Abstract Background Metastasis-directed stereotactic body radiotherapy (MD-SBRT) has shown promise in retrospective and phase II studies for oligometastatic hormone-sensitive prostate cancer. However, prospective randomized phase III data—particularly in newly diagnosed cases and in combination with androgen deprivation therapy and next-generation androgen receptor pathway inhibitors—are limited. The METRO trial investigates the addition of MD-SBRT to standard of care in patients with prostate-specific membrane antigen (PSMA) PET/CT-detected oligometastatic disease. Methods METRO is a multicentre, double arm, open-label, phase III randomized trial comparing MD-SBRT plus standard of care versus standard of care alone in patients with one to three PSMA PET/CT-detected distant metastases. The PSMA-RADS scale is used to support inclusion, and only patients with PSMA-RADS 4 or 5 lesions in bone or non-regional lymph nodes are eligible. Standard of care includes time-limited androgen deprivation therapy and/or androgen receptor pathway inhibitor, as well as local radiotherapy to the prostate or prostate bed. Patients are stratified by disease type (synchronous or metachronous) and metastasis location (lymph node/bone). The primary endpoint is biochemical progression-free survival; secondary endpoints include time to castration-resistant prostate cancer, adverse events, and health-related quality of life. The intervention is prescribed either 30 Gy in 3 fractions or 40 Gy in 5 fractions and delivered by stereotactic treatment principles. Discussion The METRO trial investigates the added value of combining MD-SBRT with time-limited intensified hormonal therapy in both synchronous and metachronous oligometastatic hormone-sensitive prostate cancer staged by PSMA‑PET/CT. The use of the PSMA-RADS scale for inclusion ensures a standardized and reproducible approach for patient selection. Trial registration ClinicalTrials.gov Identifier: NCT04983095.

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers (PCa) and is targeted in both diagnostic and therapeutic applications. Preclinical studies suggest that short-term androgen blockade may upregulate PSMA expression, potentially enhancing lesion detectability with [68Ga]Ga-PSMA-11 positron emission computed tomography (PET) and the therapeutic efficacy of PSMA-targeted radioligands. However, clinical data remains limited and inconsistent. The aim of this study was to assess the impact of short-term non-steroidal androgen blockade therapy (NSAA) on lesion PSMA expression and cellularity using dynamic [68Ga]Ga-PSMA-11PET and diffusion-weighted magnetic resonance imaging (MR) for simultaneous estimation of binding potential (BPND) and apparent diffusion coefficient (ADC) in hormone-naïve patients with high-risk PCa without bone metastases. A significant serum prostate specific antigen (PSA) decline was observed in 7/8 patients (median PSA fold change − 88.3

Supplementary Figure 1 from Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

Supplementary Table S1 from The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Supplementary Table S2 from The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer

Supplementary Figure 2 from Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2018PD56-02 A NOVEL RISK SCORE (P-SCORE) BASED ON A 3-GENE SIGNATURE FOR ESTIMATING RISK OF PROSTATE CANCER SPECIFIC MORTALITY Chunde Li, ZHUOCHUN PENG, Dimitris Chatzianastasio, Fabian Söderdahl, Jeffrey Yachnin, and Sten Nilsson Chunde LiChunde Li More articles by this author , ZHUOCHUN PENGZHUOCHUN PENG More articles by this author , Dimitris ChatzianastasioDimitris Chatzianastasio More articles by this author , Fabian SöderdahlFabian Söderdahl More articles by this author , Jeffrey YachninJeffrey Yachnin More articles by this author , and Sten NilssonSten Nilsson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2634AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A previously reported 3-gene signature (IGFBP3, F3 and VGLL3) has been identified and shown improved predictive value for estimating risk of prostate cancer specific mortality for newly diagnosed prostate cancer patients. This study summarizes the development of a novel risk score (P-score) based on this 3-gene signature in a larger modern cohort with 8-12 years survival data for the purpose of better treatment decision for patients with newly diagnosed prostate cancer. METHODS The 3-gene signature was measured in FFPE material from diagnostic core needle biopsies of 596 prostate cancer patients. Patients were selected from a population-based cohort in Stockholm, Sweden, with a clinical follow-up time of 8 to 12 years. Out of 596 patients, 296 were deceased, 123 (21%) died of prostate cancer and 173 (29%) died of other diseases. A competing risk model was used to estimate a risk score (P-score) using the 3-gene signature combined with PSA value, Gleason score and tumor stage at time of diagnosis. Out of 596 patients, 317 patients who were not treated with radical therapy were selected as the estimation cohort to develop P-score. The P-score was subsequently validated with an independent validation cohort of 279 patients with mixed treatments. The P-score was modeled using the estimation dataset, and has a range of 0 to 15 with 1 as the smallest unit. A cox proportional model was used to analyze the hazard ratios of the P-score under a multivariate mode. Moreover, the prediction performance Harrell's C index was estimated. RESULTS In the estimation dataset, multivariate cox proportional analysis of the prostate cancer-specific survival shows that P-score has the HR of 1.49 (1.39-1.59), P<0.0001 compared to the EAU risk groups (HR 1.26 (0.86-1.84), P=0.2458). This was confirmed in the validation cohort with the HR of 1.56 (1.33-1.84), P<0.0001 compared to EAU risk group (HR 1.18 (0.70-1.99), P=0.3156). Prediction performance evaluation for cancer-specific survival time led to a concordance index of C=0.8457 for the P-score in the estimation dataset, compared to C= 0.7817 for the EAU risk groups. In the validation dataset, the P-score showed an even better improvement with C=0.8236 compared to EAU risk group with C=0.7312. Looking at the subgroup of patients with Gleason score=7 (n=273), P-score has C=0.7265 while EAU risk groups have a concordance index of C=0.6071 in the estimation dataset. The similar better improvement pattern was confirmed in the validation dataset, P-score (C=0.7945) outperformed EAU risk groups (C=0.6169) within the Gleason score=7 subgroup. CONCLUSIONS The P-score risk score, based on a 3-gene signature and clinical information, is estimated and validated showing significantly improved cancer-specific risk prediction performance than EAU risk groups. It is justified to consider the use of P-score in clinical practice for better decision of treatment options. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1062 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Chunde Li More articles by this author ZHUOCHUN PENG More articles by this author Dimitris Chatzianastasio More articles by this author Fabian Söderdahl More articles by this author Jeffrey Yachnin More articles by this author Sten Nilsson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Background Somatostatin prevents cell proliferation by inducing apoptosis. Downregulation of the XAF1 transcript may occur during the development of prostate cancer. It is interesting to evaluate the potential regulatory effects of somatostatin on XAF1 expression during the development of prostate cancer cells. Methods XAF1 mRNA and protein expression in human prostate epithelial cells RWPE-1, androgen dependent prostate cancer LNCaP, and androgen independent DU145 and PC3 cells were evaluated using RT-PCR and Western blot. The regulation of XAF1 mRNA and protein expression by somatostatin and its analogue Octreotide was evaluated. Results Substantial levels of XAF1 mRNA and proteins were detected in RWPE-1 cells, whereas prostate cancer cells LNCaP, DU145 and PC3 exhibited lower XAF1 expression. Somatostatin and Octreotide up-regulated XAF1 mRNA and protein expression in all prostate cancer cell lines. Conclusions XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy.

