scholarly journals Periprostatic fat tissue transcriptome reveals a signature diagnostic for high-risk prostate cancer

2018 ◽  
Vol 25 (5) ◽  
pp. 569-581 ◽  
Author(s):  
Stefano Mangiola ◽  
Ryan Stuchbery ◽  
Geoff Macintyre ◽  
Michael J Clarkson ◽  
Justin S Peters ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adipose Tissue ◽  
High Risk ◽  
Cross Validation ◽  
Validation Cohort ◽  
Second Phase ◽  
High Risk Prostate Cancer ◽  
Diagnostic Potential ◽  
High Risk Disease ◽  
Risk Prostate Cancer

Evidence suggests that altered adipose tissue homeostasis may be an important contributor to the development and/or progression of prostate cancer. In this study, we investigated the adipose transcriptional profiles of low- and high-risk disease to determine both prognostic potential and possible biological drivers of aggressive disease. RNA was extracted from periprostatic adipose tissue from patients categorised as having prostate cancer with either a low or high risk of progression based on tumour characteristics at prostatectomy and profiled by RNA sequencing. The expression of selected genes was then quantified by qRT-PCR in a cross-validation cohort. In the first phase, a total of 677 differentially transcribed genes were identified, from which a subset of 14 genes was shortlisted. In the second phase, a 3 gene (IGHA1,OLFM4,RERGL) signature was refined and evaluated using recursive feature selection and cross-validation, obtaining a promising discriminatory utility (area under curve 0.72) at predicting the presence of high-risk disease. Genes implicated in immune and/or inflammatory responses predominated. Periprostatic adipose tissue from patients with high-risk prostate cancer has a distinct transcriptional signature that may be useful for detecting its occult presence. Differential expression appears to be driven by a local immune/inflammatory reaction to more advanced tumours, than any specific adipose tissue-specific tumour-promoting mechanism. This signature is transferable into a clinically usable PCR-based assay, which in a cross-validation cohort shows diagnostic potential.

Methylation-guided stratification of patients with high-risk prostate cancer for the prediction of clinical failure.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 155-155
Author(s):  
Kirill Litovkin ◽  
Steven Joniau ◽  
Evelyne Lerut ◽  
Annouschka Laenen ◽  
Olivier Gevaert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
High Risk ◽  
Methylation Level ◽  
Validation Cohort ◽  
Clinical Stage ◽  
Marker Genes ◽  
Clinical Failure ◽  
High Risk Prostate Cancer ◽  
Risk Prostate Cancer

155 Background: To explore differential DNA methylation of APC, CCDN2, GSTP1, PTGS2, and RARBas a tool to predict clinical failure (CF) in surgically treated patients with high-risk prostate cancer (PCa), as defined by a clinical stage T3a or higher, a biopsy Gleason score of 8 to 10 and/or pre-operative prostatic serum antigen levels more than 20 ng/ml. Methods: A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the marker genes. Formalin-fixed, paraffin-embedded radical prostatectomy samples from 218 patients with high-risk PCa, classified in a training and validation cohort, were analyzed. Kaplan-Meier analysis and Cox multivariate models were used. Results: First, high-risk PCa patients were ranked according to their GSTP1 methylation level, which varied from 0 to 80% in both cohorts. Next, we categorizedthe tumors into three groups based upon the GSTP1 methylation level: low methylation (LM, methylation less than 15%), moderate methylation ([MM], methylation 15 to 50%) and high methylation (HM, methylation more than 50%). When all five marker genes were combined, the median methylation values in the LM groups did not exceed 6% in both cohorts. In contrast, the median methylation values for the marker genes in the HM groups reached 45% in the training cohort and 50% in the validation cohort. Finally, the median methylation values in the MM groups amounted to 18% and 28% for the training and validation cohorts, respectively. Remarkably, patients belonging to the LM, HM, and the combined LM+HM groups had a 2- to 11-fold higher risk of CF as compared to those of the MM group, when correcting for established clinico-pathologic prognostic factors. In addition, the combined LM+HM group showed a significant association with cancer-related death in a multivariate analysis (Hazard ratio, 3.59) compared to the MM group, when both cohorts were combined for analysis. Conclusions: We found that differential methylation of GSTP1 allows the stratification of high-risk PCa patients into three molecular episubtypes, i.e. low, moderate and high DNA methylation level groups. Surprisingly, our data revealed that both low and high methylation levels of GSTP1 are independent predictors of CF.

