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1.  Randomized Controlled Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing Hormone Agonist–Induced Bone Loss in Men With Prostate Cancer 
Purpose
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.
Patients and Methods
In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than −2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.
Results
Mean (± SE) BMD of the posteroanterior lumbar spine decreased by 3.1% ± 1.0% in men assigned to placebo and increased by 4.0% ± 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% ± 0.7% in men assigned to placebo and increased by 0.7% ± 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.
Conclusion
In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.
doi:10.1200/JCO.2006.07.3361
PMCID: PMC3047397  PMID: 17369566
2.  Emerging players in prostate cancer: long non-coding RNAs 
Recent observations of novel long non-coding RNAs (lncRNAs) have considerably altered our understanding of cell biology. The role of lncRNAs as tumor suppressors or oncogenes has been extensively studied. Over-expression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, anti-sense gene regulation, alternative splicing, and impeding DNA repair. Prostate cancer is the most common type of cancer and frequent cause of cancer-related mortality in men worldwide. Unraveling the molecular and biological processes that contribute to prostate cancer development and progression is a challenging task. In prostate cancer, aberrant expression of lncRNAs has been associated with disease progression. In this review, we highlight the emerging impact of lncRNAs in prostate cancer research, with a particular focus on the mechanisms and functions of lncRNAs. Increased research on lncRNAs will lead to a greater understanding of prostate cancercinogenesis and progression and may lead to novel clinical applications. LncRNAs have great potential to become new biomarkers for detection, prognostication and prediction in prostate cancer.
PMCID: PMC4297325  PMID: 25606575
Long non-coding RNAs; lncRNAs; prostate cancer
3.  Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors 
Purpose
The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (ARs) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone activated mutant ARs.
Experimental Design
AR was examined by targeted sequencing in metastatic tumor biopsies from 18 CRPC patients who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
Results
The progesterone-activated T878A mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant treated patient, but not in a second clonally related resistant focus which instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of CRPC patients treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wildtype AR.
Conclusions
These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.
doi:10.1158/1078-0432.CCR-14-1220
PMCID: PMC4359958  PMID: 25320358
4.  Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer 
Nature Communications  2016;7:10982.
Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA-mediated sponge regulatory network that affects the expression of many protein-coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12.4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization-dependent function. Our findings not only suggest an important role of lncRNA-mediated sponge regulation in cancer, but also underscore the critical influence of cytoplasmic localization on the efficacy of a sponge lncRNA.
Long non-coding RNAs (lncRNA; >200 base pair nucleic acids with little protein-coding capacity) are emerging as potentially important regulators of oncogenesis. Here the authors show tumour suppressive lncRNA sponge function for the protein products of prostate cancer driver genes.
doi:10.1038/ncomms10982
PMCID: PMC4796315  PMID: 26975529
5.  Role of diet in prostate cancer: The epigenetic link 
Oncogene  2014;34(36):4683-4691.
Diet is hypothesized to be a critical environmentally related risk factor for prostate cancer development, and specific diets and dietary components can also affect prostate cancer progression; however, the mechanisms underlying these associations remain elusive. As for a maturing organism, prostate cancer’s epigenome is plastic, and evolves from the pre-neoplastic to the metastatic stage. In particular, epigenetic remodeling relies on substrates or cofactors obtained from the diet. Here we review the evidence that bridges dietary modulation to alterations in the prostate epigenome. We propose that such diet-related effects offer a mechanistic link between the impact of different diets and the course of prostate cancer development and progression.
doi:10.1038/onc.2014.422
PMCID: PMC4476943  PMID: 25531313
Diet; prostate cancer; epigenetic; epigenome; metabolism
6.  Comparison of Prostate-Specific Membrane Antigen–Based 18F-DCFBC PET/CT to Conventional Imaging Modalities for Detection of Hormone-Naïve and Castration-Resistant Metastatic Prostate Cancer 
Conventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first-in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), to detect metastatic hormone-naïve (HNPC) and castration-resistant prostate cancer (CRPC).
Methods
Seventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. 18F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM.
Results
On the lesion-by-lesion analysis, 18F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. 18F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, 18F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of 18F-DCFBC PET (0.92) was superior to CIM (0.71). 18F-DCFBC tumor uptake was increased at the later PET time point (∼2.5 h after injection), with background uptake showing a decreasing trend on later PET.
