Prostate Risk Assessment Postsurgical Score Research Articles

Association of Genomic Prostate Score at positive margin with recurrence after radical prostatectomy.

To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR). We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk. All patients underwent RP with or without adjuvant radiation therapy (ART). The statistical analysis employed Cox proportional hazards regression models for outcome of BCR weighted for case-cohort design. In univariable analysis, every 20-unit increase in the GPS was associated with a nearly threefold increase in risk of BCR (hazard ratio [HR] per 20 units 2.82, P < 0.001). In a multivariable Cox model adjusted for age, race, Cancer of the Prostate Risk Assessment Postsurgical score, Grade Group at the positive margin, and ART, the GPS was significantly associated with BCR (HR 1.56 per 20 units; 95% confidence interval 1.11-2.19; P = 0.011). The study is limited by its retrospective and single institution design. The GPS at the positive surgical margin could help stratify prognosis and inform clinical decision-making regarding adjuvant therapy after RP.

Transcriptomic Heterogeneity of Expansile Cribriform and Other Gleason Pattern 4 Prostate Cancer Subtypes

BackgroundProstate cancers featuring an expansile cribriform (EC) pattern are associated with worse clinical outcomes following radical prostatectomy (RP). However, studies of the genomic characteristics of Gleason pattern 4 subtypes are limited. ObjectiveTo explore transcriptomic characteristics and heterogeneity within Gleason pattern 4 subtypes (fused/poorly formed, glomeruloid, small cribriform, EC/intraductal carcinoma [IDC]) and the association with biochemical recurrence (BCR)-free survival. Design, setting, and participantsThis was a retrospective cohort study including 165 men with grade group 2–4 prostate cancer who underwent RP at a single academic institution (2016–2020) and Decipher testing of the RP specimen. Patients with Gleason pattern 5 were excluded. IDC and EC patterns were grouped. Median follow-up was 2.5 yr after RP for patients without BCR. Outcomes measurements and statistical analysisPrompted by heterogeneity within pattern 4 subtypes identified via exploratory analyses, we investigated transcriptomic consensus clusters using partitioning around medoids and hallmark gene set scores. The primary clinical outcome was BCR, defined as two consecutive prostate-specific antigen measurements >0.2 ng/ml at least 8 wk after RP, or any additional treatment. Multivariable Cox proportional-hazards models were used to determine factors associated with BCR-free survival. Results and limitationsIn this cohort, 99/165 patients (60%) had EC and 67 experienced BCR. Exploratory analyses and clustering demonstrated transcriptomic heterogeneity within each Gleason pattern 4 subtype. In the multivariable model controlled for pattern 4 subtype, margin status, Cancer of the Prostate Risk Assessment Post-Surgical score, and Decipher score, a newly identified steroid hormone–driven cluster (hazard ratio 2.35 95% confidence interval 1.01–5.47) was associated with worse BCR-free survival. The study is limited by intermediate follow-up, no validation cohort, and lack of accounting for intratumoral and intraprostatic heterogeneity. ConclusionsTranscriptomic heterogeneity was present within and across each Gleason pattern 4 subtype, demonstrating there is additional biologic diversity not captured by histologic subtypes. This heterogeneity can be used to develop novel signatures and to classify transcriptomic subtypes, which may help in refining risk stratification following RP to further guide decision-making on adjuvant and salvage treatments. Patient summaryWe studied prostatectomy specimens and found that tumors with similar microscopic appearance can have genetic differences that may help to predict outcomes after prostatectomy for prostate cancer. Our results demonstrate that further gene expression analysis of prostate cancer subtypes may improve risk stratification after prostatectomy. Future studies are needed to develop novel gene expression signatures and validate these findings in independent sets of patients.

Expression of miR-24-1-5p in Tumor Tissue Influences Prostate Cancer Recurrence: The PROCA-life Study.

