PSA Recurrence Research Articles

Salvage LND after radical prostatectomy for PSA recurrence: Robotic

Salvage LND after radical prostatectomy for PSA recurrence: Robotic

Circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy

BackgroundThe Stephenson nomogram is widely used to estimate the success of salvage radiotherapy (sXRT) for prostate cancer (PCa) recurrence after radical prostatectomy (RP). ObjectiveTo determine whether multiparametric pelvic magnetic resonance imaging (mpMRI) performed for biochemical recurrence after RP improves prognostication of sXRT relative to the Stephenson nomogram. Design, setting, and participantsMen undergoing RP at our institution from 2003 to 2012 who had biochemical recurrence evaluated by mpMRI within 12 mo of sXRT were retrospectively reviewed. Exclusion criteria included PCa treatment prior to RP, adjuvant XRT after RP, salvage cryotherapy before sXRT, and hormone refractory disease prior to sXRT. Outcome measurements and statistical analysisMultivariable Cox regression analyses (adjusting for Stephenson nomogram covariates) associated mpMRI findings with prostate-specific antigen (PSA) recurrence and metastasis after sXRT. The mpMR images were compared in a binary fashion: no lesion versus vesicourethral/seminal vesical bed/prostate fossa lesions. Results and limitationsAmong 473 sXRT patients, 57%(204) had lesions on mpMRI: 26%(124) vesicourethral, 28%(135) seminal vesical bed/prostatic fossa, 7%(34) nodal, and 1%(3) bone. Median PSA at mpMRI with lesions was 0.46 versus 0.40ng/ml without lesions. After excluding nodal/bone lesions, 29% of men developed PSA recurrence and 14% metastasis (median follow-up 45 mo after sXRT). For patients with a pre-sXRT PSA of ≤0.5ng/ml, negative mpMRI was associated with increased PSA recurrence (39% vs 12%, p<0.01) and metastasis (16% vs 2%, p<0.01) at 4 yr after sXRT. For patients with a PSA of ≤0.5ng/ml, the addition of mpMRI to the propensity score (created using variables from the original Stephenson nomogram) improved the c-statistic from 0.71 to 0.77 for PSA recurrence (hazard ratio [HR] 3.60, p<0.01) and from 0.66 to 0.77 for metastasis (HR 6.68, p<0.01). Limitations include evolutions in MRI technique and lack of a cohort of men undergoing mpMRI electing against sXRT. ConclusionsPre-sXRT mpMRI improves clinicopathologic variables to estimate sXRT success, particularly in the early sXRT setting. Patient summaryMen who have biochemically recurrent prostate cancer after radical prostatectomy often receive salvage radiotherapy. In our study, multiparametric pelvic magnetic resonance imaging prior to salvage radiotherapy was a significant predictor of prostate-specific antigen failure and metastasis after radiotherapy.

Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

BackgroundTo determine the potential role of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).MethodsOne hundred twenty-nine patients (pts) with 68Ga-PSMA PET/CT were retrospectively analysed. Potentially influencing factors (androgen deprivation therapy, amount of 68Ga-PSMA-HBED-CC, PSA doubling time ≤/> 10 months, PSA before PET/CT, T−/N-category and Gleason score) were evaluated by logistic regression analysis. The detection rate of PSMA PET/CT was compared to contrast enhanced CT and its impact on RT management analysed.ResultsOne hundred twenty-nine patients (pts) (20 at initial diagnosis, 49 with PSA relapse and 60 with PSA persistence after radical prostatectomy) received PSMA PET/CT prior to RT. The majority of pts. (71.3%) had PET-positive findings (55.1% of pts. with PSA recurrence, 75% of pts. with PSA persistence and 100% of newly diagnosed pts). Median PSA before PET/CT in pts. with pathological findings (n = 92) was 1.90 ng/ml and without (n = 37) 0.30 ng/ml. PSA level at time of PET/CT was the only factor associated with PET-positivity. In pts. with a PSA ≤ 0.2 ng/ml, the detection rate of any lesion was 33.3%, with a PSA of 0.21–0.5 ng/ml 41.2% and with a PSA of 0.51–1.0 ng/ml 69.2%, respectively. Regarding the anatomic distribution of lesions, 42.2% and 14.7% of pts. with relapse or persistence had pelvic lymph node and distant metastases. In pts. at initial diagnosis the detection rate of pelvic lymph nodes and distant metastases was 20% and 10%. 68Ga-PSMA PET/CT had a high detection rate of PCa recurrence outside the prostatic fossa in pts. being considered for salvage RT (22.4% PET-positive pelvic lymph nodes and 4.1% distant metastases). Compared to CT, PSMA PET/CT had a significantly higher sensitivity in diagnosing rates of local recurrence/primary tumour (10.1% vs. 38%), lymph nodes (15.5% vs. 38.8%) and distant metastases (5.4% vs. 14.0%). This resulted in a modification of RT treatment in 56.6% of pts.ConclusionsThe detection of PCa is strongly associated with PSA level at time of 68Ga-PSMA PET/CT. PSMA PET/CT differentiates between local, regional and distant metastatic disease with implications for disease management. PSMA PET/CT allows for tumour detection in post-prostatectomy pts. with PSA ≤ 0.5 ng/ml considered for salvage RT.

Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients

Toevaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75Gy with ≥5years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2ng/mL. Median follow-up was 9.2years (interquartile range, 6.9-11.3years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6months (interquartile range, 16.1-38.5months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes.

DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.

Androgen receptor (AR) activation is critical for prostate cancer development and progression, including castration-resistance. The nuclear export signal of AR (NESAR) plays an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in prostate cancer specimens and its expression was correlated with Gleason scores and PSA recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to prostate cancer progression through Siah2.

FOXA1 expression is a strong independent predictor of early PSA recurrence in ERG negative prostate cancers treated by radical prostatectomy.

FOXA1 (Fork-head box protein A1, HNF-3a) is a transcription factor involved in androgen signaling with relevance for lineage-specific gene expression of the prostate. The expression was analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with tumor phenotype, biochemical recurrence, androgen receptor expression, ETS-related gene (ERG) status and other recurrent genomic alterations. FOXA1 expression was detectable in 97.6% of 8227 interpretable cancers and considered strong in 28.5%, moderate in 46.2% and weak in 22.9% of cases. High FOXA1 expression was associated with TMPRSS2:ERG rearrangement and ERG expression (P < 0.0001). High FOXA1 expression was linked to high Gleason grade, advanced pathological tumor (pT) stage and early PSA recurrence in ERG negative cancers (P < 0.0001), while these associations were either weak or absent in ERG positive cancers. In ERG negative cancers, the prognostic role of FOXA1 expression was independent of Gleason grade, pathological tumor stage, lymph node stage, surgical margin status and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features such as biopsy Gleason grade, preoperative PSA, cT stage and FOXA1 expression (P < 0.0001). Within ERG negative cancers, FOXA1 expression was also strongly associated with PTEN and 5q21 deletions (P < 0.0001). High expression of FOXA1 is an independent prognostic parameter in ERG negative prostate cancer. Thus, FOXA1 measurement might provide clinically useful information in prostate cancer.

Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis.

Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant TFF3 promoter hypomethylation (p ≤ 0.010) as well as overexpression (p < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression (p < 0.001), as well as with high Gleason score (p < 0.001), advanced pathological T-stage (p < 0.001), and prostate-specific antigen (PSA) recurrence after RP (p = 0.013; univariate Cox regression analysis). There were no significant associations between TFF3 promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date.

Relationships between serum PSA levels, Gleason scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer.

