Prostate Cancer Incidence Rates Research Articles

Recent trends in prostate cancer in Canada.

Prostate cancer is the most common type of cancer in Canadian men. Screening recommendations have changed substantially over the last 25 years. Since 2011 (United States) and 2014 (Canada), taskforce guidelines have recommended against screening using the prostate-specific antigen (PSA) test in low-risk men of all ages. This work reports on trends in prostate cancer incidence, mortality, and stage at diagnosis in Canada from 1992 to 2015. Prostate cancer incidence, mortality, and stage at diagnosis were retrieved from Statistics Canada's Canadian Cancer Registry and Canadian Vital Statistics - Death Database. Joinpoint analysis was used to examine trends over time. The age-standardized incidence rate (ASIR) of prostate cancer peaked in 1993 and 2001, and declined thereafter. From 2011 to 2015, the ASIR declined by 9.3% per year. The age-standardized mortality rate (ASMR) decreased continuously from 1992 to 2015, but fell most rapidly (2.9% per year) after 2001. Data from two provinces show that, from 2005 to 2015, the rate of Stage I and Stage II cancers decreased by 3.2% per year, while the rate of Stage III and Stage IV cancers remained relatively stable. Incidence of prostate cancer has declined substantially in recent years. Most of the decline seems to be in localized cases (Stage I and Stage II). Changes in incidence have mirrored changes to PSA screening recommendations. Future work should continue to monitor trends over time at the national level, especially as they relate to screening recommendations.

MP18-03 THE CHINESE ANTI-CANCER ASSOCIATION GENITOURINARY CANCER COMMITTEE PROSTATE CANCER SCREENING PROGRAM: A PRELIMINARY REPORT AFTER RECRUITMENT OF 2162 MEN

INTRODUCTION AND OBJECTIVES:There is marked regional differences in the prostate cancer (PCa) incidence and mortality rates rate between China and the West. The incidence of PCa is increasing rapid...

Cancer burden in the Caribbean: an overview of the Martinique Cancer Registry profile

BackgroundCancer indicators are essential information for cancer surveillance and cancer research strategy development. The Martinique Cancer Registry (MCR) is a population-based cancer Registry (PBCR) that has been recording cancer data since its creation in 1981. This article provides cancer incidence and mortality data for all cancers and for major tumor sites.MethodsThe registry collects all new cancer cases, details of the individual affected, tumor site and follow-up. World-standardized incidence and mortality rates were calculated, by tumor site and sex for solid tumors from the MCR database for the study period 2001–2015.ResultsOver the period 2001–2015, a total of 22,801 new cases were diagnosed; 13,863 in men (60.8%) and 8938 in women (39.2%). In 2011–2015, 1631 new cases were diagnosed per year. Age-standardized (to the world population) incidence rates for all cancers, were 289.8 per 100,000 men and 171.0 per 100,000 women. Breast, colon-rectum and stomach were the most common cancer sites in women. Prostate, colon-rectum and stomach were the main sites in men. Martinique has higher incidence rates of prostate and stomach cancer than mainland France.ConclusionsProstate and stomach cancers have high incidence and rank first among the four major tumor sites. Providing data for the French zone of the Caribbean is essential to contributing to the development of high-priority public health measures for the Caribbean zone.

108 - International comparison in the Risk Calculator-based age-standardized incidence rate of prostate cancer between Japan and the Netherlands

108 - International comparison in the Risk Calculator-based age-standardized incidence rate of prostate cancer between Japan and the Netherlands

A genetic risk score to personalize prostate cancer screening, applied to population data.

