Prostate Cancer Aggressiveness In Men Research Articles

Abstract 2149: West African genetic ancestry and origin of the BRCA1 locus in Jamaican men with high grade prostate cancer

Abstract Introduction: Men of West African (WA) ancestry are at higher risk for prostate cancer than men of European (EU) or Asian descent. Caribbean populations provide an opportunity to identify potential founder mutations that contribute to cancer risk. Jamaica has among the highest rates of prostate cancer incidence and mortality in the world and the majority of the population are of WA ancestry. However, there is a significant amount of genetic admixture of EU and Asian ancestry from historic migration patterns. Thus, the population provides a unique cohort for studying the complex interplay between genetic ancestry and prostate cancer. In this pilot study, we characterized the overall and gene locus-specific ancestry of Jamaican prostate cancer patients to explore potential associations with clinicopathologic disease features. We specifically focused this analysis on the BRCA1 locus based on its known association with inherited prostate cancer risk and also with breast cancer risk in patients from the Caribbean. Methods: A retrospective cohort of 31 Jamaican men (non-US citizens/residents) who travelled to the University of Miami (2015-2020) specifically for robotic prostatectomy were included in the analysis. DNA was prepared from normal prostate tissue and analyzed using the Illumina Global Screening Array version 3 with Multi-Disease Drop-In that includes more than 650,000 genetic markers. Both overall genetic ancestry and allele specific ancestries were determined for each study subject. Clinical and pathological features (age, PSA, stage, grade group (GG)) were also recorded and analyzed using descriptive statistics. Results: Median age was 67 years, median pre-op PSA was 6.7. The majority of patients were cT1c (91%) and GG 2 (29%) on biopsy. On final pathology most men were ≥pT3 (51%) and the proportion of GG 1, 2 and ≥ 3 was 3%, 52% and 45% respectively. The mean overall West African genetic ancestry was 51.2% (SD 28.4%). Overall % West African ancestry was not associated with pathological GG. In contrast, 50% of the men who were homozygous for African ancestry alleles at the BRCA1 locus had high-grade prostate cancer (GG 3, 4, 5) versus 37% of the men with non-African or heterozygous BRCA1 genotypes. Conclusions: In a select cohort of Jamaican men, we found that half of patients with BRCA1 alleles derived from West African ancestry also have high grade prostate cancer. BRCA1 of African ancestral origin may contribute to the relatively high prevalence of aggressive prostate cancer in men from Jamaica. Work in progress focuses on an expanded study of associations between allele-specific genetic ancestry and prostate cancer in high-risk populations. Citation Format: Sandra M. Gaston, Anthony J. Griswold, Oleksandr N. Kryvenko, Tianjie Gu, Guan-Nan Zhang, Nachiketh S. Prakash, Yuval Avda, Tarek Ajami, Chad R. Ritch. West African genetic ancestry and origin of the BRCA1 locus in Jamaican men with high grade prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2149.

Abstract 1182: Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry

Abstract Background: There is a growing body of evidence supporting the contributions of germline rare variants to the susceptibility of prostate cancer (PCa), especially aggressive PCa. Our previous exome sequencing analysis highlighted 36 aggressive PCa candidate genes in populations of European ancestry. Here we investigated whether rare germline pathogenic, likely pathogenic, or deleterious (P/LD/D) variants in these genes were associated with overall and aggressive PCa risk in men of African ancestry. Methods: This exome sequencing analysis consists of 7,176 prostate cancer cases and 4,873 controls from the Research on Prostate Cancer in Men of African Ancestry (RESPOND) study. Among the PCa cases, 3,283 are aggressive cases (tumor stage T3/T4, regional lymph node involvement, metastatic disease, Gleason score >= 8.0, prostate-specific antigen [PSA] level >= 20 ng/mL or PCa as the underlying cause of death) including 1,074 metastatic cases, and 1,752 are non-aggressive cases (Gleason score ⇐ 7.0, PSA < 20 ng/mL, and tumor stage T1/T2). P/LP/D variants analyzed were rare (minor allele frequency < 1% in controls) and had either a Variant Effect Predictor impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. The association between P/LP/D carrier status with risk of overall PCa, aggressive PCa, and metastatic PCa was evaluated in logistic regression models, adjusting for age and the top ten principal components. All statistical tests are two-sided. Results: Of the 36 PCa candidate genes, BRCA2 was the most frequently affected gene, with 1.7% of cases and 1.1% of controls harboring a germline P/LP/D variant, followed by MUTYH (1.5%/1.3%) ATM (0.93%/0.49%), MSH5 (0.70%/0.51%) and HOXB13 (0.70%/0.35%). Nominally significant associations with overall PCa were observed for ATM (OR=1.83, 95% CI=1.14-2.92, P=0.012), BRCA2 (OR=1.52, 95% CI=1.10-2.10, P=0.011), HOXB13 (OR=2.10, 95% CI=1.12-3.66, P=0.008), and PALB2 (OR=3.46, 95% CI=1.18-10.1, P=0.02). In case-case analyses (aggressive vs. non-aggressive cases), the association with aggressive PCa was nominally significant for ATM (OR=5.10, 95% CI=1.96-13.3, P=8.7 × 10−4) and BRCA2 (OR=2.00, 95% CI=1.19-3.38, P=0.009) and was suggestive for PALB2 (OR=2.99, 95% CI=0.83-10.7, P=0.09). Similar associations with metastatic PCa were also observed for these three genes. Conclusion: The associations of BRCA2, ATM, and PALB2 with overall PCa and aggressive PCa observed in men of African ancestry are consistent with findings from our previous study in men of European ancestry. These findings further support the importance of these genes in the consideration of screening and active surveillance for high-risk and advanced disease. Citation Format: Fei Chen, Burcu F. Darst, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A. Adjei, James Mensah, Pedro W. Fernandez, Akindele O. Adebiyi, Oseremen Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, David V. Conti, Christopher A. Haiman. Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1182.

