Screen-detected Prostate Cancer Research Articles

Association of race with incidence, characteristics, and mortality from incidental prostate cancer: Analysis of two North American contemporary cohorts.

Non-Hispanic Black (NHB) men are at higher risk both for incidence and mortality from prostate cancer (PCa) compared to Non-Hispanic White (NHW) men, but these findings arise from biopsy-detected PCa reports. We aimed to compare the incidence, subsequent management and cancer-specific mortality (CSM) of incidental PCa among NHB and NHW men, using two different North American cohorts. The Surveillance, Epidemiology and End-Result (SEER: 2004-2017) and our institutional Henry Ford Health (HFH: 1995-2022) databases were queried to identify men diagnosed with incidental PCa. Cumulative incidence estimates were used to calculate CSM differences between NHB and NHW men. Competing-risk multivariable regression analysis tested the impact of race on CSM, after accounting for all available covariates. A total of 418 and 6,124 incidental PCa cases were recorded in HFH and SEER database respectively. No pathological differences were observed between NHB and NHW men in both the cohorts, except for prostate-specific antigen (PSA) value at diagnosis, which was higher in NHB men. At 10-years, the CSM rates were 5.5% vs 7.2% in our cohort and 8.6% vs 10.3% in the SEER cohort for NHW and NHB men, respectively (all Gray's test p-value > 0.05). At multivariable, race was not an independent predictor of CSM in our HFH cohort (HR: 1.46, 95% CI: 0.57-3.71, p = 0.6). In the SEER cohort, NHB men were 34% less likely to die from PCa from 1 year to the next (95% CI: 0.49-0.90, p = 0.008), when compared with NHW men. In the comparison of incidental PCa findings between NHB and NHW men, both groups had similar pathological characteristic and survival outcomes. These findings are different from the 'conventional' screening-detected PCa and suggest that racial differences have minimal to no adverse effects on PCa-specific mortality after incidental diagnosis.

Overdiagnosis for screen-detected prostate cancer incorporating patient comorbidities

Abstract Background Evidence regarding the likelihood of overdiagnosis in prostate cancer (CaP) screening with PSA are mainly based on clinical trials, which include younger population with fewer comorbidities than those receiving the test in clinical practice. We aimed to assess the likelihood of overdiagnosis and associated variables using real-world data. Methods Retrospective cohort of men >40 years with PCa, who had been diagnosed being asymptomatic and after a positive PSA test in the previous 12 months in two hospitals (2004-2022). The probability of overdiagnosis was estimated considering the life expectancy of the Spanish male in the year 2022 and the Charlson Comorbidity Index (lead time 10 years). PSA values and Gleason score were included as independent variables. Results Of the 2,331 patients in the cohort, 1,070 (46%) met the inclusion criteria for this analysis. The median follow-up time was 5.7 years (IQR 3.2-8.6). The median age was 71 years (IQR 65-78) and 37% had more than one comorbidity. At diagnosis, the median life expectancy was 12 years (IQR 4-18) and the probability of overdiagnosis was 30.8% (IQR 17.6-52.4). Patients with PSA levels >10 mg/dl tended to be older and with more comorbidities than those with PSA levels 4-10 mg/dl, and thus, with shorter life expectancy. The median probability of overdiagnosis was higher in patients with PSA levels >10 mg/dl (41.4%, IQR 21.5-73.9) than in those with PSA levels 4-10 mg/dl (20.1%, IQR 12.8-30.4), p < 0.001. Correspondingly, patients with Gleason score ≥8 were more likely to be overdiagnosed (median 42.6%, IQR 23.6-68.6) than those with Gleason score ≤6 (median 20.1%, IQR 12.8-30.4) (p < 0.001). Conclusions In clinical practice, older patients with comorbidities showed high PSA levels and Gleason score ≥8, presenting low life expectancy at diagnosis and, therefore, high probability of overdiagnosis. This highlights the importance of considering the patient’s comorbidities when ordering a new PSA test. Key messages • A detailed assessment of the prevalence of comorbidities among CaP patients in real-life settings has significant implications for patient management. • The decision to make an early diagnosis should be based on individual life expectancy, where comorbidity is at least as important as age.

Prostate Cancer Screening in Young Men.

