High Aggressive Prostate Cancer Research Articles

Cigarette smoking and prostate cancer aggressiveness among African and European American men

PurposeSmoking is a modifiable lifestyle factor that has not been established as a prostate cancer risk factor, nor emphasized in prostate cancer prevention. Studies have shown that African American (AA) smokers have a poorer cancer prognosis than European Americans (EAs), while having a lower prevalence of heavy smoking. We examined the relationship between cigarette smoking and prostate cancer aggressiveness and assessed racial differences in smoking habits on the probability of high-aggressive prostate cancer.MethodsUsing data from the North Carolina-Louisiana Prostate Cancer Project (n = 1,279), prostate cancer aggressiveness was defined as high or low based on Gleason scores, serum prostate-specific antigen levels, and tumor stage. Cigarette smoking was categorized as current, former, or never smokers. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsSelf-reported current (OR = 1.99; 95% CI 1.30–3.06) smoking was associated with high-aggressive prostate cancer relative to never smokers. When stratified by self-reported race, the odds of having high-aggressive cancer increased among AA current (OR = 3.58; 95% CI 2.04–6.28) and former smokers (OR = 2.21; 95% CI 1.38–3.53) compared to AA never smokers, but the odds were diminished among the EA stratum (Pself-reported race x smoking status = 0.003).ConclusionCigarette smoking is associated with prostate cancer aggressiveness, a relationship modulated by self-reported race. Future research is needed to investigate types of cigarettes smoked and metabolic differences that may be contributing to the racial disparities observed.

Abstract 2172: Associations between plant- and animal-based dietary patterns and aggressive prostate cancer in the North Carolina-Louisiana prostate cancer project (PCaP)

Abstract Objective: Results of studies examining the association between a plant-based diet or animal food intake and prostate cancer have been mixed. Few studies have focused on aggressive prostate cancer in a racially diverse population. We examined the association between healthy and unhealthy plant-based and animal-based diet scores and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project, a case-only study of Black and White men in the United States. Methods: Eighteen food groups were created and classified as healthy plant foods, unhealthy plant foods, or animal foods using dietary data collected from an interviewer-administered modified version of the National Cancer Institute Diet History Questionnaire among 909 Black and 991 White men with a histologically confirmed diagnosis of prostate cancer. High aggressive prostate cancer (n=332) was defined as Gleason sum ≥8; or PSA> 20ng/ml; or Gleason sum ≥7 and clinical stage T3-T4, and the comparison group was all other prostate cancer cases (n=1,568). Logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (95% CI) for high aggressive prostate cancer by tertiles of dietary pattern scores. Results: A decreased odds of aggressive prostate cancer was observed among men in the upper compared to the bottom tertile for healthy plant-based diet score (OR: 0.82, 95% CI: 0.58, 1.15) and unhealthy plant-based diet score (OR: 0.89, 95%CI: 0.63, 1.25) while an increased odds was observed comparing extreme tertiles of the animal-based diet score (OR: 1.17. 95% CI: 0.84-1.65) after adjustment for multiple covariates, though confidence intervals were imprecise and not statistically significant. Associations tended to be stronger among White men than among Black men; e.g., for the animal-based diet score, ORs (95% CIs) were 1.41 (0.86, 2.37) and 1.02 (0.63, 1.66) for White and Black men, respectively. Conclusions: Consuming a plant-based dietary pattern may be associated with lower odds of aggressive prostate cancer while an animal-based dietary pattern may be associated with higher odds, though associations were weak and not statistically significant. Keywords: Healthy plant-based diet, unhealthy plant-based diet, animal-based diet, aggressive prostate cancer, racial disparities Conflict of interest: None Funding: PCaP is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. This research was made possible in part by Grant Numbers R01-CA259415 from NIH-NCI and T32-GM081740 from NIH-NIGMS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or NIH. Citation Format: Jessica Sainyo, Susan E. Steck, Longgang Zhao, L. Joseph Su, Lenore Arab, David Turner, Ebonee N. Butler, Jeannette T. Bensen, Elizabeth T.H. Fontham, James L. Mohler. Associations between plant- and animal-based dietary patterns and aggressive prostate cancer in the North Carolina-Louisiana prostate cancer project (PCaP) [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 2172.

Development and Validation of an Explainable Radiomics Model to Predict High-Aggressive Prostate Cancer: A Multicenter Radiomics Study Based on Biparametric MRI.

In the last years, several studies demonstrated that low-aggressive (Grade Group (GG) ≤ 2) and high-aggressive (GG ≥ 3) prostate cancers (PCas) have different prognoses and mortality. Therefore, the aim of this study was to develop and externally validate a radiomic model to noninvasively classify low-aggressive and high-aggressive PCas based on biparametric magnetic resonance imaging (bpMRI). To this end, 283 patients were retrospectively enrolled from four centers. Features were extracted from apparent diffusion coefficient (ADC) maps and T2-weighted (T2w) sequences. A cross-validation (CV) strategy was adopted to assess the robustness of several classifiers using two out of the four centers. Then, the best classifier was externally validated using the other two centers. An explanation for the final radiomics signature was provided through Shapley additive explanation (SHAP) values and partial dependence plots (PDP). The best combination was a naïve Bayes classifier trained with ten features that reached promising results, i.e., an area under the receiver operating characteristic (ROC) curve (AUC) of 0.75 and 0.73 in the construction and external validation set, respectively. The findings of our work suggest that our radiomics model could help distinguish between low- and high-aggressive PCa. This noninvasive approach, if further validated and integrated into a clinical decision support system able to automatically detect PCa, could help clinicians managing men with suspicion of PCa.

