Cancer-specific Mortality In Men Research Articles

Prediction of prostate cancer specific mortality in men undergoing radiotherapy with or without hormonal treatment, risk stratification based on clinical characteristics and PSA treatment response

Prediction of prostate cancer specific mortality in men undergoing radiotherapy with or without hormonal treatment, risk stratification based on clinical characteristics and PSA treatment response

Editorial Comment.

No AccessJournal of UrologyAdult Urology1 Aug 2022Editorial CommentThis article comments on the following:Absolute Prostate Specific Antigen after 6 Months of Androgen Deprivation Therapy Is a Predictor of Overall and Cancer-Specific Mortality in Men with Hormone-Sensitive Prostate Cancer E. David Crawford E. David CrawfordE. David Crawford Department of Urology, University of California San Diego, La Jolla, California More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002676.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 208(2), p. 324 Reference 1. : Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group trial 9346 (INT-0162). J Clin Oncol 2006; 24: 3984. Google Scholar © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyMar 28, 2022, 12:00:00 AMAbsolute Prostate Specific Antigen after 6 Months of Androgen Deprivation Therapy Is a Predictor of Overall and Cancer-Specific Mortality in Men with Hormone-Sensitive Prostate Cancer Volume 208Issue 2August 2022Page: 324-324 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information E. David Crawford Department of Urology, University of California San Diego, La Jolla, California More articles by this author Expand All Advertisement PDF DownloadLoading ...

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer

BackgroundDrugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro.MethodsA cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs.ResultsThe use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31–1.23).ConclusionsAED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.

A Systematic Review of Decipher Genomic Classifier Risk Scores for Prostate Cancer in African-Americans

Background: Prostate Cancer (PCa) is a non-cutaneous malignancy in men, and Decipher being a genomic test, has gained increasing attention in estimating the risk of developing a recurrence or metastatic PCa disease in patients. Therefore, this study is focused on evaluating the association of Decipher score risk with recurrence of prostate cancer patients based on their medical, genetic predictors, and demographics (e.g., races) by conducting a systematic review. Moreover, the study has also assessed whether Decipher score risk can be a good predictor for prostate patients’ metastasis and prostate cancer-specific mortality in men and clinical decision-making regarding patient treatment recommendations. Methods:: The research study has reviewed 74 research articles, and the systematic review results have been presented in the form of themes. The studies' review indicated that Decipher acts as a genomic metastasis signature to predict metastatic disease among patients and make better decisions about treating the disease. Moreover, this genomic test can also be used in conjunction with Magnetic Resonance Imaging (MRI) for identifying the lesions that may carry the biological potential for early metastases. Furthermore, this review also identified that treatment options for PCa might range from Adjuvant Radiation Treatment (ART) and Salvage Radiation Therapy (SRT) to Radical Prostatectomy (RP); however, the selection of treatment methodology depends upon the GC score and risk stratification. Results: The results further suggested that the occurrence of PCa is two folds greater among African- Americans (AA) men as compared to non-AA men. Thus, the increasing incidence of PCa among AA and discrimination within AA's health and socio-economic conditions plays a significant role in treating AA. In this scenario, the Decipher test score plays an essential role in making treatment decisions. Conclusion: To conclude, further trials are still required for validating the Decipher biomarkers, and scientists should enhance the decipher test ability to be run on a patient's blood samples instead of tumor tissue, which will help patients use decipher as a screening test at the asymptomatic level.

Absolute Prostate Specific Antigen after 6 Months of Androgen Deprivation Therapy Is a Predictor of Overall and Cancer-Specific Mortality in Men with Hormone-Sensitive Prostate Cancer.