To investigate the relationship between serum PSA level, Gleason score of PCa and the outcomes of Ga68-PSMA PET/CT in patients with recurrent PCa. A total of 109 consecutive patients (median age 71years; range 48-89years) who had PSA recurrence after RP and/or hormonotherapy and/or radiotherapy were included in this study. Local recurrences, lymph node metastasis (pelvic, abdominal and/or supradiaphragmatic), bone metastases (oligometastatic/multimetastatic) and other metastatic sites (lung, liver, brain, etc) were documented. In 91(83.4%) patients at least one lesion characteristic for PCa was detected by68Ga-PSMA PET/CT. The median serum total PSA (tPSA) was 6.5 (0.2-640)ng/ml.There was a significant difference between 68Ga-PSMA PET/CT positive and negative patients in terms of serum total PSA value. No statistical significance was found between positive and negative 68Ga-PSMA PET/CT findings in terms of Gleason score. Local recurrence was detected in 56 patients. whereas lymph node metastases were demonstrated in 46 patients. Pelvic nodal disease was the most frequent presentation followed by abdominal and supradiaphragmaticnodal involvement. Bone metastases [oligometastasis, (n = 20); multimetastasis, (n = 35)⦌ were also detected in 55 patients. In the ROC analysis for the study cohort, the optimal cut-off value of total serum PSA was determined as 0.67ng/ml for distinguishing between positive and negative 68Ga-PSMA PET/CT images, with an area under curve of 0.952 (95% CI 0.911-0.993). 68Ga-PSMA PET/CT was found to be an effective tool for the detection of recurrent PCa. Even though no relationship was detected between the GS and 68Ga-PSMA PET/CT findings, serum total PSA values may be used for estimating the likelihood of positive 68Ga-PSMA PET/CT results.

Does Early Prostate Specific Antigen Doubling Time after Radical Prostatectomy, Calculated Prior to Prostate Specific Antigen Recurrence, Correlate with Prostate Cancer Outcomes? A Report from the SEARCH Database Group

Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis. Prostate specific antigen doubling time is traditionally calculated using prostate specific antigen values 0.2 ng/ml or greater. We determined whether early prostate specific antigen doubling time, calculated from the first detectable postoperative prostate specific antigen up to and including the first recurrence value, correlates with prostate cancer outcomes. Cox models were used to examine the association between early prostate specific antigen doubling time and castration resistant prostate cancer, metastases, and all cause and prostate cancer specific mortality in 674 men who underwent radical prostatectomy between 1988 and 2014 and had a biochemical recurrence. Early prostate specific antigen doubling time was examined as a log transformed continuous and a categorical variable. After adjusting for multiple clinicopathological characteristics, log transformed early prostate specific antigen doubling time was not associated with any outcome. However, when early doubling time was categorized as 15 or greater, 9 to 14.9, 3 to 8.9 and less than 3 months, on multivariable analysis men with early doubling time less than 3 months were at increased risk for castration resistant prostate cancer (HR 6.20, p = 0.004), metastases (HR 5.26, p = 0.001), prostate cancer specific mortality (HR 5.06, p = 0.026) and all cause mortality (HR 1.63, p = 0.065) compared to those with an early doubling time of 15 months or greater. However, the association with all cause mortality was not significant. Those with an early prostate specific antigen doubling time of 3 to 8.9 months were at increased risk for castration resistant prostate cancer (HR 3.56, p = 0.015), all cause mortality (HR 1.67, p = 0.006) and prostate cancer specific mortality (HR 3.17, p = 0.044) but not metastases (p = 0.13). Early prostate specific antigen doubling time less than 9 months, calculated using prostate specific antigen values before and up to biochemical recurrence, is associated with an increased risk of castration resistant prostate cancer, metastases, and prostate cancer specific and all cause mortality among men with biochemical recurrence after radical prostatectomy. Early prostate specific antigen doubling timeallows for risk stratification at biochemical recurrence and before prostate specific antigen doubling timeis calculable, enabling these men to be referred for early aggressive secondary treatment and/or clinical trials.