Simple SummaryProstate cancer is a major cause of health loss and death worldwide, and better tools to assess risk levels in individual patients are needed. MicroRNAs (miRNAs) are small molecules with critical regulatory roles in cell functions and are also involved in prostate cancer development. The aim for this study was to investigate the role of miR-24-1-5p regarding prognosis in men diagnosed with prostate cancer and treated with radical prostatectomy. We collected prostate cancer tissue from 142 men already enrolled in a population-based cohort study who underwent prostatectomy. We examined the tissue expression of miR-24-1-5p in prostate cancer using in situ hybridization (ISH) and semi-quantitative scoring. We found that a high miR-24-1-5p expression was associated with a doubled risk of recurrence of prostate cancer.The role of miR-24-1-5p and its prognostic implications associated with prostate cancer are mainly unknown. In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), all men had a general health examination at study entry and were followed between 1994 and 2016. Patients with available tissue samples after a prostatectomy with curative intent were identified (n = 189). The tissue expression of miR-24-1-5p in prostate cancer was examined by in situ hybridization (ISH) in tissue microarray (TMA) blocks by semi-quantitative scoring by two independent investigators. Multivariable Cox regression models were used to study the associations between miR-24-1-5p expression and prostate cancer recurrence. The prostate cancer patients had a median age of 65.0 years (range 47–75 years). The Cancer of the Prostate Risk Assessment Postsurgical Score, International Society of Urological Pathology grade group, and European Association of Urology Risk group were all significant prognostic factors for five-year recurrence-free survival (p < 0.001). Prostate cancer patients with a high miR-24-1-5p expression (≥1.57) in the tissue had a doubled risk of recurrence compared to patients with low expression (HR 1.99, 95% CI 1.13–3.51). Our study suggests that a high expression of miR-24-1-5p is associated with an increased risk of recurrence of prostate cancer after radical prostatectomy, which points to the potential diagnostic and therapeutic value of detecting miR-24-1-5p in prostate cancer cases.

The Natural History of Untreated Biopsy Grade Group Progression and Delayed Definitive Treatment for Men on Active Surveillance for Early-Stage Prostate Cancer.

For men with clinically localized prostate cancer outcomes of continuing active surveillance (AS) after biopsy progression are not well understood. We aim to determine the impact of continuing AS and delayed definitive treatment after biopsy progression on oncologic outcomes. Participants in our prospective AS cohort (1990-2018) diagnosed with grade group (GG) 1, localized prostate cancer, with prostate specific antigen <20 who were subsequently upgraded to ≥GG2, and underwent further surveillance (biopsy/imaging/prostate specific antigen) were identified. Patients were stratified by post-progression followup into 3 groups: continue AS untreated, pursue early radical prostatectomy (RP) ≤6 months, or undergo late RP within 6 months to 5 years of progression. Patients receiving other treatments were excluded. We compared characteristics between groups and examined the associations of early vs late RP with risk of adverse pathology (AP) at RP and recurrence-free survival (RFS) after RP. Of 531 patients with biopsy progression and further surveillance 214 (40%) remained untreated, 192 (36%) pursued early RP and 125 (24%) underwent late RP. Among patients who underwent early vs late RP, there was no difference in GG (p=0.15) or AP (55% vs 53%, p=0.74) rate at RP, or 3-year RFS (80% vs 87%, log-rank p=0.64) after RP. In multivariable models, only Cancer of Prostate Risk Assessment post-surgical score was associated with risk of RFS (HR=1.42 per point, 95% CI 1.24-1.64). Among patients continuing AS after biopsy progression, 60% underwent surgery within 5 years. Delayed surgery after progression was not associated with higher risk of AP or RFS. This suggests select patients may be able to safely delay treatment after progression.

Cell-cycle risk score more accurately determines the risk for metastases and death in prostatectomy patients compared with clinical features alone.