We sought to determine if absolute prostate specific antigen (PSA) value after 6 months of androgen deprivation therapy (ADT) is predictive of subsequent survival in patients with prostate adenocarcinoma. We performed a retrospective review of men receiving care within the Veterans Health Administration who initiated ADT for prostate adenocarcinoma. We used low- (≤0.2 ng/ml), intermediate- (>0.2 to 4 ng/ml) and high-risk (>4 ng/ml) absolute PSA values after 6-9 months of ADT, previously described in Southwest Oncology Group trial 9346. The primary endpoints were all-cause mortality and prostate cancer-specific mortality (PCSM). Kaplan-Meier survival curves for each PSA category were estimated and log-rank test was conducted. We employed Cox regression analysis adjusted for covariates and inverse propensity score weights associated with PSA categories to estimate the PSA category association with PCSM and all-cause mortality. We identified 9,170 patients in our cohort. Following ADT induction, 3,508 patients had low, 3,419 had intermediate and 2,243 had high PSA values. Two- and 5-year survival rates for low, intermediate and high PSA groups were 93.9% and 85.2% vs 88.6% and 71.2% vs 63.6% and 38.6%, respectively (p <0.0001). Patients in the high and intermediate PSA categories had a 15-fold and 3-fold higher risk of PCSM compared to those with PSA <0.2 ng/ml (p <0.0001). Absolute PSA in hormone-sensitive prostate cancer after 6-9 months of ADT is a predictor of overall mortality and PCSM. This measure can rapidly assess the efficacy of new interventions in phase 2 clinical trials.

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 &lt; 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.

Application of a novel machine learning framework for predicting non-metastatic prostate cancer-specific mortality in men using the Surveillance, Epidemiology, and End Results (SEER) database

Accurate prognostication is crucial in treatment decisions made for men diagnosed with non-metastatic prostate cancer. Current models rely on prespecified variables, which limits their performance. We aimed to investigate a novel machine learning approach to develop an improved prognostic model for predicting 10-year prostate cancer-specific mortality and compare its performance with existing validated models. We derived and tested a machine learning-based model using Survival Quilts, an algorithm that automatically selects and tunes ensembles of survival models using clinicopathological variables. Our study involved a US population-based cohort of 171 942 men diagnosed with non-metastatic prostate cancer between Jan 1, 2000, and Dec 31, 2016, from the prospectively maintained Surveillance, Epidemiology, and End Results (SEER) Program. The primary outcome was prediction of 10-year prostate cancer-specific mortality. Model discrimination was assessed using the concordance index (c-index), and calibration was assessed using Brier scores. The Survival Quilts model was compared with nine other prognostic models in clinical use, and decision curve analysis was done. 647 151 men with prostate cancer were enrolled into the SEER database, of whom 171 942 were included in this study. Discrimination improved with greater granularity, and multivariable models outperformed tier-based models. The Survival Quilts model showed good discrimination (c-index 0·829, 95% CI 0·820-0·838) for 10-year prostate cancer-specific mortality, which was similar to the top-ranked multivariable models: PREDICT Prostate (0·820, 0·811-0·829) and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (0·787, 0·776-0·798). All three multivariable models showed good calibration with low Brier scores (Survival Quilts 0·036, 95% CI 0·035-0·037; PREDICT Prostate 0·036, 0·035-0·037; MSKCC 0·037, 0·035-0·039). Of the tier-based systems, the Cancer of the Prostate Risk Assessment model (c-index 0·782, 95% CI 0·771-0·793) and Cambridge Prognostic Groups model (0·779, 0·767-0·791) showed higher discrimination for predicting 10-year prostate cancer-specific mortality. c-indices for models from the National Comprehensive Cancer Care Network, Genitourinary Radiation Oncologists of Canada, American Urological Association, European Association of Urology, and National Institute for Health and Care Excellence ranged from 0·711 (0·701-0·721) to 0·761 (0·750-0·772). Discrimination for the Survival Quilts model was maintained when stratified by age and ethnicity. Decision curve analysis showed an incremental net benefit from the Survival Quilts model compared with the MSKCC and PREDICT Prostate models currently used in practice. A novel machine learning-based approach produced a prognostic model, Survival Quilts, with discrimination for 10-year prostate cancer-specific mortality similar to the top-ranked prognostic models, using only standard clinicopathological variables. Future integration of additional data will likely improve model performance and accuracy for personalised prognostics. None.