Background: Prostate cancer (PCa) screening strategies are being developed and evaluated in several countries. However, most of the evidence regarding PCa screening has been generated in study populations aged 50 and older. Aims: This study summarizes findings of a screening trial in younger men and discuss those findings in the context of other screening trials. Methods: Non-systematic review. Results: Screening of 45-year-old men resulted in a low PCa detection rate. Nonetheless, almost 70% of screen-detected PCa at this age was clinically significant. In young men ISUP GG 1 screen-detected cancers warrant rigorous follow-up. A baseline, midlife prostate-specific antigen (PSA) value at age 45 may safely exclude the vast majority of men from further screening investigations for at least 5 years. At age 45, a confirmatory PSA value reduces the number of subsequent tests almost by half. Sequential magnetic resonance imaging (MRI) as a reflex test subsequent to an elevated PSA ≥ 3 ng/mL needs further investigation in young men. Conclusions: Screening in young men needs to be carefully investigated in order to avoid overscreening and overdiagnosis.

Machine-learning Algorithm-based Risk Prediction and Screening-detected Prostate Cancer in A Benign Prostate Hyperplasia Cohort.

Prostate cancer (PCa) is lethal. Our aim in this retrospective cohort study was to use machine learning-based methodology to predict PCa risk in patients with benign prostate hyperplasia (BPH), identify potential risk factors, and optimize predictive performance. The dataset was extracted from a clinical information database of patients at a single institute from January 2000 to December 2020. Patients newly diagnosed with BPH and prescribed alpha blockers/5-alpha-reductase inhibitors were enrolled. Patients were excluded if they had a previous diagnosis of any cancer or were diagnosed with PCa within 1 month of enrolment. The study endpoint was PCa diagnosis. The study utilized the extreme gradient boosting (XGB), support vector machine (SVM) and K-nearest neighbors (KNN) machine-learning algorithms for analysis. The dataset used in this study included 5,122 medical records of patients with and without PCa, with 19 patient characteristics. The SVM and XGB models performed better than the KNN model in terms of accuracy and area under curve. Local interpretable model-agnostic explanation and Shapley additive explanations analysis showed that body mass index (BMI) and late prostate-specific antigen (PSA) were important features for the SVM model, while PSA velocity, late PSA, and BMI were important features for the XGB model. Use of 5-alpha-reductase inhibitor was associated with a higher incidence of PCa, with similar survival outcomes compared to non-users. Machine learning can enhance personalized PCa risk assessments for patients with BPH but more research is necessary to refine these models and address data biases. Clinicians should use them as supplementary tools alongside traditional screening methods.

Prostate cancer characteristics: A descriptive analysis of clinical features at presentation in the last decade in a black African community.

Background:Prostate cancer, previously reported as relatively rare in Nigeria, is currently the leading cancer and leading cause of cancer-related death in men. Late presentation appears to persist despite higher incidence rates and instituted awareness programs. This study assesses current prostate cancer indices at presentation to a 3rd tier referral hospital in South-east Nigeria and compares these indices with reported indices from previous decades.Materials and Methods:Retrospectively, the medical records of men presenting with histologically confirmed prostate cancer from January 2009 to April 2018 were reviewed. Age, spectrum and duration of clinical features, serum total prostate-specific antigen (tPSA), and prostate biopsy specimen Gleason Score (GS) at presentation were retrieved for the analysis using the SPSS software version 21. Obtained mean values and proportions were compared to reports from previous decades for observable shifts.Results:The medical records of 331 men 51–90 years of age (mean: 69.8 ± 8.0 years) were retrieved. Six (1.8%) men (median tPSA = 28.0 ng/ml; range 10.0–121.4 ng/ml) had screening-detected prostate cancer. About 72.0%, 52.0%, and 30.3% of men present with symptoms after 3 months, 6 months, and 12 months, respectively, and about 55.1% had other clinical features of disease progression beyond lower urinary tract symptoms. Symptom duration, serum tPSA (median 31.4 ng/ml; range 4.0–710.0 ng/ml), and % fPSA (median 20.6%; range 57.1%–8.6%) at presentation, as well as prevalent poorly-differentiated tumor (GS ≥7 [4 + 3] 62.2%) are yet to shift from reports from previous decades.Conclusions:Prostate cancer indices at presentation in South-eastern Nigeria, a resource-poor community in sub-Saharan Africa are yet to positively shift despite efforts at prostate cancer awareness.