Conclusion
PET imaging with 18F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current imaging methods.
doi:10.2967/jnumed.115.163782
PMCID: PMC4730886  PMID: 26493203
prostate-specific membrane antigen; metastatic prostate cancer; positron emission tomography; computed tomography; bone scan
7.  ANDROGEN RECEPTOR CAG REPEAT POLYMORPHISM AND RISK OF TMPRSS2:ERG POSITIVE PROSTATE CANCER 
Background
The androgen receptor (AR) is an essential gene in prostate cancer pathogenesis and progression. Genetic variation in AR exists, including a polymorphic CAG repeat sequence that is inversely associated with transcriptional activity. Experimental data suggest that heightened AR activity facilitates formation of TMPRSS2:ERG, a gene fusion present in approximately 50 percent of tumors of prostate cancer patients.
Methods
We undertook a nested case-control study to investigate the hypothesis that shorter CAG repeat length would be associated with prostate cancer risk defined by TMPRSS2:ERG status. The study included 291 men with prostate cancer (147 ERG-positive) and 1,221 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression.
Results
Median CAG repeat length (Interquartile range) among controls was 22 (20–24). Men with shorter CAG repeats had an increased risk of ERG-positive (OR=1.07 per 1 repeat decrease, 95% CI 1.00–1.14), but not ERG-negative prostate cancer (OR=0.99 per 1 repeat decrease, 95% CI 0.93–1.05).
Conclusions
These data suggest that shorter CAG repeats are specifically associated with development of TMPRSS2:ERG positive prostate cancer.
Impact
Our results provide supportive evidence that androgen signaling underlies the development of prostate tumors that harbor TMPRSS2:ERG. Moreover, these results suggest that TMPRSS2:ERG may represent a unique molecular subtype of prostate cancer with an etiology distinct from TMPRSS2:ERG negative disease.
doi:10.1158/1055-9965.EPI-14-0020
PMCID: PMC4184923  PMID: 24925673
Prostate cancer; androgen receptor; TMPRSS2:ERG fusion; genetic polymorphism; case-control
8.  A Transient Increase in Eosinophils is Associated with Prolonged Survival in Men with Metastatic Castration-Resistant Prostate Cancer Who Receive Sipuleucel-T 
Cancer immunology research  2014;2(10):988-999.
Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from 3 randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442, n = 512), D9901 (NCT00005947, n = 127), and D9902A (NCT01133704, n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory, and if data were available from baseline and ≥1 post-treatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105/377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival (HR = 0.713; 95% confidence interval [CI], 0.525–0.970; P = 0.031) and trend in overall survival (HR = 0.753; 95% CI, 0.563–1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.
doi:10.1158/2326-6066.CIR-14-0073
PMCID: PMC4185225  PMID: 25189164
sipuleucel-T; immunotherapy; prostate cancer; eosinophil; survival
9.  Expression Differences of Circulating MicroRNAs in Metastastic Castration Resistant Prostate Cancer and Low-risk, Localized Prostate Cancer 
The Prostate  2012;73(4):346-354.
Background
Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investigated circulating miRNAs in prostate cancer that may be associated with the progression of hormone-sensitive primary tumors to metastatic castration resistant prostate cancer (CRPC) after androgen deprivation therapy.
Methods
Using genome-wide expression profiling by TaqMan Human MicroRNA Arrays (Applied Biosystems) and/or quantitative real-time polymerase chain reaction, we compared the expression levels of miRNAs in serum samples from 28 patients of low-risk localized disease, 30 of high-risk localized disease and 26 of metastatic CRPC.
Results
we demonstrated that serum samples from patients of low-risk, localized prostate cancer and metastatic CRPC patients exhibit distinct circulating miRNA signatures. MiR-375, miR-378*, and miR-141 were significantly over-expressed in serum from CRPC patients compared to serum from low-risk localized patients, while miR-409-3p was significantly under-expressed. In prostate primary tumor samples, miR-375 and miR-141 also had significantly higher expression levels compared to those in normal prostate tissue.