Unmarried men have worse oncologic outcomes after radical cystectomy for nonmetastatic urothelial bladder cancer

BackgroundUnmarried status is an established risk factor for worse cancer control outcomes and survival in various malignancies. We tested the effect of marital status on the rate of nonorgan confined disease as well as on cancer-specific mortality (CSM) in patients who underwent radical cystectomy for nonmetastatic urothelial bladder cancer (UCUB). MethodsWithin the Surveillance, Epidemiology and End Results database (2007-2015), we identified 11,167 patients (8,639 men and 2,528 women) who underwent radical cystectomy for nonmetastatic UCUB. Temporal trend analyses, logistic regression models, cumulative incidence plots, competing-risks regression models and landmark analyses were used. ResultsOverall, 2,454 men (28.4%) and 1,363 women (53.9%) were unmarried. Unmarried men had a higher rate of nonorgan-confined disease at radical cystectomy (OR: 1.24, CI 1.10–1.33; P < 0.001). Moreover, in men, unmarried status was an independent predictor of higher CSM (HR: 1.24, CI 1.12–1.37) In women, unmarried status neither predicted nonorgan-confined disease at radical cystectomy (OR: 1.07, CI 0.91–1.26; P = 0.37) nor was it associated with CSM (HR: 1.13, CI 0.88–1.31; P = 0.14). In 6-month landmark analyses, unmarried status remained an independent predictor of higher CSM in men (HR: 1.20, CI 1.08–1.33). ConclusionsUnmarried men have more advanced tumor stage at radical cystectomy and worse CSM compared to married men. Interestingly, marital status did not affect oncologic outcomes in women. These data suggest a gender-specific effect of marital status in UCUB.

Sex difference in recurrence and survival after liver resection for hepatocellular carcinoma: A multicenter study

BackgroundThere is a striking sex difference in the incidence of hepatocellular carcinoma, with a strong predominance for men; however, the impact of sex on the incidence of recurrence after curative resection of hepatocellular carcinoma remains controversial. This study aimed to assess sex differences in the risks of recurrence and mortality for patients treated with curative resection of hepatocellular carcinoma. MethodsWe retrospectively reviewed data from 1,435 hepatocellular carcinoma patients treated with curative resection (1,228 men and 207 women) between 2004 and 2014 at 5 institutions in China. Patients’ baseline characteristics, operative variables, and rates of early recurrence (≤2 years after resection), late recurrence (>2 years after resection), and cancer-specific mortality were evaluated and compared. To clarify the true oncologic impact of sex, multivariable competing-risks regression analyses were performed to identify predictors associated with early and late recurrence, as well as cancer-specific mortality. ResultsThe early recurrence rates between men and women were similar (43.3% vs 42.0%, P = .728), but the late recurrence and rates of cancer-specific mortality in men were greater compared with women (17.2% vs 11.2%, P = .044; and 42.8% vs 34.3%, P = .022, respectively). Multivariable competing-risks regression analyses revealed no sex difference in early recurrence; however, men had greater late recurrence rate (hazard ratio, 1.752; 95% confidence interval, 1.145–2.682; P = .010) and rate of cancer-specific mortality (hazard ratio, 1.307; 95% confidence interval, 1.015–1.683; P = .038). ConclusionThere was no difference in early recurrence rate (≤2 years after resection between men and women, but men had significantly greater late recurrence (>2 years) and rates of cancer-specific mortality after hepatocellular carcinoma resection than women.

