Abstract African American (AA) men have an approximately 60% higher incidence of prostate cancer and are at 2 times greater risk of dying of prostate cancer than European Americans (EA). Environmental and socio-economic factors as well as a number of genetic alterations have been previously interrogated as possible explanations for this disparity. Currently, little is known about the specific biological pathway differences in prostate cancer between AA and EA men that may help explain the greater burden borne by AA men with this disease. In this study, we seek to unravel and compare the prostate cancer metabolome of AA and EA men by employing state of the art metabolomic profiling and bioinformatic techniques. Based on the premise that metabolites are end products of enzyme action, we sought to identify a racially distinct biochemical signature for prostate cancer. Fifty-six prostate cancer tissue samples from AA and EA men and their adjacent benign tissues (i.e., matched normal/tumor pairs) were analyzed using an unbiased liquid chromatography-coupled mass spectrometry approach. Differential metabolites were mapped into pathways and combined with bioinformatics-based bioprocess mapping to categorize metabolic differences observed in cancers of AA and EA origin. Our data indicate a specific and largely mutually exclusive metabolic signature for AA and EA derived prostate cancers. These findings may have important clinical implications and, importantly, shed new light on the biological basis of prostate cancer racial disparity. Citation Format: Shaiju Kakkandan VareedKatrin Panzitt, Sumanta Basu, Vasanta Putluri, Tiffany Dorsey, Tiffany Wallace, Nagireddy Putluri, Sayeeduddin Mohammed, Michael Ittmann, Rick Kittles, George Michailidis, Stefan Ambs, Ganesh Palapattu, Arun Sreekumar. Metabolomic profiling and the biochemical basis of prostate cancer racial disparity. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A35.
131 Background: There is increasing awareness that anterior-predominant prostate cancers (PCa) are poorly sampled by 12-core transrectal ultrasound-guided (TRUS) prostate biopsies. Approximately one-fifth of all prostate tumors occur in this area, and many are high grade and extend beyond the prostatic capsule. An epigenetic assay, detecting PCa-specific DNA-methylation of GSTP1, RASSF1 and APC has shown to be a significant predictor for the presence of PCa in histopathologically cancer-negative biopsies through a cancer-associated field effect. It is currently unknown whether the field effect from an anterior-predominant cancer may be detected in standard posteriorly-directed sextant biopsy specimens. Methods: Seven patients with at least one prior negative TRUS biopsy were subsequently diagnosed with anterior-only PCa based on a transperineal mapping template prostate biopsy (MTPB). Three patients were diagnosed with low-grade Gleason score (GS) 6 tumors and four patients with GS ≥7 tumors. The outcome of the MTPB was compared with the result of the epigenetic test performed on the prior cancer-negative TRUS biopsy. Results: MTPB included a median of 68 cores (IQR 53-76). A total of 6 patients (86%) were methylation-positive at initial biopsy, suggesting that the field effect from these anterior-predominant cancers extends to the region of TRUS biopsy sampling. No methylation was found for one patient with only one GS6 positive core at MTPB and a tumor volume of 4%. Methylation intensities were higher for patients with GS ≥7 compared to those with GS6. A logistic regression model combining these intensities with traditional risk factors (PSA, age, TRUS-biopsy pathology and DRE) indicated higher risk scores for high-grade tumors. Conclusions: Aberrant DNA-methylation patterns are present in normal-appearing tissue from TRUS biopsy of patients with anteriorly located tumors. Although a small study, this is a unique cohort that underwent extensive sampling at re-biopsy demonstrating the presence of an anterior-predominant tumor. These results indicate that an epigenetic assay may be valuable even in patients with negative posteriorly-directed TRUS biopsies to detected anterior-predominant PCa.
The MyProstateScore test was validated for improved detection of clinically significant (grade group ≥2) prostate cancer relative to prostate specific antigen based risk calculators. We sought to validate an optimal MyProstateScore threshold for clinical use in ruling out grade group ≥2 cancer in men referred for biopsy.Biopsy naïve men provided post-digital rectal examination urine prior to biopsy. MyProstateScore was calculated using the validated, locked multivariable model including only serum prostate specific antigen, urinary prostate cancer antigen 3 and urinary TMPRSS2:ERG. The MyProstateScore threshold approximating 95% sensitivity for grade group ≥2 cancer was identified in a training cohort, and performance was measured in 2 external validation cohorts. We assessed the 1) overall biopsy referral population and 2) population meeting guideline based testing criteria (ie, prostate specific antigen 3-10, or <3 with suspicious digital rectal examination).Validation cohorts were prospectively enrolled from academic (977 patients, median prostate specific antigen 4.5, IQR 3.1-6.0) and community (548, median prostate specific antigen 4.9, IQR 3.7-6.8) settings. In the overall validation population (1,525 patients), 338 men (22%) had grade group ≥2 cancer on biopsy. The MyProstateScore threshold of 10 provided 97% sensitivity and 98% negative predictive value for grade group ≥2 cancer. MyProstateScore testing would have prevented 387 unnecessary biopsies (33%), while missing only 10 grade group ≥2 cancers (3.0%). In 1,242 patients meeting guideline based criteria, MyProstateScore ≤10 provided 96% sensitivity and 97% negative predictive value, and would have prevented 32% of unnecessary biopsies, missing 3.7% of grade group ≥2 cancers.In a large, clinically pertinent biopsy referral population, MyProstateScore ≤10 provided exceptional sensitivity and negative predictive value for ruling out grade group ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with prostate specific antigen.