The Association Between Age, Prostate Cancer Risk, and Higher Gleason Score in a Long-term Screening Program: Results from the Göteborg-1 Prostate Cancer Screening Trial

BackgroundStudies have suggested associations between greater age, increased risk of prostate cancer (PC), and higher Gleason score. ObjectiveThe present study aimed at investigating these associations within the Göteborg-1 randomized, population-based PC screening trial. Design, setting, and participantsThe screening arm of the Göteborg-1 screening trial comprises 10000 randomly selected men (aged 50–64 yr at randomization) from the Göteborg region of Sweden. Between 1995 and 2014, they were biennially invited to prostate-specific antigen (PSA) testing to an upper age limit of 70 yr (range 67–71 yr). PSA ≥3 ng/ml triggered a prostate biopsy (sextant biopsy 1995–2009, thereafter a ten-core biopsy). Outcome measurements and statistical analysisThe impact of age on Gleason score, given a screen-detected PC, was investigated with multinomial logistic regression analyses adjusted for year of testing and screening round. Results and limitationsOverall, 7625 men had at least one PSA test and 1022 men were diagnosed with PC. For men with screen-detected PC, age was associated with the risk of clinically significant PC above and beyond screening round and year of testing (p < 0.001). For each 1-yr increase in age, the risk of being diagnosed with a Gleason score ≥3 + 4 cancer (vs <7) increased by 11% (95% confidence interval [CI] 4.7–17), whereas the risk of being diagnosed with a Gleason score ≥4 + 3 cancer (vs <7) increased by 8.5% (95% CI –1.6 to 20). ConclusionsThe increased risk of a higher Gleason score in older men should be considered when counseling men regarding early diagnosis and treatment for PC. Patient summaryWe found that older age increased both the risk of prostate cancer and the risk of more aggressive prostate cancer.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

SummaryBackgroundLynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.MethodsThe IMPACT study is an international, prospective study. Men aged 40–69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.FindingsBetween Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1–2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3–7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0–2·6), MSH6 carriers was 3·0% (four of 135; 0·8–7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0–68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3–46·0).InterpretationAfter the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.FundingCancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Prostate cancer in the British Asian population: A case-control study

Objectives: To study demographic and disease variables at presentation, diagnosis and treatment of prostate cancer in British South Asian (SA) men and compare with their Caucasian counterparts. Methods: A retrospective review of prostate cancer cases between 2010 and 2015 identified patients of SA descent who were matched for age, residential location and year of diagnosis with two Caucasian patients. Disease characteristics, treatment and short-term outcomes were recorded and compared. Results: A total of 1274 patients were diagnosed, of which 50 (3.9%) were SA. SA patients had less screen-detected prostate cancer (12% versus 31%, p=0.02), more co-morbidity and more high-risk disease (57% versus 37%, p=0.03). Active surveillance was the preferred treatment option (32%) with 2% having surgery compared with 22% ( p=0.003) from the Caucasian cohort. Logistic regression showed these disparities to be related to the different presentations. Conclusion: SA men with prostate cancer are less likely to be diagnosed following asymptomatic screening and the majority have high-risk disease at presentation. These differences lead to SA men preferring active surveillance to radical surgery. Given the increasing British Asian population, the findings demonstrate a need for research and public health interventions to better understand and address the differences noted between these groups.

Height, body mass index and prostate cancer risk and mortality by way of detection and cancer risk category.

Obesity is a risk factor for advanced, but not localised, prostate cancer (PCa), and for poor prognosis. However, the detection of localised PCa through asymptomatic screening might influence these associations. We investigated height and body mass index (BMI) among 431 902 men in five Swedish cohorts in relation to PCa risk, according to cancer risk category and detection mode, and PCa-specific mortality using Cox regression. Statistical tests were two-sided. Height was positively associated with localised intermediate-risk PCa (HR per 5 cm, 1.03, 95% CI 1.01-1.05), while overweight and obesity were negatively associated with localised low- and intermediate-risk PCa (HRs per 5 kg/m2 , 0.86, 95% CI 0.81-0.90, and 0.92, 95% CI 0.88-0.97). However, these associations were partially driven by PCa's detected by asymptomatic screening and, for height, also by symptoms unrelated to PCa. The HR of localised PCa's, per 5 kg/m2 , was 0.88, 95% CI 0.83 to 0.92 for screen-detected PCa's and 0.96, 95% CI 0.90 to 1.01 for PCa's detected through lower urinary tract symptoms. BMI was positively associated with PCa-specific mortality in the full population and in case-only analysis of each PCa risk category (HRs per 5 kg/m2 , 1.11-1.22, P for heterogeneity = .14). More active health-seeking behaviour among tall and normal-weight men may partially explain their higher risk of localised PCa. The higher PCa-specific mortality among obese men across all PCa risk categories in our study suggests obesity as a potential target to improve the prognosis of obese PCa patients.

