to receipt of palliative radiation treatment and the barriers to access in patients with prostate cancer in Ontario, Canada. <h3>Materials/Methods</h3> Population-based administrative databases from Ontario, Canada were used to identify patients 65 years or older with prostate cancer who were eligible for Ontario Drug Benefit 2002-2018 (n = 138,976), received continuous androgen deprivation therapy (ADT, n = 37,578), and died of prostate cancer-specific death between 2013 and 2017 (n = 3,575). Baseline and treatment characteristics were analyzed for association with receipt of radiotherapy in a 2-year observation period prior to death. <h3>Results</h3> 48.4% of patients who were included in the study received palliative radiotherapy to bone in the two years preceding death despite 51.3 % presenting with metastasis. Potential barriers to access to radiation treatment in patients with lethal castration-resistant prostate cancer in Ontario include cancer center consultation, type of oncologist involved, patient distance to cancer center, or socioeconomic factors, such as income quartile and rurality index. <h3>Conclusion</h3> The role of palliative radiotherapy has become increasingly recognized constituting nearly half the courses of radiation therapy delivered in Ontario. However, unimpeded access to radiation therapy continues to be a challenge, as evident from a high proportion of patients dying of prostate cancer in Ontario who never received palliative radiotherapy. We aimed to identify socioeconomic factors that might have accounted for the gap between the actual and optimal rates of receipt of radiotherapy to be able to improve the quality of life of many incurable patients.

Long-term survival after low-dose-rate brachytherapy for prostate cancer: the Royal Surrey experience.

To assess the long-term treatment efficacy of low-dose-rate (LDR) brachytherapy for the treatment of localized prostate cancer. Cause-of-death annotation in our prospective database was supplemented with death certificate information obtained via an internal audit of patients treated from 1999 to 2017 with LDR prostate brachytherapy as monotherapy or as combination with androgen deprivation therapy and/or external beam radiotherapy. Overall and disease-specific survival were the primary outcomes, estimated with Kaplan-Meier and competing risks multi-state models. Clinical variables influencing mortality were assessed with Cox proportional hazards regression in a sub-analysis of men to assess the predictive value of prostate-specific antigen (PSA) level at 48 months post implant. The audit process began in October 2017 and culminated in June 2020 with a curated series of 2936 patients. All-cause and prostate cancer-specific death prevalence were 11% and 2.9%, respectively. The median (range) follow-up time was 10 (3-21) years and the median (range) time to death from any cause was 9 (3-21) years. At 15 years post implant the overall and prostate cancer-specific survival probability were 81% and 95%, respectively. The 15-year cumulative incidence rates of death not due and due to prostate cancer were 14% and 5%, respectively. A greater risk of death due to prostate cancer was conferred by increasing age at therapy (hazard ratio [HR] 1.1, P < 0.001), advanced clinical stages relative to T1a-T2a (HR 1.9, P = 0.048 for T2b; HR 2.7, P = 0.023 for T2c-T3b) and a 48-month PSA level >1.0 ng/mL (HR 6.8, P < 0.001). This study constitutes the largest retrospective analyses of long-term mortality outcomes from prospectively collected prostate brachytherapy data and confirms the excellent treatment efficacy of LDR prostate brachytherapy for localized prostate cancer. T2 clinical stage subdivisions and 48-month PSA level >1.0 ng/mL appear to be strong indicators of prostate cancer-related survival.

High rate of local control and cure at 10 years after treatment of prostate cancer with external beam radiotherapy and high-dose-rate brachytherapy: a single centre experience

