Reduce Prostate Cancer Mortality Research Articles

When is prostate cancer really cancer?

Prostate cancer (PC) is a major cause of cancer-related deaths worldwide, with far more diagnoses than deaths annually. Recent discussions have challenged whether Grade Group 1 (GG1) PC should be labeled "cancer" due to its indolent nature. To address this question, an international symposium convened stakeholders from various fields. We summarize key discussion points: autopsy studies reveal GG1 is so common in aging males as to be perhaps a normal aspect of aging. Pure GG1 has no capacity to metastasize. Modern diagnostic pathways focus on detecting higher-grade disease, explicitly omitting biopsy if GG 2 or higher is not suspected, so GG1 has effectively become an "incidentaloma." Recent spatial transcriptomics of prostate sections identifies a continuum of genomic changes-including alterations characteristic of malignancy in histologically normal regions, so the designation of cancer based entirely on conventional pathology findings increasingly seems arbitrary at least to an extent. Pathologists discussed heterogeneity and diagnostic challenges, suggesting "acinar neoplasm" as one possible alternative label. GG1 should not be considered "normal," and absolutely requires ongoing active surveillance; whether patients would adhere to surveillance absent a cancer diagnosis is unknown. Patient perspectives highlighted the adverse effects of overtreatment and the burden of a cancer diagnosis. The anticipated impact on screening and treatment varies across health-care systems, but many believe public health would on balance greatly improve if GG1-along with lesions in other organs with no capacity to cause symptoms or threaten life-were labeled something other than "cancer." Ultimately, our goal is to reduce PC mortality while minimizing harms associated with both overdiagnosis and overtreatment.

Abstract B083: Community-based knowledge-to-action translation to improve early detection of prostate cancer among Black individuals

Abstract Introduction: Black individuals have 70-80% higher incidence and 120% higher mortality from prostate cancer when compared to all other groups in the US. This is the largest racial disparity in cancer-related mortality in the US and has persisted over the last five decades despite improvements in the diagnosis and treatment of prostate cancer. Our previous work demonstrated that intensified screening practices could reduce prostate cancer mortality among Black individuals. Challenges impede the translation of these findings into real-world interventions and practices. The objective of this study was to design a patient-centered and culturally tailored knowledge toolkit to improve the knowledge and awareness of prostate-specific antigen (PSA) testing in Black individuals to facilitate informed shared-decision making between Black patients and primary care providers. Methods: Using a community-partnered participatory research approach, we convened a working group of Black prostate cancer survivors and community advocates, and clinicians, researchers, and health communications specialists. During monthly meetings, the working group followed Graham’s Knowledge-to-Action framework to synthesize information from: 1) peer-reviewed literature on the use of shared decision-making aids; 2) interviews conducted by our research team with Black individuals regarding barriers and facilitators to access PSA testing; and 3) community input on PSA testing and prostate cancer early detection. We then facilitated four iterative design sessions with the working group to develop recommendations for toolkit content, framing, and format. Results: With the working group, we designed a comprehensive set of resources to increase knowledge and awareness of PSA testing for early detection of prostate cancer among Black individuals. The design framework includes detailed recommendations on the content, framing, and format for resources contained in the toolkit. Recommendations encompass: 1) interactive web-based documents that cover comprehensive information about prostate cancer risk and screening; 2) printable shared decision-making documents that present evidence-based information about the use of PSA testing to guide conversations between Black individuals and their primary care providers; and 3) educational videos focused on prostate cancer fundamentals and dispelling common misconceptions about prostate cancer risk and screening, with content delivered by Black prostate cancer survivors and interviews with Black providers and prostate cancer researchers. Conclusion: This study addressed the need for a community-developed approach to increasing knowledge and awareness about prostate cancer screening and early detection in an accessible, culturally tailored, and accurate manner. We used a collaborative process that centered the experiences of Black prostate cancer survivors and advocates in the design of a toolkit that can facilitate decision-making discussions between Black individuals and their care providers for use of PSA testing for prostate cancer screening. Citation Format: Jenney R. Lee, Sung Min Kim, Yohali Burrola- Mendez, Dante' Morehead, Marty Chakoian, Michael Ware, Kojo Ward, Floyd Gossett, Vida Henderson, Patricia Egwuatu, Burcu Darst, John Masembe, Erika M. Wolff, Yaw A Nyame. Community-based knowledge-to-action translation to improve early detection of prostate cancer among Black individuals [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B083.