The volume and thickness of preprostatic fat on MRIs are not associated with prostate cancer aggressiveness in men undergoing radical prostatectomy.

Periprostatic fat has a metabolic activity on the prostate via cytokines that act paracrine on several signaling pathways including tumorigenesis. We investigated whether there was an association between preprostatic fat abundance and prostate cancer (PCa) aggressiveness. We performed a retrospective study including patients who underwent radical prostatectomy in our center from the prospective RESCAP database. Preoperative MRIs were re-read and different measurements of preprostatic fat (PPF) were performed. The maximum thickness (PPFmax) and the minimum thickness (PPFmin) were measured on a median T2 sagittal section. The total volume of preprostatic fat (PPFV) and volume normalized by prostate volume (NPPFV) were calculated semi-automatically by segmentation on continuous axial sections of 3mm. The association of these parameters with the aggressiveness criteria of PCa (ISUP 3-5 on biopsies and on operative specimen, intermediate or high-risk disease according to D'AMICO, PSA>10, upgrading risk at radical prostatectomy) was measured as well as the association between normal, overweight, and obese BMI classes and the aggressiveness criteria used. One hundred and twenty-one men were included in this study. In both the univariate analysis and the multivariate analysis, none of the preprostatic fat measurements (PPFmax, PPFmin, PPFV and NPPFV) were associated with PCa aggressiveness criteria. There was also no association between BMI class and tumor aggressiveness. In this study, there is no association between the abundance of preprostatic fat and PCa aggressiveness according to the periprostatic fat measurements achieved. III.

Validation of the cell cycle progression score to differentiate indolent from aggressive prostate cancer in men diagnosed through transurethral resection of the prostate biopsy.

BackgroundValidation of biomarker‐based prognostic models to improve risk stratification in men with localized prostate cancer (PrCa) remains a clinical need. It has previously been shown that the cell cycle progression (CCP) test provides significant, independent prognostic information for men who were incidentally diagnosed with PrCa after transurethral resection of the prostate (TURP) and were conservatively managed.AimThe results have been extended in a newly analyzed retrospective cohort of UK men diagnosed through TURP biopsy (TURP1B; N = 305).Methods and ResultsThe CCP score was derived from TURP biopsy tissue and combined with a modified UCSF Cancer of the Prostate Risk Assessment score (CAPRA) to generate the clinical cell‐cycle risk score (CCR). The primary endpoint was PrCa‐specific mortality (PSM). Hazard ratios (HR) were calculated for a one‐unit change in score. Median follow‐up was 9.6 (IQR: 5.4, 14.1) years, and 67 (22%) men died from PrCa within 10 years of diagnosis. The median CCP score was 1.1 (IQR: 0.6, 1.7). In univariate analyses, CCR proved a significant prognosticator of PSM (HR per unit score change = 2.28; 95% CI: 1.89, 2.74; P = 1.0 × 10−19). In multivariate analyses, CCR remained a significant prognosticator of PSM after adjusting for CAPRA (HR per unit score change = 4.36; 95% CI: 2.65, 7.16; P = 1.3 × 10−8), indicating that its molecular component, CCP, provides significant, independent prognostic information.ConclusionThese findings validate a combined clinicopathologic and molecular prognostic model for conservatively managed men who are diagnosed through TURP, supporting the use of CCR to inform clinical management.

Independent and Joint Effects of Testosterone Replacement Therapy and Statins use on the Risk of Prostate Cancer Among White, Black, and Hispanic Men.