Gene expression profiling has identified MUC1 as being significantly overexpressed in prostate cancer with poor clinical outcome after radical surgery, but the molecular mechanisms are still unclear. In this paper, we examined whether the genetic variation in MUC1 alters prostate cancer risk and progression. We identified five haplotype-tagging single-nucleotide polymorphisms that describe inherited genetic variation in and around MUC1. Individual single-nucleotide polymorphisms as well as haplotypes were tested for association with prostate cancer risk and prognosis in 2760 cases and 1722 controls from the Swedish population. We found no association between any single-nucleotide polymorphism or haplotype in the MUC1 and risk of prostate cancer. Stratifying for disease severity or age of onset did not alter the results. Moreover, we observed no association with MUC1 variation and prostate cancer-specific survival. Common variants in MUC1 and the surrounding region are not associated with risk or prognosis of prostate cancer in Swedish men.

MUC1 is expressed on the apical surface of glandular epithelium. With functions including protection, adhesion and signaling, MUC1 has been implicated in prostate cancer. There are many splice variants, the best characterized of which are MUC1/1 and MUC1/2 which are determined by a SNP (rs4072037, 3506G>A).Blood DNA from the general population, BPH, sporadic and hereditary prostate cancer subjects were genotyped for the rs4072037 SNP. G allele frequencies were significantly reduced in hereditary prostate cancer (15%) compared to population, BPH or sporadic prostate cancer samples (27%, 39% and 26% respectively). In addition, the G allele was lost from 3 of 8 heterozygous sporadic prostate tumor samples compared to matched blood DNA. Bioinformatics analysis of MUC1 protein sequences provides insight into differences between the variants which may be functionally relevant. The literature indicates discrepancies between immuno-histochemical studies, possibly due to the variety of MUC1 epitopes targeting diverse regions of the molecule. The contradictory findings in cell lines highlight the problem associated with inadequate experimental systems.This is the first report of genetic differences in MUC1 between blood and prostatic cancer tissue. This finding is important as proof of principle, given that many association studies focus on blood DNA rather than on the tumor DNA. As yet, potential functional differences between splice variants has been paid little attention. Antibodies which discriminate between the variants and standardization of methods would help to clarify whether there is a role for MUC1 as a prognostic marker.

Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform fusion. In this specimen set, the presence of a TMPRSS2-ERG fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS fusions.

Abstract Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease. [Cancer Res 2007;67(18):8504–10]

Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

Previous studies in hereditary and sporadic prostate cancer have indicated the existence of a tumor suppressor gene in chromosomal region 19p13. The BRG1 gene in this region is one of the possible candidates, based on both the frequency of inactivating mutations in human cancer cell lines, including the prostate cancer cell line DU145, and its functional properties. To our knowledge, no studies have been done to evaluate possible involvement of the BRG1 gene in clinical prostate cancer. To accomplish this, we carried out a complete mutation analysis of all 35 BRG1 exons in tumor and constitutional DNA samples from 21 prostate cancer patients. We report the absence of somatic mutations in the panel of samples employed, but the existence of five germline single nucleotide polymorphisms (SNPs) in CpG islands of the BRG1 gene, among them, three novel ones. In conclusion, the study excludes the presence of common BRG1 mutations in prostate cancer.

Analysis of genomic alterations on urological malignancies by fluorescence in situ hybridization