BackgroundProstate cancer treatment aims to prevent metastases and disease‐specific mortality. Pathologic parameters have limited ability to predict these outcomes, but biomarkers can improve risk discrimination. We evaluated the ability of cell‐cycle progression and combined cell‐cycle risk scores to predict metastases and disease‐specific mortality after prostatectomy.MethodsEligibility included (1) treatment with radical prostatectomy (1985–1997); (2) cell‐cycle progression score; (3) preoperative prostate‐specific antigen; (4) no neoadjuvant therapy; and (5) clinical follow‐up (N = 360). Cancer of the prostate risk assessment postsurgical score was combined with cell cycle progression into the prespecified combined cell‐cycle risk score. Hazard ratios (HRs) are reported per unit score.ResultsIn total, 11% (41/360) developed metastases and 9% (33/360) experienced disease‐specific mortality. Combined cell‐cycle risk score predicted metastases and disease‐specific mortality post‐radical prostatectomy (p < 1 × 10−8). Adjusting for cancer of the prostate risk assessment postsurgical score, the combined cell‐cycle risk score remained a predictor of metastases (HR = 3.03 [95% confidence interval (CI): 1.49, 6.20]; p = .003] and disease‐specific mortality (HR = 3.40 [95% CI: 1.52, 7.59]; p = .004). Of patients with biochemical recurrence, 25% (41/163) developed metastases. Cancer of the prostate risk assessment postsurgical score was predictive of metastases postbiochemical recurrence but was improved by the addition of cell cycle progression (HR = 1.70 [95% CI: 1.14, 2.53]; p = .012). The combined cell‐cycle risk was also prognostic of metastases post‐biochemical recurrence (HR = 1.56 [95% CI: 1.20, 2.03]; p = .001).ConclusionCombined cell‐cycle risk and cell cycle progression scores predict metastases and disease‐specific mortality post‐radical prostatectomy and should help identify patients at greatest risk of treatment failure who might benefit from earlier intervention.

Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy

BackgroundProstate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. ObjectiveTo evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. Design, setting, and participantsA multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml. Outcome measurements and statisitical analysisCumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. Results and limitationsThe median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. ConclusionsDespite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Patient summaryDecipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

BackgroundThe clinical metrics used to date to assess the progression risk of newly diagnosed prostate cancer patients only partly represent the true biological aggressiveness of the underlying disease. ObjectiveValidation of the prognostic biomarker phosphodiesterase-4D7 (PDE4D7) in predicting longitudinal biological outcomes in a historical surgery cohort to improve postsurgical risk stratification. Design, patients, and methodsRNA was extracted from biopsy punches of resected tumors from 550 patients. PDE4D7 was quantified using one-step quantitative reverse transcription-polymerase chain reaction. PDE4D7 scores were calculated by normalization of PDE4D7 to reference genes. Multivariate analyses were adjusted for clinical prognostic variables. Outcomes tested were: prostate-specific antigen relapse, start of salvage treatment, progression to metastases, overall mortality, and prostate cancer-specific mortality. The PDE4D7 score was combined with the clinical risk model Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) using multivariate regression modeling; the combined score was tested in post-treatment progression free survival prediction. Outcome measurements and statistical analysisCorrelations with outcomes were analyzed using multivariate Cox regression and logistic regression statistics. Results and limitationsThe PDE4D7 score was significantly associated with time-to-prostate specific antigen failure after prostatectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.41–0.67 for each unit increase, p<0.0001). After adjustment for postsurgical prognostic variables the HR was 0.56 (95% CI: 0.43–0.73, p<0.0001). The PDE4D7 score remained significant after adjusting the multi-variate analysis for the CAPRA-S model categories (HR=0.54, 95% CI=0.42–0.69, p<0.0001). Combination of the PDE4D7 score with the CAPRA-S demonstrated a significant incremental value of 4–6% in 2-yr (p=0.004) or 5-yr (p=0.003) prediction of progression free survival after surgery. The combined model of PDE4D7 and CAPRA-S improves patient selection with very high risk of fast disease relapse after primary intervention. ConclusionsThe PDE4D7 score has the potential to provide independent risk information and to restratify patients with clinical intermediate- to high-risk characteristics to a very low-risk profile. Patient summaryIn this report, we studied the potential of a novel biomarker to predict outcomes of a cohort of prostate cancer patients who underwent surgery more than 10 yr ago. We found that a gene called phosphodiesterase-4D7 added extra information to the available clinical data. We conclude that the measurement of this gene in tumor tissue may contribute to more effective treatment decisions.