The associations of testosterone therapy (TTh) and statins use with prostate cancer remain conflicted. However, the joint effects of TTh and statins use on the incidence of prostate cancer, stage and grade at diagnosis, and prostate cancer-specific mortality (PCSM) have not been studied.We identified White (N = 74,181), Black (N = 9,157), and Hispanic (N = 3,313) men diagnosed with prostate cancer in SEER-Medicare 2007-2016. Prediagnostic prescription of TTh and statins was ascertained for this analysis. Weighted multivariable-adjusted conditional logistic and Cox proportional hazards models evaluated the association of TTh and statins with prostate cancer, including statistical interactions between TTh and statins.We found that TTh (OR = 0.74; 95% CI, 0.68-0.81) and statins (OR = 0.77; 95% CI, 0.0.75-0.88) were inversely associated with incident prostate cancer. Similar inverse associations were observed with high-grade and advanced prostate cancer in relation to TTh and statins use. TTh plus statins was inversely associated with incident prostate cancer (OR = 0.53; 95% CI, 0.48-0.60), high-grade (OR = 0.43; 95% CI, 0.37-0.49), and advanced prostate cancer (OR = 0.44; 95% CI, 0.35-0.55). Similar associations were present in White and Black men, but among Hispanics statins were associated with PCSM.Prediagnostic use of TTh or statins, independent or combined, was inversely associated with incident and aggressive prostate cancer overall and in NHW and NHB men. Findings for statins and aggressive prostate cancer are consistent with previous studies. Future studies need to confirm the independent inverse association of TTh and the joint inverse association of TTh plus statins on risk of prostate cancer in understudied populations. PREVENTION RELEVANCE: The study investigates a potential interaction between TTh and statin and its effect on incident and aggressive prostate cancer in men of different racial and ethnic backgrounds. These results suggest that among NHW and non-Hispanic Black men TTh plus statins reduced the odds of incident prostate cancer, high-grade and advance stage prostate cancer.

Using Prostate Imaging-Reporting and Data System (PI-RADS) Scores to Select an Optimal Prostate Biopsy Method: A Secondary Analysis of the Trio Study

BackgroundWhile magnetic resonance imaging (MRI)-targeted biopsy (TBx) results in better prostate cancer (PCa) detection relative to systematic biopsy (SBx), the combination of both methods increases clinically significant PCa detection relative to either Bx method alone. However, combined Bx subjects patients to higher number of Bx cores and greater detection of clinically insignificant PCa. ObjectiveTo determine if prebiopsy prostate MRI can identify men who could forgo combined Bx without a substantial risk of missing clinically significant PCa (csPC). Design, setting, and participantsMen with MRI-visible prostate lesions underwent combined TBx plus SBx. Outcome measurements and statistical analysisThe primary outcomes were detection rates for grade group (GG) ≥2 and GG ≥3 PCa by TBx and SBx, stratified by Prostate Imaging-Reporting and Data System (PI-RADS) score. Results and limitationsAmong PI-RADS 5 cases, nearly all csPCs were detected by TBx, as adding SBx resulted in detection of only 2.5% more GG ≥2 cancers. Among PI-RADS 3–4 cases, however, SBx addition resulted in detection of substantially more csPCs than TBx alone (8% vs 7.5%). Conversely, TBx added little to detection of csPC among men with PI-RADS 2 lesions (2%) relative to SBx (7.8%). ConclusionsWhile combined Bx increases the detection of csPC among men with MRI-visible prostate lesions, this benefit was largely restricted to PI-RADS 3–4 lesions. Using a strategy of TBx only for PI-RADS 5 and combined Bx only for PI-RADS 3–4 would avoid excess biopsies for men with PI-RADS 5 lesions while resulting in a low risk of missing csPC (1%). Patient summaryOur study investigated an optimized strategy to diagnose aggressive prostate cancer in men with an abnormal prostate MRI (magnetic resonance imaging) scan while minimizing the risk of excess biopsies. We used a scoring system for MRI scan images called PI-RADS. The results show that MRI-targeted biopsies alone could be used for men with a PI-RADS score of 5, while men with a PI-RADS score of 3 or 4 would benefit from a combination of MRI-targeted biopsy and systematic biopsy.This trial is registered at ClinicalTrials.gov as NCT00102544.