Up-regulation of Biglycan is Associated with Poor Prognosis and PTEN Deletion in Patients with Prostate Cancer

Biglycan (BGN), a proteoglycan of the extracellular matrix, is included in mRNA signatures for prostate cancer aggressiveness. To understand the impact of BGN on prognosis and its relationship to molecularly defined subsets, we analyzed BGN expression by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Seventy-eight percent of 11,050 interpretable cancers showed BGN expression, which was considered as low intensity in 47.7% and as high intensity in 31.1% of cancers. BGN protein expression rose with increasing pathological tumor stage, Gleason grade, lymph node metastasis and early PSA recurrence (P<.0001 each). Comparison with our molecular database attached to the TMA revealed that BGN expression was linked to presence of TMPRRS2:ERG fusion and PTEN deletion (P<.0001 each). In addition, BGN was strongly linked to androgen-receptor (AR) levels (P<.0001), suggesting a hormone-depending regulation of BGN. BGN up-regulation is a frequent feature of prostate cancer that parallels tumor progression and may be useful to estimate tumor aggressiveness particularly if combined with other molecular markers.

An assessment of Prostate Cancer Research International: Active Surveillance (PRIAS) criteria for active surveillance of clinically low-risk prostate cancer patients.

Active surveillance is a strategy to delay or prevent treatment of indolent prostate cancer. The Prostate Cancer Research International: Active Surveillance (PRIAS) criteria were developed to select patients for prostate cancer active surveillance. The objective of this study was to compare pathological findings from PRIAS-eligible and PRIAS-ineligible clinically low-risk prostate cancer patients. A D'Amico low-risk cohort of 1512 radical prostatectomy patients treated at The Ottawa Hospital or Memorial Sloan Kettering Cancer Centre between January 1995 and December 2007 was reviewed. Pathological outcomes (pT3 tumours, Gleason sum ≥7, lymph node metastases, or a composite) and clinical outcomes (prostate-specific antigen [PSA] recurrence, secondary cancer treatments, and death) were compared between PRIAS-eligible and PRIAS-ineligible cohorts. The PRIAS-eligible cohort (n=945) was less likely to have Gleason score ≥7 (odds ratio [OR] 0.61; 95% confidence interval [CI] 0.49-0.75), pT3 (OR 0.41; 95% CI 0.31-0.55), nodal metastases (OR 0.37; 95% CI 0.10-1.31), or any adverse feature (OR 0.56; 95% CI 0.45-0.69) compared to the PRIAS-ineligible cohort. The probability of any adverse pathology in the PRIAS-eligible cohort was 41% vs. 56% in the PRIAS-ineligible cohort. At median follow-up of 3.7 years, 72 (4.8%) patients had a PSA recurrence, 24 (1.6%) received pelvic radiation, and 13 (0.9%) received androgen deprivation. No difference was detected for recurrence-free and overall survival between groups (recurrence hazard ratio [HR] 0.71; 95% CI 0.46-1.09 and survival HR 0.72; 95% CI 0.36-1.47). Low-risk prostate cancer patients who met PRIAS eligibility criteria are less likely to have higher-risk cancer compared to those who did not meet at least one of these criteria.

BMI and serum lipid parameters predict increasing risk and aggressive prostate cancer in Chinese people.

ObjectivesTo determine if obesity and serum lipid parameters are associated with increased risk and more aggressive prostate cancer in Chinese populationMaterials and MethodsWe conducted a retrospective cohort analysis including 3102 patients. Kruskal-Wallis test for continuous variables and the chi-squared tests for categorical variables were used for univariate comparison of the differences in patient characteristics across BMI categories between different groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association between prostate cancer and the various patient characteristics. Multivariable Cox proportional hazards regression was performed to assess the risk of prostate cancer recurrenceResults974 consecutive men were diagnosed as prostate cancer and 700 patients subsequently received radical prostatectomy immediately, and 1031 patients were pathologically diagnosed as biopsy negative. The level of low-density-lipoprotein cholesterol (LDL-c) and total cholesterol was significantly higher and the high-density-lipoprotein cholesterol (HDL-c) level is much lower in prostate cancer patients. Patients with low level of HDL-c, who subsequently received radical prostatectomy, had increased risk of high risk disease. In addition, patients with normal weight were less likely to develop a biochemical recurrence. Combined analysis revealed that obese patients had significantly higher rates of PSA recurrence over time than nonobese patients.ConclusionsIn our study, lipid parameters are supposed to be associated with prostate cancer risk and aggressiveness. Obese men are at increased risk of PSA recurrence after radical prostatectomy.

