Prostate Cancer Prevention Trial Research Articles

MP40-19 WEST-AFRICAN ANCESTRY CAN AID PREDICTION OF HIGH-GRADE PROSTATE CANCER IN BLACK-TAILORED RISK CALCULATOR

You have accessJournal of UrologyCME1 Apr 2023MP40-19 WEST-AFRICAN ANCESTRY CAN AID PREDICTION OF HIGH-GRADE PROSTATE CANCER IN BLACK-TAILORED RISK CALCULATOR Neil Mistry, Zequn Sun, Norma Marshall, Rick Kittles, Edward Schaeffer, Peter Gann, and Adam Murphy Neil MistryNeil Mistry More articles by this author , Zequn SunZequn Sun More articles by this author , Norma MarshallNorma Marshall More articles by this author , Rick KittlesRick Kittles More articles by this author , Edward SchaefferEdward Schaeffer More articles by this author , Peter GannPeter Gann More articles by this author , and Adam MurphyAdam Murphy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003278.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The Kaiser Permanent Prostate Cancer (KPPC), Prostate Cancer Prevention Trial (PCPT) and Prostate Biopsy Collaborative Group (PBCG) risk calculators (RCs) improve the detection of high-grade, Gleason Grade Group ≥2 prostate cancer (HGPCa) but result in excessive biopsies in Black men. Genetic West African Ancestry (WA) is associated with increased risk of HGPCa, but its impact on RC accuracy is unknown. We aimed to validate a tailored RC to improve accuracy and assess if WA can augment accuracy. METHODS: We recruited men undergoing prostate biopsy from 5 Chicago clinics from 2009-2014. We split the sample into development (75%) and validation (25%) cohorts. A second cohort from the same sites from 2016-2019 provided external validation. Exclusion criteria were non-Black race and PSA >50 ng/ml. We created 2 binary logistic regressions to predict HGPCa using clinical variables alone and including WA. Model accuracy was assessed using area under curve (AUC). RESULTS: 393 Black men were included for development/internal validation, and 354 for external validation. Table 1 shows model performance and comparisons to prior RCs. CONCLUSIONS: A tailored RC improves HGPCa prediction in Blacks compared to popular RCs. Including genetic ancestry as a risk factor alongside clinical variables may help alleviate PCa disparities faced by Black men. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e553 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neil Mistry More articles by this author Zequn Sun More articles by this author Norma Marshall More articles by this author Rick Kittles More articles by this author Edward Schaeffer More articles by this author Peter Gann More articles by this author Adam Murphy More articles by this author Expand All Advertisement PDF downloadLoading ...

Racial and Ethnic Disparity in Preference-Weighted Quality of Life: Findings from the Selenium and Vitamin E Cancer Prevention Trial.

Differences in preference-weighted health-related quality of life (HRQOL) scores by race/ethnicity may be due to social factors. Here, Short-Form Six-Dimension (SF-6D) scores are analyzed among men in a prostate cancer prevention trial to explore such differences. Selenium and vitamin E cancer prevention trial participants who completed the SF-6D at baseline, and in at least 1 of follow-up years 1, 3, and 5 were included. This study compared mean SF-6D scores across race/ethnicity at each point using a linear mixed model controlling for demographic and clinical characteristics. At baseline, 9691 men were eligible for analysis, of whom 7556 (78%) were non-Hispanic White, 1592 (16.4%) were non-Hispanic Black, and 543 (5.6%) were Hispanic. Hispanic and White participants had higher unadjusted mean SF-6D scores than Black participants at every time point (P < 0.05), while white participants had lower mean scores than Hispanic participants at every time point after baseline (P < 0.05). After adjusting for covariates, statistically significant differences in HRQOL among the 3 groups persisted. Hispanic participants had higher preference scores than White participants by 0.073 (P < 0.001), 0.075 (P < 0.001), and 0.040 (P < 0.001) in follow-up years 1, 3, and 5, respectively. Black participants had lower scores than White participants by 0.009 (P = 0.004) and 0.008 (P = 0.02) in follow-up years 1 and 3, respectively. The results suggest there is a preference-weighted HRQOL difference by race/ethnicity that cannot be explained by social and clinical variables alone. Understanding how individuals belonging to different racial/ethnic categories view their own HRQOL is necessary for culturally competent care and cost-effectiveness analyses.