Abstract B090: Molecular mechanisms of microRNA-1205 in aggressive prostate cancer in men of African ancestry

Abstract High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance towards second generation ADTs leads to the progression of AR-independent neuroendocrine PCa (NEPC) phenotypes, which are observed in nearly 1 in 5 men with mCRPC and is associated with short survival rates. Moreover, men of African ancestry (moAA) have a higher NEPC incidence and mortality rates, compared to Caucasian males. PCa neuroendocrine differentiation (PCND) is observed in treatment related NEPC, however, this mechanism is poorly understood. Therefore, further understanding of PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important PCa susceptibility region containing genetic variants associated with increased PCa incidence among moAA. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We have previously reported that miR-1205 is underexpressed in a cohort of histologically confirmed PCa tissue obtained from moAA, when compared to normal tissue and is also underexpressed in vitro in CRPC cells, when compared to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC-derived xenograft male NOD/SCID gamma mice, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we demonstrated that miR-1205 directly targets Fry-like (FRYL). FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in PCND. To examine miR-1205 regulation of FRYL in NEPC, we examined RNA sequencing data from a cohort of histologically confirmed NEPC tissues (n=14) and PCa adenocarcinoma tissues (n=30) obtained from TCGA using the cBioPortal platform. We observed increased FRYL mRNA expression in NEPC tissues when compared to PCa adenocarcinoma tissues. In vitro data revealed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of induced PCND differentiation using LNCaP cells when compared to undifferentiated LNCaP cells. Lastly, we performed RNA pulldown, and subsequent RNA sequencing to identify the molecular targets of miR-1205. Interestingly, we observed that in addition to FRYL, the AURKA gene, which is amplified during PCND, was significantly enriched. In conclusion, these data suggest that miR-1205 regulation of FRYL may be a critical mechanism in NEPC. Further understanding this molecular mechanism may provide novel insights into overcoming ADT resistance in aggressive PCa that disproportionally affects moAA. Citation Format: Michelle K Naidoo, Fayola Levine, Xavier Graña-Amat, Olorunseun Ogunwobi. Molecular mechanisms of microRNA-1205 in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B090.

Abstract PR09: MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry

Abstract Men of African ancestry (moAA) have increased likelihood for development of aggressive prostate cancer (PCa). PCa deaths are often associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy (ADT). The 8q24 chromosomal locus is a highly susceptible PCa region that carries risk genetic variants associated with increased incidence of aggressive PCa in moAA. This region also carries frequent amplifications of the PVT1 gene, a nonprotein coding gene that encodes microRNA-1205 whose function was previously unknown. We examined miR-1205 mRNA expression in a cohort of normal (n=22), benign prostatic hyperplasia (n=42), and PCa (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA in Ibadan, Nigeria. A Tukey post hoc test revealed decreased miR-1205 expression in benign prostatic hyperplasia (4.61 ± 7.5) and PCa (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5), suggesting that miR-1205 may function as a tumor suppressor and loss of miR-1205 is characteristic of PCa in moAA. In vitro studies revealed decreased miR-1205 expression in CRPC (C4-2B and 22RV1) cells when compared to non-CRPC (LNCaP) cells, suggesting a role for miR-1205 in CRPC. Furthermore, we observed significant inhibition of tumor growth in NOD/SCID gamma mice implanted with C4-2B cells that were administered our novel synthetic analog of miR-1205 (patent pending) when compared to mice treated with a scramble oligonucleotide, indicating that miR-1205 can suppress CRPC tumors. We identified Fry-like (FRYL) as a putative target of miR-1205 using a miSVR computer algorithm and subsequently observed FRYL and AR overexpression in prostate tumors compared to normal tissue from fourteen PCa patients when whole-transcriptome analysis was performed using the Galaxy web platform. Moreover, FRYL was overexpressed in CRPC cells when compared with non-CRPC cells, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 3′ UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 3′ UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor by directly targeting FRYL mRNA in PCa cells. FRYL is predicted to regulate dendritic branching, leading to our hypothesis that FRYL plays a role in the development of PCa with neuroendocrine differentiation (PCND), a resulting mechanism due to ADT resistance. We observed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of inducing PCND in LNCaP cells, suggesting that miR-1205 regulation of FRYL mRNA may play a role in PCND development. Further understanding miR-1205 regulation of FRYL may provide novel insights into the molecular mechanisms of aggressive PCa. This abstract is also being presented as Poster B068. Citation Format: Michelle K. Naidoo, Fayola Levine, Tamara Gillot, Thahmina Ali, Konstantinos Krampis, Akintunde Orunmuyi, E.O. Olapade-Olaopa, Olorunseun O. Ogunwobi. MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry [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 PR09.

Peri-prostatic adipose tissue measurements using MRI predict prostate cancer aggressiveness in men undergoing radical prostatectomy.