MP21-10 THE VARIABLE IMPACT OF RACE AND MORE IMPORTANT FACTORS ON PROSTATE CANCER MORTALITY

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I1 Apr 2018MP21-10 THE VARIABLE IMPACT OF RACE AND MORE IMPORTANT FACTORS ON PROSTATE CANCER MORTALITY Heidi Hanson, Christopher Martin, Brock O'Neil, Erik Mayer, Claire Leiser, and William Lowrance Heidi HansonHeidi Hanson More articles by this author , Christopher MartinChristopher Martin More articles by this author , Brock O'NeilBrock O'Neil More articles by this author , Erik MayerErik Mayer More articles by this author , Claire LeiserClaire Leiser More articles by this author , and William LowranceWilliam Lowrance More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.701AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES African American race has been linked to increased risk for prostate cancer mortality by both biological and epidemiologic mechanisms. Based on this information, many experts suggest African American race as an important prostate cancer risk factor, potentially exposing these men to variations in screening or treatment. However, some studies that adjust for access to care or other healthcare related variables have failed to find an increase in risk among African Americans. In our study, we intend to measure the relative impact of individual, disease specific, and county level factors on the risk of cancer specific mortality in men with prostate cancer. METHODS Using SEER data linked to the Area Health Resource File we identified men with prostate cancer diagnosed at age 60-79 between 2004-2012. For these patients we analyzed the affect of both individual and county level characteristics and their relative contribution to risk of prostate cancer specific mortality. Stage is based on information collected under the Collaborative Stage Data Collection System (CS) and coded using the CS algorithm. Tumor grade was based on gleason grading system. Patients with unknown clinical values were placed into a separate unknown category. RESULTS Figure 1 shows the variable importance measures. As expected, stage, Gleason score, and PSA are the most important predictors of prostate cancer survival. County level measures of the number of doctors, social vulnerability, and median family income are also important variables in predicting prostate cancer mortality. CONCLUSIONS The major determinants of mortality in prostate cancer were disease specific factors. Although African American race had a measurable impact, factors related to healthcare access and quality of care (factors known to be associated with African American race) had a stronger affect. Our results suggest the elevated risk identified in African Americans is largely driven by confounding factors associated with African American race. Thus, if factors other than biology or tumor characteristics underlie the elevations in risk found in African Americans, reducing the racial disparities in care rather than individualizing care based on race is more likely to improve prostate cancer outcomes. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e266 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Heidi Hanson More articles by this author Christopher Martin More articles by this author Brock O'Neil More articles by this author Erik Mayer More articles by this author Claire Leiser More articles by this author William Lowrance More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study

BackgroundThe purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.MethodsWe applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.ResultsThe PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).ConclusionsThis validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

Validation of a genomic risk classifier to predict metastasis and prostate cancer-specific mortality in men with positive lymph nodes.

125 Background: Men with lymph node involvement (LNI) at prostatectomy (RP) are at high risk of dying from prostate cancer. However, survival following RP is highly variable, with some men apparently cured. Nomograms developed for men with LNI have been based on series where all or the vast majority of men received adjuvant treatment. Because administration of adjuvant treatment is not universal, even for LNI, we evaluated whether the Decipher genomic classifier (GC) can improve upon clinical models to predict metastasis within 5 years (MET5) and prostate cancer specific mortality within 10 years (PCSM10) in a cohort of LNI patients, the majority of whom did not receive adjuvant treatment. Methods: 141 patients from 4 institutions (Johns Hopkins, Mayo Clinic, Leuven, MD Anderson) had LNI at RP, had adequate tissue and clinical data for analysis of MET5, and 86 were analyzed for PCSM10. 43% of men received adjuvant therapy. RP tumor tissue was analyzed by Affymetrix Human Exon 1.0 ST GeneChip; the GC was calculated based on 22 genes in the previously trained and validated algorithm. Logistic regression evaluated whether the GC, dichotomized as high risk (GC score &gt; 0.6) vs low-intermediate risk (≤0.6), improved prediction of MET5 and PCSM10 beyond that achieved with established clinical prognostic factors. Results: 62 men (43%) developed MET5, and 35 (41%) developed PCSM10. For both MET5 and PCSM10 CAPRA-S, number of positive lymph nodes, and age were significant; adjuvant therapy was not significant. GC was a significant independent strong prognostic factor when added to the clinical model for prediction of MET5, odds ratio = 4.04 (95% CI: 1.48, 11.02), p = 0.006, and prediction of PCSM10, odds ratio = 6.71 (95% CI: 2.01, 22.38), p = 0.002. Addition of GC to the clinical model improved the AUC from 0.77 to 0.79 for MET5, and from 0.65 to 0.74 for PCSM10. Conclusions: The Decipher GC significantly improves upon clinical variables to predict metastasis and prostate cancer specific mortality in men at high risk due to LNI. This is the first study to show a genomic classifier predicts outcomes in men with LNI; validation is needed to determine if Decipher can improve treatment decisions in men with LNI.