Background and purpose To analyse the cumulative incidence of any failure (AF), prostate cancer-specific failure (PCSF), any death (AD), prostate cancer-specific death (PCSD), and local control in 2387 men with prostate cancer (PC), consecutively treated with combined high-dose-rate brachytherapy (HDRBT) and external beam radiotherapy (EBRT) from 1998 to 2010. Material and methods A retrospective, single-institution study of men with localised PC. The mean age was 66 years and 54.7% had high-risk PC according to the Cambridge prognostic group (CPG) classification. The treatment was delivered as EBRT (2 Gy × 25) and HDRBT (10 Gy × 2) with combined androgen blockade (CAB). The median follow-up was 10.2 years. Results The cumulative incidence of PCSD at 10 years was 5% [CI 95% 0.04–0.06]. The 10 years PCSD per risk group were: low (L) 0.4%, intermediate favourable (IF) 1%, intermediate unfavourable (IU) 4.3%, high-risk favourable (HF) 5.8%, and high-risk unfavourable (HU) 13.9%. The PCSF rate at 10 years was 16.5% [CI 95% 0.15–0.18]. The PCSF per risk group at 10 years were: L 2.5%, IF 5.5%, IU 15.9%, HF 15.6%, and HU 38.99%. PCSF occurred in 399 men, of whom 15% were found to have local failure. The estimated frequency of local failure in the entire cohort was 1.2%. Conclusions HDRBT combined with EBRT is an effective treatment with long-term overall survival and excellent local control for patients with PC. The low rate of local recurrence among men with relapse suggests that these patients were micro metastasised at time of treatment, which calls for improved methods to detect disseminated disease.

Analysis of Circulating Immune Biomarkers by Race in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Sipuleucel-T.

Among racial subgroups, Black men have the highest prostate cancer–specific death rate, yet they also exhibit prolonged overall survival compared with White men when treated with standard therapies, including sipuleucel-T. Differential immune responses may play a role in these observations. We compared circulating immune markers from 54 men (18 Black and 36 White) with metastatic castrate-resistant prostate cancer who received sipuleucel-T and were enrolled on an immune monitoring registry. Markers included longitudinal serum cytokine concentrations, humoral responses, and cellular immunity from baseline until 52 weeks after sipuleucel-T administration. Black men had statistically significantly higher median concentrations of TH2-type (interleukin [IL]-4, IL-10, and IL-13) and inflammatory cytokines (IL-2, IL-12, and IL-6) compared with prostate-specific antigen-matched White men both at baseline and 52 weeks after sipuleucel-T (2-sided P < .05). No differences by race were seen in either the antigen-specific T-cell response or the humoral responses to the immunizing antigen PA2024 and select secondary antigens.

Abstract 822: Can the genetic risk of prostate cancer be attenuated by a healthy lifestyle

Abstract Introduction: Inherited genetic factors contribute significantly to prostate cancer risk and explains 58% of the variability in prostate cancer incidence. It is unclear if the increased genetic risk of prostate cancer, including progression to lethal disease, can be offset by adherence to a healthy lifestyle. Methods: Using a validated polygenic risk score (PRS) for overall prostate cancer, we quantified the genetic risk of prostate cancer in 10,443 men in the Health Professionals Follow-up Study for whom genotype data was available. We applied a validated lifestyle score for lethal prostate cancer (including healthy weight, vigorous physical activity, not smoking, and high consumption of tomatoes, fatty fish, and reduced intake of processed meat) and examined the incidence of overall and lethal (metastatic disease or prostate cancer-specific death) prostate cancer from the date of blood (1993-1999) or cheek collection (2005-2006) through 2014 (2016 for lethal disease). Multivariable Cox proportional hazards models were used to estimate the risk of overall and lethal prostate cancer by joint categories of genetic risk (PRS quartiles) and a time-varying lifestyle score (1-2: least healthy, 3: moderate healthy, and 4-6: most healthy). Both unweighted and inverse probability weighted (IPW) models (to account for possible bias arising from the genotype sampling design) were applied. Lifetime cumulative incidence was estimated using regression standardization. Results: We observed 2,111 prostate cancer and 238 lethal prostate cancer events during a median follow-up of 18 and 22 years, respectively. The PRS enabled risk stratification for both overall and lethal prostate cancer, with men in the highest genetic risk quartile having a 5.4-fold increased risk of overall prostate cancer (HRipw = 5.39, 95% CI = 4.59-6.33) and a 3.5-fold increased risk of lethal prostate cancer (HRipw = 3.53, 95% CI = 2.34-5.32) compared with men in the lowest genetic risk quartile. Among men in the highest genetic risk quartile, adhering to a healthy lifestyle was significantly associated with a decreased risk of lethal prostate cancer (HRipw = 0.54, 95% CI = 0.31-0.94) compared with the least healthy lifestyle. Adhering to healthy lifestyle was not associated with a decreased risk of overall prostate cancer (HRipw = 1.01, 95% CI = 0.84-1.22). In the group of men with highest genetic risk, having a healthy lifestyle at study entry was associated with a lifetime cumulative incidence of lethal prostate cancer of 3%, lower than for men having the least healthy lifestyle (6%) and similar to the population average (3%). Conclusion: In this large prospective cohort of US men, inherited genetic factors increased the risk of both overall and lethal prostate cancer. The associated decreased risk of aggressive disease in those with a favorable lifestyle may suggest that the excess genetic risk of lethal prostate cancer could be offset by adhering to a healthy lifestyle. Citation Format: Anna Plym, Yiwen Zhang, Konrad Stopsack, Bénédicte Delcoigne, Adam S. Kibel, Edward Giovannucci, Kathryn L. Penney, Lorelei A. Mucci. Can the genetic risk of prostate cancer be attenuated by a healthy lifestyle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 822.