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.

Feasibility and accuracy of prostate cancer risk calculators in prediction of prostate cancer, extraprostatic extension as well as the risk of lymph nodes metastasis.

The aim of this article was to evaluate the accuracy of European Randomized study of Screening for Prostate Cancer (ERSPC 4) and Prostate Cancer Prevention Trial (PCPT 2.0) risk calculator on predicting high-grade prostate cancer (HGPCa) and accuracy of Partin and Briganti nomograms on organ confined (OC) or extraprostatic cancer (EXP), seminal vesicles invasion (SVI) and risk of lymph nodes metastasis. A cohort of 269 men aged between 44-84 years, who underwent radical prostatectomy was retrospectively analysed. Based on estimated calculator risk, patients were divided into risk groups: low (LR), medium (MR) and high (HR). Results obtained with calculators were compared to post-surgical final pathology outcome. In ERPSC4, the average risk for HGPC was LR = 5%, MR = 21%, and HR = 64%. In PCPT 2.0, the average risk for HG was: LR - 8%, MR - 14%, and HR - 30%. In the final results, HGPC was observed in: LR = 29%, MR = 67%, and HR = 81%. In Partin, LNI was estimated to occur in: LR = 1%, MR = 2%, and HR = 7.5% and in Briganti: LR = 1.8%, MR = 11.4%, and HR = 44.2% while finally it was found in: LR = 1.3%, MR = 0%, and HR = 11.6%. ERPSC 4 and PCPT 2.0 corresponded well with each other as well as Partin and Briganti. ERPSC 4 was more accurate in predicting HGPC than PCPT 2.0. Partin was more accurate as for LNI than Briganti. In this study group a large underestimation was observed in reference to Gleason grade.

The effect of lowering cholesterol through diet on serum prostate-specific antigen levels: A secondary analysis of clinical trials.

Statins appear to lower serum prostate-specific antigen (PSA) and improve prostate cancer (PCa) outcomes through cholesterol-dependent and independent mechanisms. While dietary modifications have an established role in serum cholesterol reduction, whether diet-driven cholesterol reductions yield similar PCa benefits to that observed with statins is unclear. We aimed to study the effect of dietdriven cholesterol reduction on serum PSA and estimated-PCa risk. A total of 291 men from six published randomized controlled trials of dietary interventions were included. Men were aged ≥40 years, free of PCa, and had baseline PSA <10.0 ng/mL. Participants received one of four diets (high-fiber, low-glycemic index, low-glycemic load, or cholesterol-lowering) for 8-24 weeks. The primary outcome evaluated the association between change from baseline low-density lipoprotein cholesterol (LDL-C) and PSA. How cholesterol reduction modified PCa risk was estimated using the Prostate Cancer Prevention Trial (PCPT) risk calculator (limited to age ≥55 years, baseline PSA ≥1.0 ng/mL). Baseline PSA was 0.90 ng/mL (interquartile range [IQR] 0.55-1.60) and LDL-C was 90 mg/dL (IQR 69-125). In multivariate regression, PSA decreased 1.9% (95% confidence interval [CI] 0.55-3.2, p=0.005) per 10% reduction in LDL-C. This regression was greater in men with baseline PSA ≥2.0 ng/mL (-5.4%, 95% CI 2.2-8.6] per 10% LDL-C reduction, p-interaction=0.001). In men with estimable PCPT risk, statin-comparable LDL-C reductions (≥15%) reduced PSA by 12% (p<0.001) and estimated PCa risk by 6.5% (p=0.005). This is the first study to show that serum cholesterol reduction through dietary interventions significantly lowered serum PSA and estimated PCa risk. Whether cholesterol-lowering diets improve PCa outcomes warrants investigation.

Serum markers, obesity and prostate cancer risk: results from the prostate cancer prevention trial.

Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor 1 (IGF1) pathways. We investigated the association of circulating serum markers (e.g. androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF1 axis analytes. Logistic regression estimated odds ratio and 95% CIs for risk of overall, low-grade (Gleason 2-6), and high-grade (Gleason 7-10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF1 axis was significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.

Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial.

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Prostate Cancer Risk Calculators for Healthy Populations: Systematic Review.

BackgroundScreening for prostate cancer has long been a debated, complex topic. The use of risk calculators for prostate cancer is recommended for determining patients’ individual risk of cancer and the subsequent need for a prostate biopsy. These tools could lead to better discrimination of patients in need of invasive diagnostic procedures and optimized allocation of health care resourcesObjectiveThe goal of the research was to systematically review available literature on the performance of current prostate cancer risk calculators in healthy populations by comparing the relative impact of individual items on different cohorts and on the models’ overall performance.MethodsWe performed a systematic review of available prostate cancer risk calculators targeted at healthy populations. We included studies published from January 2000 to March 2021 in English, Spanish, French, Portuguese, or German. Two reviewers independently decided for or against inclusion based on abstracts. A third reviewer intervened in case of disagreements. From the selected titles, we extracted information regarding the purpose of the manuscript, analyzed calculators, population for which it was calibrated, included risk factors, and the model’s overall accuracy.ResultsWe included a total of 18 calculators from 53 different manuscripts. The most commonly analyzed ones were the Prostate Cancer Prevention Trial (PCPT) and European Randomized Study on Prostate Cancer (ERSPC) risk calculators developed from North American and European cohorts, respectively. Both calculators provided high diagnostic ability of aggressive prostate cancer (AUC as high as 0.798 for PCPT and 0.91 for ERSPC). We found 9 calculators developed from scratch for specific populations that reached a diagnostic ability as high as 0.938. The most commonly included risk factors in the calculators were age, prostate specific antigen levels, and digital rectal examination findings. Additional calculators included race and detailed personal and family history.ConclusionsBoth the PCPR and ERSPC risk calculators have been successfully adapted for cohorts other than the ones they were originally created for with no loss of diagnostic ability. Furthermore, designing calculators from scratch considering each population’s sociocultural differences has resulted in risk tools that can be well adapted to be valid in more patients. The best risk calculator for prostate cancer will be that which has been calibrated for its intended population and can be easily reproduced and implemented.Trial RegistrationPROSPERO CRD42021242110; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242110