Abstract C096: The GR-LEDGF/p75 transcriptional network as a promising target to reduce therapy cross-resistance in prostate cancer

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality in U.S. men, with African American (AA) men showing higher incidence and mortality compared to European American men. In addition, AA men are more likely to be diagnosed with more aggressive PCa resulting in reduction of treatment options, especially as tumors develop therapy resistance. Thus, understanding the mechanisms underlying PCa therapy resistance is crucial for developing new therapeutic options. The upregulation of the Lens Epithelium Derived Growth Factor p75 (LEDGF/p75) by glucocorticoid receptor (GR) is a novel mechanism of PCa therapy resistance recently identified by our group. GR upregulation in PCa bypasses the blockade of androgen receptor by inhibitors such as enzalutamide and abiraterone. LEDGF/p75 is an oncogenic transcription co-activator that promotes DNA damage repair and cancer cell survival against environmental stressors including chemotherapeutic drugs such as docetaxel (DTX). An emerging concern in PCa treatment is therapy cross-resistance, in which the molecular mechanisms of resistance to a particular drug confer resistance to another drug. Our recent studies showed that GR upregulates and interacts with LEDGF/p75 forming a transcriptional complex that includes other oncoproteins such as Menin, JPO2, c-Myc and HRP2, and promotes DTX resistance (DTX-R) in PCa cells. In addition, we reported that both GR and LEDGF/p75 are upregulated in enzalutamide resistant (ENZ-R) PCa cells. We hypothesized that the GR- LEDGF/p75 transcriptional network plays a role in PCa therapy cross-resistance to both ENZ and DTX and is a promising therapeutic target. Cell viability assays revealed that ENZ-R in PCa cells confers cross-resistance to DTX. Western blot analysis revealed upregulation of members of the GR-LEDGF/p75 network such as GR, LEDGF/p75, Menin and c-Myc in ENZ-R PCa cells, consistent with similar observations in DTX-R PCa cells. Upon knockdown of GR and LEDGF/p75 in DTX-R PCa cells, we identified by RNA-seq analysis overlapping DEGs associated with both ENZ-R and DTX-R, suggesting that the GR-LEDGF/p75 transcriptional network may contribute to therapy cross-resistance. Consistent with this, mining of publicly available RNA-seq databases identified 46 overlapping differentially expressed genes (DEGs) between ENZ-R and DTX-R PCa cells. Pathway analysis of DEGs regulated by both GR and LEDGF/p75 revealed significant enrichment of Apoptosis, p53, and DNA repair pathways, which are associated with therapy resistance. Ongoing studies are evaluating the anti-cancer properties and synergistic/additive potential of various inhibitors of the GR-LEDGF/p75 transcriptional network in cellular models of ENZ-R and DTX-R. These studies provide novel mechanistic insights into PCa therapy cross-resistance and may lead to the development of novel therapeutic strategies to reduce PCa mortality disparities. Citation Format: Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Kai Wen Cheng, Isaac Kremsky, Charles Wang, Carlos A. Casiano. The GR-LEDGF/p75 transcriptional network as a promising target to reduce therapy cross-resistance in prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C096.

Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States

BackgroundIn the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States.MethodsA comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.ResultsThree randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis.ConclusionsThese guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.)

Mortality reduction and cumulative excess incidence (CEI) in the prostate-specific antigen (PSA) screening era

The extent to which PSA screening is related to prostate cancer mortality reduction in the United States (US) is controversial. US Surveillance, Epidemiology, and End Results Program (SEER) data from 1980 to 2016 were examined to assess the relationship between prostate cancer mortality and cumulative excess incidence (CEI) in the PSA screening era and to clarify the impact of race on this relationship. CEI was considered as a surrogate for the intensity of prostate cancer screening with PSA testing and subsequent biopsy as appropriate. Data from 163,982,733 person-years diagnosed with 544,058 prostate cancers (9 registries, 9% of US population) were examined. Strong inverse linear relationships were noted between CEI and prostate cancer mortality, and 317,356 prostate cancer deaths were avoided. Eight regions of the US demonstrated prostate cancer mortality reduction of 46.0–63.7%. On a per population basis, the lives of more black men than white men were saved in three of four registries with sufficient black populations for comparison. Factor(s) independent of CEI (potential effects of treatment advances) explained 14.6% of the mortality benefit (p-value = 0.3357) while there was a significant main effect of CEI (effect = −0.0064; CI: [−0.0088, −0.0040]; p-value < 0.0001). Therefore, there is a strong relationship between CEI and prostate cancer mortality reduction that was not related to factors independent of screening utilization. Minority populations have experienced large mortality reductions in the context of PSA mass utilization.