Differences in Toxicity and Outcomes in Clinical Trial Participants From Minority Populations.

Black men have a higher prevalence of and mortality rate from prostate cancer compared with White men and have been shown to present with more aggressive and later-stage disease. How prostate cancer treatment affects these racial disparities is still unclear. Several studies have shown that Black men who receive treatment have a more pronounced decrease in prostate cancer-specific death; however, there remains a large disparity in all-cause mortality. This disparity may be in part related to a higher risk of death resulting from comorbidities, given the higher rates of cardiovascular disease and diabetes in Black men, both of which are complicated by the use of androgen-deprivation therapy. To further understand these disparities, it is important that we analyze the racial differences in adverse event rates and severity. Increasing the percentage of Black men in clinical trials will improve the understanding of the biologic drivers of racial disparities in prostate cancer. To evaluate the potential differences in adverse event reporting and demonstrate the feasibility of enrolling equal numbers of Black and White men in trials, we performed a prospective, multicenter study of abiraterone plus prednisone with androgen-deprivation therapy in men with metastatic castration-resistant prostate cancer, stratified by race. Racial differences in prostate-specific antigen kinetics and toxicity profile were demonstrated. Higher rates and severity of adverse events related to adrenal hormone suppression, including hypertension, hypokalemia, and hypomagnesemia, were seen in the Black cohort, not previously reported. Increased enrollment of Black men in prostate cancer clinical trials is imperative to further understand the impact of race on clinical outcomes and treatment tolerability.

Transcript analysis of commercial prostate cancer risk stratification panels in hard-to-predict grade group 2-4 prostate cancers.

Improved prognostication is needed to minimize overtreatment in grade group (GG) 2-4 prostate cancer. Our aim was to determine, at messenger RNA (mRNA) level, the performance of the genes in the commercial panels Decipher, Oncotype DX, Prolaris, and mutational panel MSK-IMPACT to predict metastasis-free and prostate cancer-specific death (PCSD) in patients with GG 2-4 prostate cancer at radical prostatectomy. The retrospective cohort consisted of GG 2-4 patients treated with radical prostatectomy (median follow-up 10.4 years). Seventy-six cases with postoperative metastasis or PCSD and 84 controls with similar clinical baseline risk, but without progression, were analyzed. Index lesion mRNA transcripts were analyzed using NanoString technology. Random forest models were trained using panel gene sets to predict clinical endpoints and area under the curve (AUC), sensitivity, specificity, Youden index, and number needed to diagnose (NND) was measured. Survival probability was assessed with Kaplan-Meier estimator. All gene sets outperformed clinical parameters and predicted metastasis-free and prostate cancer-specific survival. However, there were significant differences between the panels. In metastasis prediction, the genes in Oncotype DX had inferior performance (area under the curve [AUC] = 0.65) compared to other panels (AUC = 0.73-0.74). Decipher, MSK-IMPACT and Prolaris showed similar NND (2.83-3.12) with Oncotype DX having highest NND (4.79). In PCSD prediction, the Prolaris gene set performed worse (AUC = 0.66) than MSK-IMPACT or Decipher (AUC = 0.72). Oncotype DX performed similarly to other panels (AUC = 0.69, p > .05). Oncotype DX demonstrated lowest NND (2.79) compared to other panels (4.22-5.66). Transcript analysis of genes included in commercial panels is feasible in survival prediction of GG 2-4 patients after radical prostatectomy and may aid in clinical decision making. There were significant differences between the panels, and overall stronger predictive gene sets are needed. Prospective investigation is warranted in biopsy materials.