MP30-14 5-ARI USAGE ASSOCIATED WITH MORE ADVANCED PROSTATE CANCER AT DIAGNOSIS

You have accessJournal of UrologyProstate Cancer: Detection & Screening III (MP30)1 Sep 2021MP30-14 5-ARI USAGE ASSOCIATED WITH MORE ADVANCED PROSTATE CANCER AT DIAGNOSIS Emily Roebuck, Wei Sha, Caroline Lu, Caroline Miller, Earle F Burgess, Claud M Grigg, Jason Zhu, Kris E Gaston, Stephen B Riggs, Justin T Matulay, Peter E Clark, and James T Kearns Emily RoebuckEmily Roebuck More articles by this author , Wei ShaWei Sha More articles by this author , Caroline LuCaroline Lu More articles by this author , Caroline MillerCaroline Miller More articles by this author , Earle F BurgessEarle F Burgess More articles by this author , Claud M GriggClaud M Grigg More articles by this author , Jason ZhuJason Zhu More articles by this author , Kris E GastonKris E Gaston More articles by this author , Stephen B RiggsStephen B Riggs More articles by this author , Justin T MatulayJustin T Matulay More articles by this author , Peter E ClarkPeter E Clark More articles by this author , and James T KearnsJames T Kearns More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002027.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) risk is often modeled at referral based on Prostate Cancer Prevention Trial (PCPT) and Prostate Biopsy Collaborative Group (PBCG) risk calculators, which account for factors such as PSA, DRE, age, race, family history, and prior biopsy history. Prospective PCa chemoprevention trials noted an increased risk of high-grade prostate cancer among men using 5-ARIs, and subsequent retrospective data associates 5-ARI use with delayed diagnoses and worse cancer outcomes than non-users. The objective of this study was to assess clinical characteristics and treatment types between 5-ARI users versus non-users at prostate biopsy and PCa diagnosis. METHODS: Men undergoing prostate biopsy at our institution between January 2018–December 2021 were retrospectively reviewed for clinical and demographic data. Patients with previously diagnosed PCa were excluded. For categorical demographic or biopsy variables, Chi-square test was used to determine if there is a significant association between these variables and 5-ARI usage. For continuous demographic variables, quantile regression was used to compare the medians between 5-ARI users and non-users. False discovery rate (FDR) adjusted P value was used for multiple tests. RESULTS: Among 842 patients, 83 men were using 5-ARIs at time of biopsy (Table 1). Demographic characteristics including age, race, marital status, BMI, or family history were similar across the two cohorts. PSA was greater among 5-ARI users (p=.054). At PCa diagnosis, 5-ARI users tended to have higher clinical T stage (p<0.0001) and NCCN risk group stratification (p=.0119). Gleason Grade Group (p=0.372), prostate volume (p=.1838), DRE (p=.5849), and treatment type (p>.05 for all) were not statistically different between users and non-users. CONCLUSIONS: While not emphasized in common risk calculators, pre-diagnostic use of 5-ARI should be considered when deciding to biopsy. Our findings demonstrate 5-ARI usage associated with more advanced clinical T stage and higher NCCN risk though not Gleason Grade, suggesting that 5-ARI is a risk factor to consider at referral and highlighting the need to optimize diagnostic care for 5-ARI users. Source of Funding: No source of funding © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e505-e505 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emily Roebuck More articles by this author Wei Sha More articles by this author Caroline Lu More articles by this author Caroline Miller More articles by this author Earle F Burgess More articles by this author Claud M Grigg More articles by this author Jason Zhu More articles by this author Kris E Gaston More articles by this author Stephen B Riggs More articles by this author Justin T Matulay More articles by this author Peter E Clark More articles by this author James T Kearns More articles by this author Expand All Advertisement Loading ...

Adherence with protocol medication use and mortality from unrelated causes in a prevention trial

Several studies have shown that non-adherence to medication use is associated with lower use of preventive services and increased mortality. We aimed to study the relationship between initial adherence to medication use and mortality in the Prostate Cancer Prevention Trial (PCPT). The PCPT randomized men age 55 and over to a finasteride or placebo arm. Duration of treatment was seven years, followed by end-of-study prostate biopsy. Extended follow-up for mortality was performed by linkage to the National Death Index. Non-adherence was defined as taking under 80% of required pills during the first or second 6-month trial period. Proportional hazards models were used to assess the relationship between adherence and all-cause mortality (excluding prostate cancer deaths). Three models were developed as follows: Model I (controlling for demographics and trial arm), Model II (Model I factors plus specific medical conditions), Model III (Model II factors plus lifestyle factors). Of 18,667 men included in the analysis, 3082 (16.5%) were non-adherent. The most common reasons for non-adherence were side effects (33.9%) and forgetting to take pills (22%). Through 5 and 10 years of follow-up, 178 (5.9%) and 483 (15.7%) non-adherent men died versus 581 (3.7%) and 1887 (12.1%) adherent men. Hazard ratios (HRs) at 5 years were 1.62 (95% CI: 1.37–1.91), 1.55 (95% CI: 1.30–1.83) and 1.49 (95% CI: 1.25–1.76) for Models I-III. HRs at ten years were lower but still statistically significant. Non-adherence to taking protocol medications was associated with increased mortality from unrelated conditions.

Impact of 5-ALPHA reductase inhibitor use on prostate cancer risk at the time of urology referral.