Clinical-genomic sub-classification of high-risk prostate cancer: Implications for tailoring therapy and clinical trial design.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 337-337
Author(s):  
Vinayak Muralidhar ◽  
Mohammed Alshalalfa ◽  
Daniel Eidelberg Spratt ◽  
Yang Liu ◽  
R. Jeffrey Karnes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Risk Stratification ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
Risk Patients ◽  
Genomic Risk ◽  
Clinical Genomic ◽  
Very High

337 Background: Current risk stratification schema have limited prognostic performance in predicting outcome within National Comprehensive Cancer Network (NCCN) high-risk to very high-risk prostate cancer. Methods: Two multicenter high-risk cohorts were used for training (n = 214) and validation (n = 151) of a novel RNA microarray-based integrated clinical-genomic Classifier Optimized for Outcome in High-risk Prostate cancer (COOHP) to classify patients as COOHP favorable high-risk, standard high-risk, or very high-risk. Cox analysis was used to model metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Model performance was compared to prior sub-classification systems using time-dependent c-indices. Results: Among NCCN high/very high-risk patients in the training cohort, 11% were classified as COOHP favorable high-risk, 70% as COOHP standard high-risk, and 18% as COOHP very high-risk. Patients with COOHP favorable high-risk disease had better rates of 5-year MFS compared to those with COOHP standard high-risk disease (94% vs 76%, hazard ratio [HR] 0.10, p = 0.02), and patients with COOHP very high-risk disease had worse 5-year MFS compared to those with COOHP standard high-risk disease (34% vs 76%, HR 3.5, p < 0.0001). Similarly, patients with COOHP very high-risk disease had worse 10-year PCSS compared to those with COOHP standard high-risk disease (36% vs 82%, HR 4.4, p < 0.0001). The c-indices for 5-year MFS and 10-year PCSS in the training cohort were 0.80 and 0.74, significantly improved compared to prior clinical and clinical-genomic risk stratification systems (0.62-0.69 for 5-year MFS and 0.56-0.63 for 10-year PCSS). These results were consistent in the validation cohort, where 5-year MFS significantly varied among the three COOHP subgroups (100% vs 89% vs 79%, p = 0.020), as did 10-year OS (100% vs 71% vs 53%, p = .040). Conclusions: A clinical-genomic risk stratification system specifically designed to discriminate prognosis in high-risk prostate cancer better identified favorable high-risk and very high-risk subsets of disease compared to prior clinical and clinical-genomic stratification systems.

Treatment timing in localized high-risk prostate cancer treated with radiation and androgen deprivation therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 359-359
Author(s):  
Shaakir Hasan ◽  
Stanislav Lazarev ◽  
Daniel Gorovets ◽  
Madhur Garg ◽  
Robert H. Press ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Androgen Deprivation Therapy ◽  
Treatment Time ◽  
Androgen Deprivation ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
Multivariable Regression ◽  
The Impact

359 Background: Data regarding the impact of overall treatment time in prostate radiotherapy predate the dose escalation era and is absent in high risk disease. We hypothesize that delays in initiating androgen deprivation therapy (ADT) and in completing fractionated radiotherapy (XRT) correlate with worse outcomes in high risk prostate cancer. Methods: Using the National Cancer Database, we identified 9,611 cases of localized high risk prostate cancer, defined as Grade groups 4 and 5 (Gleason 8-10), PSA < 40, and T1-T3N0M0, treated with conventionally fractionated XRT (74-81 Gy, median 78 Gy) and ADT between 2010-2014 with at least 12 months follow-up (median 40). Receiver operating characteristic (ROC) analyses determined a-priori values for days to initiation of treatment (ADT or XRT) and number of “missed” treatment days (number of days beyond the minimum required to complete XRT). Multivariable regression models with propensity matching conveyed the relative impact of these timing parameters on survival. Results: The median time from diagnosis to treatment intervention was 63 days and median missed XRT treatment days was 2.2. The greatest difference in survival was seen when intervention was initiated beyond 74 days from diagnosis (HR=1.21, P=0.045) and when more than 3 XRT treatment days were missed (HR=1.27, P=0.006). Only missed treatment days correlated with survival as a continuous variable (HR=1.028, P<0.001) on multivariable analysis. On a multivariable regression model propensity-matched for missed treatment days, independent predictors for worse survival include older age, higher comorbidity score, dose below 78 Gy, grade group 5, and PSA > 20. Greater than 3 missed treatment days remained an independent predictor; adjusted HR = 1.23 (P=0.002). The lone predictors of missed treatments was African American race (OR=1.21). Conclusions: Although outcomes in prostate cancer are not typically thought to be associated with treatment time, our study, the largest such analysis to date, revealed a strong independent correlation between timely completion of XRT and survival in high risk disease. The association between survival and time to initiating ADT was not nearly as strong.

scholarly journals Impact of Age at Diagnosis on Prostate Cancer Treatment and Survival