Abstract P035: Associations between meat and fish intake and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP)

Abstract Objective: Results of studies examining the association between intake of meat or fish and prostate cancer have been mixed. However, few of the previous studies have included a racially diverse population or focused on aggressive prostate cancer. We aimed to examine the association between intake of meat and fish and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project, a case-only study of Black and White men in the United States. Methods: Meat and fish intakes in the year prior to diagnosis were estimated using an interviewer-administered modified version of the National Cancer Institute Diet History Questionnaire in 909 Black and 991 White men with a recent histologically confirmed diagnosis of prostate cancer. High aggressive prostate cancer (n=332) was defined as Gleason sum ≥8, or PSA> 20ng/ml, or Gleason sum ≥7 AND clinical stage T3-T4, and the comparison group was all other prostate cancer cases (n=1,568). Logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (95% CI) for high aggressive prostate cancer by tertile of meat and fish intake variables, with adjustment for age, energy intake, race, study site, education, family history of prostate cancer, prostate cancer screening history, Charlson comorbidity index, NSAIDs use, smoking status, alcohol intake, and intake of vegetables, fruits, and milk. Results: We observed increased odds of aggressive prostate cancer among men in the second tertile compared to the first tertile for total red meat (OR:1.23. 95% CI: 0.91 – 1.68) and unprocessed red meat (OR:1.30. 95% CI: 0.96 – 1.76), though confidence intervals were imprecise and associations in the top tertile were weaker. For processed meat, a non-statistically significant increased odds of aggressive prostate cancer was observed among men in the third tertile compared to the first tertile (OR:1.27. 95% CI: 0.91 – 1.78). ORs for higher intake of fish and poultry were in the inverse direction but were weak and not statistically significant. Conclusions: In this racially diverse case-only study, we observed weak positive associations between red and processed meat and aggressive prostate cancer, and little evidence of an association with fish or poultry intake. While high temperature cooking and charring of meat is known to increase carcinogen formation, one limitation of our study was the lack of information on cooking methods or doneness of the meat consumed. Additional research is warranted among racially diverse populations that considers cooking methods and doneness preferences. Citation Format: Jessica Sainyo, Susan E. Steck, L. Joseph Su, Lenore Arab, Jeannette T. Bensen, Elizabeth T.H. Fontham, James L. Mohler. Associations between meat and fish intake and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP). [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P035.

Prostate cancer aggressiveness and financial toxicity among prostate cancer patients.

Financial toxicity (FT) is a growing concern among cancer survivors that adversely affects the quality of life and survival. Individuals diagnosed with aggressive cancers are often at a greater risk of experiencing FT. The objectives of this study were to estimate FT among prostate cancer (PCa) survivors after 10-15 years of diagnosis, assess the relationship between PCa aggressiveness at diagnosis and FT, and examine whether current cancer treatment status mediates the relationship between PCa aggressiveness and FT. PCa patients enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP) were recontacted for long-term follow-up. The prevalence of FT in the PCaP cohort was estimated. FT was estimated using the COmprehensive Score for Financial Toxicity, a validated measure of FT. The direct effect of PCa aggressiveness and an indirect effect through current cancer treatment on FT was examined using causal mediation analysis. More than one-third of PCa patients reported experiencing FT. PCa aggressiveness was significantly independently associated with high FT; high aggressive PCa at diagnosis had more than twice the risk of experiencing FT than those with low or intermediate aggressive PCa (adjusted oddsratio[aOR] = 2.13, 95% CI = 1.14-3.96). The proportion of the effect of PCa aggressiveness on FT, mediated by treatment status, was 10%, however, the adjusted odds ratio did not indicate significant evidence of mediation by treatment status (aOR = 1.05, 95% CI = 0.95-1.20). Aggressive PCa was associated with high FT. Future studies should collect more information about the characteristics of men with high FT and identify additional risk factors of FT.