Proteomic Tissue-Based Classifier for Early Prediction of Prostate Cancer Progression.

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.

Irreversible electroporation (IRE): a narrative review of the development of IRE from the laboratory to a prostate cancer treatment.

Whilst whole-gland radical treatment is highly effective for prostate cancer control, it has significant impact on quality of life and is unnecessary 'over-treatment' in many men with screening-detected prostate cancer. Improvements in prostate biopsy and imaging have led to increased interest in partial gland ablation to reduce treatment-related morbidity. Several energies for focal ablation have been trialled. Irreversible electroporation (IRE) is a novel technology that ablates tissue by delivering direct current between electrodes. This narrative review documents the history of electroporation including its scientific basis, early data from pre-clinical animal studies, and contemporary clinical outcomes from the use of IRE in prostate cancer. A literature search using the Medical Literature Analysis and Retrieval System Online (MEDLINE), the Excerpta Medica dataBASE (EMBASE), PubMed and Google Scholar was undertaken to identify historical perspectives and current clinical data relating to IRE for prostate cancer. The history of electroporation and its implementation as a prostate cancer treatment was following the basic scientific principles, in vitro data, then animal studies, and now short- to medium-term clinical cohorts in humans. The results of IRE on >283 patients have been published in several papers, with preserved rates of (pad-free) continence in 91-100% of men and preserved erectile function in 79-100% of men. In-field recurrence rates range from 0% to 33%. The current state of evidence for IRE for the treatment of primary and salvage prostate cancer is considered as Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) stage 2B. IRE is a new focal ablative technology for the treatment of localised prostate cancer in carefully selected men. Published cohorts report encouraging short-term oncological and functional outcomes; however, longer-term data are needed to validate this treatment before it can be recommended for widespread clinical use.

Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received

BackgroundThe ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. ObjectiveTo determine report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participantsThis study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. InterventionTwo cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment. Outcome measurements and statistical analysisHealth-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitationsAccording to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa. ConclusionsAnalyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summaryMore than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

Prostate cancer (PCa) is recognized as a disease possessing not only great variation in its geographic and racial distribution but also tremendous variation in its potential to cause morbidity and death and it, therefore, ought not to be considered a homogenous disease entity. Morbidity and death from PCa are disproportionately higher in men of African ancestry (MAA) who are generally observed to have more aggressive disease and worse outcomes following treatment compared to men of European ancestry (MEA). The higher rates of PCa among MAA relative to MEA appear to be multifactorial and related to inherent differences in biological aggressiveness; a continued lack of awareness of the disease and methods of prevention; a lower prevalence of screen-detected PCa; comparatively lower access to quality healthcare as well as systemic and institutionalized disparities in the administration of optimal care to MAA in developed countries such as the United States of America where high-quality care is available. Even when access to quality healthcare is assured in equal access settings, it appears that MAA still have worse outcomes after PCa treatment stage-for-stage and grade-for-grade compared to MEA, suggesting that, inherent racial, ethnic and biological differences are paramount in predicting poor outcomes. This review has explored the different contributing factors to the current disparities in PCa incidence and mortality rates with emphasis on the incongruence in how research has been conducted in understanding the disease towards developing therapies.

Personalized Risks of Over Diagnosis for Screen Detected Prostate Cancer Incorporating Patient Comorbidities: Estimation and Communication.