Drugs for metabolic conditions and prostate cancer death in men on GnRH agonists.

To evaluate whether drugs for metabolic conditions influence prostate cancer-specific mortality in men starting gonadotrophin-releasing hormone (GnRH) agonists, as it is unclear whether metabolic syndrome and its related drugs is affecting treatment response in men with prostate cancer on GnRH agonists. We selected all men receiving GnRH agonists as primary treatment in the Prostate Cancer data Base Sweden (PCBaSe) (n = 9267). Use of drugs for metabolic conditions (i.e. anti-diabetes, anti-dyslipidaemia, and antihypertension) in relation to all-cause, cardiovascular disease (CVD), and prostate cancer-specific death were studied using multivariate Cox proportional hazard and Fine and Gray competing regression models. In all, 6322 (68%) men used at least one drug for a metabolic condition at GnRH agonist initiation: 46% on antihypertensive drugs only, 32% on drugs for dyslipidaemia and hypertension, and ~10% on drugs for more than two metabolic conditions. Cox models indicated a weak increased risk of prostate cancer death in men who were on drugs for hypertension only (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.03-1.23) or drugs for hyperglycaemia (HR 1.19, 95% CI 1.06-1.35) at GnRH agonist initiation. However, upon taking into account competing risk from CVD death, none of the drugs for metabolic conditions were associated with an increased risk of prostate cancer death. We did not find evidence for a better or worse response to GnRH agonists in men with prostate cancer who were also on drugs for hypertension, dyslipidaemia, or hyperglycaemia.

Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features

BackgroundRisk of prostate cancer-specific mortality (PCSM) is highly variable for men with adverse pathologic features at radical prostatectomy (RP); a majority will die of other causes. Accurately stratifying PCSM risk can improve therapy decisions. ObjectiveValidate the 22 gene Decipher genomic classifier (GC) to predict PCSM in men with adverse pathologic features after RP. Design, setting, and participantsMen with adverse pathologic features: pT3, pN1, positive margins, or Gleason score >7 who underwent RP in 1987–2010 at Johns Hopkins, Cleveland Clinic, Mayo Clinic, and Durham Veteran's Affairs Hospital. We also analyzed subgroups at high risk (prostate-specific antigen >20 ng/ml, RP Gleason score 8–10, or stage >pT3b), or very high risk of PCSM (biochemical recurrence in<2 yr [BCR2], or men who developed metastasis after RP [MET]). Outcome measurements and statistical analysisLogistic regression evaluated the association of GC with PCSM within 10 yr of RP (PCSM10), adjusted for the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S). GC performance was evaluated with area under the receiver operating characteristic curve (AUC) and decision curves. Results and limitationsFive hundred and sixty-one men (112 with PCSM10), median follow-up 13.0 yr (patients without PCSM10). For high GC score (> 0.6) versus low-intermediate (≤ 0.6), the odds ratio for PCSM10 adjusted for CAPRA-S was 3.91 (95% confidence interval: 2.43–6.29), with AUC=0.77, an increase of 0.04 compared with CAPRA-S. Subgroup odds ratios were 3.96, 3.06, and 1.95 for high risk, BCR2, or MET, respectively (all p<0.05), with AUCs 0.64–0.72. GC stratified cumulative PCSM10 incidence from 2.8% to 30%. Combined use of case-control and cohort data is a potential limitation. ConclusionsIn a large cohort with the longest follow-up to date, Decipher GC demonstrated clinically important prediction of PCSM at 10 yr, independent of CAPRA-S, in men with adverse pathologic features, BCR2, or MET after RP. Patient summaryDecipher genomic classifier may improve treatment decision-making for men with adverse or high risk pathology after radical prostatectomy.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study

The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men). The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation.