To evaluate the effect of peri-prostatic adipose tissue (PPAT) measurements using preoperative MRI on the prediction of prostate cancer (PCa) aggressiveness in men undergoing radical prostatectomy (RP). We performed a retrospective study on 179 consecutive patients receiving RP from June 2016 to October 2018. Clinical characteristics were collected. PPAT measurements including peri-prostatic fat area (PPFA) and peri-prostatic fat area to prostate area (PA) ratio (PPFA/PA) were calculated by MRI. Multivariable logistic regression analysis was performed to identify independent predictors of PCa lymph node metastasis (LNM). The predictive performance was estimated through ROC curves. Nomograms were created based on the predictors. Pathologic Gleason score positively correlated with digital rectal examination (DRE), PSA, PPFA/PA, P504S, and Ki-67 (all P < 0.05). ROC curves revealed that high PPFA and high PPFA/PA were associated with LNM (both P < 0.05). Multivariate analysis revealed that high PPFA/PA, pathologic Gleason score, pT stage, and Ki-67 were independently predictive of LNM. The nomograms were created and the C-index was 0.945. PPFA/PA is an independent predictor for LNM along with Gleason score, pT stage, and Ki-67. PPFA/PA may help predict LNM in men undergoing RP, thus providing adjunctive information for therapeutic strategy and prognosis.

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Cell cycle progression score differentiates indolent from aggressive prostate cancer in men diagnosed by TURP.

e16560 Background: Improved selection of men with localized prostate cancer for conservative management remains a clinical need. We previously showed that the Cell Cycle Progression (CCP) score provides a significant amount of independent prognostic information in men with prostate cancer who opt for conservative management. Here, we extend those results by evaluating the performance of the CCP score in a newly analyzed cohort of conservatively managed men and in a large pooled cohort of men who deferred initial curative therapy. Methods: The CCP score (based on 31 CCP genes and 15 housekeepers) was derived from FFPE tumor sections as previously described. For this study, the CCP score was evaluated in several independent cohorts: 1) a newly studied retrospective cohort from the U.K. diagnosed by a transurethral resection of the prostate (TURP1B, N = 192); 2) a previously studied cohort from the U.K. diagnosed by TURP (TURP1A, N = 200); and 3) two previously studied cohorts from the U.K. diagnosed by needle biopsy (TAPG1, N = 180 and TAPG2, N = 585). The combined cohort included 1,157 conservatively managed men with complete clinical data. Median follow-up for all cohorts was 9.8 years. Hazard ratios (HR) are for a one-unit change in score, and the endpoint for this study was disease specific mortality (DSM). Results: The CCP score was a highly significant predictor of DSM in TURP1B. The univariate HR was 2.96 (95% CI 2.32, 4.04, p = 3.6x10-9), and the multivariate HR after adjusting for CAPRA was 2.27 (95% CI 1.59, 3.23, p = 1.3x10-5). These results are very similar to the HRs obtained in TURP1A cohort, and the test for HR heterogeneity was not significant after adjusting for CAPRA (p = 0.30). In the pooled analyses, the interaction between CCP and cohort was not significant after adjusting for clinical variables. Interestingly, sample type (TURP vs. Needle biopsy) was prognostic even after adjusting for clinical variables. Summaries of the pooled analyses are given in Table. Conclusions: The CCP score adds a significant amount of independent prognostic information for outcome in conservatively managed men. As such, it can be used to help select appropriate patients for deferred treatment regimens like AS or watchful waiting. [Table: see text]

Periprostatic fat adipokine expression is correlated with prostate cancer aggressiveness in men undergoing radical prostatectomy for clinically localized disease.

To investigate the relationship between periprostatic adipose tissue (PPAT) adipokine expression and prostate cancer (PCa) aggressiveness using both pathological features of radical prostatectomy (RP) and multiparametric magnetic resonance imaging ( MRI) variables. Sixty-nine men were recruited to assess immunohistochemical expression of tumour necrosis factor (TNF)α and vascular endothelial growth factor (VEGF) of periprostatic fat of RP specimens. Per cent immunopositivity was quantified on scanned slides using the Aperio Positive Pixel Count algorithm for PPAT TNFα, VEGF and androgen receptors. Periprostatic fat volume (PFV) was segmented on contiguous T1 -weighted axial MRI slices from the level of the prostate base to apex. PFV was normalized to prostate volume (PV) to account for variations in PV (normalized PFV = PFV/PV). MRI quantitative values (Kep , Ktrans and apparent diffusion coefficient) were measured from the PCa primary lesion using Olea Sphere software. Patients were stratified into three groups according to RP Gleason score (GS): ≤6, 7(3 + 4) and ≥7(4 + 3). The mean rank of VEGF and TNFα was significantly different between the groups [H(2) = 11.038, P = 0.004] and [H(2) = 13.086, P = 0.001], respectively. Patients with stage pT3 had higher TNFα (18.2 ± 8.95) positivity than patients with stage pT2 (13.27 ± 10.66; t [67] = -2.03, P = 0.047). TNFα expression significantly correlated with Ktrans (ρ = 0.327, P = 0.023). TNFα (P = 0.043), and VEGF (P = 0.02) correlated with high grade PCa (GS ≥ 7) in RP specimens and also correlated significantly with upgrading of GS from biopsy to RP histology. The expression levels of TNFα and VEGF on immunostaining significantly correlated with aggressivity of PCa. As biomarkers, these indicate the risk of having high grade PCa in men undergoing RP.