Abstract Background: AA men with PCa will die at a rate nearly 2.5 times higher than their EA counterparts. Presently, no mechanism has been described to explain the differences observed between AA and EA men with PCa; yet, many have interrogated the role of social and anthropometric data on PCa outcomes within these populations. Therefore, to obtain better insights into the molecular aspects of PCa disparities, we examined metabolomic and gene expression profiles of PCa and matched adjacent benign tissue from AA and EA men. Metabolomics is defined as the study of all the small molecule metabolites produced by cellular processes in the body. We hypothesize that racially distinct metabolic pathways may contribute to PCa health disparities and also delineate mechanistic biological pathways. Methodology: A total of 190 polar and mid-polar metabolites were measured using mass spectrometry across 50 and 28 PCa/benign tissue pairs from AA and EA men, respectively. Likewise, gene expression microarray analysis was performed on 48 and 21 PCa/benign tissue pairs from AA and EA men, and gene set enrichment (GSEA) analysis was performed. Ancestry informative markers were genotyped and ancestry estimates were determined. Metabolic profiles of AA and EA PCa and benign adjacent pairs were compared using paired t-tests. FDR corrected p-values were used to detect differential metabolites and genes. Biological validation was performed using tissue microarrays, qPCR, and western blots. Results: Unique biochemical alterations associated with AA tumors were identified. Relative to EA tumors, AA tumors had significant alterations in the cysteine/methionine pathway; specifically accumulations of adenosine were most prominent in AA PCa, as well as urine. Protein and transcript levels of Adenosine Deaminase (ADA), an enzyme that converts SAM-derived adenosine to inosine was significantly down regulated in AA PCa, a finding validated in both tissue and cell lines. GSEA analysis revealed that genes involved in the immune system were prominent among AA PCa compared to EA PCa. To this end, significant inverse correlations between ADA and CD4+, CD8+, and CD68+ levels were also identified. Conclusions: Taken together, this integromics approach generated data that alludes to the existence of an efficient immune escape mechanism in AA PCa, which may explain the disparity facing AA men with PCa. Citation Format: Stacy M. Lloyd, Jie Gohlke, Sumanta Basu, Salil Bhowmik, Vasanta Putluri, Kimal Rajapakshe, Cristian Coarfa, Michael Ittmann, Ganesh Palapattu, Nagireddy Putluri, George Michailidis, Arun Sreekumar. An Integromics Approach Identifies Immune Escape as a Potential Mechanism for Prostate Cancer Disparities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr PR10.
167 Background: Short PSA doubling time (PSADT) after biochemical recurrence (BR) post radical prostatectomy (RP) is known to predict worse outcomes following salvage external beam radiation therapy (SRT). The ideal PSADT cut-off, however, in this context remains uncertain. In this study, we sought to identify the best PSADT cut-off for predicting clinical outcomes following SRT for BR after RP. Methods: 575 patients who received SRT at a single institution for BR after RP were retrospectively reviewed in an IRB approved analysis. The impact of PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) was assessed using Kaplan-Meier and Cox Proportional Hazards models. Results: Median follow up was 56.7 months post SRT. PSADTs could be calculated for 277 patients. PSADT strongly predicted BF, DM, PCSM, and OS on univariate analysis regardless of cut-off point. There was no statistical difference in BF, DM, PCSM, or OS between patients with PSADT <3 (n=40) and 3-6 months (n=61) or between 6-10 (n=62) and >10 months (n=114). A difference existed in BF (p<0.01 HR: 2.2 [95%CI: 1.4-3.5]) and DM (p=0.02 HR: 2.2 [95%CI: 1.2-4.3]) between PSADT of 3-6 and 6-10 months. PSADT ≤6 had the largest positive predictive value (PPV) for BF (70%), DM (36%), and PCSM (13%) at 5 years. There was no difference in negative predictive value between a PSADT >10 vs. >6 months for BF, DM, PCSM, and OS with 5 year rates of (60% vs. 60%, 86% vs. 86%, 99% vs. 98%, and 95 vs. 94% respectively). On multivariate analysis PSADT ≤6 was a strong predictor of BF (p<0.01 HR: 2.1 [95%CI: 1.5-3.0]), DM (p=0.01 HR: 2.0 [95%CI: 1.2-3.4]), and PCSM (p=0.04 HR: 2.3 [95%CI: 1.1-5.2]), with a trend towards predicting OS (p=0.12 HR: 1.5 [95%CI: 0.9-2.6]). Conclusions: A PSADT ≤6 months was the best predictor of outcomes in our data set, particularly for DM and PCSM. Currently, the most common predictive nomogram for SRT uses PSADT <10 months as the cut-off point for BF. These results suggest that using a PSADT of ≤6 months may improve the ability to predict clinically significant outcomes and hence identify men who may benefit from additional therapy.