Validation of a Genomic Risk Classifier to Predict Prostate Cancer-specific Mortality in Men with Adverse Pathologic Features

BackgroundRisk of prostate cancer-specific mortality (PCSM) is highly variable for men with adverse pathologic features at radical prostatectomy (RP); a majority will die of other causes. Accurately stratifying PCSM risk can improve therapy decisions. ObjectiveValidate the 22 gene Decipher genomic classifier (GC) to predict PCSM in men with adverse pathologic features after RP. Design, setting, and participantsMen with adverse pathologic features: pT3, pN1, positive margins, or Gleason score >7 who underwent RP in 1987–2010 at Johns Hopkins, Cleveland Clinic, Mayo Clinic, and Durham Veteran's Affairs Hospital. We also analyzed subgroups at high risk (prostate-specific antigen >20 ng/ml, RP Gleason score 8–10, or stage >pT3b), or very high risk of PCSM (biochemical recurrence in<2 yr [BCR2], or men who developed metastasis after RP [MET]). Outcome measurements and statistical analysisLogistic regression evaluated the association of GC with PCSM within 10 yr of RP (PCSM10), adjusted for the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S). GC performance was evaluated with area under the receiver operating characteristic curve (AUC) and decision curves. Results and limitationsFive hundred and sixty-one men (112 with PCSM10), median follow-up 13.0 yr (patients without PCSM10). For high GC score (> 0.6) versus low-intermediate (≤ 0.6), the odds ratio for PCSM10 adjusted for CAPRA-S was 3.91 (95% confidence interval: 2.43–6.29), with AUC=0.77, an increase of 0.04 compared with CAPRA-S. Subgroup odds ratios were 3.96, 3.06, and 1.95 for high risk, BCR2, or MET, respectively (all p<0.05), with AUCs 0.64–0.72. GC stratified cumulative PCSM10 incidence from 2.8% to 30%. Combined use of case-control and cohort data is a potential limitation. ConclusionsIn a large cohort with the longest follow-up to date, Decipher GC demonstrated clinically important prediction of PCSM at 10 yr, independent of CAPRA-S, in men with adverse pathologic features, BCR2, or MET after RP. Patient summaryDecipher genomic classifier may improve treatment decision-making for men with adverse or high risk pathology after radical prostatectomy.

CAPRA-S predicts outcome for adjuvant and salvage external beam radiotherapy after radical prostatectomy.

We aimed to evaluate the predictive value of the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) for patients treated with radical prostatectomy followed by subsequent external beam radiotherapy (EBRT). A total of 373 patients treated with EBRT between January 2000 and June 2015 were identified in the institutional database. Followup and complete CAPRA-S score were available for 334 (89.5%) patients. CAPRA-S scores were sorted into previously defined categories of low- (score 0-2), intermediate- (3-5), and high-risk (6-12). Time to biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) >0.20 ng/mL after EBRT. Survival analyses were performed using the Kaplan-Meier method and comparisons were made using the log-rank test. Overall median time from surgery to EBRT was 18 months (interquartile range [IQR] 8-36) and median followup since EBRT was 48 months (IQR 28-78). CAPRA-S predicted time to BCR (<0.001), time to palliative androgen-deprivation therapy (ADT) (p=0.017), and a trend for significantly predicting overall survival (OS, p=0.058). On multivariate analysis, the CAPRA-S was predictive of time to BCR only (low-risk vs. intermediate-risk; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.043-0.48, p=0.001). The last PSA measurement before EBRT as a continuous and grouped variable proved highly significant in predicting all outcomes tested, including OS (p≤0.002). CAPRA-S predicts time to BCR and freedom from palliative ADT, and is borderline significant for OS. Together with the PSA before EBRT, CAPRA-S is a useful, predictive tool. The main limitation of this study is its retrospective design.

External Validation of the Cancer of the Prostate Risk Assessment Postsurgical Score for Prediction of Disease Recurrence after Radical Prostatectomy.