Abstract 3680: Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer

Abstract Background: Smoking has not been an established risk factor for prostate cancer (PCa), and has not been emphasized in PCa prevention. However, recent studies have shown increasing evidence that there is a higher risk of biochemical recurrence, PCa mortality, and metastasis among current smokers, presenting an urgent need in re-evaluating the association between smoking and aggressive PCa. This study aimed to determine whether smoking increase the likelihood of developing a more aggressive prostate cancer. Methods: Equal numbers of African Americans (AAs) and European Americans (EAs) by smoking status (never/former/current) matched with PCa aggressiveness, BMI, 5-year age group, and year of baseline recruitment, totaling 480 participants, were included in the metabolomics study. For metabolomics analysis, fold change and BH-adjusted p-value from t-test adjusted for age for univariate analysis, and PCA adjusted for age and PLS-DA supervised statistical analysis for multivariate analysis were employed to decipher the underlying metabolomic patterns, and identify significantly dysregulated metabolites for the variables of interest. Results: AA participants were significantly younger (mean=61.4, SD=7.7) compared with EAs (mean=63.5, SD=7.5). Current smokers had a 2.4 times higher risk of high aggressive PCa. When stratified by race, the risk diminished for EAs but increased for AAs. Global metabolic profiles detected a total of 1,487 compounds of known identity. After excluding metabolites with missing values in more than 20% of the samples and with small standard variation, we observed a distinct cluster of participants from AA aggressive PCa patients and current smokers that were separated from EAs and never smokers. With BH-adjusted p-value < 0.05 and fold change > 2, we identified 10 significantly dysregulated metabolites between AA and EA among high aggressive PCa and current smokers. Further, 36 metabolites between current and never smokers among AA high aggressive PCa were significantly dysregulated, but none of them are annotated as tobacco metabolites. Conclusion: Our study presented distinctive metabolomics profiles specific to AA current smokers who had high aggressive PCa. Furthermore, the distinctive patterns were not driven by the tobacco metabolites, with the potential to identify metabolites that might help to understand the relationships between smoking and aggressive PCa in AA. Citation Format: Se-Ran Jun, L. Joseph Su, Eryn Matich, Ping-Ching Hsu. Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer [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 3680.

Recreational and occupational physical activity in relation to prostate cancer aggressiveness: the North Carolina-Louisiana Prostate Cancer Project (PCaP).

To examine associations between recreational and occupational physical activity and prostate cancer aggressiveness in a population-based, case-only, incident prostate cancer study. Data were analyzed from the cross-sectional North Carolina-Louisiana Prostate Cancer Project of African-American (n = 1,023) and European-American (n = 1,079) men newly diagnosed with prostate cancer (CaP). High-aggressive CaP was defined as Gleason sum ≥ 8, or prostate-specific antigen > 20ng/ml, or Gleason sum ≥ 7 and clinical stage T3-T4. Metabolic equivalent tasks (MET) were estimated from self-reported recreational physical activity in the year prior to diagnosis assessed retrospectively via a validated questionnaire and from occupational physical activity based on job titles. Associations between physical activity variables and high-aggressive prostate cancer were estimated using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple confounders. There was suggestive evidence that walking for 75-150min/week for exercise is associated with lower odds of high-aggressive prostate cancer compared to no walking (OR = 0.69, 95% CI 0.47-1.01). Physical activity at the current job was associated with 24% lower odds of high-aggressive prostate cancer (highest vs. lowest tertile OR = 0.76, 95% CI 0.56-1.04). However, total MET-h/week of recreational physical activity and accumulation of high-level physical activity at the longest-held job were not associated with high-aggressive prostate cancer. Results did not vary by race. The odds of high-aggressive prostate cancer were lower among men who walk for exercise and those engaged in occupations with high activity levels.

Abstract PO-161: Racial differences in the association of one-carbon metabolism polymorphisms and prostate cancer aggressiveness

Abstract Introduction: Prostate Cancer (PCa) disproportionately affects African Americans, as AA men are more commonly diagnosed with aggressive PCa and twice as likely to have mortality from the disease compared to European Americans (EA). The one- carbon metabolism pathway has been extensively studied for cancer development, yet little research has been reported on its association with aggressiveness of cancer at diagnosis. The purpose of our study is to determine whether there is difference by race for the impact of a DHFR 19bp polymorphism together with multiple single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes on a cohort of men diagnosed with either low-aggressive or high-aggressive PCa. Methods: DNA samples from a population-based study of 1,498 PCa subjects in the North Carolina- Louisiana Prostate Cancer Project were analyzed. The DHFR 19bp polymorphism was targeted by utilizing two TaqMan TAMRA probes, one with a FAM fluorescent probe to identify the insertion allele and one with a VIC fluorescent probe to identify the deletion allele. Six SNPs were genotyped via TaqMan SNP genotyping assays by Applied Biosystems. Chi-Square analyses were performed to examine differences in genotype between race. A multivariable logistic regression model adjusted for confounders was utilized to estimate the association of the 19bp DHFR polymorphism and one-carbon metabolism SNPs with PCa aggressiveness. Results: A total of 152 participants were excluded due to insufficient DNA samples, resulting in a sample of 1,346 participants. The analysis consisted of 993 low-aggressive and 345 high aggressive PCa cases. Chi-square analyses revealed significant frequency differences between AAs and EAs for the 19bp DHFR deletion polymorphism (31.2% vs 17.6%), as well as MTHFR rs1801131, MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, and MTHFD2 rs7587117 (P values < 0.0001). After adjusting for confounders, the cohort was stratified based on DHFR polymorphism status. Among subjects with the 19bp DHFR double deletion, individuals with heterozygous MTR rs1805087 (AG) were significantly less likely to have aggressive PCa (OR = 0.27 [0.10, 0.74]) when compared to individuals with the GG genotype. Among the group that had at least one copy of wild-type DHFR, heterozygous individuals (GA) at MTHFD1 rs2236225 had a significantly lower chance of aggressive PCa diagnosis (OR = 0.60 [0.38, 0.95]) compared to individuals with the AA genotype. Conclusion: Substantial differences exist between AAs and EAs in regard to polymorphisms within the one-carbon metabolism pathway. There appears to be significant interaction among genes involved that can be attributable to the racial distribution of genetic polymorphisms. Studies examining the association between folate metabolism and PCa should consider the modulation effect of gene-gene interaction when analyzing the polymorphisms collectively. Citation Format: C. Tyler Ratliff, Lora J. Rogers, L. Joseph Su. Racial differences in the association of one-carbon metabolism polymorphisms and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-161.