226 Background: 5-alpha reductase inhibitors (5-ARIs) are commonly used medications for the treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia. One of the consequences of 5-ARI use is a 50% drop in serum PSA without a concomitant reduction in prostate cancer (PCa) risk. Previous work has suggested that 5-ARI use is associated with worse PCa-specific outcomes. The objective of this study was to evaluate the impact of 5-ARI use on patients’ PCa risk at the time of referral from primary care to urology. Methods: This retrospective cohort study included all men ≥ 40 years who had a PSA resulted between 2018-2019 and were seen in an ambulatory setting. PSA testing was determined through laboratory data in the electronic health record (EHR). Clinical and demographic data were collected for all men. 5-ARI use was determined through orders in the EHR. Men were assigned PCa risk according to both the Prostate Biopsy Collaborative Group (PBCG) and Prostate Cancer Prevention Trial (PCPT) risk calculators. PSA values were doubled for 5-ARI users prior to calculating risk. Referral to urology for PCa risk was determined using the narrative reason for referral associated with the referral order. Results: Between 2018-2019, 91,368 men had a PSA test, including 2,939 5-ARI users, and 88,429 non-users. Uncorrected median PSA and the proportion of men referred to urology for PCa risk were similar between the two groups (p = 0.60 and p = 0.17, respectively). Of men referred to urology for PCa risk, 5-ARI users had similar uncorrected PSA to non-users (p=0.86) but higher risk for high grade PCa once PSA correction was performed, median (IQR) 48% (24%) vs 28% (18%) using the PBCG and 21% (17%) vs 10% (10%) using the PCPT (p &lt; 0.01 for both) (Table). Conclusions: Men taking 5-ARIs have significantly higher risk for high-grade PCa at time of referral to urology than non-users in this cohort. As the unadjusted PSA at referral to urology for PCa risk was the same between 5-ARI users and non-users, this indicates that the effect of 5-ARI use on serum PSA levels is not routinely accounted for when assessing PCa risk. Further study on interventions to account for 5-ARI use when screening for PCa are warranted. [Table: see text]

Association of Serum Carotenoids and Retinoids with Intraprostatic Inflammation in Men without Prostate Cancer or Clinical Indication for Biopsy in the Placebo Arm of the Prostate Cancer Prevention Trial

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, β-carotene, β-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6–10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except β-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

A Latent Disease Model to Reduce Detection Bias in Cancer Risk Prediction Studies.

In studies of cancer risk, detection bias arises when risk factors are associated with screening patterns, affecting the likelihood and timing of diagnosis. To eliminate detection bias in a screened cohort, we propose modeling the latent onset of cancer and estimating the association between risk factors and onset rather than diagnosis. We apply this framework to estimate the increase in prostate cancer risk associated with black race and family history using data from the SELECT prostate cancer prevention trial, in which men were screened and biopsied according to community practices. A positive family history was associated with a hazard ratio (HR) of prostate cancer onset of 1.8, lower than the corresponding HR of prostate cancer diagnosis (HR = 2.2). This result comports with a finding that men in SELECT with a family history were more likely to be biopsied following a positive PSA test than men with no family history. For black race, the HRs for onset and diagnosis were similar, consistent with similar patterns of screening and biopsy by race. If individual screening and diagnosis histories are available, latent disease modeling can be used to decouple risk of disease from risk of disease diagnosis and reduce detection bias.

Prostate Cancer Risk Calculator Apps in a Taiwanese Population Cohort: Validation Study.