181 Background: Genetic risk stratification may inform the decision of whether—and at what age—a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS) for accurate prediction of age of onset of aggressive PCa and for improved screening PSA performance. The PHS is a weighted sum of 54 SNP genotypes. Here, we applied the PHS to population data to assess its potential impact on individualized screening. Methods: Age-specific PCa incidence data were obtained for men aged 40-70 years from the United Kingdom (Cancer Research UK, 2013-2015) and fit to an exponential curve as a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT study data, annualized incidence rate curves were calculated for the following percentiles of genetic risk: 1, 5, 20, 50, 80, 95, and 99. The proportion of incidence classified as aggressive (Gleason score ≥7) was estimated as 59.7%, the reported result from the CAP trial. PHS was combined with incidence data to give a risk-equivalent age, when a man with given PHS percentile will have the same risk of aggressive PCa as that of a typical man at age 50 years. Results: The age-specific incidence rate of PCa for the UK population was modeled as: 0.004 e0.203(age-40) ( R2 = 0.957, p = 0.001). Table shows risk-equivalent age for each genetic risk percentile. For example, a man with a PHS in the 95th percentile reached PCa risk equivalent to a typical 50-year-old man at age 44 years; conversely, a man with a PHS in the first percentile does not reach this risk level until age 60 years. Initiation of screening discussions could be adjusted accordingly. Conclusions: PHS may inform PCa screening with individualized estimates of risk-equivalent age for aggressive PCa. Risk-equivalent age for aggressive prostate cancer, by PHS percentile. [Table: see text]

Epidemiology of Prostate Cancer

Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Prostate cancer may be asymptomatic at the early stage and often has an indolent course that may require only active surveillance. Based on GLOBOCAN 2018 estimates, 1,276,106 new cases of prostate cancer were reported worldwide in 2018, with higher prevalence in the developed countries. Differences in the incidence rates worldwide reflect differences in the use of diagnostic testing. Prostate cancer incidence and mortality rates are strongly related to the age with the highest incidence being seen in elderly men (> 65 years of age). African-American men have the highest incidence rates and more aggressive type of prostate cancer compared to White men. There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise. Screening is highly recommended at age 45 for men with familial history and African-American men. Up-to-date statistics on prostate cancer occurrence and outcomes along with a better understanding of the etiology and causative risk factors are essential for the primary prevention of this disease.

Patient Characteristics at Prostate Cancer Diagnosis in Different Races at an Academic Center Serving a Diverse Population.

In the United States, the prostate cancer (PCa) incidence and death rate has been greater in non-Hispanic black (NHB) men than in non-Hispanic white (NHW) men and slightly lower in Hispanic men than in NHW men. We compared the sociodemographic and baseline prognostic factors at the diagnosis of PCa in different races/ethnicities at a large, academic center serving an ethnically diverse population. The Montefiore Medical Center Cancer Registry was used to generate a comprehensive list of all patients with PCa diagnosed from 2004 to 2014. The clinical Looking Glass (a proprietary searchable database of patient information) and individual patient medical record review were used to obtain data, including age at diagnosis, socioeconomic status (SES), clinical Gleason score, clinical stage, and prostate-specific antigen level at diagnosis. The patients were classified by self-identified race/ethnicity as Hispanic, NHB, NHW, or other. The χ2 test was used for categorical variables, and analysis of variance or the Kruskal-Wallis test was used for continuous variables. We identified 2352 patients with newly diagnosed PCa during the study period, including 778 Hispanic, 1046 NHB, 486 NHW, and 42 other. The NHW men were significantly older at diagnosis (Hispanic, 63.2 years; NHB, 63.4 years; NHW, 67 years; other, 63.0 years; P< .0001). The mean SES for the Hispanic and NHB men was significantly lower (SES below average: Hispanic, 92.8%; NHB, 91.3%; NHW, 56.6%; other, 75%; P<.0001). The Gleason score at diagnosis differed among these race groups (Gleason score≤6 PCa: Hispanic, 42.8%; NHB, 39.1%; NHW, 52.2%; other, 50%; Gleason score 8-10: Hispanic, 15.8%; NHB, 17.6%; NHW, 14.3%; other, 16.7%; P= .0005). The proportion of men with metastatic disease at diagnosis also differed significantly among the groups (Hispanic, 7.5%; NHB, 9.0%; NHW, 4.3%; other, 9.5%; P=.0139). Using pairwise comparisons, the odds ratio for a higher Gleason score at presentation between NHB and NHW was 1.592 (P< .001) and was 1.378 for Hispanic versus NHW (P= .0200). The pairwise comparison for metastatic disease at diagnosis showed an odds ratio of 2.186 for NHB versus NHW (P= .0087). After adjusting for SES, the odds ratio for a higher Gleason score comparing NHB and NHW was 1.55 (P= .001). Although the odds of metastatic disease were greater in Hispanic men than in NHW men (odds ratio, 1.784), the differences were not statistically significant (P=.1197). At our center, the clinical features of men from different racial groups differed significantly at the time of newly diagnosed PCa. Differences included age at diagnosis, SES, Gleason score, and proportion with metastatic disease. Our pairwise comparisons between different ethnic groups suggested that PCa in Hispanic men might be more similar to that in NHB than to that in NHW patients and are generally more aggressive at diagnosis.