Abstract PO-201: Smoking as a risk factor for the aggressive prostate cancer for African-American men from the North Carolina–Louisiana Prostate Cancer Project (PCaP)

Abstract Background. Significant racial disparities exist in PCa, with the incidence in African- Americans (AAs) being 50% higher than European Americans (EAs) and PCa mortality rates in AAs being more than two-fold higher. However, the disparity cannot be explained by screening, access to treatment, and genetics can only partially explain the disparity that does little to confer actionable clinical relevance. Currently, only 3 definitive risk factors for PCa have been identified: age, race, and family history of PCa. Smoking has not been an established risk factor for prostate cancer (PCa), and has not been emphasized in PCa prevention. However, recent studies have shown increasing evidence that there is a higher risk of biochemical recurrence, PCa mortality, and metastasis among current smokers, presenting an urgent need in re- evaluating the association between smoking and aggressive PCa. This study aimed to determine whether smoking increase the likelihood of developing a more aggressive prostate cancer. Methods. The study used data from the North Carolina–Louisiana Prostate Cancer Project (PCaP), which is a population-based study of incident PCa conducted between years 2004-2009 in 2 southern states where significant racial disparities in PCa are observed. Because PCa is over diagnosed and most PCa is not clinically relevant, this study will include only subjects with high (Gleason score ≥ 8; PSA > 20 ng/mL; Gleason score = 7 and stage T3–T4) or low (Gleason score < 7 and stage T1–T2 and PSA <10 ng/mL) PCa aggressiveness. 1,497 participants were included in the analysis. Chi square and t-tests were used for the variables of interest and possible confounders, and multivariable logistic regression models were used for the odds ratio estimate. Results. There were 44.9% AAs and 55.1% EAs in the study. AA participants were significantly younger (mean=61.8, SD=7.9) compared with EAs (mean=64.0, SD=7.9), with lower education levels, shorter smoking cessation period, less screening tests in the past, less cigarettes per day, and higher Gleason sum. From the analysis, more AAs (57.6%) and those who were current smokers (22.7%) were diagnosed with high aggressive PCa. Current smokers had a 2.4 times- higher risk of high aggressive PCa (unadjusted OR=2.42, adjusted OR=2.39); when stratified by race, the risk diminished for EAs (OR=1.30) but increased for AAs (OR=3.36). Conclusion. Our study shows increased risk of aggressive PCa for current smokers, especially among AAs. Previous study had shown that self-reported cigarettes per day predicts smoke intake more poorly in AAs than in EAs. Thus, there is an urgent need in validated research using biomarkers to confirm the relationship of smoking and aggressive PCa, since cigarette smoking is preventable but have not been emphasized in PCa prevention. Citation Format: Ping-Ching Hsu, Shelbie Stahr, Christopher Brazeal, Elizabeth H. Fontham, L. Joseph Su. Smoking as a risk factor for the aggressive prostate cancer for African-American men from the North Carolina–Louisiana Prostate Cancer Project (PCaP) [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-201.

Identification of Plasma Glycosphingolipids as Potential Biomarkers for Prostate Cancer (PCa) Status.

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in United States men. Controversy continues over the effectiveness of prostate-specific antigen (PSA) for distinguishing aggressive from indolent PCa. There is a critical need for more specific and sensitive biomarkers to detect and distinguish low- versus high-risk PCa cases. Discovery metabolomics were performed utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) on plasma samples from 159 men with treatment naïve prostate cancer participating in the North Carolina-Louisiana PCa Project to determine if there were metabolites associated with aggressive PCa. Thirty-five identifiable plasma small molecules were associated with PCa aggressiveness, 15 of which were sphingolipids; nine common molecules were present in both African-American and European-American men. The molecules most associated with PCa aggressiveness were glycosphingolipids; levels of trihexosylceramide and tetrahexosylceramide were most closely associated with high-aggressive PCa. The Cancer Genome Atlas was queried to determine gene alterations within glycosphingolipid metabolism that are associated with PCa and other cancers. Genes that encode enzymes associated with the metabolism of glycosphingolipids were altered in 12% of PCa and >30% of lung, uterine, and ovarian cancers. These data suggest that the identified plasma (glyco)sphingolipids should be further validated for their association with aggressive PCa, suggesting that specific sphingolipids may be included in a diagnostic signature for PCa.