Hospital competition, quality, and cost of prostate cancer care.

235 Background: Hospital competition is important for addressing the disparity in quality and cost of prostate cancer care. Study objective was to examine the association of hospital competition with process of care (time to treatment, treatment and overuse) and outcomes (medial care use, complications, mortality and cost) in Medicare fee-for-service beneficiaries with prostate cancer. Methods: This was a population-based cohort study of Surveillance, Epidemiological, and End Results-Medicare (SEER-Medicare) data from 1995- 2016, linked with American Medical Association for physician data and American Hospital Association for hospital level data. Eligible patients were men 66 years or older with localized or advanced stage prostate cancer at diagnosis. The Hirschman-Herfindahl index (HHI) was computed for all serving hospitals based on number of competitors, i.e., number of hospitals situated within the hospital referral region(HRR). The Overuse Index (OI) was used to composite measure of overuse during treatment (one year after diagnosis) and follow-up care phase. Outcomes were overall and prostate cancer-specific survival, complications, readmissions, ER visits, and cost. We used survival analysis, including competing risk analysis, Poisson (zero inflated) models for count data, and GLM (log-link) models for cost data. Propensity score and instrumental variable approaches were used to minimize potential biases. Results: In our study cohort of 434,264, 85% of patients had localized disease stage, and 15% had advanced stage. For both localized and advanced stage groups, age, race and ethnicity, geographic region, comorbidity, socio-economic status, and primary treatment differed by hospital competition (high competition vs. low competition). Hospitals within high competition area were more likely to perform surgery, whereas hospitals within low competition area were more likely to perform radiation therapy. Among localized disease patients, low hospital competition was associated with higher hazard of overall mortality (HR = 1.08, 95% CI = 1.07 - 1.10) and prostate cancer-specific mortality (HR = 1.13, 95% CI = 1.09 - 1.17) and higher odds of ER visits (OR = 1.13, 95% CI = 1.11 - 1.15). For advanced stage patients, low hospital competition was associated with higher hazard of overall mortality (HR = 1.11, 95% CI = 1.08 - 1.15) and prostate cancer-specific death (HR = 1.15, 95% CI = 1.09 - 1.18) and higher odds of ER visits (OR = 1.16, 95% CI = 1.11 - 1.22). Higher scores of the OI were associated with higher total medical costs per capita per year, and not associated with overall mortality. Conclusions: This novel study showed that higher hospital competition is associated with improved quality of care (reduced mortality, complications and ER visits) and increased/lower direct medical care cost among patients with localized or advanced stage prostate cancer. Policy measures should be implemented to improve hospital competition.

125 - The deleterious association between proton pump inhibitors and prostate cancer-specific death – a population-based cohort study

125 - The deleterious association between proton pump inhibitors and prostate cancer-specific death – a population-based cohort study

Oncological outcomes of 356 patients undergoing salvage focal ablative HIFU or cryotherapy following radiation failure.