Conclusions
Circulating microRNAs, particularly miR-375, miR-141, miR-378* and miR-409-3p, are differentially expressed in serum samples from prostate cancer patients. In the search for improved minimally invasive methods to follow cancer pathogenesis, the correlation of disease status with the expression patterns of circulating miRNAs may indicate the potential importance of circulating miRNAs as prognostic markers for prostate cancer progression.
doi:10.1002/pros.22572
PMCID: PMC3980954  PMID: 22887127
circulating microRNAs; prostate cancer; castration resistant prostate cancer
10.  Imaging, procedural, and clinical variables associated with tumor yield on bone biopsy in metastatic castration-resistant prostate cancer 
Background
Understanding the mechanisms driving disease progression is fundamental to identifying new therapeutic targets for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Due to the prevalence of bone metastases in mCRPC, obtaining sufficient tumor tissue for analysis has historically been a challenge. In this exploratory analysis, we evaluated imaging, procedural, and clinical variables associated with tumor yield on image-guided bone biopsy in men with mCRPC.
Methods
Clinical data were collected prospectively from men with mCRPC enrolled on a phase II trial with serial metastasis biopsies performed according to standard clinical protocol. Imaging was retrospectively reviewed. We evaluated the percent positive biopsy cores (PPC), calculated as the number of positive cores divided by the total number of cores collected per biopsy.
Results
Twenty-nine men had 39 bone biopsies. Seventy-seven percent of bone biopsies had at least 1 positive biopsy core. We determined that lesion size and distance from the skin to the lesion edge correlated with tumor yield on biopsy (median PPC 75% versus 42% for lesions > 8.8 cm3 versus ≤ 8.8 cm3, respectively, p=0.05; median PPC 33% versus 71% for distance ≥ 6.1 versus < 6.1 cm, respectively, p=0.02). There was a trend towards increased tumor yield in patients with increased uptake on radionuclide bone scan, higher calcium levels, and shorter duration of osteoclast-targeting therapy, though this was not statistically significant. Ten men had 14 soft tissue biopsies. All soft tissue biopsies had at least 1 positive biopsy core.
Conclusions
This exploratory analysis suggests there are imaging, procedural, and clinical variables which impact image-guided bone biopsy yield. In order to maximize harvest of prostate cancer tissue, we have incorporated a prospective analysis of the metrics described here as part of a multi-institutional project aiming to use molecular characterization of mCRPC tumors to direct individual therapy.
doi:10.1038/pcan.2014.28
PMCID: PMC4566855  PMID: 25091040
Bone; Castration-resistant prostate cancer; Genomics; Metastasis biopsy; Tumor yield
11.  Development of multinuclear polymeric nanoparticles as robust protein nanocarriers** 
One limitation of current biodegradable polymeric nanoparticles is their inability to effectively encapsulate and sustainably release proteins while maintaining protein bioactivity. Here we report the engineering of a PLGA-polycation nanoparticle platform with core-shell structure as a robust vector for the encapsulation and delivery of proteins and peptides. We demonstrate that the optimized nanoparticles can load high amounts of proteins (>20% of nanoparticles by weight) in aqueous solution by simple mixing via electrostatic interactions without organic solvents, forming nanospheres in seconds with diameter <200 nm. We also investigate the relationship between nanosphere size, surface charge, PLGA-polycation composition, and protein loading. The stable nanosphere complexes contain multiple PLGA-polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel nanoparticle platform and nanotechnology strategy for the delivery of proteins and other relevant molecules.
doi:10.1002/anie.201404766
PMCID: PMC4143165  PMID: 24990548
nanoparticle; PLGA; polycation; protein delivery; structure-function
12.  BRAF mutations in metanephric adenoma of the kidney 
European urology  2012;62(5):917-922.
Background
Metanephric Adenoma (MA) of the kidney is a rare indolent tumor that may be difficult to differentiate from other small renal masses. Genetic alterations associated with MA remain largely unknown.
Objectives
We aimed at defining genetic events in MA of the kidney and determining their influence in the management of this disease.
Design, setting, and participants
Multiplexed mass spectrometric genotyping was performed on 29 MA cases after tumor DNA extraction. We also conducted a mutational screen in additional 129 renal neoplasms. Immunohistochemistry was performed on the MA cases to assess molecular markers of signaling pathway activation. Patients’ baseline characteristics as well as follow up data were captured.
Statistical analysis
We used descriptive statistics for baseline clinical characteristics and incidence of mutations; Wilcoxon rank-sum test was used to correlate patient characteristics and mutational status.