Objective. The cancer of the prostate risk assessment (CAPRA-S) postsurgical score predicts recurrence, metastasis, and cancer-specific survival after radical prostatectomy (RP). We evaluated the relation between CAPRA-S score and biochemical recurrence (BCR) in prostate cancer after RP in our clinic. Materials and Methods. This study was performed on 203 patients with prostate carcinoma who underwent open RP and regional lymph node dissection in our clinic between 2008 and 2013. We calculated the CAPRA-S scores including prostate-specific antigen (PSA) at diagnosis, pathology Gleason score, surgical margin, seminal vesicle invasion, extracapsular extension, and lymph node involvement. The patients were divided into 3 risk groups (low, intermediate, and high risk) according to risk scores. Results. Recurrence occurred in 17.8% of the patients (36 patients out of 203 patients) with a median of 11.7-month follow-up. The average recurrence-free survival time is 44.6 months. Surgical margin invasion and seminal vesicle invasion significantly correlated with BCR especially in high risk group (11 and 13 of 15 patients, p < 0.05, resp.). Conclusion. CAPRA-S score can be easily calculated and it is useful in clinical practice in order to timely propose adjuvant therapies after surgery.

Pathological features of localized prostate cancer in China: a contemporary analysis of radical prostatectomy specimens.

There has been a rapid increase in the incidence of prostate cancer in China, especially in areas with boosted economic development. In this study, we analyzed the pathological features of a contemporary series of radical prostatectomy cases. A total of 230 consecutive, whole-mounted radical prostatectomy specimens collected from 2012 to 2014 were reviewed. The median age of the patients was 68 years, and 64.3% of patients presented with prostate specific antigen alone. Pathological examination indicated that a high proportion (77.4%) of patients had intermediate- or high-risk disease according to the Cancer of the Prostate Risk Assessment Post-Surgical score. After surgery, only 28 patients met the criteria for active surveillance (organ-confined Gleason ≥6 disease). The Prostate Cancer Research International Active Surveillance criteria achieved a sensitivity of 57.1% and a specificity of 98.0% for identifying candidates. The probability of Gleason score upgrading was 24.8% in the entire group and 59.0% in biopsy-confirmed Gleason ≥6 disease. The predominant tumor was located in the transition zone in 14.8% of cases, while only three patients (1.3%) had a predominant tumor located in the anterior region. Patients with transition zone-predominant tumor were likely to have been referred with urinary symptoms and high prostate specific antigen levels. The results of this study highlight the contemporary pathological features of localized prostate cancer in urban China. There was an increased trend towards asymptomatic cases, though most patients had intermediate- or high-risk disease and were suitable for definitive treatment. The low prevalence of dominant cancer in the anterior region may reflect race-based pathological differences.

Understanding the Relationship Between Tumor Size, Gland Size, and Disease Aggressiveness in Men With Prostate Cancer

To determine the relationship between prostate gland and tumor volume in men undergoing radical prostatectomy (RP) for prostate cancer. We hypothesized that larger tumors within smaller prostate glands are associated with more aggressive disease characteristics. Records of patients undergoing RP from 2000-2008 at a single institution were reviewed retrospectively. The dominant nodule was considered to be the largest focus of cancer within the prostate, and the dominant nodule-to-prostate volume ratio (DNVR) was calculated according to the ratio of the dominant nodule volume to the gland weight. Cox regression was performed to assess the relationship between DNVR and both pathologic outcomes (Cancer of the Prostate Risk Assessment post-Surgical score) and biochemical recurrence (BCR). At a median follow-up of 3.7years, 174 patients (7.2%) suffered BCR. There was no linear correlation between tumor volume and gland size (R=-0.09). DNVR above the median (≥0.033cc/gm) was closely associated with high clinicopathologic risk as measured by Cancer of the Prostate Risk Assessment post-Surgical score (hazard ratio, 35.53; 95% confidence interval, 14.42-87.55 for high- vs low-risk groups). In the univariable analysis, both tumor diameter and DNVR were associated withincreased risk of BCR. However, in the multivariable model, only tumor diameter remained a significant predictor of BCR (hazard ratio, 2.02; 95% confidence interval, 1.04-3.91). Increased DNVR appears to be a characteristic of aggressive prostate tumors, although it did not predict BCR in the present study. However, these data support the association between tumor diameter and BCR after RP for prostate cancer independent of other key clinicopathologic features.

The 6-item CAPRA-S score predicted cancer recurrence after radical prostatectomy

Source Citation Punnen S, Freedland SJ, Presti JC Jr, et al. Multi-institutional validation of the CAPRA-S score to predict disease recurrence and mortality after radical prostatectomy. Eur Urol. 2013;S0302-2838:00352-7. 23587869