BackgroundMobile health apps have emerged as useful tools for patients and clinicians alike, sharing health information or assisting in clinical decision-making. Prostate cancer (PCa) risk calculator mobile apps have been introduced to assess risks of PCa and high-grade PCa (Gleason score ≥7). The Rotterdam Prostate Cancer Risk Calculator and Coral–Prostate Cancer Nomogram Calculator apps were developed from the 2 most-studied PCa risk calculators, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the North American Prostate Cancer Prevention Trial (PCPT) risk calculators, respectively. A systematic review has indicated that the Rotterdam and Coral apps perform best during the prebiopsy stage. However, the epidemiology of PCa varies among different populations, and therefore, the applicability of these apps in a Taiwanese population needs to be evaluated. This study is the first to validate the PCa risk calculator apps with both biopsy and prostatectomy cohorts in Taiwan.ObjectiveThe study’s objective is to validate the PCa risk calculator apps using a Taiwanese cohort of patients. Additionally, we aim to utilize postprostatectomy pathology outcomes to assess the accuracy of both apps with regard to high-grade PCa.MethodsAll male patients who had undergone transrectal ultrasound prostate biopsies in a single Taiwanese tertiary medical center from 2012 to 2018 were identified retrospectively. The probabilities of PCa and high-grade PCa were calculated utilizing the Rotterdam and Coral apps, and compared with biopsy and prostatectomy results. Calibration was graphically evaluated with the Hosmer-Lemeshow goodness-of-fit test. Discrimination was analyzed utilizing the area under the receiver operating characteristic curve (AUC). Decision curve analysis was performed for clinical utility.ResultsOf 1134 patients, 246 (21.7%) were diagnosed with PCa; of these 246 patients, 155 (63%) had high-grade PCa, according to the biopsy results. After confirmation with prostatectomy pathological outcomes, 47.2% (25/53) of patients were upgraded to high-grade PCa, and 1.2% (1/84) of patients were downgraded to low-grade PCa. Only the Rotterdam app demonstrated good calibration for detecting high-grade PCa in the biopsy cohort. The discriminative ability for both PCa (AUC: 0.779 vs 0.687; DeLong’s method: P<.001) and high-grade PCa (AUC: 0.862 vs 0.758; P<.001) was significantly better for the Rotterdam app. In the prostatectomy cohort, there was no significant difference between both apps (AUC: 0.857 vs 0.777; P=.128).ConclusionsThe Rotterdam and Coral apps can be applied to the Taiwanese cohort with accuracy. The Rotterdam app outperformed the Coral app in the prediction of PCa and high-grade PCa. Despite the small size of the prostatectomy cohort, both apps, to some extent, demonstrated the predictive capacity for true high-grade PCa, confirmed by the whole prostate specimen. Following our external validation, the Rotterdam app might be a good alternative to help detect PCa and high-grade PCa for Taiwanese men.

The association between serum sex steroid hormone concentrations and intraprostatic inflammation in men without prostate cancer and irrespective of clinical indication for biopsy in the placebo arm of the Prostate Cancer Prevention Trial.

Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

Vitamin D Pathway and Other Related Polymorphisms and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial.

Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case-control study in the Prostate Cancer Prevention Trial (PCPT). Cases (n = 1,128) and controls (n = 1,205) were frequency matched on age, first-degree relative with prostate cancer, and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy confirmed. We selected 21 SNPs in vitamin D-related genes (VDR, GC, C10orf88, CYP2R1, CYP24A1, CYP27B1, DHCR7, and NADSYN1) to test genotype and genotype-treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D-genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, body mass index, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and GC/rs222016 (finasteride OR = 1.37, placebo OR = 0.85; P interaction < 0.05), GC/rs222014 (finasteride OR = 1.36, placebo OR = 0.85; P interaction < 0.05), and CYP27B1/rs703842 (finasteride OR = 0.76, placebo OR = 1.10; P interaction < 0.05) among Caucasians, and C10orf88/rs6599638 (finasteride OR = 4.68, placebo OR = 1.39; P interaction < 0.05) among African-Americans. VDR/rs1544410 and CYP27B1/rs703842 had significant treatment interactions for high-grade disease among Caucasians (finasteride OR = 0.81, placebo OR = 1.40; P interaction < 0.05 and finasteride OR = 0.70, placebo OR = 1.28; P interaction < 0.05, respectively). Vitamin D-related SNPs influenced serum 25(OH)D, but gene-serum 25(OH)D effect modification for prostate cancer was marginally observed only for CYP24A1/rs2248359. In conclusion, evidence that vitamin D-related genes or gene-serum 25(OH)D associations influence prostate cancer risk is modest. We found some evidence for gene-finasteride interaction effects for prostate cancer in Caucasians and African-Americans. Results suggest only minimal associations of vitamin D with total or high-grade prostate cancer.