2011 ◽  
Vol 29 (2) ◽  
pp. 235-241 ◽  
Author(s):  
Seth K. Bechis ◽  
Peter R. Carroll ◽  
Matthew R. Cooperberg
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Disease Risk ◽  
Local Therapy ◽  
Older Men ◽  
Cancer Specific Survival ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
Cancer Of The Prostate

Purpose Older men are more likely to be diagnosed with high-risk prostate cancer and to have lower overall survival. As a result, age often plays a role in treatment choice. However, the relationships among age, disease risk, and prostate cancer–specific survival have not been well established. Patients and Methods We studied men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database with complete risk, treatment, and follow-up information. High-risk patients were identified by using the validated Cancer of the Prostate Risk Assessment (CAPRA) score. Competing risks regression was used to identify the independent impact of age on cancer-specific survival. We also analyzed the effect of local treatment on survival among older men with high-risk disease. Results In all, 26% of men age ≥ 75 years presented with high-risk disease (CAPRA score 6 to 10). Treatment varied markedly with age across risk strata; older men were more likely to receive androgen deprivation monotherapy. Controlling for treatment modality alone, or for treatment and risk, age did not independently predict cancer-specific survival. Furthermore, controlling for age, comorbidity, and risk, older men with high-risk tumors receiving local therapy had a 46% reduction in mortality compared with those treated conservatively. Conclusion Older patients are more likely to have high-risk prostate cancer at diagnosis and less likely to receive local therapy. Indeed, underuse of potentially curative local therapy among older men with high-risk disease may in part explain observed differences in cancer-specific survival across age strata. These findings support making decisions regarding treatment on the basis of disease risk and life expectancy rather than on chronologic age.

Which patients with localized prostate cancer account for the greatest proportion of prostate cancer deaths?

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 130-130 ◽  
Author(s):  
Michelle Nezolosky ◽  
Paul L. Nguyen ◽  
David Dewei Yang
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Disease Risk ◽  
Risk Group ◽  
Specific Antigen ◽  
Absolute Number ◽  
High Rate ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer

130 Background: We sought to determine which groups of patients, stratified by risk group and age, account for the greatest absolute number of deaths due to prostate cancer. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 437,150 men diagnosed with prostate cancer from 2004 to 2014. Men were excluded if they had N1 or M1 disease, risk group could not be determined, or if prostate cancer was not their first malignancy. Men were categorized as having low (Gleason ≤6, prostate-specific antigen [PSA] < 10 ng/mL, and cT1-T2a), intermediate (Gleason 7, PSA 10-20 ng/mL, or cT2b-T2c), or high risk disease (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4). We calculated the cumulative incidence of prostate cancer-specific mortality (PCSM). Results: Median follow-up was 4.8 years. The overall incidences of diagnosis of low, intermediate, and high risk disease were 29.7% (n = 129,925), 48.0% (n = 209,643), and 22.3% (n = 97,582), respectively. 5-year PCSM for men with low, intermediate, and high risk disease was 0.5%, 1.4%, and 9.4%, respectively, and the 10-year PCSM was 1.6%, 4.0%, and 16.8%. Within 10 years of diagnosis, 6.5% (n = 905) of patients who died of prostate cancer were low risk, 27.4% (n = 3,834) were intermediate risk, and 66.2% (n = 9,278) were high risk. In particular, patients age 70 or older accounted for 49.9% of all high risk prostate cancer diagnoses, but 65.3% of deaths due to high risk prostate cancer. Conclusions: While high risk disease accounted for only 22.3% of the diagnoses, it accounted for 66.2% of the prostate cancer deaths within 10 years of diagnosis. Therefore, high risk patients account for the vast majority of prostate cancer deaths and should remain the focus of the majority of our research efforts. In addition, older patients with high risk disease die of prostate cancer at a disproportionately high rate, which runs counter to the notion that the disease is less of a threat to survival in older men.

Genomic validation of three-tiered sub-classification of high-risk prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 17-17
Author(s):  
Vinayak Muralidhar ◽  
Jingbin Zhang ◽  
Daniel Eidelberg Spratt ◽  
Felix Y Feng ◽  
Elai Davicioni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Intermediate Risk ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Genomic Markers ◽  
Risk Prostate Cancer ◽  
Clinical Genomic ◽  
Very High

17 Background: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥ 8, or prostate-specific antigen [PSA] > 20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. Methods: We identified 3,220 patients with NCCN unfavorable intermediate-risk (n=2,000) or high-risk (n=1,220) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA > 20 ng/mL or cT1c, Gleason 4+4=8, PSA < 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score ≥ 8, or PSA > 20 ng/mL). We used a set of 37 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Results: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, 81.6% had a high-risk Decipher score, respectively (p < 0.001). Among 36 other genomic signatures, 33 had a similar increasing trend across the three sub-classes of high-risk (p < 0.05 after correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 5, 7, and 14 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.5%, 19.7%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score and would be re-classified as clinical-genomic high-risk. Conclusions: Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.