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance

PurposeAge at prostate cancer (PCa) diagnosis has been positively associated with PCa-specific mortality, and for men on active surveillance (AS), a higher risk of biopsy grade reclassification (BGR) to Gleason score ≥3+4 (grade group [GG]≥2); however, the association between age and BGR to an aggressive phenotype (Gleason score ≥4+3 [GG≥3]) has not been explored. Materials & MethodsFrom 1995-2016, 1625 men aged 41-81y with NCCN very-low (68%) or low (32%) risk PCa were followed on AS. We determined rates of BGR to GG≥3. Competing risk analysis was used to evaluate the association between age at enrollment and risk of BGR. Additionally, in men who underwent radical prostatectomy (RP) after BGR, we assessed rates of RP grade reclassification (RPGR; i.e. RP GG>biopsy GG). ResultsThe 5-year incidence of BGR to GG≥3 was 4%, 7% and 14% in men <60y, 60-69y and ≥70y, respectively (p<0.001). In univariate analysis, older age was associated with BGR to GG≥3 (HR=2.43 per 10-year increase, p<0.001). In multivariable analysis adjusting for year of diagnosis, race, PSA density and cancer volume at diagnosis, older age remained associated with BGR to GG≥3 (HR=2.19 per 10-year increase; p<0.001). In men who underwent RP after BGR, older men had higher rates of RPGR (p<0.05). ConclusionsFor men on AS, older age at time of diagnosis was positively associated with BGR to GG≥3, and RPGR. These observations imply that for many older men, AS (as opposed to watchful waiting) remains a more appropriate management strategy.

Abstract B61: c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry

Abstract Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student's t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score &amp;lt;8. Thus, miR-1207-3p and FNDC1 may be useful for risk stratification in PCa in MoAA. Next, we observed that our novel synthetic biotinylated miR-1207-3p duplex (NB1207, patent pending) significantly inhibited c-Myc protein expression in 7 PCa cell lines when compared with a biotinylated scramble duplex (NB-1, patent pending). RNA pulldown assay determined that c-Myc is not a direct molecular target of miR-1207-3p. However, siRNAs against FNDC1, FN1, and AR revealed significant suppression of c-Myc expression by &amp;gt;75% in the MoAA-derived indolent E006AA PCa cell line and the MoAA-derived aggressive/castration-resistant E006AA-hT PCa cell line, indicating that c-Myc is downstream of AR. c-Myc expression is higher in the E006AA-hT PCa cell line when compared to the E006AA PCa cell line, suggesting that c-Myc is associated with aggressive PCa. Moreover, NB1207 significantly inhibited migration and induced apoptosis in E006AA and E006AA-hT PCa cell lines. Next, we compared the efficacy of NB1207 in inhibiting proliferation to the commercially available drugs for treatment of CPRC (enzalutamide and abiraterone). NB1207 inhibited proliferation in the CRPC cell line E006AA-hT by nearly 50% while enzalutamide and abiraterone had no effect. In conclusion, miR-1207-3p regulates c-Myc expression via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. miR-1207-3p may be a biomarker for risk stratification in PCa in MoAA. NB1207 has potential for therapeutic targeting of c-Myc for treatment of aggressive PCa in MoAA. Citation Format: Dibash K. Das, Akintunde T. Orunmuyi, Gabriel Olabiyi Ogun, S. Adekola Adebayo, A. Ayo Salako, Adeodat Ilboudo, Cuong Bach, E. O. Olapade-Olaopa, Olorunseun O. Ogunwobi. c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry [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 B61.

Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels.

PurposeTestosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP.Materials and methodsRetrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively.ResultsOf the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49–0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48–0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70–1.13) or any CaP (HR 0.90; 95% CI 0.81–1.01). No association between cumulative testosterone dose or formulation and CaP was observed.ConclusionsAmong men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.

Normalized periprostatic fat MRI measurements can predict prostate cancer aggressiveness in men undergoing radical prostatectomy for clinically localised disease

Periprostatic and pelvic fat have been shown to influence prostate cancer behaviour through the secretion of chemokines and growth factors, acting in a paracrine mode. We have measured periprostatic fat volume (PFV) with normalisation to prostate gland volume on pelvic magnetic resonance imaging (MRI) and have correlated this with grade (Gleason score; GS) and pathological staging (pT) of prostate cancer (PCa) following radical prostatectomy (RP). PFV was determined using a segmentation technique on contiguous T1-weighted axial MRI slices from the level of the prostate base to the apex. The abdominal fat area (AFA) and subcutaneous fat thickness (SFT) were measured using T1-weighted axial slices at the level of the umbilicus and the upper border of the symphysis pubis, respectively. PFV was normalised to prostate volume (PV) to account for variations in PV (NPFV = PFV/PV). Patients were stratified into three risk groups according to post-operative GS: ≤6, 7(3 + 4), and ≥7(4 + 3). NPFV was significantly different between the groups (p = 0.001) and positively correlated with post-operative GS (ρ = 0.294, p < 0.001). There was a difference in NPFV between those with upgrading of GS from 6 post prostatectomy (2.43 ± 0.98; n = 26) compared to those who continued to be low grade (1.99 ± 0.82; n = 17); however, this did not reach statistical significance (p = 0.11).