Global acetylome profiling indicates EPA impedes but OA promotes prostate cancer motility through altered acetylation of PFN1 and FLNA.

Prostate cancer (PCa) is one of the leading causes of cancer morbidity and mortality in men. Metastasis is the main cause of PCa-associated death. Recent evidence indicated a significant reduction in PCa mortality associated with higher ω-3 polyunsaturated fatty acids (PUFAs) consumption. However, the underlying mechanisms remained elusive. In this study, we applied global acetylome profiling to study the effect of fatty acids treatment. Results indicated that oleic acid (OA, monounsaturated fatty acid, MUFA, 100 µM) elevates while EPA (eicosapentaenoic acid, 100 µM) reduces the acetyl-CoA level, which alters the global acetylome. After treatment, two crucial cell motility regulators, PFN1 and FLNA, were found with altered acetylation levels. OA increased the acetylation of PFN1 and FLNA, whereas EPA decreased PFN1 acetylation level. Furthermore, OA promotes while EPA inhibits PCa migration and invasion. Immunofluorescence assay indicated that EPA impedes the formation of lamellipodia or filopodia through reduced localization of PFN1 and FLNA to the leading edge of cells. Therefore, perturbed acetylome may be one critical step in fatty acid-affected cancer cell motility. This study provides some new insights into the response of ω-3 PUFAs treatment and a better understanding of cancer cell migration and invasion modulation.

Disparities in prostate cancer mortality and clinical trial availability across vulnerable populations.

24 Background: Clinical trials provide high-level evidence and test novel therapies that have significantly improved cancer outcomes. However, disparities in clinical trial participation and cancer mortality persist across race/ethnicity and vulnerable populations, notably in patients with prostate cancer (PCa). Adverse social determinants of health (SDOH) and systemic barriers may underlie these disparities. Identifying and overcoming these barriers may improve access to and representation in clinical trials, thereby promoting equitable advancement and applicability of science. For these reasons, we evaluate the association between clinical trial availability, cancer mortality, and population-level SDOH in PCa. Methods: Using custom data linkage from ClinicalTrials.gov, Surveillance Epidemiology and End Results (SEER) Registry, and the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), we performed a cross-sectional analysis of county-level PCa clinical trial data, cancer incidence and mortality rates, and population-level SDOH. We included Phase 2 and Phase 3 interventional PCa clinical trials with start dates from 2007 to 2022. The total number of clinical trials over the study period was calculated per county and population-adjusted for 100,000 residents. Counties were stratified into quintiles based on SVI (i.e., least vulnerable to most vulnerable). Population-adjusted clinical trial availability, cancer incidence, and cancer mortality were compared across SVI quintiles. Multivariable logistic and linear regression analyses were performed to evaluate the association between SVI and clinical trial availability and cancer mortality, respectively. Results: The mean number of PCa trials per 100,000 residents was 25.6, with the most vulnerable counties having fewer clinical trials compared to the least vulnerable counties (mean 18.1 vs. 50.0, p&lt;0.05). Further, the most vulnerable counties had a lower PCa incidence rate per 100,000 residents (mean 393.8 vs. 411.7, p&lt;0.05), but a higher PCa mortality rate per 100,000 residents (mean 85.7 vs. 72.0, p&lt;0.05). On multivariable regression analysis, the most vulnerable counties were associated with significantly decreased odds of having any PCa clinical trial (OR 0.3, 95% CI 0.2 – 0.4) and significantly increased PCa mortality (10.8, 95% CI 7.4 – 14.3), while the presence of any PCa clinical trial was associated with significantly decreased PCa mortality (-6.9, 95% CI -9.1 – -4.7). Conclusions: The most vulnerable counties were far less likely to have any PCa clinical trials despite having a significantly higher PCa mortality rate. The presence of a PCa clinical trial was associated with a reduction in PCa mortality. These vulnerable counties represent scientifically underserved populations that may benefit from equity-driven clinical trial enrollment and cancer care infrastructure expansion.