Results and Limitations
We identified the BRAF V600E mutation in 26/29 MA cases. These results were validated in all cases using the commercially available BRAF Pyro Kit (QIAGEN). In contrast, BRAF mutations were rare in the other 129 non-MA renal neoplasms that were screened. We detected a BRAF mutation (V600E) only in one papillary RCC case. In all MA tumors, we documented expression of p-MEK, p-ERK, accompanied by immunoreactivity for p16 (INK4a). All patients were treated with a partial or radical nephrectomy and, after a median follow-up of 26.5 months, there were no local or distant recurrences. Limitations include the retrospective nature of this study.
Conclusions
BRAF V600E mutations are present in ~90% of all MA cases, serving as a potential valuable diagnostic tool in the differential diagnosis of small renal masses undergoing a percutaneous biopsy. Further, the presence of BRAFV600E and MAPK activation in a largely benign tumor supports the necessity for secondary events (e.g. p16 loss) in BRAF driven oncogenesis.
doi:10.1016/j.eururo.2012.05.051
PMCID: PMC4516083  PMID: 22727996
13.  The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness 
Background
Our previous work suggested that there was no significant association between plasma steroid hormone levels and prostate cancer (CaP) tumor grade at diagnosis. In this study, we systematically tested the hypothesis that inherited variations in the androgen and estrogen metabolic pathways may be associated with plasma levels of steroid hormones, or CaP aggressiveness at diagnosis.
Methods
Plasma hormone levels including total testosterone, total estradiol and sex hormone-binding globulin were measured in a cohort of 508 patients identified with localized CaP. D’Amico risk classification at diagnosis was also determined. 143 single nucleotide polymorphisms (SNPs) from 30 genes that are involved in androgen and estrogen metabolism were selected for analysis. The global association of genotypes with plasma hormone levels and CaP aggressiveness (D’Amico risk classification) was statistically analyzed. Q-values were estimated to account for multiple testing.
Results
We observed significant associations between plasma testosterone level and SNPs in HSD17B2 (rs1424151), HSD17B3 (rs9409407) and HSD17B1 (rs12602084), with P values of 0.002, 0.006 and 0.006, respectively. We also observed borderline significant associations between prostate aggressiveness at diagnosis and SNPs in AKR1C1 (rs11252845; P = 0.005), UGT2B15 (rs2045100; P = 0.007) and HSD17B12 (rs7932905; P = 0.008). No individual SNP was associated with both clinical variables.
Conclusions
Genetic variants of genes in hormone metabolic pathways may influence plasma androgen levels or CaP aggressiveness. However, it appears that the inherited variations affecting plasma hormone levels differ from those affecting disease aggressiveness.
doi:10.1158/1940-6207.CAPR-11-0283
PMCID: PMC3773969  PMID: 21900597
Prostate cancer; Hormone metabolism; Single-nucleotide Polymorphisms
14.  Inherited Variations in AR, ESR1, and ESR2 Genes Are Not Associated With Prostate Cancer Aggressiveness or With Efficacy of Androgen Deprivation Therapy 
Background
Sex steroid hormone receptors mediate essential processes in normal prostate growth and contribute to prostate cancer development.
Method
In this study, we investigated the association between common inherited variation of the AR, ESR1, and ESR2 genes and two clinically relevant traits: the risk of developing aggressive prostate cancer and the response to androgen deprivation therapy (ADT) in a hospital-based cohort. A total of 43 tagging single nucleotide polymorphisms covering the loci of AR (n = 4), ESR1 (n = 32), and ESR2 (n = 7) were successfully genotyped in 4,073 prostate cancer cases.
Results
None of these single nucleotide polymorphisms were significantly associated with disease aggressiveness as assessed by the D'Amico risk classification, pathologic stage, or the response to ADT.
Conclusions
Our results suggest that common genetic variations in AR, ESR1, or ESR2 are not strongly associated with prostate cancer aggressiveness or response to ADT.
Impact
Our study did not find convincing evidence of inherited variations in the major receptors for androgens and estrogens and their associations with prostate cancer traits.
doi:10.1158/1055-9965.EPI-10-0216
PMCID: PMC3755451  PMID: 20615892
15.  Observation Versus Initial Treatment for Men With Localized, Low-Risk Prostate Cancer A Cost-Effectiveness Analysis 
Annals of internal medicine  2013;158(12):853-860.