Abstract 425: Nuclear morphometry predicts prostate cancer progression

Abstract Introduction: The progression of prostate cancer (PCa) involves tissue morphometric changes, which laid the base for current pathological diagnosis of prostate cancer with the Gleason Scoring system. Nuclear morphometry (NM) changes contribute significantly to these tissue morphometric changes, but accurate and autonomous quantification of NM changes are challenging. Here we created a macro to quantify the changes of size, shape, DNA content, etc., and used these parameters to predict PCa progression in 80 men that underwent radical prostatectomy (RP). Materials &amp; Methods: Two tissue microarrays (TMAs) with 80 RP PCa cases, stratified by Gleason scores (GS) were used for this study. The two continuous sections of TMAs were stained with H&amp;E and Feulgen reagents and the H&amp;E slides were used for pathological diagnosis of PCa. Both kinds of slides were scanned with Aperio scanner and image of each core were separated using Aperio ImageScope software. The H&amp;E or Feulgen stained nuclei of cancer core were quantified using Smart Segmentation of ImagePro® Premier 9.1 software. For each core, data of all ROIs were pooled and the covariance of each parameter were generated. Data were first analyzed alone and then in combination using multivariate logistic regression (MLR) to predict the aggressive RP cases or biochemical recurrence (BCR). Decision curve analysis (DCA) was used for the MLR models to evaluate their power and effectiveness for clinical decision making. For all analysis, a p&amp;lt;0.05 is considered as statistically significant. Results: Using multivariate logistic regression (MLR), to differentiate aggressive PCa (Gleason score 4+3 &amp; &amp;gt; = 8) from less aggressive PCa (Gleason score 3+3 &amp; 3+4) on the TMAs of RP cases, our Feulgen NM model generated a receiver operating characteristic curve-area under the curve (ROC-AUC) of 0.90 with a sensitivity of 75.51% and specificity of 86.21% while our H&amp;E NM model yield an ROC-AUC of 0.96 with a sensitivity of 82.00% and specificity of 90.00%. DCA analysis both showed better decision using both models compared with considering the patients as all or none of them as aggressive. Both models also show strength in differentiating two Gleason score 7 (3+4 vs 4+3). Feulgen NM model showed moderate power in the prediction of BCR based on the MLR (ROC-AUC = 0.79) and DCA analysis, while H&amp;E MLR model performed better with a ROC-AUC of 0.86. Further Kaplan-Meier analysis of BCR with GS and NM (H&amp;E and Feulgen) showed that the combination of GS with either Feulgen or H&amp;E NM showed significant power in the differentiation patients with BCR survival time (HR = 3.14 &amp; 3.89, respectively). Conclusions: Our accurate quantification of tissue morphometry demonstrated its translational clinical relevance since it can predict PCa aggressiveness in men that have undergone RP. Future application of this tool in active surveillance biopsies may provide an early diagnosis and prognosis prediction of PCa patients effectively. Citation Format: Guangjing Zhu, Aniq ur rehman Gajdhar, Jonathan I. Epstein, Neil Carleton, Christine Davis, Luciane Tsukamoto Kagohara, Robert W. Veltri. Nuclear morphometry predicts prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 425.

MiR-1207-3p Is a Novel Prognostic Biomarker of Prostate Cancer

MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR-1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P < .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA.

Abstract B18: Development of novel therapeutic splice-switching oligonucleotides against aggressive prostate cancer in men of African descent