Variation in national use of long-term ADT by disease aggressiveness among men with unfavorable-risk prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 54-54
Author(s):  
Vinayak Muralidhar ◽  
Brandon Arvin Virgil Mahal ◽  
Gally Reznor ◽  
Toni K. Choueiri ◽  
Christopher Sweeney ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Intermediate Risk ◽  
Nccn Guidelines ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
High Risk Cancer ◽  
Very High

54 Background: Current National Comprehensive Cancer Network (NCCN) guidelines uniformly recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer. We sought to determine whether the use of long-term ADT varied by the subcategory of disease, including the recently-defined subcategories of high-risk disease (favorable, other, and very-high) versus intermediate-risk disease. Methods: We identified 5,836 patients with NCCN intermediate-, high-, or very high-risk prostate cancer diagnosed between 2004 and 2007 and managed with external beam radiation therapy (EBRT) using the Surveillance, Epidemiology, and End Results database linked to Medicare claims data. Patients were stratified by risk group: intermediate-risk, favorable high-risk (previously defined and validated as T1c, Gleason 4+4=8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL), other high-risk, or very high-risk. We used competing risks regression to estimate the rates of long-term (≥ 2 years) ADT in each of these groups. Differences were compared using multivariable regression modeling, adjusting for year of diagnosis, race, marital status, income level, age, and comorbidity. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive 2 years of ADT than others with high-risk disease (21.9% vs. 29.3%, adjusted hazard ratio [AHR] 0.78, 95% confidence interval [CI] 0.67-0.90, p = 0.001), and similarly likely as those with intermediate-risk disease (AHR 1.08, 95% CI 0.94-1.25, p = 0.288). Others with high-risk disease were less likely to receive 2 years of ADT than those with very high-risk cancer (29.3% vs 36.4%, AHR 0.84, 95% CI 0.74-0.96, p = 0.010). Conclusions: Patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Despite NCCN guidelines recommending long-term ADT for all high-risk or very high-risk prostate cancer, our results might reflect the view that these patients represent a heterogeneous group, with favorable high-risk cancer possibly warranting less aggressive therapy than other high-risk or very high-risk disease.

Management of high-risk prostate cancer with 5-treatment stereotactic body radiotherapy: Long-term results.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 94-94 ◽  
Author(s):  
Josephine Kang ◽  
Alan J. Katz
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Stereotactic Body Radiotherapy ◽  
Long Term Results ◽  
Intermediate Risk ◽  
Pelvic Radiation ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer

94 Background: Stereotactic Body Radiotherapy (SBRT) is an emerging treatment modality with excellent control rates for low- and intermediate-risk prostate cancer. The role of SBRT for high-risk disease, however, is less studied. The standard treatment (RT) for high-risk prostate cancer entails 8-9 weeks of daily RT with long-term androgen deprivation therapy (ADT). In comparison to this, SBRT is completed in 5 sessions, and offers convenience, low toxicity, and equivalent biochemical disease control rates as standard RT in the low- and intermediate-risk setting. We now present long-term results for SBRT in a cohort of patients with high-risk disease. Methods: We evaluated patients treated from 2006-2010 with SBRT alone (n = 52) to dose of 35-36.25 Gy in 5 fractions, or pelvic radiation to 45 Gy followed by SBRT boost of 19-21 Gy in 3 fractions (n = 46). Androgen deprivation therapy was administered to 55% of patients. Quality of life and bladder/bowel toxicity was assessed using the Expanded Prostate Index Composite (EPIC) and RTOG toxicity scale at regular time intervals. Results: Median followup was 84 months. 8-year biochemical disease-free survival (bDFS) was 61.3%. On univariate analyses,PSA was significant for bDFS (p = 0.001), whereas pelvic radiation (p = 0.97), T-stage (p = 0.79), ADT (p = 0.77), Gleason score (p = 0.78) were not. On multivariate analysis, only PSA remained significant (p = 0.003) for bDFS. Overall toxicity was mild, with 5.1% Grade 2 urinary, 3% Grade 3 urinary and 7.1% Grade 2 bowel toxicity. Use of pelvic radiotherapy was associated with significantly higher bowel toxicity (p = .001). EPIC bowel and bladder scores declined for the first six months and then returned towards baseline. Conclusions: Five-treatment SBRT appears to be a safe and effective treatment for high-risk prostate carcinoma now with median 84 month follow up. The addition of pelvic radiation or ADT does not confer any bDFS benefit with this modality. Our data suggests that SBRT alone may be the optimal approach. SBRT may be a good treatment alternative to discuss particularly for patients unable to undergo ADT or unwilling to receive standard 8-9 week RT. Prospective studies are required to corroborate our results.

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