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author:("kanto, Philip")
1.  Targeted Androgen Pathway Suppression in Localized Prostate Cancer: A Pilot Study 
Journal of Clinical Oncology  2013;32(3):229-237.
Purpose
Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes.
Patients and Methods
Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration.
Results
Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greatest percentage decline in serum testosterone, androsterone, and dehydroepiandrosterone sulfate (P < .05 for all). Staining for AR and the androgen-regulated genes prostate-specific antigen and TMPRSS2 was strongly suppressed in benign glands and moderately in malignant glands (P < .05 for all). Two patients had pathologic complete response, and nine had ≤ 0.2 cm3 of residual tumor (defined as a near-complete response), with the largest numbers of complete and near-complete responses in the ZBDK group.
Conclusion
Addition of androgen synthesis inhibitors lowers prostate androgens below that achieved with standard therapy, but significant AR signaling remains. Tissue-based analysis of steroids and AR signaling is critical to informing the search for optimal local and systemic control of high-risk prostate cancer.
doi:10.1200/JCO.2012.48.6431
PMCID: PMC3887479  PMID: 24323034
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.  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
4.  18F-FDG-PET/CT and 18F-NaF-PET/CT in men with castrate-resistant prostate cancer 
To evaluate 18F-labeled-fluorodeoxyglucose (18F-FDG-) and 18F-labeled-sodium fluoride (18F-NaF-) positron emission tomography/computed tomography (PET/CT) as biomarkers in metastatic castrate-resistant prostate cancer (mCRPC). Nine men (53-75 years) in a phase 1 trial of abiraterone and cabozantinib had 18F-FDG-PET/CT, 18F-NaF-PET/CT and standard imaging (99mTc-labeled-methylene-diphosphonate (99mTc-MDP) bone scan and abdominal/pelvic CT) at baseline and after 8 weeks of therapy. Baseline disease was classified as widespread 18F-FDG-avid, oligometastatic 18F-FDG-avid (1 site), or non-18F-FDG-avid. Metabolic response was classified using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Treatment response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Prostate Cancer Working Group 2 (PCWG2) guidelines and days on trial (DOT) were recorded. All men were followed for 1 year or until progression. Four men had 18F-FDG-avid disease: two with widespread (DOT 53 and 76) and two with oligometastatic disease (DOT 231 and still on trial after 742+ days). Five men had non-18F-FDG-avid disease; three remained stable or improved (2 still on trial while one discontinued for non-oncologic reasons; DOT 225-563+), and 2 progressed (DOT 285 and 532). Despite the small sample size, Kaplan-Meier analysis showed a significant difference in progression free survival (PFS) between men with widespread 18F-FDG-avid, oligometastatic 18F-FDG-avid and non-18F-FDG-avid disease (p < 0.01). All men had 18F-NaF-avid disease. Neither 18F-NaF-avid disease extent nor intensity was predictive of treatment response. 18F-FDG-PET/CT may be superior to 18F-NaF-PET/CT and standard imaging in men with mCRPC on abiraterone and cabozantinib. 18F-FDG-PET/CT may have potential to stratify men into 3 groups (widespread vs. oligometastatic 18F-FDG-avid vs. non-18F-FDG-avid mCRPC) to tailor therapy. Further evaluation is warranted.
PMCID: PMC4299771  PMID: 25625029
PET/CT; FDG; NaF; prostate cancer; bone scan
5.  Whole-exome sequencing and clinical interpretation of FFPE tumor samples to guide precision cancer medicine 
Nature medicine  2014;20(6):682-688.
Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients; however, multiple innovations are necessary for clinical implementation. These include: (1) rapid and robust WES from formalin-fixed paraffin embedded (FFPE) tumor tissue, (2) analytical output similar to data from frozen samples, and (3) clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival FFPE tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a “long tail” of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15/16 patients. In one patient, previously undetected findings guided clinical trial enrollment leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine.
doi:10.1038/nm.3559
PMCID: PMC4048335  PMID: 24836576
6.  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
7.  Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib 
Cancer discovery  2014;4(5):546-553.
Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
doi:10.1158/2159-8290.CD-13-0353
PMCID: PMC4122326  PMID: 24625776
8.  The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance) 
Cancer  2013;119(20):3636-3643.
Background
Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel.
Methods
CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm.
Results
Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366).
Conclusions
As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.
doi:10.1002/cncr.28285
PMCID: PMC3795898  PMID: 23913744
9.  Integrative analysis of 1q23.3 copy number gain in metastatic urothelial carcinoma 
Purpose
Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum-based chemotherapy.