Screening history and risk of death from prostate cancer: a nested case–control study within the screening arm of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC)

PurposeWe assessed the risk of death from prostate cancer (PCa) in relation to men’s screening histories, i.e., screening attendance among men who were offered screening.MethodsMen in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996–2007.Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa.Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis.The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression.ResultsHaving ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45–0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51–0.87).The effect by time since last screen for the risk of PCa death was significantly lower 2–7 years since last screen.ConclusionAmong men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.

Abstract A049: Community partnership to empower Black men to drive research to identify barriers to prostate cancer early detection and equitable care

Abstract Introduction: Black men have a two-fold higher rate of prostate cancer death in the US compared with other men, the largest racial inequity in US cancer-related deaths. Annual PSA testing among Black men starting at age 45 years would reduce mortality compared with current screening practices. However, the US Preventive Service Task Force (USPSTF) guidelines do not make screening recommendations specifically for Black men. Black men comprised only 0-3% of practice-informing PSA screening trial cohorts. Given the burden of prostate cancer among Black men, capacity must be built to empower Black men and their communities to develop and execute clinical trials that may provide guidance on early detection strategies. Methods: We conducted semi-structured interviews to examine prostate cancer screening access among Black men in the Pacific Northwest, and we surveyed primary care physicians (PCPs) and urologists in the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region to assess knowledge, attitudes, and practices about prostate cancer screening. Interviews were recorded and transcribed; consensus coding and thematic analysis were used to identify structural barriers associated with screening access. Anonymous online surveys were distributed to physicians via email using REDCap. Results: 29 men participated in semi-structured interviews. We identified three equity-related barriers related to prostate cancer screening access: (1) lack of information on the benefits and harms of prostate cancer screening, (2) lack of PCP knowledge about prostate cancer disparities confronted by Black men, and (3) lack of trusted relationships with PCPs to support shared decision-making about prostate cancer screening. 32 urologists and 31 PCPs completed the survey. Nearly all urologists and PCPs were aware of the 2018 USPSTF guidelines regarding PSA testing (93.8% and 96.7%, respectively). 75% of urologists and 6.5% of PCPs agreed that PSA testing can significantly reduce prostate cancer mortality. Conclusion: Findings from the survey support the perception reported by interviewees that there is variation in knowledge and support for prostate cancer screening for early detection of prostate cancer among Black men. Our combined findings further demonstrate that (1) Black men have unique needs around early detection of prostate cancer and (2) patient partnerships can identify these areas of need and best inform patient-centered design of practice-changing research studies. Future Directions: With funding from the Patient Centered Outcomes Research Institute we will apply these findings by (1) building engagement and research capacity among a cohort of Black men with a history of prostate cancer and their advocates, (2) identifying community derived research priorities around the early detection of prostate cancer in Black men, and (3) developing a research agenda to inform future large, patient-centered, comparative effectiveness clinical trials in early detection of prostate cancer in Black men. Citation Format: Jenney R. Lee, Dante' Morehead, Ben Young, Victor Tolbert, John Masambe, Garrett Britt, Lars Neuenschwander, Kyle Schuppe, Richard Pelman, Debi Johnson, Sung Min Kim, Erika M. Wolff, John L. Gore, Yaw A. Nyame. Community partnership to empower Black men to drive research to identify barriers to prostate cancer early detection and equitable care [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A049.

Latin America and the Caribbean Code Against Cancer 1st Edition: Medical interventions including hormone replacement therapy and cancer screening

Prostate, breast, colorectal, cervical, and lung cancers are the leading cause of cancer in Latin America and the Caribbean (LAC) accounting for nearly 50% of cancer cases and cancer deaths in the region. Following the IARC Code Against Cancer methodology, a group of Latin American experts evaluated the evidence on several medical interventions to reduce cancer incidence and mortality considering the cancer burden in the region. A recommendation to limit the use of HRT was issued based on the risk associated to develop breast, endometrial, and ovarian cancer and on growing concerns related to the over-the-counter and without prescription sales, which in turn bias estimations on current use in LAC. In alignment with WHO breast and cervical cancer initiatives, biennial screening by clinical breast examination (performed by trained health professionals) from the age of 40 years and biennial screening by mammography from the age of 50 years to 74, as well as cervical screening by HPV testing (either self-sampling or provider-sampling) every 5–10 years for women aged 30–64 years, were recommended. The steadily increasing rates of colorectal cancer in LAC also led to recommend colorectal screening by occult blood testing every two years or by endoscopic examination of the colorectum every 10 years for both men and women aged 50–74 years. After evaluating the evidence, the experts decided not to issue recommendations for prostate and lung cancer screening; while there was insufficient evidence on prostate cancer mortality reduction by prostate-specific antigen (PSA) testing, there was evidence of mortality reduction by low-dose computed tomography (LDCT) targeting high-risk individuals (mainly heavy and/or long-term smokers) but not individuals with average risk to whom recommendations of this Code are directed. Finally, the group of experts adapted the gathered evidence to develop a competency-based online microlearning program for building cancer prevention capacity of primary care health professionals.