Abstract PR14: Dietary folate and prostate cancer tumor aggressiveness differences between African Americans and European Americans

Abstract Introduction: Folate is a water-soluble B vitamin, which is involved in DNA synthesis and repair and in regulation of gene expression through DNA methylation as a methyl donor. Despite the confirmed beneficial effect on the prevention of neural tube defect, concerns have been raised on high intakes of folate and its synthetic form, folic acid, may promote carcinogenesis or cancer progression. African American (AA) males tend to have a more aggressive prostate cancer tumor diagnosis compared to European American (EA) males. Objective: This aim of this study is to examine the association between folic acid intake in the year prior to PCa diagnosis among AAs and EAs. Using a population-based case-only study, an examination of folic acid was conducted to evaluate the effects of dietary folate on prostate cancer aggressiveness. Methods: Data from the North Carolina-Louisiana Prostate Cancer Project (PCaP) questionnaire were used to evaluate 1,497 participants (AA n = 722 and EA n = 775) with a low or high aggressiveness prostate cancer to assess dietary folate intake one year prior to PCa diagnosis using the National Cancer Institute Dietary History Questionnaire. High-aggressive disease was defined as Gleason sum ≥8, or prostate-specific antigen (PSA) >20 ng/mL, or Gleason score ≥7 and clinical stage T3-T4, while low-aggressive disease was defined as Gleason sum <7 and stage T1—T2 and PSA <10 ng/mL. All four variables for dietary folate (natural folate, synthetic folate, folate, and dietary folates) were examined. Multivariate logistic regression was used to assess dietary folate and prostate cancer aggressiveness. Confounding variables considered for this analysis include age, BMI, total energy (kcal), education level, and first-degree family history of PCa. Additionally, dietary folate was categorized into tertiles. Models were stratified by race and the dose-response relationship was evaluated. Results: Folate intakes, regardless natural folate (mean = 354.5 vs 304.1), synthetic folate (176.3 vs 157.5), or total dietary folate equivalent (654.0 vs 571.5), were higher among AA than EA, respectively. Based on the tertile categorization, the highest dietary folate was significantly associated with high-aggressive prostate cancer when compared to the lowest intake group among AA and EA combined (odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.04 – 1.90) after adjusted for confounders. Stratified model by race showed that there is an increased trend in PCa aggressiveness and increased folate intake (2nd tertile OR = 1.03, 95%CI = 0.67 – 1.56; 3rd tertile OR = 1.41, CI = 1.11 – 2.48), p-value for trend = 0.01. The association was not observed among EA. The trend is very similar regardless of natural or synthetic folate. Conclusion: It appeared that AA with high folic acid intake had a greater chance of being diagnosed with high-aggressiveness PCa, while the association was not observed among EA. The finding suggests that the metabolism of folate may be different between AA and EA, possibly due to genetic polymorphisms. This abstract is also being presented as Poster C034. Citation Format: Daniela Ramirez Aguilar, Susan E Steck, Hui-Yi Lin, LJ Su. Dietary folate and prostate cancer tumor aggressiveness differences between African Americans and European Americans [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 PR14.

Association among plasma 1,25(OH)2 D, ratio of 1,25(OH)2 D to 25(OH)D, and prostate cancer aggressiveness.

BackgroundAfrican‐American (AA) men tend to present with more aggressive prostate cancer (Gleason score >7) than European‐American (EA) men. Vitamin D and its metabolites are implicated in prostate cancer biology with vitamin D deficiency, indicated by its metabolite levels in serum or plasma, usually observed in AA men.ObjectiveTo determine if 1, 25‐dihydroxy vitamin D3 [1,25(OH)2D] plasma levels in AA and EA prostate cancer patients alter the risk of having aggressive prostate cancer.DesignResearch subjects from the North Carolina‐Louisiana Prostate Cancer Project (AA n = 435 and EA n = 532) were included. Plasma metabolites 1,25(OH)2D and 25‐hydroxyvitamin D3 [25(OH)D] were measured using liquid chromatography with tandem mass spectrophotometry. Research subjects were classified into low (Gleason sum < 7, stage T1‐T2, and Prostate‐specific antigen (PSA) < 9 ng/mL) or high (Gleason sum > 8 or Gleason sum = 7 with 4 + 3, or PSA > 20 ng/mL, or Gleason sum = 7 and stage T3‐T4) aggressive disease.ResultsResearch subjects in the second and third tertiles of plasma levels of 1, 25(OH)2D had lower odds of high aggressive prostate cancer (AA [ORT2vsT1: 0.66, 95%CI: 0.39‐1.12; ORT3vsT1: 0.83, 95%CI: 0.49‐1.41] and EA [ORT2vsT1: 0.68, 95%CI: 0.41‐1.11; ORT3vsT1: 0.67, 95%CI: 0.40‐1.11]) compared with the first tertile, though confidence intervals included the null. Greater 1,25(OH)2D/25(OH)D molar ratios were associated with lower odds of high aggressive prostate cancer more evidently in AA (ORQ4vsQ1: 0.45, CI: 0.24‐0.82) than in EA (ORQ4vsQ1: 0.64, CI: 0.35‐1.17) research subjects.ConclusionsThe 1,25(OH)2D/25(OH)D molar ratio was associated with decreased risk of high aggressive prostate cancer in AA men, and possibly in EA men. Further studies analyzing vitamin D polymorphisms, vitamin D binding protein levels, and prostatic levels of these metabolites may be useful. These studies may provide a better understanding of the vitamin D pathway and its biological role underlying health disparities in prostate cancer.

The association of metformin use with prostate cancer aggressiveness among Black Americans and White Americans in a population-based study.