Shared patient-physician decision making regarding the treatment of prostate cancer detected by prostate specific antigen screening involves a complex calculus weighing cancer risk and patient life expectancy. We sought to quantify these competing risks using the probability that the cancer was over diagnosed, ie would not have been clinically diagnosed (diagnosed without screening) during the remaining lifetime of the patient. Using an established model of prostate cancer screening and clinical diagnosis we simulated screen detected cases and determined whether a modeled clinical diagnosis would occur before noncancer death. Time of noncancer death was based on comorbidity adjusted population lifetables. Logistic regression models were fitted to the simulated data and used to estimate over diagnosis probabilities given patient age, prostate specific antigen level, Gleason sum and comorbidity category. An online calculator was developed to communicate over diagnosis estimates. Face validity and ease of use were assessed by surveying 32 clinical experts. Estimated probabilities of over diagnosis ranged from 4% to 78% across clinicopathological variables and comorbidity status. When ignoring comorbidity, the estimated probability of over diagnosis in a 70-year-old man with prostate specific antigen 9.4 ng/ml and Gleason 6 was 34%. With severe comorbidities the estimate increased to 51%. Such a personalization may help inform the choice between active surveillance and definitive treatment. Based on responses from 20 of 32 experts we modified the explanation of over diagnosis for the online calculator and the input method for comorbid conditions. The probability of over diagnosis is strongly influenced by comorbidity status in addition to age. Personalized estimates incorporating comorbidity may contribute to shared decision making between patients and providers regarding personalized treatment selection.

Abstract 3165: Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data

Abstract Introduction: Although many (~40%) of the screen-detected prostate cancers are indolent (Gleason Score &amp;lt;= 6) and pose minimal risk for progression, advanced stage prostate cancer is a lethal disease with 5-year survival rates around 29%. The challenge is to identify biomarkers for early detection of aggressive disease, when the cancer is still organ confined. Such markers would be also used to better select patients with indolent and low risk cancers for active surveillance. Material and Methods: To identify a panel of protein markers that could predict prostate cancer progression, we developed ultra-sensitive, high-pressure, high-resolution separations coupled with intelligent selection and multiplexing-selected reaction monitoring (PRISM-SRM) assays for 52 protein markers. Candidate protein markers were identified and selected from existing prostate cancer genomics data sets and validated lists of known prostate cancer drivers. The PRISM-SRM assays used heavy isotope-labeled synthetic peptides as internal standards for quantitative proteomics analysis. Study comprised of a prostate cancer patient cohort with organ confined primary tumors (N=338) presenting following post-surgery features: 53 (15.7%) metastatic progression, 124 (36.7%) biochemical recurrence (BCR), and 161 (47.6%) no progression after more than ten years of follow-up after radical prostatectomy. Index tumor region for each case was scraped from representative 10-m sections of formalin-fixed paraffin embedded (FFPE)-whole-mounted prostatectomy specimens and processed for PRISM-SRM analysis. Results: Overall, PRISM-SRM analysis of the FFPE tissue samples enabled the detection of 42 (80.8%) out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 (40.4%) of these candidates at the protein level. Kruskal-Wallis testing was used for statistical evaluation of the PRISM-SRM results and comparison of relative protein levels between the “no progression”, BCR and “metastatic progression” groups. Several prostate differentiation/androgen receptor signaling related proteins (FOLH1, PSA and NCOA) and tumor progression-related proteins (TGFB1, CCND1 and SPRC) had significantly different expression levels between the three groups, and showed initial promise in predicting progression to invasive cancer, BCR and metastasis. Conclusion: Ultra-sensitive targeted proteomics can be used to select and verify performance of early prognostic markers based on the analysis of prostatectomy specimens. The top performing markers appeared able to predict progression from organ confined cancer to BCR and metastasis. Citation Format: Yuqian Gao, Yi-Ting Wang, Hui Wang, Denise Young, Jennifer Cullen, Yingjie Song, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Inger Rosner, Karin Rodland, Isabell Sesterhenn, Shiv Srivastava, Tao Liu. Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3165.

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Prostate Cancer Screening in Men of African Descent: 15-year Results of the Tobago Prostate Cancer Survey

