A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy.
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ABSTRACT: Background
A pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and variation in pathology reporting may miss aggressive disease.Methods
The 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4.Results
Adjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67; p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26; p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630-0.660) within GG 3 + 3, but not GG 3 + 4.Conclusions
The 4Kscore can help guide the clinical decision whether additional risk assessment-such as confirmatory biopsy-is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.
SUBMITTER: Haese A
PROVIDER: S-EPMC7434907 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAccurate markers for prostate cancer (PC) risk stratification could aid decision-making for initial management strategies. The 4Kscore has an undefined role in predicting outcomes after radical prostatectomy (RP).MethodsWe included 1476 patients with 4Kscore measured prior to RP at two institutions. The 4Kscore was assessed for prediction of adverse pathology at RP and biochemical recurrence (BCR) relative to a clinical model. We pre-specified that all analyses would be assessed in biopsy Grade Group 1 (GG1) or 2 (GG2) PC patients, separately.ResultsThe 4Kscore increased discrimination for adverse pathology in all patients (delta area under the receiver operative curve (AUC) 0.009, 95% confidence interval (CI) 0.002, 0.016; clinical model AUC 0.767), driven by GG1 (delta AUC 0.040, 95% CI 0.006, 0.073) rather than GG2 patients (delta AUC 0.005, 95% CI -0.012, 0.021). Adding 4Kscore improved prediction of BCR in all patients (delta C-index 0.014, 95% CI 0.007, 0.021; preop-BCR nomogram C-index 0.738), again with larger changes in GG1 than in GG2.ConclusionsThis study validates prior investigations on the use of 4Kscore in men with biopsy-confirmed PC. Men with GG1 PC and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC.
| S-EPMC8980060 | biostudies-literature
Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChip® miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GS≥7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA ≥10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS ≥ 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers.
2013-05-09 | GSE46738 | GEO
Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChipM-BM-. miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GSM-bM-^IM-%7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA M-bM-^IM-%10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS M-bM-^IM-% 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers. Fifty-three patients underwent a radical prostatectomy performed by the same surgeon (MS) to treat localized PC between August 2000 and June 2002. The mean age was 65 years (SD: 7.5, range: 49 - 77). The mean Gleason score was 7 (SD: 1.1, range: 5 - 10); 15 tumors had a score of 5 or 6, and 38 had a score between 7 and 10. Twenty-four (45.3%) of the patients had pT2 tumors, and 29 (54.7%) had pT3 tumors. The control group consisted of three patients with lower urinary tract symptoms, a mean age of 55.3 years and a diagnosis of benign prostatic hyperplasia (BPH) who consented to open surgery.
2013-05-09 | E-GEOD-46738 | biostudies-arrayexpress
Project description:After radical prostatectomy (RP), biochemical recurrence (BCR) is associated with an increased risk of developing distant metastasis and prostate cancer specific and overall mortality. The two-centre study included 521 consecutive patients undergoing RP for positive pre-biopsy magnetic resonance imaging (MRI) and pathologically proven prostate cancer (PCa), after which a combination scheme of fusion-targeted biopsy (TB) and systematic biopsy was performed. We assessed correlations between MRI characteristics, International Society of Urological Pathology (ISUP) grade group in TB, and outcomes after RP. We developed an imaging-based risk classification for improving BCR prediction. Higher Prostate Imaging and Reporting and Data System (PI-RADS) score (p = 0.013), higher ISUP grade group in TB, and extracapsular extension (ECE) on the MRI were significantly associated with more advanced disease (pTstage), higher ISUP grade group (p = 0.001), regional lymph nodes metastasis in RP specimens (p < 0.001), and an increased risk of recurrence after surgery. A positive margin status was significantly associated with ECE-MRI (p < 0.001). Our imaging-based classification included ECE on MRI, ISUP grade group on TB, and PI-RADS accurately predicted BCR (AUC = 0.714, p < 0.001). This classification had more improved area under the curve (AUC) than the standard d'Amico classification in our population. Validation was performed in a two-centre cohort. In this cohort, PI-RADS score, MRI stage, and ISUP grade group in MRI-TB were significantly predictive for disease features and recurrence after RP. Imaging-based risk classification integrating these three factors competed with d'Amico classification for predicting BCR.
| S-EPMC7760513 | biostudies-literature
Project description:Accurate estimation of recurrence risk is needed for optimal treatment of clinically localized prostate cancer (PCa) patients. We combined classical clinicopathological predictors of biochemical recurrence (BCR) and molecular markers into a new risk score for predicting BCR after radical prostatectomy (RP). A retrospective study which included 122 PCa patients who attended our department between 2000 and 2007 was conducted. Total RNA was isolated from formalin-fixed paraffin embedded PCa tissue. Gene expression patterns were analyzed in 21 selected samples from 7 localized, 6 locally advanced, and 8 metastatic PCa patients using Illumina microarrays. Expression levels of 41 genes were validated by quantitative PCR in an independent retrospective series of 101 patients with ≥ 10 years follow-up who underwent RP for clinically localized PCa. Univariate and multivariate logistic regression analysis were used to identify individual predictors of BCR. A risk score (RS) for predicting BCR including clinicopathological and gene expression data was developed and Kaplan-Meier curves were generated. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin. In a median follow-up of 120 months (range 3-190), 37 patients developed BCR (36.6%). Expression levels of 7,930 transcripts differed between clinically localized and locally advanced-metastatic PCa groups (FDR<0.1). A set of 41 genes were validated by quantitative PCR. Regression analysis showed that expression of ASF1B and MCL1 as well as Gleason score, extracapsular extension, seminal vesicle invasion and positive margins were independent prognostic factors of BCR. A RS generated using these gene expression and clinicopathological variables was able to discriminate between two groups of patients with a significantly different probability of BCR (HR 6.24; CI 3.23-12.4, p<0.01), improving the individual discriminative performance of each of these variables on their own. Direct interactions between the two genes of the model were not found. In conclusion, identification of new gene expression patterns associated with a high probability of BCR in clinically localized PCa patients treated with RP, and their combination with clinicopathological variables in a robust, easy-to-use and reliable classifier may contribute to improve PCa risk stratification and, consequently, to tailor treatment and surveillance strategies in these patients.