Prognostic value of bone scan index as an imaging biomarker in metastatic prostate cancer: a meta-analysis.

BackgroundThe prognostic value of the bone scan index (BSI) in metastatic prostate cancer (mPCa) remained controversial. Therefore, we performed a meta-analysis to determine the predictive value of BSI and survival in patients with mPCa.Materials and MethodsA literature search was performed in PubMed, Embase, Web of Science and Cochrane library databases. Hazard ratios (HRs), concordance indices (C-indices) were extracted to estimate the relationship between BSI and survival in patients with mPCa. Subgroup analyses were conducted on different types of mPCa, ethnics, cut-off values and sample sizes.Results14 high quality studies involving 1295 patients with mPCa were included in this meta-analysis. The pooled results indicated that high basline BSI and elevated BSI change on treatment (ΔBSI) were significantly predictive of poor overall survial (HR = 1.29, P < 0.001; HR = 1.27, P < 0.001, respectively). Baseline BSI was also significantly related to cancer specific survival (HR = 1.65, P = 0.019) and prostate specific antigen recurrence survival (HR = 2.26, P < 0.001). Subgroup analysis supported main results. Moreover, BSI could increase the C-indices of predictive models.ConclusionsBaseline BSI and ΔBSI may be beneficial to mPCa prognosis in clinical monitor and treatment. Further high quality studies with larger sample size are required in the future.

Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer

BackgroundAnimal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.MethodsTo better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p).ResultsERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability.ConclusionThe results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.

Abstract LB-326: A novel oncomiR negatively regulates PTEN pathway in prostate cancer

Abstract Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that a novel microRNA, microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Kaplan-Meier and ROC analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy. Note: This abstract was not presented at the meeting. Citation Format: Nadeem S. Bhat, Melissa Colden, Prerna Arora, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Taku Katu, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-sumida, Shigekatsu Maekawa, Guoren Deng, Rajvir Dahiya, Shahana Majid. A novel oncomiR negatively regulates PTEN pathway in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-326. doi:10.1158/1538-7445.AM2017-LB-326

Salvage radiotherapy for macroscopic local recurrences after radical prostatectomy : Anational survey on patterns of practice.

Although salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy provides better oncological outcomes when delivered early, in the absence of detectable disease many patients are treated for macroscopic locally recurrent tumors. Due to limited data from prospective studies, we hypothesized an important variability in the SRT management of these patients. Our aim was to investigate current practice patterns of SRT for local macroscopic recurrence after radical prostatectomy. A total of 14 Swiss radiation oncology centers were asked to complete asurvey on treatment specifications for macroscopic locally recurrent disease including information on pretherapeutic diagnostic procedures, dose prescription, radiation delivery techniques and androgen deprivation therapy (ADT). Treatment recommendations on ADT were analyzed using the objective consensus methodology. The majority of centers recommended pretreatment magnetic resonance imaging (MRI) of the pelvis and choline positron emission tomography (PET). The median prescribed dose to the prostate bed was 66 Gy (range 65-72 Gy) with aboost to the macroscopic lesion used by 79% of the centers with amedian total dose of 72 Gy (range 70-80 Gy). Intensity-modulated rotational techniques were used by all centers and daily cone beam computed tomography (CT) was recommended by 43%. The use of concomitant ADT for any macroscopic recurrence was recommended by 43% of the centers while the remaining centers recommended it only for high-risk disease, which was not consistently defined. We observed ahigh variability of treatment paradigms when SRT is indicated for macroscopic local recurrences after prostatectomy. These data reflect the need for more standardized approaches and ultimately further research in this field.