Metformin has been associated with a reduced incidence of prostate cancer and improved prostate cancer outcomes. However, whether race modifies the association between metformin use and prostate cancer aggressiveness remains uncertain. The association between metformin use and prostate cancer aggressiveness was examined separately in Black Americans (Blacks) and White Americans (Whites). The study population consisted of 305 Black and 195 White research participants with incident prostate cancer and self-reported diabetes from the North Carolina-Louisiana Prostate Cancer Project. High-aggressive prostate cancer was defined using a composite measure of Gleason sum, prostate-specific antigen, and clinical stage. Multivariable logistic regression was used to assess the association between metformin use and high-aggressive prostate cancer at diagnosis, separately among Whites and Blacks, with adjustment for age, screening history, site, education, insurance, and body mass index. Metformin use was associated positively with high-aggressive prostate cancer in Blacks (OR 2.01; 95% CI 1.05, 3.83). By contrast, a weak inverse association between metformin use and high-aggressive prostate cancer was found in Whites (OR 0.80, 95% CI 0.34, 1.85). The association between metformin use and prostate cancer aggressiveness may be modified by race.

Dietary patterns based on the Mediterranean diet and DASH diet are inversely associated with high aggressive prostate cancer in PCaP

BackgroundSeveral foods and nutrients have been linked to the development of prostate cancer, but the association between healthy dietary patterns and prostate cancer aggressiveness is less studied. The aim of this study was to evaluate the relationship between the Mediterranean diet (MED) and Dietary Approaches to Stop Hypertension (DASH) diet scores and prostate cancer aggressiveness by race. MethodsData from the population-based, case-only North Carolina–Louisiana Prostate Cancer Project (PCaP) were used to examine the association between diet quality, measured by MED and DASH scores, and prostate cancer aggressiveness in 1899 African American (AA) and European American (EA) research subjects. Dietary intake was assessed using a modified National Cancer Institute Diet History Questionnaire. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for high versus low-intermediate aggressive prostate cancer. ResultsHigher MED scores were inversely associated with high aggressive prostate cancer overall (OR: 0.66; 95% CI: 0.46, 0.95 for high versus low scores); results were similar for AA and EA men. A weaker inverse association between DASH scores and prostate cancer aggressiveness was found (OR: 0.76; 95% CI: 0.55, 1.06). ConclusionsHigher diet quality, as represented by a Mediterranean-style diet or DASH diet, may reduce the odds of high aggressive prostate cancer.

Abstract B72: DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men

Abstract Background: African-American (AA) men are more often diagnosed with early-onset aggressive prostate cancer than European American (EA) men. Prostate cancer health disparities between AA and EA men are attributed to socioeconomic as well as biologic differences existing between the two groups. The purpose of this study is to investigate how genetic and epigenetic alterations, specifically DNA methylation, contribute to early-onset aggressive prostate cancer in AA men. Methods: We performed 450K methylation array and RNA-sequencing on radical prostatectomy specimens from AA (n=32) and EA (n=5) men treated at Roswell Park Cancer Institute (RPCI). To increase analytical power, we included AA (n=22) and EA (n=172) patients from The Cancer Genome Atlas (TCGA) database. We found no significant difference in the average age between EA and AA men in the RPCI cohort, but the TCGA cohort consisted of AA men who had significantly lower average and median age compared to EA men (57 and 56 vs 61 and 62; p=0.019). We assessed baseline androgen receptor (AR) protein levels in matched benign and malignant AA (n=95) and EA (n=93) radical prostatectomy tissues from RPCI using immunohistochemistry. Gleason score &amp;lt;3+4 and &amp;gt;4+3 were classified as low and high aggressive tumors, respectively. Results: Unsupervised hierarchical clustering of DNA methylation levels in prostate cancers revealed 9 clusters. We focused on the 2 largest clusters, Cluster 1 (n=133) and Cluster 3 (n=73). Cluster 1 consisted predominantly of low aggressive disease (p=0.00002) with lower serum prostate specific antigen (PSA) values (8.97 vs 13.35 ng/ml) compared to Cluster 3. Following this trend, AA patients, but not EA patients, in Cluster 1 had better overall (57 vs 50 months, p=0.48) and disease-free time (47 vs 22 months, p=0.01) as compared to Cluster 3. ERG (ETS-related gene) fusion-positive prostate cancer is believed to be more aggressive than fusion-negative prostate cancer due to increased ERG gene transcription. We did not observe a difference in fusion status between the two DNA methylation clusters. However, overall DNA methylation was higher in fusion-negative samples as compared to fusion-positive samples in the TCGA dataset. ERG is known to bind to and reduce PSA, a direct downstream AR target. In the TCGA dataset, AA fusion-negative patients had higher average and median preoperative PSA values (18.38, 20.15 ng/ml) as compared with AA fusion-positive (7.51, 6.70 ng/ml), EA fusion-positive (9.43, 7.00 ng/ml), and EA fusion-negative patients (11.47, 7.50 ng/ml). There was no significant difference in the AR transcript and AR protein levels between fusion-positive and -negative AA and EA men. AR protein expression in RPCI cohort tissue microarrays showed that adjacent nontumor tissues from AA men had higher percent AR positive nuclei (p&amp;lt;0.05) compared to adjacent nontumor tissues from EA men. Conclusions: Analysis of the RPCI and TCGA cohorts indicated that DNA methylation separated low and high aggressive prostate cancer in AA men. Further analysis will include more patients as well as identify differences in specific CpG loci between Cluster 1 and Cluster 3. Our results suggest that DNA methylation alterations can be important in patients with ERG fusion-negative disease since these prostate cancers exhibit higher levels of overall DNA methylation. Lastly, our observations of higher AR expression in adjacent nontumor tissues suggest that there are underlying genetic variations that contribute to early-onset high aggressive prostate cancer in AA men compared to EA men. Citation Format: Swathi Ramakrishnan, Xuan Peng, Qianya Qi, Qiang Hu, Gissou Azabdaftari, Elena Pop, James Mohler, Kristopher Attwood, Li Yan, Jianmin Wang, Anna Woloszynska-Read. DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men [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 B72.