Pattern of care of prostate cancer patients across the Martinique: results of a population-based study in the Caribbean

BackgroundThe French West-Indies rank first for both prostate cancer incidence and mortality rates. Analyzing diagnostic and therapeutic procedures among patients with prostate cancer, using data from a population-based cancer registry, is essential for cancer surveillance and research strategies.MethodsThis retrospective observational cohort study was based on data from the Martinique Cancer Registry. Records of 452 patients diagnosed with prostate cancer in 2013 were retrieved from the registry. Data extracted were: socio-demographic and clinical characteristics, circumstances of diagnosis, PSA level at diagnosis, Gleason score and risk of disease progression. Stage at diagnosis and patterns of care among prostate cancer patients were analyzed.ResultsMean age at diagnosis was 67 ± 8 years; 103 (28.5%) were symptomatic at diagnosis. Digital rectal exam was performed in 406 (93.8%). Clinical stage was available in 385 (85.2%); tumours were localized in 322/385 (83.6%). Overall, 17.9% were at low risk, 36.4% at intermediate and 31.9% at high risk; 13.8% were regional/metastatic cancers. Median PSA level at diagnosis was 8.16 ng/mL (range 1.4–5000 ng/mL). A total of 373 patients (82.5%) received at least one treatment, while 79 (17.5%) had active surveillance or watchful waiting. Among patients treated with more than one therapeutic strategy, the most frequent combination was external radiotherapy with androgen deprivation (n = 102, 22.6%).ConclusionsThis study provides detailed data regarding the quality of diagnosis and management of patients with prostate cancer in Martinique. Providing data on prostate cancer is essential for the development of high-priority public health measures for the Caribbean.

ONCOUROLOGIC PATHOLOGY IN THE AMUR REGION OF THE FAR EASTERN FEDERAL DISTRICT

The purpose of study was an assessment of the incidence and mortality rates for kidney, prostate and bladder cancer in the Amur region of the Far Eastern Federal District. Material and methods. Incidence and mortality rates for kidney, prostate and bladder cancer, cancer registry data, and ten-year follow-up data were used. Results . During the period 2007–16, the incidence and mortality rates for kidney, prostate and bladder cancer steadily increased in the Amur region. The trends in the morbidity and mortality were determined for all groups of the study population. The quality of the service activity indicated by the index of reliability of patients’ registry was estimated. As a prognostic test, the values of «disease severity» («disease burden») were studied. Based on these values, the assumptions about the most favorable prognosis and quality of life in patients with kidney cancer relative to patients with prostate and bladder cancers were made. Conclusion. The cancer incidence and mortality rates still remain high and the number of cases continues to increase in the Amur region. The results of the study were recommended by the authors for the practical use in the cancer services of the Amur Region for the development of targeted medical, social and economic programs.

Cancer Statistics for Hispanics/Latinos, 2018.

Cancer is the leading cause of death among Hispanics/Latinos, who represent the largest racial/ethnic minority group in the United States, accounting for 17.8% (57.5 million) of the total population in the continental United States and Hawaii in 2016. In addition, more than 3 million Hispanic Americans live in the US territory of Puerto Rico. Every 3 years, the American Cancer Society reports on cancer occurrence, risk factors, and screening for Hispanics in the United States based on data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the Centers for Disease Control and Prevention. For the first time, contemporary incidence and mortality rates for Puerto Rico, which has a 99% Hispanic population, are also presented. An estimated 149,100 new cancer cases and 42,700 cancer deaths will occur among Hispanics in the continental United States and Hawaii in 2018. For all cancers combined, Hispanics have 25% lower incidence and 30% lower mortality compared with non-Hispanic whites, although rates of infection-related cancers, such as liver, are up to twice as high in Hispanics. However, these aggregated data mask substantial heterogeneity within the Hispanic population because of variable cancer risk, as exemplified by the substantial differences in the cancer burden between island Puerto Ricans and other US Hispanics. For example, during 2011 to 2015, prostate cancer incidence rates in Puerto Rico (146.6 per 100,000) were 60% higher than those in other US Hispanics combined (91.6 per 100,000) and 44% higher than those in non-Hispanic whites (101.7 per 100,000). Prostate cancer is also the leading cause of cancer death among men in Puerto Rico, accounting for nearly 1 in 6 cancer deaths during 2011-2015, whereas lung cancer is the leading cause of cancer death among other US Hispanic men combined. Variations in cancer risk are driven by differences in exposure to cancer-causing infectious agents and behavioral risk factors as well as the prevalence of screening. Strategies for reducing cancer risk in Hispanic populations include targeted, culturally appropriate interventions for increasing the uptake of preventive services and reducing cancer risk factor prevalence, as well as additional funding for Puerto Rico-specific and subgroup-specific cancer research and surveillance.

Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis.

Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement.

Total Medicare Costs Associated With Diagnosis and Treatment of Prostate Cancer in Elderly Men

Localized prostate cancer diagnosis and treatment among elderly men who are not likely to benefit represents a potential source of low-value health care services. To quantify the costs to the Medicare program associated with detection and treatment of prostate cancer among elderly men in the United States. This nationwide, population-based, retrospective cohort study uses the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify men 70 years or older diagnosed with localized prostate cancer between 2004 and 2007 and to ascertain Medicare costs associated with diagnosis and workup, treatment, follow-up, and morbidity management of the disease. National Medicare costs were estimated using per-person costs, stage-adjusted prostate cancer incidence rates by age from SEER 2007 through 2011, and 2010 Census population estimates by age. Estimated costs to the Medicare program overall, and in each (mutually exclusive) category related to diagnosis and workup, treatment, follow-up, and morbidity management. This nationwide, population-based, retrospective cohort study included 49 692 men with nonmetastatic prostate cancer from the SEER-Medicare database (all participants were 70 years or older; 25 981 [52.3%] were 76 years or older). The median per-patient cost within 3 years after prostate cancer diagnosis was $14 453 (interquartile range [IQR], $4887-$27 899). The majority of this cost was attributable to treatment costs (median, $10 558; IQR, $1990-$23 718). Patients with a Gleason score of 6 or lower who pursued initial conservative management (no treatment within 12 months of diagnosis) had a 3-year median total cost of $1914 per patient. The estimated total 3-year cost to the Medicare program associated with the annual detection of prostate cancer in men 70 years or older is approximately $1.2 billion. Increasing active surveillance use in those with Gleason score of 6 or lower could reduce this cost by $320 million. There is substantial cost to the Medicare program associated with the diagnosis and treatment of localized prostate cancer among elderly men in the United States, despite the fact that these men are unlikely to die of prostate cancer. The majority of costs are related to treatment. Reducing provision of low-value health care services among this patient population could result in significant health care savings.

Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location.

Although research has reported that prostate cancer (PCa) incidence and mortality rates are among the highest for African Americans, the data is inconclusive regarding PCa rates in native African men, Black men residing in other countries, and men in Asia, Europe, and the Americas. Data reveals that prostate-specific antigen (PSA) testing and disease incidence have risen significantly in developing and Asian countries, and PCa has become one of the leading male cancers in many of those nations.The objective of this study was to review published peer-reviewed studies that address PCa in different regions of the world to get a better understanding of how PCa incidence, prevalence, detection, and mortality are influenced by race, ethnicity, and geography. A secondary goal was to compare PCa data from various world regions to contextualize how disproportionate the incidence and mortality rates are among men from the African diaspora versus men of European, Hispanic, and Asian descent, as well as to highlight the need for more robust screening and treatment guidelines in developing countries.There are differences in incidence and mortality rates between men of African, Asian, Hispanic, and European ancestry, confirming the involvement of genetic factors. However, differences between men of the same race and ethnicity who live in different countries suggest that environmental factors may also be implicated. Availability and access to diagnostic and health-care services as well as recommendations regarding PCa testing vary from country to country and contribute to the variability in incidence and mortality rates.