5582 Background: Patients that have previously failed radiotherapy for prostate cancer is usually limited to systemic therapy due to morbidity from salvage prostatectomy. We reviewed the outcomes following focal salvage ablative therapy with HIFU or cryotherapy within the UK’s HEAT and ICE registries. Methods: 356 consecutive patients underwent focal ablative treatment after initial radiation treatment failure (28/1/2004-1/10/2019, 194 (54.5%) underwent HIFU (posterior recurrence) and 162 (45.5%) underwent cryotherapy (mostly anterior or T3b). Primary outcome was failure-free survival (FFS) defined as no systemic therapy, whole-gland treatment, metastases or prostate cancer-specific death. Secondary outcomes were adverse events and overall survival. Results: Median (IQR) age was 69years (65-73) and PSA (IQR) was 4.0ng/ml (1-7-7.2). Overall median (IQR) follow-up was 41.3 months (21.4-58.5). Quadrant ablation was performed in 128 (36.0%), hemi-ablation performed in 64 (18.0%), hockey-stick in 5 (1.4%) and 159 (43.8%) had unknown ablative patterns. Due to histological or MRI proven recurrence/residual disease, 31 (8.7%) underwent further focal salvage re-treatment. FFS (95%CI) at 3 and 6 years were 81% (76-87%) and 75% (68-83%) respectively. Median (IQR) time to failure was 15.5 months (19.7). Overall survival (95%CI) at 3 and 6 years were 97% (95-100%) and 88% (81-96%) respectively. Prostate-specific mortality was 2.8%. Overall 3 (0.8%) patients were managed for fistula formation, 16 (4.5%) were treated for UTIs. Conclusions: Salvage focal ablative therapy for radio-recurrent prostate cancer is safe and provides good short to medium-term oncological control. The FORECAST study is awaited to further determine oncological outcomes in this cohort.

Androgen receptor variants: RNA-based mechanisms and therapeutic targets.

Prostate cancer is the second leading cause of male cancer death in the United States. The androgen receptor (AR) transcription factor is a master regulator of normal glandular homeostasis in the prostate, as well as growth and survival of prostate cancer cells. Therefore, AR-targeted therapies are effective for improving overall survival of patients with advanced prostate cancer that is incurable by surgery or radiation. However, prostate cancer will inevitably progress on AR-targeted therapies to a castration-resistant prostate cancer (CRPC) phenotype that accounts for virtually all prostate cancer-specific death. mRNA transcript variants of the AR gene are expressed in CRPC cells and can be translated to produce AR variant (AR-V) proteins that function as ligand-independent, constitutively active transcription factors. AR-Vs are able to support growth of CRPC cells by promoting expression of AR target genes that are normally suppressed by AR-targeted therapies. Knowledge of mechanisms that govern expression of AR-Vs is incomplete. Studies have shown genomic rearrangements of the AR gene underlie expression of diverse AR-Vs in certain CRPC tumors, but post-transcriptional processes represent a broader regulatory mechanism for expression of AR-Vs in CRPC. This review focuses on alternative splicing, 3' end processing, miRNA-mediated mRNA repression, of AR and AR-V expression and the potential these mechanisms hold as therapeutic targets for CRPC.

Self-reported Prostate Cancer Progression Status Is Accurate: A Validation Study.

Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression. We conducted a validation study of self-reported prostate cancer progression in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and in a prostate cancer cohort enrolled in a Fred Hutchinson Cancer Research Center (FHCRC)-based study. We calculated measures of validity for self-reported progression, including sensitivity, specificity, positive predictive value, and negative predictive value using medical records as the gold standard. Our results suggest that ascertaining prostate cancer progression-related events (i.e., prostate-specific antigen elevation, recurrence, metastasis, and use of secondary treatment) through self-report may be a viable option for identifying men whose disease has progressed after diagnosis or initial therapy, particularly when multiple questions related to progression are included in the assessment (aggregate cluster of questions: sensitivity = 0.76 [PLCO]; 0.93 [FHCRC], specificity = 0.80 [PLCO]; 0.97 [FHCRC]). With an aggregate positive predictive value of 0.50 (PLCO), however, our PLCO results suggest that additional medical record verification of self-reported progression events may be necessary to rule out false positives. Most individuals reporting no evidence of progression-related events, however, were true negatives (aggregate negative predictive value = 0.92 [PLCO]; 0.98 [FHCRC]). Thus, there may be limited utility to investing resources in chart review to confirm self-reported nonevents. Ascertaining prostate cancer progression through self-report provides an efficient and valid approach to enhancing existing cancer cohorts with updated data on progression status. See video abstract at, http://links.lww.com/EDE/B658.