Calcium, magnesium, and whole-milk intakes and high-aggressive prostate cancer in the North Carolina–Louisiana Prostate Cancer Project (PCaP)

Calcium and dairy product intakes have been positively associated with prostate cancer risk. An imbalance in concentrations of calcium and magnesium has been associated with multiple chronic diseases, although few studies have examined the relation with prostate cancer aggressiveness. The goal of this study was to examine the association between dietary intakes of calcium and magnesium, the calcium-to-magnesium ratio (Ca:Mg), and dairy products and prostate cancer aggressiveness. Dietary intake was assessed with the use of an interviewer-administered modified National Cancer Institute Diet History Questionnaire in 996 African American and 1064 European American men with a recent histologically confirmed diagnosis of prostate cancer from the North Carolina-Louisiana Prostate Cancer Project (PCaP). High-aggressive disease was defined as Gleason sum ≥8, or prostate-specific antigen (PSA) >20 ng/mL, or Gleason score ≥7 and clinical stage T3-T4. The comparison group was all other prostate cancer cases. Logistic regression was used to determine the adjusted ORs and 95% CIs for high-aggressive prostate cancer by tertile of diet and supplement exposures. There was a positive association across tertiles of dietary Ca:Mg intake, with odds of high-aggressive prostate cancer in the upper tertiles as follows-OR for tertile 2 compared with tertile 1: 1.38 (95% CI: 1.01, 1.88); OR for tertile 3 compared with tertile 1: 1.46 (95% CI: 1.06, 2.02). When stratified by race, the positive association was more pronounced in African American men (OR for tertile 3 compared with tertile 2: 1.62; 95% CI: 1.04, 2.53). Men who reported the highest daily consumption of whole-fat milk had a 74% increased odds of high-aggressive prostate cancer compared with non-whole-fat milk drinkers, which was attenuated after adjustment for potential mediating factors, such as saturated fat and Ca:Mg intake. Among both African American and European American men diagnosed with prostate cancer, a higher Ca:Mg and whole-milk intake were associated with higher odds of high-aggressive prostate cancer. This study was registered at www.clinicaltrials.gov as NCT03289130.

Race and BMI modify associations of calcium and vitamin D intake with prostate cancer

BackgroundAfrican Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples.MethodsA total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables.ResultsIn the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 1.98, 95% C.I.: 1.01–3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 0.38, 95% C.I.: 0.18–0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70–10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02–0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m2), but not among men with high BMI (≥27.8 kg/m2). Interactions of race and BMI with vitamin D intake were significant (PInteraction < 0.05).ConclusionCalcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

The association of diabetes and obesity with prostate cancer aggressiveness among Black Americans and White Americans in a population-based study.

Few studies have investigated the role of race in the association of diabetes and obesity with prostate cancer aggressiveness. Here we evaluate the independent association between diabetes and obesity with prostate cancer aggressiveness in White Americans and Black Americans. Our cross-sectional, case-only study consisted of 1,058 White Americans and 991 Black Americans from the North Carolina-Louisiana Prostate Cancer (PCaP) project. Diabetes status was determined by self-report. Obesity was determined using body mass index and calculated based on anthropometric measurements. High aggressive prostate cancer was defined as Gleason sum ≥8, or prostate-specific antigen >20ng/ml, or Gleason sum=7 and clinical stage cT3-cT4. The association between diabetes and obesity with high aggressive prostate cancer at diagnosis was evaluated using multivariable logistic regression and adjusted for potential confounders. Diabetes was not associated with high aggressive prostate cancer in the overall sample (OR 1.04; 95% CI 0.79, 1.37), White Americans (OR 1.00; 95% CI 0.65, 1.57) or Black Americans (OR 1.07; 95% CI 0.75, 1.53). Obesity, independent of diabetes, was positively associated with high aggressive prostate cancer in White Americans (OR 1.98; 95% CI 1.14, 3.43), but not in the overall sample (OR 1.37; 95% CI 0.99, 1.92) or Black Americans (OR 1.09; 95% CI 0.71, 1.67). Diabetes was not associated with prostate cancer aggressiveness, overall, or in either race group. Obesity, independent of diabetes, was associated with high aggressive prostate cancer only in White Americans.

Saturated fat intake and prostate cancer aggressiveness: results from the population-based North Carolina-Louisiana Prostate Cancer Project.

