[Show abstract][Hide abstract]ABSTRACT: The bone marrow microenvironment represents a “metastatic niche” in which prostate cancer cells may persist and evade cytotoxic therapy. In order to study the biology of prostate cancer dissemination, we have established a safe and efficient method for performing pubic bone marrow aspiration at the time of radical prostatectomy. We herein describe our experience with this technique.
Preview · Article · May 2016 · Urology Case Reports
[Show abstract][Hide abstract]ABSTRACT: Purpose:
There is a clear need to improve risk stratification and identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets.
We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4y). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score.
Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell cycle progression (CCP) signature, and CAPRA-S).
To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes.
No preview · Article · Dec 2015 · Clinical Cancer Research
[Show abstract][Hide abstract]ABSTRACT: Objectives:
To evaluate the association between the Prostate Health Index (PHI) and adverse pathology in a cohort of African-American (AA) men undergoing radical prostatectomy (RP).
Eighty consecutive AA men with PSA of 2-10 ng/ml underwent measurement of PSA, free PSA (fPSA), and p2PSA prior to RP. PHI was calculated as [(p2PSA/fPSA) x (PSA)(½)]. Biomarker association with pT3 disease was assessed using logistic regression, and covariates were added to a baseline multivariable model including digital rectal examination (DRE). Biomarker ability to predict pT3 disease was measured using the area under the ROC curve (AUC).
Sixteen men (20%) demonstrated pT3 disease on final pathology. Mean age, PSA, and %fPSA were similar in men with and without pT3 disease (all p > 0.05), while PHI was significantly greater in men with pT3 disease (mean 57.2 vs. 46.6, p=0.04). Addition of PHI to the baseline multivariable model improved discriminative ability by 12.9% (p=0.04) and yielded greater diagnostic accuracy than models including other individual biomarkers.
In African-American men with PSA of 2-10 ng/ml, PHI was predictive of pT3 prostate cancer and may help to identify men at increased risk of adverse pathology. Additional studies are needed to substantiate these findings and identify appropriate thresholds for clinical use.
[Show abstract][Hide abstract]ABSTRACT: Background:
It remains unclear whether men selecting active surveillance (AS) are at increased risk of unfavorable longer term outcomes as compared with men who undergo immediate treatment.
To compare adverse pathologic outcomes in men with favorable-risk prostate cancer who underwent delayed prostatectomy after surveillance (DPAS) to those who elected immediate prostatectomy (IRP).
Design, setting, and participants:
We conducted a retrospective analysis of a prospective AS registry from 2004 to 2014. From the Johns Hopkins AS program (n=1298), we identified a subset of men who underwent DPAS (n=89) and was representative of the entire cohort, not just those that were reclassified to higher risk. These men were compared with men who underwent IRP (n =3788).
Outcome measurements and statistical analysis:
We measured adverse pathologic features (primary Gleason pattern ≥4, seminal vesicle invasion [SVI], or lymph node [LN] positivity). Multivariable models were adjusted for age, prostate-specific antigen density, and baseline risk classification.
Results and limitations:
Delayed prostatectomy occurred at a median of 2.0 yr (range: 0.6-9.0) after diagnosis. The DPAS and IRP cohorts demonstrated similar proportions of men with primary Gleason pattern ≥4 (17% vs 20%; p=0.11), SVI (3.3% vs 3.2%; p=0.53), LN positivity (2.3% vs 1.2%; p=0.37), and overall adverse pathologic features (21.3% vs 17.0%; p=0.32). The adjusted odds ratio of adverse pathology was 1.33 (95% confidence interval, 0.82-2.79; p=0.13) for DPAS as compared with IRP. Limitations include a modest cohort size and a limited number of events.
In men with favorable-risk cancer, the decision to undergo AS is not independently associated with adverse pathologic outcomes.
This report compares men with favorable-risk prostate cancer who elected active surveillance with those who underwent immediate surgery accounting for evidence that approximately one-third of men who choose surveillance will eventually undergo treatment. Our findings suggest that men who are closely followed with surveillance may have similar outcomes to men who elect immediate surgery, but additional research is needed.
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed.
Germline ASPN D-repeat-length was retrospectively analyzed in 1600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 non-cancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer.
Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 (HR=1.72, 95%CI=1.05-2.81, P=0.032) and heterozygosity for ASPN D13/14 (HR=1.86, 95%CI=1.03-3.35, P=0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR=0.44, 95%CI=0.21-0.94, P=0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient based data.
We observed associations between ASPN D variants and oncologic outcomes including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression.
No preview · Article · Oct 2015 · Clinical Cancer Research