Cancer Specific Mortality in Men Diagnosed with Prostate Cancer before Age 50 Years: A Nationwide Population Based Study

We compared clinical characteristics and cancer specific mortality in men diagnosed with prostate cancer before vs after age 50 years. A total of 919 men 35 to 49 years old and 45,098 men 50 to 66 years old who were diagnosed with prostate cancer between 1998 and 2012 were identified in PCBaSe (Prostate Cancer data Base Sweden). Cancer specific mortality was compared among age groups (35 to 49, 50 to 59, 60 to 63 and 64 to 66 years) with and without adjusting for cancer characteristics, comorbidity and education in a multivariable Cox proportional hazards model. Clinical cancer characteristics indicated that most nonmetastatic cancer in men younger than 50 years was detected after prostate specific antigen testing. The proportion of nonmetastatic vs metastatic disease at diagnosis was similar in all age groups. A strong association between younger age and poor prognosis was apparent in men in whom metastatic disease was diagnosed before age 50 to 55 years. The crude and adjusted HRs of cancer specific mortality were 1.41 (95% CI 1.12-1.79) and 1.28 (95% CI 1.01-1.62) in men diagnosed before age 50 and at age 50 to 59 years, respectively. In men with nonmetastatic disease crude cancer specific mortality increased with older age but adjusted cancer specific mortality was similar in all age groups. Our findings suggest that an aggressive form of metastatic prostate cancer is particularly common in men younger than 50 to 55 years. Genetic studies and trials of intensified systemic treatment are warranted in this patient group.

A novel technique to predict non-cancer and cancer-specific mortality in men with prostate cancer.

e16608Background: Treatment decisions in localized prostate cancer hinge on an accurate estimation of patient survival, yet we lack robust survival prediction tools. Current cancer prediction model...

Men presenting with prostate-specific antigen (PSA) values of over 100ng/mL.

To investigate overall survival and prostate cancer-specific mortality in men with prostate cancer presenting with a PSA level <100ng/mL at the time of diagnosis. Five-thousand seven hundred and sixteen patients with prostate cancer and a recorded diagnostic PSA level extracted from the South Australian Prostate Cancer Clinical Outcomes Collaborative (SA-PCCOC) database. Men included were diagnosed between January 1998 and August 2013. Patients were divided into groups according to diagnostic PSA level: <20, 20-≤100, 100-≤200ng/mL, 200-≤500ng/mL, and >500ng/mL. Outcomes measured include overall survival and prostate cancer-specific mortality. Clinical stage, Gleason score and the presence of bony metastasis was evaluated to determine if they were prognostic factors in patients with PSA over 100 at diagnosis. Cox proportional hazards and competing risks regression were used to model overall survival and prostate cancer-specific mortality outcomes respectively. Of this cohort, 241 patients (4.2%) had a diagnostic PSA level >100ng/mL. Patients with PSA >100ng/mL have a significant reduction in five (29.1% vs 62.5% vs 87%) and ten-year (18.2% vs 36.7% vs 70.7%) overall survival when compared to men with diagnostic PSA 20-100 and <20ng/mL respectively. In this group, prostate cancer-specific mortality was associated with Gleason score and metastases, but not PSA level at diagnosis. Overall survival was associated with PSA level, Gleason score and age. There was a linear increase in risk (overall survival) as PSA increased until 200 and no association thereafter. Models of overall survival and prostate cancer-specific mortality incorporating a risk stratification developed by Izumi etal. predicted overall survival but not prostate cancer-specific mortality. The use of this stratification did not improve model accuracy. Only a small number of men (4.2%) with prostate cancer present with PSA >100ng/mL at diagnosis. Overall survival at five and ten years was significantly poorer in patients with PSA >100ng/mL. In this cohort of men presenting with PSA >100 at diagnosis, PSA level was not associated with prostate cancer-specific mortality. Gleason score and metastases are significant prognostic factors in this group of men.