Epidemiologic and laboratory evidence supports a role for cholesterol in prostate cancer (PC). Dietary saturated fat content impacts serum cholesterol levels. However, epidemiologic associations between saturated fat and PC aggressiveness are inconsistent. We hypothesized that high saturated fat intake would be associated with increased PC aggressiveness, and that statin use would modify this association. Of 1854 PC cases in the North Carolina-Louisiana PC Project, 321 (17%) were classified as high aggressive (Gleason sum ⩾8, PSA>20 ng ml-1, or Gleason sum ⩾7 and clinical stage T3-4) or low/intermediate aggressive (all other cases). Using low/intermediate aggressive cases as the referent group, we examined the association between tertiles of total fat-adjusted saturated fat intake and high aggressive PC using logistic regression, overall and stratified by race and statin use. We examined total fat-adjusted polyunsaturated and monounsaturated fatty acids (PUFA and MUFA, respectively), trans fat and cholesterol intake in secondary analysis. High total fat-adjusted saturated fat intake was associated with an elevated odds ratio (OR) for aggressive PC (ORT3vsT1 1.51; 95% CI 1.10-2.06; P-trend=0.009), with an attenuated association in statin users (ORT3vsT1 1.16; 95% CI 0.67-2.01; P-trend=0.661) compared with non-users (ORT3vsT1 1.71; 95% CI 1.16-2.51; P-trend=0.053). High total fat-adjusted cholesterol intake was associated with aggressive PC in European Americans (ORT3vsT1 1.62; 95% CI 1.02-2.58; P-trend=0.056), but not African Americans (ORT3vsT1 0.92; 95% CI 0.60-1.42; P-trend=0.750). High total fat-adjusted PUFA was inversely associated with PC aggressiveness (ORT3vsT1 0.75; 95% CI 0.55-1.03), although this was not significant. No associations were found between total fat-adjusted MUFA or trans fat and PC aggressiveness. High total fat-adjusted saturated fat intake was associated with increased PC aggressiveness, with a suggestion of a stronger effect in men not using statins. The association between total fat-adjusted cholesterol intake and PC aggressiveness was most pronounced in European Americans.

Abstract 806: SNPs in vitamin D-related genes are associated with prostate cancer aggressiveness in the North Carolina-Louisiana Prostate Cancer Project (PCaP)

Abstract Introduction: African Americans have higher incidence of, and mortality from, prostate cancer (PCa) compared to other racial/ethnic groups. Frequency of polymorphisms in genes involved in vitamin D metabolism, transport, and activity differ by race/ethnicity. Examining the association between polymorphisms in vitamin D-related genes and PCa aggressiveness may explain differing susceptibility to aggressive PCa among individuals and across different racial/ethnic groups. Methods: TagSNPs (n = 315) in 13 genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1, CYP2R1, CYP3A4, DHCR7, CASR, NADSYN1, RXRA, RXRB, RXRG) were genotyped using Illumina GoldenGate or Sequenom assays in 524 African-American and 657 European-American men with newly-diagnosed PCa from PCaP. DNA extracted from blood samples collected at enrollment was stored at -80C prior to analyses. Research subjects were classified as high aggressive if Gleason sum ≥8, or Gleason score (4+3), or PSA &amp;gt;20 ng/ml, or Gleason score (3+4) AND clinical stage = T3-T4. The comparison group (low aggressive) included research subjects with Gleason sum &amp;lt;7 AND Stage T1-T2 AND PSA &amp;lt; 9 ng/ml. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated for high aggressive PCa for each SNP using logistic regression with adjustment for age and proportion of African ancestry. Associations were considered statistically significant at p&amp;lt;0.05. A polygenic score based on a previous study of SNP predictors of serum 25-hydroxy-vitamin D levels was calculated utilizing SNPs in the GC, CYP24A1, CYP2R1, and NADSYN1 genes. Results: Among African Americans, 21 SNPs were associated with PCa aggressiveness. The variant allele was associated negatively or positively with high aggressive PCa in eleven and ten SNPs, respectively. For example, two SNPs in the vitamin D binding protein gene known as GC, were inversely associated (rs222054: OR, 0.55, 95%CI, 0.38-0.80; and rs16847028: OR, 0.61, 95%CI, 0.39-0.94). Among European Americans, the variant allele was inversely associated with high aggressive PCa for four SNPs in three genes (CASRrs3863977; CYP24A1rs4809960; RXRArs1007971; and RXRArs3118526), and positively associated with high aggressive PCa for three SNPs in the CYP27B1 gene (rs703842, rs4646536, and rs10877013). There was no association between higher number of ‘low vitamin D’ alleles in the four SNPs that comprised the polygenic score and PCa aggressiveness for either race. Conclusions: Polymorphisms in genes involved in vitamin D etabolism and activity, the vitamin D binding protein and calcium sensing receptor were associated with PCa aggressiveness, and there was no overlap in SNPs between race groups. Our ongoing work will examine interaction between polymorphisms of vitamin D-related genes and vitamin D metabolite levels on PCa aggressiveness. Citation Format: Susan E. Steck, Anna Woloszynska-Read, Samuel Antwi, Hongmei Zhang, Lenore Arab, Elizabeth T.H. Fontham, James Mohler, L. Joseph Su, Feifei Xiao, Gary Smith, Donald Trump, Candace Johnson, Jeannette Bensen. SNPs in vitamin D-related genes are associated with prostate cancer aggressiveness in the North Carolina-Louisiana Prostate Cancer Project (PCaP). [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 806.