Objective: To compare all-cause-mortality in screening-detected prostate cancer cases versus non-cases after a median 12.2-year follow-up. Methods: In this prospective, population-based study of 3089 Afro-Caribbean men aged 40–79 years in Tobago, Trinidad and Tobago, West Indies, all men were screened for prostate cancer (serum prostate specific antigen and/or digital rectal exam) one to three times between 1997 and 2007 and followed for mortality to 2012. Among 502 men diagnosed with prostate cancer, 81 younger men underwent radical retropubic prostatectomy. Minimal treatment was available for older men. Survival curves compared all-cause-mortality in cases versus non-cases within 10-year age groups at first screening. Results: There were 350 all-cause-deaths over 34 089 person-years of follow-up. All-cause-survival curves in men aged 60 years or above at first screening did not diverge between cases and non-cases until after 10–12 years of follow-up (p &gt; 0.36). In contrast, among men first screened at age 50–59 years, survival was lower in cases, with survival curves diverging at seven years (p = 0.003). Survival in men aged 50–59 years who underwent prostatectomy was similar to survival in non-cases (p = 0.63). Conclusion: Among men aged 60 years or above, the absence of excess all-cause-mortality among screening-detected prostate cancer cases provides argument against the utility of routine prostate cancer screening in this older population of African descent. However, the significantly poorer survival in men aged 50–59 years with screening-detected prostate cancer, compared with screened men without prostate cancer, along with the potential for prostate cancer treatment to improve survival, supports the continuation of prostate cancer screening in this age group, pending further research to assess the risks and benefits.

P034 - Predicting biochemical recurrence and prostate cancer specific mortality following biochemical recurrence after radical prostatectomy: Head-to-head comparison of six prediction models in a cohort of screen detected prostate cancer patients

P034 - Predicting biochemical recurrence and prostate cancer specific mortality following biochemical recurrence after radical prostatectomy: Head-to-head comparison of six prediction models in a cohort of screen detected prostate cancer patients

Abstract B006: Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk

Abstract Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression. Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.

Abstract 3332: Genome-wide DNA methylation profiling of peripheral blood leukocytes identifies predictors of aggressive prostate cancer

Abstract Background: Prostate cancer (PCa) is the most commonly diagnosed cancer for men in the United States. Most of the PSA screening-detected PCa are slow-growing and not life-threatening. However, the majority of PSA-detected PCa receive aggressive treatment, which is often associated with significant morbidity. Clinical variables, such as Gleason Score (GS), PSA level, and tumor stage, are not sufficient to distinguish aggressive from indolent diseases at diagnosis. Biomarkers are urgently needed for more accurate prediction of individual tumor behavior and patient prognosis. DNA methylation has shown profound impact on cancer development and progression. In this study, we performed a genome-wide DNA methylation profiling of peripheral blood leukocytes to identify predictors of aggressive PCa. Methods: We performed leukocyte DNA methylation profiling in 140 GS=6 PCa patients and 147 GS ≥ 8 patients using the Illumina's Methylation 450K BeadChip. The differential methylated CpG position (DMP) was identified using the ChAMP analysis package implemented in R. Top differentially methylated CpG sites between less aggressive (GS=6) and more aggressive (GS≥ 8) patients were used to develop a signature to best cluster these two groups using semi-supervised recursively partitioned mixture modeling (SS-RPMM) algorithm. The white blood cell subtype composition was analyzed with RefbaseEWAS method. Ingenuity pathway analysis was used to find the enriched pathways that may determine aggressive prostate cancer. Results: Analyzing all the assayed CpG sites together, the mean methylation level appeared to be lower in GS ≥ 8 patients than in GS=6 patients. This global DNA hypomethylation was only significant at CpG sites located within gene body, shore, shelf, opensea and 3' UTR regions, but not in promoter and regions close to transcription start sites. There were many individual hypermethylated CpG sites in GS ≥ 8 patients that are mostly located in CpG islands within promoter and in the vicinity of transcription start sites. We then split the patients into a training (70 GS=6 and 73 GS ≥ 8 patients) and testing set (70 GS=6 and 74 GS ≥ 8 patients) to identify and validate a CpG methylation signature that best differentiates GS=6 and GS≥ 8 patients. The signature can identify a subgroup of aggressive PCa patients with higher risks of biochemical recurrence (HR=2.57, 95% Cl, 0.99-6.68). We also analyzed the white blood cell subtypes in patients and found that natural killer (NK) cell proportion is significantly decreased in patients who experienced biochemical recurrence (P=0.045), indicating weakened immune response. Conclusion: These data suggest that DNA methylation in peripheral blood leukocytes may serve as valuable biomarkers to supplement clinical variables to predict aggressive PCa at diagnosis and worse prognosis of PCa patients. Citation Format: Yuyan Han, Jia Li, Mutian Zhang, Jeri Kim, Xifeng Wu, Deqiang Sun, Jian Gu. Genome-wide DNA methylation profiling of peripheral blood leukocytes identifies predictors of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3332.