Effect of exposure to alpha blockers on cancer-specific and overall mortality in men with prostate cancer: a population-based cohort study

BackgroundProstate cancer is the second most common cause of deaths from cancer in men in the UK, accounting for 13% of male cancer mortality in 2010. Conventional treatment results in cure for some patients but does not prevent the metastasis that occurs frequently in others. Radical new therapies are needed to tackle this cancer progression. Alpha blockers are often given for cardiovascular indications and benign prostatic hyperplasia. In mouse models, they reduce angiogenesis and suppress metastasis. This study aimed to determine the effect of alpha blockers on mortality outcomes in a population-based cohort of men with prostate cancer. MethodsThis cohort study used data on 18 654 men with incident prostate cancer from linked UK Clinical Practice Research Datalink, Hospital Episode Statistics, and the National Cancer Intelligence Network between 1998 and 2010. All alpha blocker use in the 6 months after diagnosis of cancer was determined and its effect on all-cause and cancer-specific mortality assessed. Data were analysed with Cox proportional hazards modelling and adjusted for confounding by age, sex, cancer stage, grade, and important comorbidities and coprescriptions. A sensitivity analysis in patients with an indication of hypertension, interaction by dose, and prediagnosis exposure were also considered. FindingsMedian follow-up was 4·5 years (IQR 2·2–7·3). Crude mortality rate was 42·2/1000 per year in patients exposed to alpha blockers and 49·6/1000 per year in those unexposed, equivalent to a decreased all-cause mortality (adjusted hazard ratio 0·839, 95% CI 0·776–0·908); crude cancer mortality rate was 20·7/1000 per year and 23·3/1000 per year, respectively, equivalent to a decreased prostate cancer mortality (0·874, 0·781–0·978). In men taking alpha blockers to treat hypertension the effect on all-cause mortality became non-significant (0·857, 0·728–1·217), but a significant decrease in prostate cancer mortality remained (0·692, 0·534–0·897) with a crude cancer mortality rate of 18·5/1000 per year and 27·7/1000 per year in those exposed and unexposed, respectively. No modifying effects were observed by dose and prediagnosis exposure. InterpretationAlpha blocker use was associated with decreased cancer-specific mortality in men with prostate cancer. FundingFunding for this project was obtained from the Rosetree Trust, Niger Delta Development Commission (NDDC), and the University of Nottingham. The funders had no involvement in the concept, design, protocol, analysis, or the writing up of this study.

Abstract 4985: Notch1 as a key mediator in promoting advanced castration-resistant prostate cancer

Abstract The first line of treatment for men with advanced prostate cancers is androgen deprivation therapy. However, the disease commonly relapses in its lethal metastatic form referred to as castration-resistant prostate cancer (CRPC). CRPC is the primary cause of prostate cancer specific mortality in men. Current therapies including chemotherapeutic agents improve median overall survival by only few months. The mechanisms that distinguish clinically localized indolent tumors from lethal CRPC are unclear. Here we demonstrate that ectopic expression of Notch1 promotes progression to poorly differentiated carcinoma when combined with pathways that are altered in advanced disease but are insufficient to drive aggressive prostate cancer alone. Notch1 driven tumors are resistant to androgen deprivation. Transcriptional profiling reveals that these tumors display features of epithelial to mesenchymal transition, a morphological change associated with tumor aggressiveness and metastasis. Our study provides the first functional evidence that Notch1 signaling axis is a key mediator in promoting advanced prostate cancer and may represent a new therapeutic target for the advanced disease. Note: This abstract was not presented at the meeting. Citation Format: Tanya Stoyanova, Claire Faltermeier, Bryan Smith, Andrew Goldstein, Xi Zhang, Justin Drake, John Lee, Sandra Orellana, Steven Blum, Donghui Cheng, Kenneth Pienta, Jiaoti Huang, Owen Witte. Notch1 as a key mediator in promoting advanced castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2015-4985