Experimental Design
We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by Nanostring nCounter to identify transcripts from the region that are associated with copy number gain. In addition, expression data from an independent cohort was used to identify candidate genes.
Results
Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 6.48; P = 0.01 and adjusted HR 5.03; 95% CI 1.43-17.73; P < 0.001). The F11R, PFDN2, PPOX, USP21 and DEDD genes, all located on 1q23.3, were closely associated with poor outcome.
Conclusions
1q23.3 copy number gain displayed association with poor survival in two cohorts of metastatic UC. The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance.
doi:10.1158/1078-0432.CCR-13-0759
PMCID: PMC3975677  PMID: 24486590
10.  Analysis of the Correlation between Endorectal MRI Response to Neoadjuvant Chemotherapy and Biochemical Recurrence in Patients with High-Risk Localized Prostate Cancer 
Background
Intermediate endpoints are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal MRI at 1.5 Tesla (1.5T erMRI) response has been utilized as an endpoint in neoadjuvant trials but has not been correlated with clinical outcomes.
Methods
Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both prior to radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence.
Results
There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response, and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (HR=0.58, 95% CI 0.25–1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (HR=2.47, 95% CI 1.00–6.13).
Conclusions
Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary endpoint in neoadjuvant chemotherapy trials.
doi:10.1038/pcan.2013.15
PMCID: PMC4026061  PMID: 23712318
Prostate cancer; neoadjuvant chemotherapy; endorectal MRI; intermediate endpoints
11.  Early Detection of Prostate Cancer: AUA Guideline 
The Journal of urology  2013;190(2):419-426.
Purpose
The guideline purpose is to provide the urologist with a framework for the early detection of prostate cancer in asymptomatic average risk men.
Materials and Methods
A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age <40; 40 to 54; 55 to 69; >70).
Results
With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.
Conclusions
The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm
doi:10.1016/j.juro.2013.04.119
PMCID: PMC4020420  PMID: 23659877
prostate cancer; prostate specific antigen; screening; early detection
12.  Identification of ALK Gene Alterations in Urothelial Carcinoma 
PLoS ONE  2014;9(8):e103325.
Background
Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome.
Methods
Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case.
Results
70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5′ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease.
Conclusions
ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.
doi:10.1371/journal.pone.0103325
PMCID: PMC4118868  PMID: 25083769
13.  FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder 
Cancer Medicine  2014;3(4):835-844.
While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.
doi:10.1002/cam4.262
PMCID: PMC4303151  PMID: 24846059
Biomarker; bladder cancer; FGFR3; metastatic urothelial carcinoma; muscle-invasive urothelial carcinoma; targeted therapy
14.  Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group 
Purpose
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
Methods
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
Results
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
Conclusion
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
doi:10.1200/JCO.2007.12.4487
PMCID: PMC4010133  PMID: 18309951
15.  Synergistic Cytotoxicity of Irinotecan and Cisplatin in Dual-Drug PSMA-Targeted Polymeric Nanoparticles 
Nanomedicine (London, England)  2012;8(5):687-698.
Aim
Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are (1) actively targeting both drugs to a specific diseased cell type and (2) delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work we report the use of targeted polymeric nanoparticles (NPs) to co-encapsulate and deliver I&C to cancer cells expressing the Prostate Specific Membrane Antigen (PSMA).
Method
We prepared targeted NPs in a single-step by mixing four different precursors inside microfluidic devices.
Results
I&C were encapsulated in 55-nm NPs and showed an 8-fold increase in internalization by PSMA-expressing LNCaP cells compared to non-targeted NPs. NPs co-encapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2.
Conclusion
The strategy of co-encapsulating both irinotecan and cisplatin in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer.
doi:10.2217/nnm.12.134
PMCID: PMC3694785  PMID: 23075285
Nanoparticles; Combination Chemotherapy; Cisplatin; Irinotecan; PSMA
16.  Punctuated Evolution of Prostate Cancer Genomes 
Cell  2013;153(3):666-677.
SUMMARY
The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy”, frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
doi:10.1016/j.cell.2013.03.021
PMCID: PMC3690918  PMID: 23622249
17.  Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer 
Prostate Cancer  2014;2014:230812.