Background
Observation is underused among men with localized, low-risk prostate cancer.
Objective
To assess the costs and benefits of observation versus initial treatment.
Design
Decision analysis simulating treatment or observation.
Data Sources
Medicare schedules, published literature.
Target Population
Men ages 65 and 75 years with newly diagnosed low-risk prostate cancer (prostate-specific antigen level <10 μg/L, stage ≤T2a, Gleason score ≤3+3).
Time Horizon
Lifetime.
Perspective
Societal.
Intervention
Treatment (brachytherapy, intensity-modulated radiation therapy, or radical prostatectomy) or observation (active surveillance [AS] or watchful waiting [WW]).
Outcome Measures
Quality-adjusted life expectancy, costs.
Results of Base-Case Analysis
Observation was more effective and less costly than initial treatment. Compared with AS, WW provided 2 additional months of quality-adjusted life expectancy (9.02 vs. 8.85 years) at a savings of $15 374 ($24 520 vs. $39 894) in men aged 65 years and 2 additional months (6.14 vs. 5.98 years) at a savings of $11 746 ($18 302 vs. $30 048) in men aged 75 years. Brachytherapy was the most effective and least expensive initial treatment.
Results of Sensitivity Analysis
Treatment became more effective than observation when it led to more dramatic reductions in prostate cancer death (hazard ratio, 0.47 vs. WW and 0.64 vs. AS). Active surveillance became as effective as WW in men aged 65 years when the probability of progressing to treatment on AS decreased below 63% or when the quality of life with AS versus WW was 4% higher in men aged 65 years or 1% higher in men aged 75 years. Watchful waiting remained least expensive in all analyses.
Limitation
Results depend on outcomes reported in the published literature, which is limited.
Conclusion
Among these men, observation is more effective and costs less than initial treatment, and WW is most effective and least expensive under a wide range of clinical scenarios.
Primary Funding Source
National Cancer Institute, U.S. Department of Defense, Prostate Cancer Foundation, and Blue Shield of California Foundation.
doi:10.7326/0003-4819-158-12-201306180-00002
PMCID: PMC4487888  PMID: 23778902
16.  Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer 
Journal of Clinical Oncology  2011;30(5):507-512.
Purpose
Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.
Patients and Methods
The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.
Results
In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
Conclusion
In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
doi:10.1200/JCO.2011.37.7002
PMCID: PMC4104290  PMID: 22184381
17.  Population-based patterns of prescription androgen use, 1976-2008 
Purpose
Prescription testosterone (T) has limited approved medical indications and is a controlled substance in Canada. Utilization studies in other Westernized countries have revealed sharp increases in T use in recent years. We examined medical use of androgens, including T, over a ≥30 year period among adult (18+) men in a population-based study set in a Canadian juridisdiction of universal health care.
Methods
Analyses were based on data from electronic records of dispensed prescriptions during 1976-2008 in Saskatchewan, Canada. All formulations of androgens listed in the provincial formulary (oral and injectable) were included. We examined demographics of users, androgen types used, switching patterns, and trends in the annual rate of use over time.
Results
There were 11,521 androgen users who were followed for an average of 11.8 years. Overall, 11 types of androgens were used and there were 86,812 dispensing events. The mean age at first use was 56.4 years (median: 58). Men had 7.5 prescription dispensing events on average (median: 2). The most commonly-used formulations were methyl-T (36.2% of users) followed by T-enanthate (32.5%), T-cypionate (22.3%) and T-undecanoate (20.0%). Most users (82%) did not switch among androgen types. The annual rate of use varied substantially over time, with a marked increase observed from 1994-1999 and a decrease from 2000-2008.
Conclusions
Androgen users were largely middle-aged and had relatively few dispensings. We hypothesize that observed secular trends in androgen use may align with drug treatment pattern changes for erectile dysfunction (ED), including the advent of phosphodiesterase type 5 inhibitors.
doi:10.1002/pds.3579
PMCID: PMC3984881  PMID: 24510484
androgens; testosterone; drug utilization; hypogonadism; pharmacoepidemiology
19.  DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors 
BMC Cancer  2015;15:242.
Background
To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease.
Methods
Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients.
Results
Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data.