Temporal Trend in Incidental Prostate Cancer Detection at Surgery for Benign Prostatic Hyperplasia

ObjectiveTo assess changes in the rate of incidental prostate cancer (PCa) after benign prostatic hyperplasia (BPH) surgery over the last decade. Materials and MethodsWe identified 1177 patients surgically treated for BPH (open prostatectomy, transurethral resection or holmium laser enucleation [HoLEP] of the prostate) in 2007-2016 at a single European academic center. Local polynomial regression was used to explore changes in the rate of incidental PCa detected after BPH surgery and of preoperative biopsy performed over time. Logistic regression analyses tested the association of incidental PCa diagnosis with year of surgery and preoperative biopsy. ResultsIncidental PCa was found in 6.4% (74) of cases, 67 (91%) with Grade group 1 disease. We observed an increased incidence of PCa diagnosis after BPH surgery over time (odds ratio [OR]: 1.12; 95%confidence interval [CI]: 1.02-1.24, P = .02) along with a concomitant decrease in the rate of preoperative prostate biopsies (OR: 0.83; 95%CI: 0.79-0.88, P < .0001). Patients undergoing a preoperative biopsy showed a lower risk of being diagnosed with PCa after surgery (OR: 0.29; 95% CI: 0.12, 0.72 P = .007). Patients treated with HoLEP had a higher chance of incidental PCa detection (OR: 2.28; 95%CI: 1.30–4.00; P = .004), although this may be related to the significantly higher number of HoLEP performed over the last years. ConclusionThe increased rate of low-risk PCa detected after BPH surgery in the last decade reflects the clinical practice changes in PCa screening and diagnosis leading to a reduced number of unnecessary biopsies and indolent cancer diagnosis.

Research progress in hydrogel in radiotherapy of localized prostate cancer

In recent years, the incidence rate of prostate cancer has been gradually elevated year by year in China. External radiotherapy yields similar clinical efficacy to surgery in the treatment of localized prostate cancer. Because the rectum is close to the prostate, the radiotherapy targeting for prostate cancer constantly causes radiation-related proctitis. Recently, multiple researchers have attempted to inject polyethylene glycol hydrogel into the rectal prostate space to separate the rectum from the prostate, thereby reducing the radiation dose coverage for the rectum and minimizing the risk of radiation-related proctitis. In this article, the application basis, radiation stability, injection technology, dosimetry and clinical efficacy of polyethylene glycol hydrogel injection were summarized. Key words: Prostate neoplasms/radiotherapy; Polyethylene glycol hydrogel; Radiation proctitis

Prostate cancer incidence rates in the world from the Cancer Incidence in Five Continents XI.

Prostate cancer incidence rates in the world from the Cancer Incidence in Five Continents XI.

Abstract B64: Race and prostate cancer: miRNA isoforms and tRNA fragments could hold some of the answers

Abstract Prostate cancer is the most frequently occurring cancer in men. Compared to White (Wh) men, Black/African American (B/Aa) men exhibit higher mortality and higher incidence rates of prostate cancer. This difference remains even after modifiable factors are taken into account, which suggests an underlying cause. Recent studies greatly improved our understanding of the biochemistry of prostate cancer. Nonetheless, many open questions remain, especially with regard to the molecular underpinnings of the observed race disparities. In this study, we analyzed 526 transcriptomic datasets from prostate adenocarcinoma (PRAD) patients. We obtained the data from The Cancer Genome Atlas (TCGA) repository. We focused on two categories of noncoding RNAs that regulate messenger RNA (mRNA) and protein abundance: (1) microRNAs (miRNAs) and their isoforms (isomiRs) and (2) tRNA-derived fragments (tRFs). Both tRFs and isomiRs regulate mRNAs and their proteins through the RNA induced silencing complex (RISC). Furthermore, tRFs have a number of other regulatory roles in healthy and diseased cells, including direct physical interactions with ribosomal proteins and initiation factors. Notably, we have demonstrated and reported previously that isomiRs and tRFs are constitutive and transcribed in a manner that depends strongly on a person's gender, race, and population origin, as well as on tissue type, tissue state, and disease type/subtype. Our analyses of the TCGA PRAD datasets revealed that both isomiRs and tRFs are disrupted in PRAD. By extension, the regulatory networks that link isomiRs and tRFs to mRNAs are also disrupted. We also uncovered transcriptomic differences and differential regulatory relationships that are aligned with patient race. Moreover, we found that the molecular differences between B/Aa and Wh PRAD patients extend to normal prostate tissue as well. These findings mirror earlier results that we obtained from both healthy individuals and cancer patients. The race-dependent regulatory profiles highlight differences in the underlying biology in B/Aa and Wh individuals that have yet to be explored. For example, the corresponding molecules could potentially be leveraged as novel biomarkers or alternative therapeutic targets. This study represents the first characterization of isomiRs and tRFs in a large cohort of PRAD patients. Citation Format: Rogan G. Magee, Aristeidis G. Telonis, Phillipe Loher, Eric Londin, Isidore Rigoutsos. Race and prostate cancer: miRNA isoforms and tRNA fragments could hold some of the answers [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B64.