Abstract A071: Use of finasteride in the Prostate, Lung, Colorectal and Ovarian Cancer Prevention (PLCO) Trial cohort: Effects of sociodemographic factors and a black box warning

Abstract Background: In 1992, finasteride, a 5α-reductase inhibitor, was approved by the Food and Drug Administration (FDA) for the treatment of benign prostatic hyperplasia (BPH). Finasteride also showed early signs of lowering prostate-specific antigen (PSA) levels, indicating that it may be useful for the prevention of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) was conducted from 1994 to 2003 and showed that finasteride reduced overall prostate cancer incidence; however, it also appeared to increase the incidence of high-grade disease. Consequently, in 2011 the FDA issued a black box warning based in part on the PCPT results. Little is known, however, about the effect this warning had on finasteride use among men after 2011. The purpose of this study was to assess the use of finasteride, for BPH or other reasons, among a sample of Prostate, Lung, Colorectal, Ovarian Cancer Prevention Trial (PLCO) participants. Specifically, we wanted to assess the effects of sociodemographic characteristics (e.g., age, race/ethnicity) and BPH on finasteride use and the effect of the FDA's black box warning on finasteride use after 2011. Method: This was a retrospective longitudinal study. Men's age, race/ethnicity, and BPH status were ascertained from questionnaires. Medication use was ascertained from linkage to Medicare Part D claims data from 2010 to 2014. Results: The sample contained 14,044 PLCO men with at least one year of part D claims data. The majority self-identified as non-Hispanic white (12,429; 88.5%); 236 (1.7%) were black, 753 (5.4%) were Asian, and 239 (1.7%) were Hispanic. Median (25th/75th) age in 2010 was 73 years (69/28). From 2010 to 2014, 11% (n=1,590) of these men used finasteride at any time. Overall, 63% (n=1,005) of the men who used finasteride reported a diagnosis of BPH. Finasteride use increased steadily over time from 5.5% in 2010 to 8.5% in 2014. Conclusion: Overall use of finasteride from 2010 to 2014 was low, and mainly in men with BPH. Finasteride use increased after the FDA's 2011 black box warning; the effect of the warning is unclear. Citation Format: Jarrett A. Johnson, Paul F. Pinsky. Use of finasteride in the Prostate, Lung, Colorectal and Ovarian Cancer Prevention (PLCO) Trial cohort: Effects of sociodemographic factors and a black box warning [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A071.

Association of finasteride with prostate cancer

Background:The Prostate Cancer Prevention Trial has shown a protective effect of finasteride on prostate cancer, but it also showed that finasteride can increase the risk of high-grade prostate cancer. Several studies have investigated the relationship between finasteride and prostate cancer, but these studies have shown inconsistent results.Ethics:The protocol was approved by the institutional review board of each study center. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki.Methods:We performed a systematic literature review and meta-analysis to assess the association between finasteride and prostate cancer. Systematic literature searches were conducted using PubMed, EMBASE, Science Direct/Elsevier, MEDLINE, CNKI, and the Cochrane Library up to October 2018 to identify studies that involved the relationship between finasteride and prostate cancer. Meta-analysis was performed using Review Manager and Stata software. Combined ORs were identified with 95% confidence intervals (95% CI) in a random or fixed effects model.Results:Eight studies were identified, including 54,335 cases of patients that used finasteride and 9197 patients who served as placebo controls. Our results illustrate that there is a significant correlation between finasteride use and prostate cancer with combined ORs of 0.70 [0.51, 0.96]. A significant correlation between finasteride use and high-grade prostate cancer was also observed with combined ORs of 2.10 [1.85, 2.38].Conclusions:This study confirms that finasteride significantly reduced the risk of prostate cancer; however, the malignant degree of prostate cancer was increased. Studies with larger sample sizes are needed to better clarify the correlation between finasteride use and prostate cancer.