PROSTATE CANCER SCREENING USING THE PROSTATE-SPECIFIC ANTIGEN (PSA) TEST

We aimed to conduct a systematic review and meta-analysis on published literature extracted from PubMed/Medline, Google scholar, and Cochrane library. The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, over diagnosis, and costs.

Talk, test, and take one click to curb prostate cancer mortality.

6541 Background: Prostate cancer remains the most commonly diagnosed cancer and the second leading cause of cancer-related death in men in the United States. BronxCare Health System (BCHS) serves the Bronx neighborhoods of Morris Heights, Fordham South, and Mount Hope, notable for the highest prostate cancer incidence rate in New York City as per the American Cancer Society Cancer Action Network report 2019, highlighting the need for prostate cancer screening among the patient population we serve. An anonymous voluntary paper survey was performed in 2019 at BCHS to determine primary care physician understanding and implementation of current PSA testing guidelines. The study showed that primary care providers at BCHS approach PSA testing in a wide variety of ways and screen a wide age range of patients suggesting a need for intervention. An electronic medical record (EMR) decision support tool activated during primary care visits for men aged 55-69 years was implemented beginning January 1, 2021 which facilitates the provider and patient engagement in a shared decision-making discussion. This a follow-up study to determine the effect of this EMR application on PSA order rates and prostate cancer diagnosis rates at BCHS. Methods: The total number of patients who had PSA and lipid panel (LP) screening were extracted from the EMR of BCHS for potentially eligible men (aged 55-69) seen during primary care visits during the years 2016-2022. LP is done annually as a part of routine screening for adults aged 55-69 and is taken as an equivalent of primary care visits. PSA screening rates were compared to LP screening rates to control for unforeseen variables. Similarly, the number of newly-diagnosed prostate cancers among the same population of men was extracted for the years 2016-2021. Data for 2022 is still not available. 2016-2020 are pre-EMR and 2021 and 2022 are post-EMR flag years. The pre and post-EMR flag PSA and prostate cancer diagnosis numbers were compared by calculating Z scores and p-values. Results: The year-wise PSA, LP, and newly-diagnosed prostate cancers (PC) are tabulated below. The proportion of men who had PSA testing among all men aged 55-69 who had LP testing in each pre-EMR flag year was compared to each post-EMR flag year. A significant increase (p &lt; 0.00001) was noted in the proportion of men who had PSA screening after implementation of the EMR application. Similarly, the proportion of men with newly-diagnosed prostate cancer among all men aged 55-69 who had PSA screening significantly increased after EMR application (p &lt; 0.00001). Conclusions: A decision support tool embedded in the EMR has been an effective approach in increasing prostate cancer screening rates and may help curb prostate cancer mortality in our patient population as early detection in right men at the right age has the potential to reduce prostate cancer mortality. [Table: see text]

PD38-11 THE STOCKHOLM3 PROSTATE CANCER SCREENING TRIAL (STHLM3): AN INTERIM ANALYSIS OF MORTALITY RESULTS AFTER 6.5 YEARS OF FOLLOW-UP