Abstract SY45-02: Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer

Abstract Background: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are 1.6- and 2.4-fold greater, respectively, than among white men. The more aggressive characteristics of AA PCa account for a significant component of the PCa disparity, in addition to social determinants of health. Differences in androgenic activities in AA versus white populations and PCa patients have been observed and, clinically, AAs have a less complete response to androgen deprivation than whites do. One of the critical androgen receptor signaling targets in PCa is AR-V7, an androgen receptor variant that lacks the ligand-binding domain, is constitutively active, and associates with castration-resistant PCa, poorer clinical outcomes, and resistance to androgen ablation/androgen receptor inhibition therapies. This work addresses the urgent need to develop a novel therapeutic strategy capable of inhibiting AR-V7. Methods: We have designed and synthesized a novel chemically modified splice switching oligonucleotide (SSO) to correct aberrant splicing leading to production of AR-V7 as well as a control scrambled SSO. After transfection of PCa cell lines derived from AA and white patients with these SSOs, we have examined AR-V7 as well as androgen receptor RNA and protein levels using qPCR and Western blot analysis, respectively. Resulting alterations in proliferation have been assessed by monitoring cell growth using an Incucyte Live-Cell Imaging System and associated software. Results: Transfection of a panel of PCa cell lines derived from AA and white patients with AR-V7 SSO decreases AR-V7 RNA and protein in a dose-dependent manner while maintaining expression levels of full-length androgen receptor. Preliminary data suggest that this biochemical response correlates with a biologically significant phenotype. AR-V7 SSO decreases proliferation in PCa cells, including proliferation in the presence of the androgen receptor inhibitor, enzalutamide, over and above the reduction seen in response to enzalutamide alone in both enzalutamide-sensitive and -resistant PCa cell lines. Further studies to examine the effects of this SSO on transactivation activity, signaling, and PCa cell biology and the therapeutic efficacy of this SSO in AA and white PCa patient-derived primary cell lines and xenografts are under way. Conclusions: These studies suggest that an SSO can be developed to modulate androgen receptor signaling, inhibiting constitutive signaling and restoring ligand dependency. Such a SSO could represent a novel therapeutic strategy with the potential to reduce PCa disparities for AA men and improve outcomes for men of all races with aggressive disease driven by this mechanism. Citation Format: Jennifer A. Freedman. Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY45-02.

Abstract PR04: Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer

Abstract Background: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are 1.6- and 2.4-fold greater, respectively, than among white men. The more aggressive characteristics of AA PCa account for a significant component of the PCa disparity, in addition to social determinants of health. Differences in androgenic activities in AA versus white populations and PCa patients have been observed and, clinically, AAs have a less complete response to androgen deprivation than whites do. One of the critical androgen receptor signaling targets in PCa is AR-V7, an androgen receptor variant that lacks the ligand-binding domain, is constitutively active and associates with castration-resistant PCa, poorer clinical outcomes, and resistance to androgen ablation/androgen receptor inhibition therapies. This work addresses the urgent need to develop a novel therapeutic strategy capable of inhibiting AR-V7. Methods: We have designed and synthesized a novel chemically modified splice switching oligonucleotide (SSO) to correct aberrant splicing leading to production of AR-V7 as well as a control scrambled SSO. After transfection of PCa cell lines derived from AA and white patients with these SSOs, we have examined AR-V7 as well as androgen receptor RNA and protein levels using qPCR and Western blot analysis, respectively. Resulting alterations in proliferation have been assessed by monitoring cell growth using an Incucyte Live-Cell Imaging System and associated software. Results: Transfection of a panel of PCa cell lines derived from AA and white patients with AR-V7 SSO decreases AR-V7 RNA and protein in a dose-dependent manner while maintaining expression levels of full-length androgen receptor. Preliminary data suggest that this biochemical response correlates with a biologically significant phenotype. AR-V7 SSO decreases proliferation in PCa cells, including proliferation in the presence of the androgen receptor inhibitor, enzalutamide, over and above the reduction seen in response to enzalutamide alone in both enzalutamide-sensitive and -resistant PCa cell lines. Further studies to examine the effects of this SSO on transactivation activity, signaling, and PCa cell biology and the therapeutic efficacy of this SSO in AA and white PCa patient-derived primary cell lines and xenografts are under way. Conclusions: These studies suggest that a SSO can be developed to modulate androgen receptor signaling, inhibiting constitutive signaling and restoring ligand dependency. Such a SSO could represent a novel therapeutic strategy with the potential to reduce PCa disparities for AA men and improve outcomes for men of all races with aggressive disease driven by this mechanism. Citation Format: Bonnie L. LaCroix, Brendon M. Patierno, Bruce A. Sullenger, Daniel J. George, Steven R. Patierno, Jennifer A. Freedman. Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr PR04.