Background. Increasing body mass index (BMI) is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT) for prostate cancer (PC) remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT). BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83%) received RT + ADT and, of these, 7 (70%) were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR): 0.18 [95% CI: 0.04–0.89]; P = 0.04), whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P = 0.04). Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.
doi:10.1155/2014/230812
PMCID: PMC4016923  PMID: 24864213
18.  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
19.  A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome After Radiation Therapy for Localized Prostate Cancer 
Purpose
To study associations between single nucleotide polymorphisms (SNPs) in RNASEL, a gene implicated in inflammation and prostate cancer risk, and outcomes following radiation therapy (RT).
Experimental Design
We followed participants in the prospective US Health Professionals Follow-Up Study treated with RT for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.
Results
We followed 434 patients treated with RT for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint (HR: 0.65; 95% CI: 0.45–0.94; p = 0.02) driven by decreased biochemical recurrence (HR: 0.60; 95% CI: 0.40 – 0.89; p = 0.01) and men treated with external beam (HR: 0.58; 95% CI: 0.36 – 0.93; p = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes following RT (p-interaction = 0.02).
Conclusion
We demonstrate an association between RNASEL SNP rs12757998 and outcome after RT for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management.
doi:10.1158/1078-0432.CCR-12-2718
PMCID: PMC3602407  PMID: 23382116
prostate cancer; radiotherapy; inflammation; outcome; single nucleotide polymorphism
20.  Natural History of Untreated Prostate Specific Antigen Radiorecurrent Prostate Cancer in Men with Favorable Prognostic Indicators 
Prostate Cancer  2014;2014:912943.
Background and Purpose. Life expectancy data could identify men with favorable post-radiation prostate-specific antigen (PSA) failure kinetics unlikely to require androgen deprivation therapy (ADT). Materials and Methods. Of 206 men with unfavorable-risk prostate cancer in a randomized trial of radiation versus radiation and ADT, 53 experienced a PSA failure and were followed without salvage ADT. Comorbidity, age and established prognostic factors were assessed for relationship to death using Cox regression analyses. Results. The median age at failure, interval to PSA failure, and PSA doubling time were 76.6 years (interquartile range [IQR]: 71.8–79.3), 49.1 months (IQR: 37.7–87.4), and 25 months (IQR: 13.1–42.8), respectively. After a median follow up of 4.0 years following PSA failure, 45% of men had died, none from prostate cancer and no one had developed metastases. Both increasing age at PSA failure (HR: 1.14; 95% CI: 1.03–1.25; P = 0.008) and the presence of moderate to severe comorbidity (HR: 12.5; 95% CI: 3.81–41.0; P < 0.001) were significantly associated with an increased risk of death. Conclusions. Men over the age of 76 with significant comorbidity and a PSA doubling time >2 years following post-radiation PSA failure appear to be good candidates for observation without ADT intervention.
doi:10.1155/2014/912943
PMCID: PMC3950926  PMID: 24701353
21.  Demystifying Immunotherapy in Prostate Cancer: Understanding Current and Future Treatment Strategies 
Immunotherapy has emerged as a viable therapeutic option for patients with prostate cancer. There are multiple potential strategies that employ the immune system including therapeutic cancer vaccines that are designed to stimulate immune cells to target antigens expressed by cancer cells. Sipuleucel-T is a vaccine currently approved for the treatment of minimally symptomatic metastatic prostate cancer, while the vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab are in phase III testing. Although there are no short term changes in disease progression or available biomarkers to assess response, these agents appear to improve survival. One hypothesis suggests that this apparent paradox can be explained by the growth moderating effects of these treatments which do not cause tumor size to diminish, but rather stall or slow their growth rate over time. For this reason the use of immunotherapy earlier in the disease process is being investigated. Another approach is to block immune regulatory mechanisms mediated by the molecules CTLA-4 and PD-1. Additional future strategies will combine immunotherapy with other standard therapies, potentially enhancing the latter’s clinical impact and thereby improving both time to progression and overall survival due to the combined effects of both treatments. Prospective trials are currently evaluating these hypotheses and will ultimately serve to optimize immunotherapy in the treatment of prostate cancer.
doi:10.1097/PPO.0b013e31828160a9
PMCID: PMC3556901  PMID: 23337757
Immunotherapy; Prostate Cancer; Therapeutic Cancer Vaccines; Immune Checkpoint Inhibitors; Combination Immunotherapy
22.  The Altered Expression of MiR-221/-222 and MiR-23b/-27b Is Associated With the Development of Human Castration Resistant Prostate Cancer 
The Prostate  2011;72(10):10.1002/pros.22456.