Volume of Gleason pattern 4 stratifies risk of metastasis and death in patients with Gleason score 3+5=8/5+3=8 positive prostate core biopsies

Implementation of Grade Groups (GrGrs) has been widely accepted for reporting prostate cancer grade since the 2014 International Society of Urological Pathology consensus meeting. Despite their undisputed value for risk stratification, some GrGr are, a priori, quite heterogeneous in that they contain multiple Gleason patterns (GPs). In this regard, the prognostic significance of GP5 in biopsies with highest GrGr4 is uncertain and evaluated in this study. A search of all core biopsies positive for prostate cancer reviewed after 2005 was performed, and 71 cases with highest GrGr4 containing GP5 (i.e., 3+5=8 or 5+3=8; referred to as GrGr4/GP5pos) eligible for inclusion were identified. In addition, 95 core biopsy cases with highest GrGr4 and no GP5 (i.e, 4+4=8; referred to as GrGr4/GP5neg) were selected for comparison. Multiple pathologic parameters, including volume and amount of GP4, and clinical variables were collected to evaluate the influence of GP5 on disease recurrence, development of metastases, and disease-specific death. GrGr4/GP5pos cases did not show, as a group, statistically significant differences in prostatectomy findings, disease recurrence, metastases, and disease-specific mortality when compared with GrGr4/GP5neg cases. In addition, the risk of all outcomes evaluated in the study did not differ between the whole GrGr4/GP5pos and GrGr4/GP5neg groups. However, Kaplan-Meier analysis found that GrGr4/GP5pos cases with a significant amount of GP4 did show a higher risk of prostate cancer-specific death as well as bone and visceral metastases. Univariate Cox regression demonstrated that preoperative prostate specific antigen (PSA), total number of positive cores, and global GrGr5 were also associated with a higher chance of disease-specific death. In a multivariate model, only global GrGr5 and PSA >20ng/dL remained statistically significant. This study suggests that the mere presence of GP5 in core biopsies with highest GrGr4 disease may not portend a worse prognosis. In these cases, accounting for the case-wide volume of GP4 by reporting a global GrGr appears to be more relevant as it identifies a subset of GrGr4/GP5pos patients with global GrGr5 who have a higher risk of metastases and prostate cancer-specific mortality.

The deleterious association between proton pump inhibitors and prostate cancer specific death.

309 Background: Proton pump inhibitors (PPIs) are a commonly prescribed class of medications. Although in-vitro and in-vivo data have shown PPIs to have anti-tumor effects, more recent studies suggest an increased cancer risk in several solid organs. Pantoprazole, a commonly prescribed PPI, has been shown to harbor a protective effect in human prostate cancer (PCa) cells. We aimed to investigate the effect of pantoprazole and other PPIs on PCa-specific death and additional PCa outcomes. Methods: In this retrospective, population-based cohort study, data were incorporated from the Institute for Clinical and Evaluative Sciences to identify all men aged 66 and above with a history of a single negative prostate biopsy between 1994 and 2016. We used multivariable Cox regression models with time-dependent covariates, to assess the effect of PPIs on PCa diagnosis, androgen deprivation therapy (ADT) use, and PCa-specific death. All models included other medications with a putative effect on PCa. All models were adjusted for age, rurality, comorbidity, and year of patient study inclusion. Results: Overall, 21,512 men were included, with a mean follow-up time of 8.06 years (SD 5.44 years). A total of 10,999 patients (51.1%) used a PPI. A total of 5,187 patients (24.1%) were diagnosed with PCa, 2,043 patients (9.5%) were treated with ADT, and 805 patients (3.7%) died from PCa. Pantoprazole was associated with a 3.0% (95% CI 0.3%-6,0%) increased rate of being treated with ADT for every six months of cumulative use, while any use of all other PPIs was associated with a 39.0% (95% CI 18.0%-64.0%) increased PCa-specific mortality. No significant association was found with PCa diagnosis. Conclusions: Upon validation of the potentially negative association of PPIs with PCa outcomes, the expansive use of PPIs may need to be reassessed, especially in PCa patients.

Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy.

To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death. During the mean follow-up period of 8.3years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0ng/mL, PSA 1.0-4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10years from the timing of BCR. Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6months when their life expectancy is within 10years.