You have accessJournal of UrologyCME1 Apr 2023PD38-11 THE STOCKHOLM3 PROSTATE CANCER SCREENING TRIAL (STHLM3): AN INTERIM ANALYSIS OF MORTALITY RESULTS AFTER 6.5 YEARS OF FOLLOW-UP Chiara Micoli, Alessio Crippa, Andrea Discacciati, Thorgerdur Palsdottir, Hari Vigneswaran, Markus Aly, Jan Adolfsson, Johan Lindberg, Peter Wiklund, James Thompson, Yvonne Brandberg, Mark Clements, Lars Egevad, Henrik Grönberg, Tobias Nordström, and Martin Eklund Chiara MicoliChiara Micoli More articles by this author , Alessio CrippaAlessio Crippa More articles by this author , Andrea DiscacciatiAndrea Discacciati More articles by this author , Thorgerdur PalsdottirThorgerdur Palsdottir More articles by this author , Hari VigneswaranHari Vigneswaran More articles by this author , Markus AlyMarkus Aly More articles by this author , Jan AdolfssonJan Adolfsson More articles by this author , Johan LindbergJohan Lindberg More articles by this author , Peter WiklundPeter Wiklund More articles by this author , James ThompsonJames Thompson More articles by this author , Yvonne BrandbergYvonne Brandberg More articles by this author , Mark ClementsMark Clements More articles by this author , Lars EgevadLars Egevad More articles by this author , Henrik GrönbergHenrik Grönberg More articles by this author , Tobias NordströmTobias Nordström More articles by this author , and Martin EklundMartin Eklund More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003336.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer screening is controversial due to high rates of overdiagnosis. The population-based screening trial STHLM3 utilized a single prostate-specific antigen (PSA) and Stockholm3 test (a prediction model based on clinical variables, blood biomarkers, and a polygenic risk score) to identify Gleason score ≥7 prostate cancer. In an interim analysis after 6.5 years of follow-up, we compared prostate cancer specific and all-cause mortality in men invited to STHLM3 to men not invited. METHODS: STHLM3 was conducted 2012-2015. Men 50-70 years of age residing in Stockholm, Sweden, were randomly invited from the general population to undergo prostate cancer testing. Men with PSA ≥3 ng/ml or Stockholm3 ≥10% were recommended prostate biopsy. We calculated cumulative incidences and risk ratios (RR) of prostate cancer diagnosis, prostate cancer mortality, and any-cause mortality after 6.5 years of follow-up in men invited to STHLM3 vs. not invited (intention-to-screen analysis). Alpha spending adjusted two-sided 98% confidence intervals were computed. RESULTS: In total, 245,905 men were eligible for STHLM3; 168,707 (69.6%) were randomly invited and 70,297 (29.4%) were not invited. Of invited men, 58,909 (35%) participated and 109,798 (65%) did not.After 6.5 years of follow-up, 91 men died of prostate cancer among men invited to STHLM3 vs. 51 among men not invited (RR 0.76; 98% CI 0.50 to 1.14). The number of prostate cancer diagnoses was higher among men invited to STHLM3 (n=5310) vs. not invited (n=1742) (RR 1.21; 98% CI 1.15 to 1.29). For all-cause mortality, there were 7784 deaths among men invited to STHLM3 vs. 3189 deaths among men not invited (RR 1.03; 98% CI 0.98 to 1.08). CONCLUSIONS: These results may cautiously suggest a potential effect on reducing prostate cancer mortality after 6.5 years of follow-up by a single intensive screening intervention using PSA and Stockholm3 in combination, to the cost of increased prostate cancer incidence. Longer-term follow-up is needed and is underway. Source of Funding: Swedish Research Council, Swedish Cancer Society © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e997 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chiara Micoli More articles by this author Alessio Crippa More articles by this author Andrea Discacciati More articles by this author Thorgerdur Palsdottir More articles by this author Hari Vigneswaran More articles by this author Markus Aly More articles by this author Jan Adolfsson More articles by this author Johan Lindberg More articles by this author Peter Wiklund More articles by this author James Thompson More articles by this author Yvonne Brandberg More articles by this author Mark Clements More articles by this author Lars Egevad More articles by this author Henrik Grönberg More articles by this author Tobias Nordström More articles by this author Martin Eklund More articles by this author Expand All Advertisement PDF downloadLoading ...

Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial

BackgroundThe risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain. ObjectiveTo study the relationship between risk reduction for PC mortality and age at first PSA screening. Design, setting, and participantsThe randomized Göteborg-1 trial invited men for biennial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invitation but exposure to opportunistic PSA testing (control, n = 10 000). InterventionRegular versus opportunistic PSA screening or no PSA. Outcome measurements and statistical analysisWe modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990–1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only). Results and limitationsYounger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the conventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration. ConclusionsGiven that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50–55 yr. Patient summaryIn this study from the Göteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men’s risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screening should start no later than at age 55 yr.