BACKGROUND
We have previously identified seven miRs-miR-221, -222, -23b, -27b, -15a, -16-1, and -203, that are differentially expressed in the hormone sensitive LNCaP cell line and the hormone resistant LNCaP-abl cell line and hypothesized that these miRs may characterize certain subtypes of human castration resistant prostate cancer (CRPC).
METHODS
Functional studies in cell culture systems have been performed to determine the effect of alternated expression level on cellular response to androgen treatment. To determine the clinical relevance of the expression patterns of these miRs, we compared the expression levels of these seven miRs in normal prostate tissues from 86 individuals, prostate tumor tissues from 34 individuals with localized hormone naïve disease, and bone-derived metastatic CRPC tissues from 17 individuals.
RESULTS
The altered expression of miR-221/-222 (as previously described) or miR-203 affected the cellular response to androgen treatment, suggesting their potential involvement in the transition to CRPC. However, the expression of miR-23b, -27b, -15a, and -16-1 did not have a significant influence in the cellular response to androgen treatment, suggesting that these miRs may not play a causative role in the CRPC phenotype. Comparison of the expression levels of these miRs in tissue samples revealed that strikingly, ~90% of the analyzed metastatic CRPC tumors could be characterized by the increased miR-221/-222 expression and the down-regulated miR-23b/-27b expression.
CONCLUSIONS
This finding suggests that altered miR-221/-222 and miR-23b/-27b expression may be associated with the CRPC process.
doi:10.1002/pros.22456
PMCID: PMC3810996  PMID: 22127852
microRNA; miR-221/-222; prostate cancer
23.  Association of Prostate Cancer Risk Loci with Disease Aggressiveness and Prostate Cancer–Specific Mortality 
Cancer prevention research (Philadelphia, Pa.)  2011;4(5):10.1158/1940-6207.CAPR-10-0292.
Genome-wide association studies have detected more than 30 inherited prostate cancer risk variants. While clearly associated with risk, their relationship with clinical outcome, particularly prostate cancer–specific mortality, is less well known. We investigated whether the risk variants are associated with various measures of disease aggressiveness and prostate cancer–specific mortality. In a cohort of 3,945 men of European ancestry with prostate cancer, we genotyped 36 single nucleotide polymorphisms (SNP): 35 known prostate cancer risk variants and one SNP (rs4054823) that was recently reported to be associated with prostate cancer aggressiveness. The majority of subjects had a diagnosis of prostate cancer between 1995 and 2004, and the cohort included a total of 580 prostate cancer–specific deaths. We evaluated associations between the 36 polymorphisms and prostate cancer survival, as well as other clinical parameters including age at diagnosis, prostate-specific antigen (PSA) at diagnosis, and Gleason score. Two SNPs, rs2735839 at chromosome 19q13 and rs7679673 at 4q24, were associated with prostate cancer–specific survival (P = 7 × 10−4 and 0.014, respectively). A total of 12 SNPs were associated with other variables (P < 0.05): age at diagnosis, PSA at diagnosis, Gleason score, and/or disease aggressiveness based on D’Amico criteria. Genotype status at rs4054823 was not associated with aggressiveness or outcome. Our results identify two common polymorphisms associated with prostate cancer–specific mortality.
doi:10.1158/1940-6207.CAPR-10-0292
PMCID: PMC3811002  PMID: 21367958
24.  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
25.  THE TMPRSS2:ERG REARRANGEMENT, ERG EXPRESSION, AND PROSTATE CANCER OUTCOMES: A COHORT STUDY AND META-ANALYSIS 
Background
Whether the genomic rearrangement TMPRSS2:ERG has prognostic value in prostate cancer is unclear.
Methods
Among men with prostate cancer in the prospective Physicians’ Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random effects models to estimate associations between rearrangement status and outcomes.
Results
The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence, and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence (HR: 0.99; 95% CI: 0.78-1.26) or lethal disease (HR: 0.93; 95% CI: 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis (RR≥T3 vs. T2: 1.23; 95% CI: 1.16-1.30) but not with biochemical recurrence (RR: 1.00; 95% CI: 0.86-1.17) or lethal disease (RR: 0.99; 95% CI: 0.47-2.09).
Conclusions
These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy.
Impact
This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy.
doi:10.1158/1055-9965.EPI-12-0042
PMCID: PMC3671609  PMID: 22736790
TMPRSS2:ERG; prostate cancer; gene fusion; biomarker; prognosis

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