MP75-11 GENOME-DRIVEN RISK STRATIFICATION IN PROSTATE CANCER IDENTIFIES LOW RISK MEN

INTRODUCTION AND OBJECTIVE: Broad-based Prostate-Specific Antigen (PSA) prostate cancer (PCa) screening has saved lives but at substantial financial and human cost due to the number of low risk men exposed to the risks of screening. We evaluated the ability of a germline genetic risk stratification assay Prompt-prostate genetic score (PGS) to identify men at low risk who could consider minimizing screening. METHODS: Patient data from the PCa Prevention Trial (PCPT) were analyzed for baseline factors. Prompt-PGS was derived by using an algorithm involving weighted odds ratios of PCa associated SNPs as previously published. We calculated various statistical parameters reflecting the performance of Prompt-PGS as a predictive tool for all-PCa and high-grade PCa (HG-PCa). The performance of PSA was also assessed by evaluating “for-cause” (abnormal rectal exam or PSA>4ng/ml) PCa detection compared to “not-for-cause” (end of study biopsy). RESULTS: A total 7596 men from the placebo arm of PCPT with complete demographic and genetic information were included in this analysis. 1208 (15.96%), 1844 (24.28%), and 924 (12.30%) were identified as Prompt-PGS high (>1.3), intermediate (0.61-1.29), and low risk (<0.6) respectively. Figure 1 shows the breakdown of PSA performance in for-cause and not-for-cause biopsy subjects (Fig 1A) as well as the breakdown of all-PCa and HG-PCa by Prompt-PGS (Fig 1B). Table 1 shows characteristics for PSA and Prompt-PGS for all and HG-PCa. When comparing tumors identified by for-cause biopsies vs not-for-cause biopsies, PSA had a sensitivity of 39.50% and 53.57% for all and HG-PCa respectively. NPV for all and HG-Pca was 82.08% and 97.32% respectively. The sensitivity of Prompt-PGS was 84.32% and 84.18% for all and HG-PCa respectively. NPV was higher for HG-PCa (96.68%) compared to all-PCa (82.98%). CONCLUSIONS: In this population, Prompt-PGS had a high NPV and sensitivity suggesting that it could improve screening efficiency by minimizing screening in men at low genetic risk.Source of Funding: N/A

5-alpha reductase inhibitors (5-ARI) and prostate cancer mortality among men with regular access to screening and health care.

39 Background: The excess risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial (PCPT) among men randomized to finasteride raised concerns that a chemoprevention benefit would be offset by increased mortality. Two 2019 publications had contrasting results whether 5-ARIs increased prostate cancer mortality. In PCPT, there was no excess prostate cancer mortality. In a VA study, 5-ARI use was associated with later stage at diagnosis and 39% higher prostate cancer mortality risk. We studied men with regular access to health care and screening to address this conflicting evidence. Methods: We performed two parallel analyses in the Health Professionals Follow-up Study. 5-ARI use was reported on biennial questionnaires starting in 1996. In line with PCPT, we studied 38,047 men for cancer incidence and mortality through 2016. In line with the VA study, we undertook a case-only study of 4,225 patients with localized/locally advanced cancers followed similarly. We estimated hazard ratios (HR) and 95% confidence intervals accounting for screening patterns, lifestyle factors, and concomitant medications. Results: 5-ARI ever-users (n = 4,101; 10.7%) were more likely to have had regular PSA screening (74% vs. 57% nonusers) and a negative prostate biopsy before diagnosis. Neither ever 5-ARI use (HR 1.08, 0.73-1.60, 445 events) nor long-term use ( &gt; 4 years, HR 1.03, 1.03-2.02) were associated with lethal prostate cancer. There was no difference in stage. Diagnostic PSA levels were lower in 5-ARIs users (10.0 vs. 16.0 ng/ml in never-users). Among nonmetastatic cases, 278 men died of prostate cancer; there was no association between 5-ARIs and prostate cancer survival (HR 0.85, 0.51-1.43). Conclusions: Our results align with PCPT and show no excess risk of lethal prostate cancer, no higher stage at diagnosis, and no excess mortality after diagnosis associated with 5-ARI. Men on 5-ARIs had more interactions with health care, which may have led to higher quality care. This contrasts with the VA study where men on 5-ARIs were diagnosed later due to suppressed PSA and had worse survival. These results show the importance of real-world data in framing the benefits and risks associated with 5-ARIs.