Screening for prostate cancer: protocol for updating multiple systematic reviews to inform a Canadian Task Force on Preventive Health Care guideline update

PurposeTo inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening for prostate cancer in adults aged 18 years and older in primary care. This protocol outlines the planned scope and methods for a series of systematic reviews.MethodsUpdates of two systematic reviews and a de novo review will be conducted to synthesize the evidence on the benefits and harms of screening for prostate cancer with a prostate-specific antigen (PSA) and/or digital rectal examination (DRE) (with or without additional information) and patient values and preferences. Outcomes for the benefits of screening include reduced prostate cancer mortality, all-cause mortality, and incidence of metastatic prostate cancer. Outcomes for the harms of screening include false-positive screening tests, overdiagnosis, complications due to biopsy, and complications of treatment including incontinence (urinary or bowel), and erectile dysfunction. The quality of life or functioning (overall and disease-specific) and psychological effects outcomes are considered as a possible benefit or harm. Outcomes for the values and preferences review include quantitative or qualitative information regarding the choice to screen or intention to undergo screening. For the reviews on benefits or harms, we will search for randomized controlled trials, quasi-randomized, and controlled studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. For the review on values and preferences, we will search for experimental or observational studies in MEDLINE, Embase, and PsycInfo. For all reviews, we will also search websites of relevant organizations, gray literature, and reference lists of included studies. Title and abstract screening, full-text review, data extraction, and risk of bias assessments will be completed independently by pairs of reviewers with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be used to assess the certainty of the evidence for each outcome.DiscussionThe series of systematic reviews will be used by the Canadian Task Force on Preventive Health Care to update their 2014 guideline on screening for prostate cancer in adults aged 18 years and older.Systematic review registrationThis review has been registered with PROSPERO (CRD42022314407) and is available on the Open Science Framework (osf.io/dm32k).

CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality

BackgroundMetastatic prostate cancer (PC) is a leading cause of cancer death in men worldwide. Targeting of the culprits of disease progression is an unmet need. Interleukin (IL)-30 promotes PC onset and development, but whether it can be a suitable therapeutic target remains to be investigated. Here, we shed light on the relationship between IL30 and canonical PC driver genes and explored the anti-tumor potential of CRISPR/Cas9-mediated deletion of IL30.MethodsPC cell production of, and response to, IL30 was tested by flow cytometry, immunoelectron microscopy, invasion and migration assays and PCR arrays. Syngeneic and xenograft models were used to investigate the effects of IL30, and its deletion by CRISPR/Cas9 genome editing, on tumor growth. Bioinformatics of transcriptional data and immunopathology of PC samples were used to assess the translational value of the experimental findings.ResultsHuman membrane-bound IL30 promoted PC cell proliferation, invasion and migration in association with STAT1/STAT3 phosphorylation, similarly to its murine, but secreted, counterpart. Both human and murine IL30 regulated PC driver and immunity genes and shared the upregulation of oncogenes, BCL2 and NFKB1, immunoregulatory mediators, IL1A, TNF, TLR4, PTGS2, PD-L1, STAT3, and chemokine receptors, CCR2, CCR4, CXCR5. In human PC cells, IL30 improved the release of IGF1 and CXCL5, which mediated, via autocrine loops, its potent proliferative effect. Deletion of IL30 dramatically downregulated BCL2, NFKB1, STAT3, IGF1 and CXCL5, whereas tumor suppressors, primarily SOCS3, were upregulated. Syngeneic and xenograft PC models demonstrated IL30’s ability to boost cancer proliferation, vascularization and myeloid-derived cell infiltration, which were hindered, along with tumor growth and metastasis, by IL30 deletion, with improved host survival. RNA-Seq data from the PanCancer collection and immunohistochemistry of high-grade locally advanced PCs demonstrated an inverse association (chi-squared test, p = 0.0242) between IL30 and SOCS3 expression and a longer progression-free survival of patients with IL30NegSOCS3PosPC, when compared to patients with IL30PosSOCS3NegPC.ConclusionsMembrane-anchored IL30 expressed by human PC cells shares a tumor progression programs with its murine homolog and, via juxtacrine signals, steers a complex network of PC driver and immunity genes promoting prostate oncogenesis. The efficacy of CRISPR/Cas9-mediated targeting of IL30 in curbing PC progression paves the way for its clinical use.

Serum PSA-based early detection of prostate cancer in Europe and globally: past, present and future.