Abstract B59: Race-related differential splicing of the insulin receptor: A novel target underlying prostate cancer disparities

Abstract Background: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are significantly greater than among white men. Much of this disparity remains after controlling for behavioral, social, and neighborhood determinants of health, which is consistent with a biologic contribution. Evidence suggests that the genetic etiology and molecular progression of PCa are different in AAs versus whites. Our laboratory has identified novel alternatively spliced genes in AA versus white PCa biopsy tissue that track with population-based prostate tumor aggressiveness. This work addresses the urgent need to interrogate novel molecular mechanisms driving more aggressive PCa in AAs to aid in development of new biomarkers and therapeutic targets for improved prognosis and treatment of aggressive disease. Methods: We have analyzed RNA from human PCa biopsy tissue from 20 AA and 15 white patients using exon arrays. From these data, we prioritized targets for further study by identifying those associated with androgen signaling and PCa and those that have also been shown to be alternatively spliced in breast, lung, and liver cancer. To validate race-related alternative splicing of the insulin receptor (INSR) gene, we have used qPCR and targeted sequencing of RNA from population-specific PCa cell lines and patient-derived explants. In addition, we have knocked down the INSR splice variants in population-specific PCa cell lines using isoform-specific siRNAs and assessed resulting alterations in proliferation using a WST-1 proliferation assay. Current studies include assessing additional resulting alterations in expression of selected key targets in INSR signaling using Western blot analysis. In addition, studies are under way to treat population-specific PCa cell lines with INSR signaling inhibitors and assess resulting alterations in PCa cell biology. Results: Exon array analysis of RNA from AA and white PCa biopsy tissue revealed 934 differentially expressed exons in 861 corresponding genes. Thirty-nine targets have been prioritized for further study. We have validated race-related alternative splicing of INSR, involving differential exon inclusion/skipping of exon 11, in population-specific PCa cell lines and patient-derived explants, with the exclusion of exon 11 occurring more often in preclinical models of white PCa. Knockdown of INSR splice variants in population-specific PCa cell lines has shown that decreased expression of the isoform excluding exon 11 inhibits proliferation while decreased expression of the isoform including exon 11 has no effect on proliferation. Further studies to assess additional resulting alterations in expression of selected key targets in INSR signaling are under way. In addition, studies are under way to treat population-specific PCa cell lines with INSR signaling inhibitors and assess resulting alterations in PCa cell biology. Conclusions: These studies identify differential splicing of INSR in AA and white PCa and the INSR isoform excluding exon 11 as contributors to prostate tumor aggressiveness. Further interrogation of this mechanism underlying PCa disparities and its effect on targeted therapeutics has the potential to reduce PCa disparities for AA men and improve outcomes for men of all races with aggressive disease driven by this mechanism. Citation Format: April Deveaux, Bi-Dar Wang, Bonnie Lacroix, Brendon Patierno, Dadong Zhang, Kouros Owzar, Norman Lee, Daniel George, Jennifer Freedman, Steven Patierno. Race-related differential splicing of the insulin receptor: A novel target underlying prostate cancer disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B59.