Conclusions
The discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1192-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1192-2
PMCID: PMC4392457  PMID: 25886454
20.  Androgen Deprivation Therapy Reversibly Increases Endothelium‐Dependent Vasodilation in Men With Prostate Cancer 
Background
Androgen deprivation therapy (ADT) is a standard treatment for patients with aggressive prostate cancer. Although ADT improves survival, it increases the risk of diabetes. Emerging evidence suggests that ADT increases adverse cardiovascular events as early as 3 months after initiation in patients with cardiovascular disease, but the mechanism is unknown. We hypothesized that ADT may impair endothelium‐dependent vasodilation due to increases in lipids and insulin resistance and may provide a link for heightened cardiovascular risk in this population.
Methods and Results
We prospectively evaluated conduit artery endothelium‐dependent and ‐independent vasodilation, lipids, and insulin resistance in 16 consecutively treated men (mean age 66±7 years; 25% with diabetes) with prostate cancer before and after 3 months of ADT. High‐resolution B‐mode ultrasound was used to assess flow‐mediated (endothelium‐dependent) and nitroglycerine‐mediated (endothelium‐independent) brachial artery vasodilation. ADT significantly increased insulin resistance, total cholesterol, HDL, and LDL. Endothelium‐dependent vasodilation was greater at 3 months than at baseline (10.8% [interquartile range: 7.7% to 14.6%] versus 8.9% [interquartile range: 4.0% to 12.6%], respectively; P=0.046, allometric P=0.037). Nitroglycerine‐mediated vasodilation did not change from baseline (P>0.2). The subset of participants on ADT for 6 months returned for reevaluation at 1 year. In this group, endothelium‐dependent vasodilation increased from baseline to 3 months and returned to baseline 6 months after ADT withdrawal (9.4% [interquartile range: 6.9% to 10.9%], 11.6% [interquartile range: 7.9% to 15.2%], and 9.0% [interquartile range: 5.1% to 12.5%], respectively; P=0.05).
Conclusions
In contrast to our expectation, ADT improved endothelium‐dependent vasodilation and its cessation returned endothelium‐dependent vasodilation to baseline. Determining the mechanism of this change requires further investigation.
doi:10.1161/JAHA.115.001914
PMCID: PMC4579953  PMID: 25896892
androgen deprivation therapy; endothelial function; inflammation; insulin resistance; prostate cancer
21.  Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits† 
Ample evidence supports genetic and functional heterogeneity in primary tumors, but it remains unclear whether circulating tumor cells (CTCs) also exhibit the same hierarchical organization. We examined the functional diversity of viable, single CTCs using an array of subnanoliter wells (nanowells). The compartmentalization of single cells by nanowells allowed clonal comparison and mapping of heterogeneity of single cells or preformed clusters of cells. By measuring the short-term viability, invasiveness and secretory profiles of individual CTCs, it was evident that only a rare subset of CTCs possessed malignant traits indicative of metastatic potential in late-stage, progressing metastatic castration-resistant prostate cancer (mCRPC) patients. These CTCs were resistant to anoikis after being in the circulation, were invasive in their epithelial state, or secreted proteases capable of cleaving peptide substrates. Every CTC observed, however, did not exhibit such metastatic potential, suggesting that enumeration of CTCs alone may be insufficient to understand metastasis or stratify patients.
doi:10.1039/c3ib40264a
PMCID: PMC4369918  PMID: 24522233
22.  SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2011;29(18):2565-2573.
Purpose
Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT.
Patients and Methods
A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays.
Results
Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (Pinteraction = .041).
Conclusion
Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.
doi:10.1200/JCO.2010.31.2405
PMCID: PMC3138634  PMID: 21606417
23.  Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression 
Journal of Clinical Oncology  2011;29(17):2378-2385.
Purpose
Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.
Patients and Methods
We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.
Results
Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.
Conclusion
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
doi:10.1200/JCO.2010.30.9880
PMCID: PMC3107752  PMID: 21537045
24.  Modification of the Association Between Obesity and Lethal Prostate Cancer by TMPRSS2:ERG  
Background
TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.
Methods
The study included 1243 participants in the prospective Physicians’ Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results
During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P interaction = .001).
Conclusions
These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.
doi:10.1093/jnci/djt332
PMCID: PMC3866157  PMID: 24292212
25.  Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer 
Nature biotechnology  2014;32(5):479-484.
Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
doi:10.1038/nbt.2892
PMCID: PMC4034575  PMID: 24752078

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