Radiotherapy of prostate cancer

Radiotherapy(RT) is one of the principle treatment options for prostate cancer. Modern RT and surgery show similar progression-free survival in localized prostate cancer. Adjuvant RT compared to observation significantly diminishes the risk of prostate-specific antigen(PSA) progression and local failure for patients at the highest risk for recurrence after radical prostatectomy, including with seminal vesicle invasion, extraprostatic extension, extensive positive margins, and detectable postoperative PSA. Salvage RT is effective at controlling local recurrence and reduces the risk of distant metastasis and prostate cancer-specific mortality (PCSM) for patients with PSA or local recurrence after prostatectomy. Hypofractionated radiotherapy of recent years' reports shows similar cancer control rates without an increased risk of late toxicity in comparison to conventional regimens. The addition of androgen-deprivation therapy(ADT) to radiation improves the overall survival and biochemical progression-free survival(bPFS) for intermediate-risk and high-risk patients. Key words: Prostatic neoplasms; Radiotherapy(RT); Adjuvant radiotherapy; Salvage radiotherapy; Hypofractionated radiotherapy

Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer \u2013 focus on overall survival

BackgroundThe aim of this study was to evaluate the long-term prognostic significance of rising PSA levels, particularly focussing on overall survival.MethodsTwo hundred ninety-five patients with localized prostate cancer were either treated with low-dose-rate (LDR) brachytherapy with I-125 seeds as monotherapy (n = 94; 145Gy), high-dose-rate (HDR) brachytherapy with Ir-192 as a boost to external beam RT (n = 66; 50.4Gy in 1.8Gy fractions EBRT + 18Gy in 9Gy fractions HDR) or EBRT alone (70.2Gy in 1.8Gy fractions; n = 135). “PSA bounce” was defined as an increase of at least 0.2 ng/ml followed by spontaneous return to pre-bounce level or lower, biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up after the end of radiotherapy was 108 months. A PSA bounce showed to be a significant factor for biochemical control (BC) and overall survival (OS) after ten years (BC10 of 83% with bounce vs. 34% without, p < 0.01; OS10 of 82% with bounce vs. 59% without bounce, p < 0.01). The occurrence of a bounce, a high nadir and the therapy modality (LDR-BT vs. EBRT and HDR-BT + EBRT vs. EBRT) proved to be independent factors for PSA recurrence in multivariate Cox regression analysis. A bounce was detected significantly earlier than a PSA recurrence (median 20 months vs. 32 months after RT; p < 0.01; median PSA doubling time 5.5 vs. 5.0 months, not significant). PSA doubling time was prognostically significant in case of PSA recurrence (OS10 of 72% vs. 36% with PSA doubling time ˃ 5 months vs. ≤ 5 months; p < 0.01).ConclusionsRising PSA levels within the first two years can usually be classified as a benign PSA bounce, with favourable recurrence-free and overall survival rates. PSA doubling time is an important predictor for overall survival following the diagnosis of a recurrence.

The value of multimodality imaging in the investigation of a PSA recurrence after radical prostatectomy in the Irish hospital setting.

The diagnostic evaluation of a PSA recurrence after RP in the Irish hospital setting involves multimodality imaging with MRI, CT, and bone scanning, despite the low diagnostic yield from imaging at low PSA levels. We aim to investigate the value of multimodality imaging in PC patients after RP with a PSA recurrence. Forty-eight patients with a PSA recurrence after RP who underwent multimodality imaging were evaluated. Demographic data, postoperative PSA levels, and imaging studies performed at those levels were evaluated. Eight (21%) MRIs, 6 (33%) CTs, and 4 (9%) bone scans had PCa-specific findings. Three (12%) patients had a positive MRI with a PSA <1.0ng/ml, while 5 (56%) were positive at PSA ≥1.1ng/ml (p=0.05). Zero patient had a positive CT TAP at a PSA level <1.0ng/ml, while 5 (56%) were positive at levels ≥1.1ng/ml (p=0.03). Zero patient had a positive bone at PSA levels <1.0ng/ml, while 4 (27%) were positive at levels ≥1.1ng/ml (p=0.01). The diagnostic yield from multimodality imaging, and isotope bone scanning in particular, in PSA levels <1.0ng/ml, is low. There is a statistically significant increase in the frequency of positive findings on CT and bone scanning at PSA levels ≥1.1ng/ml. MRI alone is of investigative value at PSA <1.0ng/ml. The indication for CT, MRI, or isotope bone scanning should be carefully correlated with the clinical question and how it will affect further management.