2024-04-23 | GSE149226 | GEO
Project description:Positive surgical margins (PSM) after radical prostatectomy are associated with a greater risk of biochemical recurrence (BCR). However, not all PSM harbour the same prognosis for recurrence. We aim to determine the impact of different PSM characteristics and their coexistence on the risk of BCR. This retrospective study included 333 patients that underwent robotic-assisted radical prostatectomy for prostate cancer between 2015-2020 at a single institution. The effect of PSM and their adverse characteristics on the risk of BCR was assessed using Cox proportional hazard models. Kaplan-Meier was used to represent BCR-free survival stratified by margin status. With a median follow-up of 34.5 months, patients with PSM had a higher incidence of BCR, higher risk of relapse and lower BCR-free survival than negative margins (p < 0.001). We established as adverse characteristics: PSM length ≥ 3 mm, multifocality and Gleason at margin > 3. PSM ≥ 3 mm or multifocal PSM were associated with an increased risk for BCR compared to favourable margins (HR 3.50; 95% CI 2.05-5.95, p < 0.001 and HR 2.18; 95% CI 1.09-4.37, p = 0.028, respectively). The coexistence of these two adverse features in the PSM also conferred a higher risk for biochemical relapse and lower BCR-free survival. Adverse Gleason in the margin did not confer a higher risk for BCR than non-adverse margins in our models. We concluded that PSM are an independent predictor for BCR and that the presence of adverse characteristics, such as length and focality, and their coexistence in the PSM are associated with a greater risk of recurrence. Nevertheless, subclassifying PSM with adverse features did not enhance the model's predictive performance in our cohort.
| S-EPMC9405399 | biostudies-literature
Project description:The metabolic syndrome (MetS) comprises a constellation of risk factors associated with an increased risk for cardiovascular disease. Components of MetS have emerged as putative risk factors for prostate carcinoma. In this study, we examine the association between three features of the MetS (obesity, hypertension and diabetes) and the risk of biochemical recurrence (BCR) after radical prostatectomy (RP).We examined data from 1428 men in the University of Michigan Prostate Cancer Data Bank who elected to have RP as their primary treatment. We calculated body mass index from patients' weight and height measured at the time of prostate cancer diagnosis. We used the University of Michigan's Electronic Medical Record Search Engine to identify subjects with hypertension and/or diabetes before their prostate cancer diagnosis.Of 1428 men who underwent RP, 107 (8%) subsequently developed BCR with a median length of follow-up post-surgery of 3.6 years. Obesity and hypertension were each associated with an increased risk of BCR (adjusted hazard ratio (aHR) = 1.37; 95% CI 0.92-2.09 and aHR = 1.51, 95% CI 1.01-2.26), whereas no association was observed between diabetes and BCR (aHR = 0.73; 95% CI 0.40-1.33).Obesity and hypertension were each associated with an increased risk for BCR of prostate cancer after RP, independent of age at diagnosis and tumor pathological features. Given the increasing rates of obesity, hypertension and prostate cancer, a better understanding of the relationship between these entities is of significant public health importance. Elucidation of the involved pathogenic mechanisms will be needed to establish causality.
| S-EPMC3860174 | biostudies-literature
Project description:MicroRNA profiling was performed using multiplex qPCR on laser micro dissected material from 36 PC patients to identify microRNAs associated with recurrence after radical prostatectomy
2014-10-23 | GSE62610 | GEO
Project description:ImportanceStratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments.ObjectiveTo evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM.Design, setting, and participantsThis population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023.Main outcomes and measuresPrimary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria.ExposuresRadical prostatectomy or radiotherapy.ResultsA total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category.Conclusions and relevanceThese findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.
| S-EPMC10495864 | biostudies-literature
Project description:Purpose: Available tools for prostate cancer (PC) diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE~miR-452~miR-224 genomic locus. Experimental design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 non-malignant and 281 PC tissue samples. GABRE promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 non-malignant, 293 PC (radical prostatectomy (RP) cohort 1) and 198 PC tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE methylation was evaluated by ROC, Kaplan-Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of post-transfection transcriptional profiling data. Results: GABRE~miR-452~miR-224 was significantly downregulated in PC compared to non-malignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC=0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular motility. Finally, in uni- and multivariate analyses, high GABRE promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2. Conclusion: The GABRE~miR-452~miR-224 locus is downregulated and hypermethylated in PC and is a new promising epigenetic candidate biomarker for PC diagnosis and prognosis. Tumor suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two PC cell lines, suggesting that epigenetic silencing of GABRE~miR-452~miR-224 may be selected for in PC.
2013-12-11 | GSE51053 | GEO