In the pre-PSA-detection era, a large proportion of men were diagnosed with metastatic prostate cancer and died of the disease; after the introduction of the serum PSA test, randomized controlled prostate cancer screening trials in the USA and Europe were conducted to assess the effect of PSA screening on prostate cancer mortality. Contradictory outcomes of the trials and the accompanying overdiagnosis resulted in recommendations against prostate cancer screening by organizations such as the United States Preventive Services Task Force. These recommendations were followed by a decline in PSA testing and a rise in late-stage diagnosis and prostate cancer mortality. Re-evaluation of the randomized trials, which accounted for contamination, showed that PSA-based screening does indeed reduce prostate cancer mortality; however, the debate about whether to screen or not to screen continues because of the considerable overdiagnosis that occurs using PSA-based screening. Meanwhile, awareness among the population of prostate cancer as a potentially lethal disease stimulates opportunistic screening practices that further increase overdiagnosis without the benefit of mortality reduction. However, in the past decade, new screening tools have been developed that make the classic PSA-only-based screening an outdated strategy. With improved use of PSA, in combination with age, prostate volume and with the application of prostate cancer risk calculators, a risk-adapted strategy enables improved stratification of men with prostate cancer and avoidance of unnecessary diagnostic procedures. This combination used with advanced detection techniques (such as MRI and targeted biopsy), can reduce overdiagnosis. Moreover, new biomarkers are becoming available and will enable further improvements in risk stratification.

Prostate Specific Antigen and Biopsy Contamination in the Göteborg-1 Randomized, Population-Based, Prostate Cancer Screening Trial

Even when a screening study has demonstrated a mortality reduction, the degree of pre-testing and contamination is of importance as it can dilute the "true" effect of screening. Our object was to describe the level of pre-testing and contamination in the Göteborg-1 prostate cancer screening trial. A total of 20,000 men, 50-64 years old, were invited in 1994 and randomized to either a screening group (offered prostate specific antigen testing every 2 years) or to a control group. Follow-up was through December 31, 2014. Outcome measurement was overall testing in the screening group and control group. A positive prostate specific antigen test was defined as a prostate specific antigen ≥3 ng/ml. In the study, 4.2% in the screening group and 4.6% men in the control group were tested before study start. During follow-up, 72% in the control group took at least 1 prostate specific antigen test (contamination) compared to 87% of men in the screening group. Of all prostate specific antigens, 24% in the screening group and 39% in the control group were above threshold. In total, 66% of the men underwent prostate biopsy within 12 months from a raised prostate specific antigen in the screening group and 28% in the control group. Similar proportions of men were prostate specific antigen-tested in both the screening group and control group, yet only a minority of contamination prostate specific antigens led to biopsy. Also, men in the screening group started screening at a younger age. These could both be explanations for our result that organized screening is more effective in reducing prostate cancer mortality than non-organized testing. When carried out properly and compared to an unscreened population, the effects of organized screening are likely even greater than previously shown in the Göteborg screening trial.

Abstract 38: Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors

Abstract Introduction: Black men have 2.1 times higher prostate cancer mortality rates than White men in the United States, yet the reasons for this disparity remain unclear. Several dietary and lifestyle factors may influence the risk of developing lethal prostate cancer. This study evaluated to what extent differences in the prevalence of modifiable risk factors by race could explain racial disparities in prostate cancer mortality. Methods: Our study utilized data from the Health Professionals Follow-up Study (HPFS, N=51,529 men, 1986-2016) and the National Health and Nutrition Examination Study (NHANES, 2000-2010). First, we used data from NHANES to estimate the prevalence of three factors among Black and White men: smoking, vitamin D, and coffee. Then, using HPFS, we generated relative risk estimates for lethal prostate cancer for each factor. To estimate the relative prostate cancer burden associated with these risk factors, we calculated the population attributable fraction (PAF) for each factor by self-identified race, defined as the reduction in mortality that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We then calculated the difference in the PAF between Black and white men to estimate the difference in mortality reduction between the two groups if all men had been entirely unexposed, assuming causality of risk factors and no effect modification by race. Results: There were notable differences in the prevalence of several risk factors by race. For example, Black men had significantly lower levels of vitamin D[MLA1], were less likely to drink coffee, and had a higher prevalence of smoking compared to white men. We estimated that eliminating these risk factors among Black men could lead to a reduction in prostate cancer mortality that is 4-14% larger compared to eliminating these risk factors among white men. Conclusions: Modifiable lifestyle and dietary factors are potentially responsible for a proportion of the racial disparity in prostate cancer mortality. Our future work will expand the modifiable factors as well as incorporating more contemporary comparisons of the prevalence of these factors to predict future disparities in prostate cancer. Citation Format: Emily Rencsok, Michelle Sodipo, Travis Gerke, Konrad Stopsack, Lorelei Mucci. Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 38.