Abstract African American (AA) men exhibit a nearly 2-fold higher incidence and 3-fold higher mortality rate from prostate cancer compared to Caucasian American (CA) men and disparities in tumor aggressiveness remain after controlling for social determinants of health. Previous work from our laboratory and others has revealed differences in gene expression that contribute to prostate cancer health disparities among AAs. Oncogenic signaling pathways exhibiting up-regulation more often in AA prostate cancer include androgen receptor (AR) and epidermal growth factor receptor (EGFR). Thus, novel therapeutic strategies capable of driving production of inhibitory AR and EGFR isoforms and capable of limiting aberrant constitutively active AR isoforms are urgently needed. Such strategies will increase our understanding of these molecular mechanisms underlying prostate cancer in AA men. In addition, such strategies have the potential to ultimately result in novel specific approaches for treatment that will help reduce prostate cancer disparities for AAs and will improve treatment of advanced stage disease in all men with aggressive disease driven by these mechanisms. Splice-switching oligonucleotides (SSOs) represent a novel therapeutic strategy to combat prostate cancer. Unlike the strategy of using RNA interference to inhibit the expression of a gene, SSOs simultaneously limit the production of pathogenic proteins and induce the expression of protein variants with therapeutic value. SSOs modulate pre-mRNA splicing by binding to target pre-mRNAs and blocking access of the splicing machinery to a particular splice site, and can be used to produce novel splice variants or correct aberrant splicing. Herein we have designed and synthesized novel SSOs targeting AR and EGFR pre-mRNAs to produce inhibitory splice variants and correct aberrant splicing as follows. We have synthesized a SSO to correct the aberrant splicing that leads to production of the constitutively active AR-V7 variant leading to restoration of ligand dependency. Transfection of prostate cancer cells with this chemically modified SSO, which targets the splice site of the cryptic exon included in AR-V7, decreases AR-V7 RNA. In addition, we have synthesized a SSO to drive production of a naturally occurring dominant-negative AR variant (AR45) leading to interference with wild type AR transactivation activity. Transfection of prostate cancer cells with this chemically modified SSO, which targets the splice site of the first exon of wild type AR and leads to inclusion of an alternative first exon encoding the unique N-terminal extension characterizing AR45, increases AR45 RNA. Furthermore, we have synthesized SSOs targeting exons in the transmembrane domain and the tyrosine kinase domain of EGFR to drive production of a soluble, naturally expressed inhibitory EGFR isoform and a dominant-negative EGFR isoform, respectively. Transfection of prostate cancer cells with these chemically modified SSOs increase RNA corresponding to these isoforms. Studies are underway to examine the effects of these SSOs on AR and EGFR signaling, respectively, and the effects of these SSOs on prostate tumor cell biology. These studies suggest that SSOs can be developed to modulate AR and EGFR signaling. Such SSOs have the potential to further our understanding of the contribution of the targeted molecular mechanisms to AA prostate cancer and have the potential to yield novel therapeutic modalities to combat prostate cancer in AA men as well as men of all races with aggressive disease driven by these mechanisms. Citation Format: Jennifer A. Freedman, Timothy J. Robinson, Bonnie LaCroix, Brendon M. Patierno, Daniel J. George, Bruce A. Sullenger, Steven R. Patierno. Development of novel therapeutic splice-switching oligonucleotides against aggressive prostate cancer in men of African descent. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B18.

Association of genetic variations of selenoprotein genes, plasma selenium levels, and prostate cancer aggressiveness at diagnosis.

Genetic variations in some of the selenoprotein genes, alone or together with an individual's selenium status, may influence risk or progression of prostate cancer. We investigated the impact of genetic variants of selenoproteins on plasma selenium levels and cancer aggressiveness at diagnosis in men with localized prostate cancer (PCa). The study cohort comprised 722 patients seen at Dana-Farber Cancer Institute who had localized/locally advanced PCa (i.e., stage T3 or less, N0, and M0) from 1994 to 2001. Fifty-five tagging single nucleotide polymorphisms (SNPs) from six selenoprotein genes (TXNRD1, TXNRD2, SEP15, GPX3, SELENBP1, and SEPP1) were analyzed. Logistic regression is used to examine associations of genotypes and plasma selenium levels with risk of aggressive disease, defined as D'Amico intermediate/high risk categories. Step down permutation was applied to adjust for multiple comparisons. Three hundred and forty-eight patients (48%) had aggressive disease at diagnosis. Two SNPs were associated with cancer aggressiveness at diagnosis (unadjusted P = 0.017 and 0.018, respectively). The odds ratio for aggressive disease in patients carrying TXNRD2 rs1005873-AG/GG genotypes or SELENBP1 rs10788804-AG/AA genotypes was 1.54 (95% CI = 1.08, 2.20) and 1.45 (95% CI = 1.07, 1.98), respectively, compared to TXNRD2 rs1005873-AA or SELENBP1 rs10788804-GG carriers. Four SNPs in TXNRD2 (rs1005873, rs13054371, rs3788310, and rs9606174) and the rs230820 in SEPP1 were associated with plasma selenium levels (unadjusted P < 0.05). Permutation adjusted P-values were not statistically significant for all these comparisons at the cut-off point of 0.05. We identified polymorphisms in selenoproteins that may influence the plasma selenium levels and may be associated with the risk of presenting with aggressive PCa in men with localized or locally advanced PCa. These results should be validated in other independent datasets.