Cancer Of The Prostate Risk Assessment Post-Surgical Research Articles

'High proliferative cribriform prostate cancer' defines a patient subgroup with an inferior prognosis.

A cribriform pattern, reactive stroma (RS), PTEN, Ki67 and ERG are promising prognostic biomarkers in primary prostate cancer (PCa). We aim to determine the relative contribution of these factors and the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score in predicting PCa prognosis. We included 475 patients who underwent radical prostatectomy (2010-12, median follow-up = 8.7 years). Cribriform pattern was identified in 57% of patients, PTEN loss in 55%, ERG expression in 51%, RS in 39% and high Ki67 in 9%. In patients with multiple samples from the same malignant focus and either PTEN loss or high Ki67, intrafocal heterogeneity for PTEN and Ki67 expression was detected in 55% and 89%, respectively. In patients with samples from two or more foci, interfocal heterogeneity was detected in 46% for PTEN and 6% for Ki67. A cribriform pattern and Ki67 were independent predictors of biochemical recurrence (BCR) and clinical recurrence (CR), whereas ERG expression was an independent predictor of CR. Besides CAPRA-S, a cribriform pattern provided the highest relative proportion of explained variation for predicting BCR (11%), and Ki67 provided the highest relative proportion of explained variation for CR (21%). In patients with a cribriform pattern, high Ki67 was associated with a higher risk of BCR [hazard ratio (HR) = 2.83, P < 0.001] and CR (HR = 4.35, P < 0.001). High Ki67 in patients with a cribriform pattern identifies a patient subgroup with particularly poor prognosis, which we termed 'high proliferative cribriform prostate cancer'. These results support reporting a cribriform pattern in pathology reports, and advocate implementing Ki67.

Novel nomogram to predict biochemical recurrence-free survival after radical prostatectomy.

Conditional survival represents the probability of subsequent survival given that patients have already survived a certain length of time. Several models predict biochemical recurrence (BCR) after radical prostatectomy. However, none of them include postoperative prostate-specific antigen (PSA). We aimed to analyze BCR-free survival evolution over time and develop a nomogram incorporating the postoperative PSA value to predict BCR-free survival. We included patients treated with robot-assisted radical prostatectomy (RARP) for prostate cancer between 2009 and 2021 and calculated conditional survival. Cox proportional hazard regression analysis was used to assess the predictive variables of BCR. We developed a nomogram predicting BCR-free survival three and five years after RARP. We used c-index and decision curve analyses to compare the nomogram with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score. We included 718 patients. The overall 3- and 5-year BCR-free survival rates were 85.1% and 75.7%, respectively. The 5-year BCR-free survival rates increased to 78.9%, 82.9%, 85.2%, and 84.7% for patients surviving 1, 2, 3, and 4years without BCR, respectively. We developed a nomogram including the pathological Gleason score and T stage, positive surgical margin, PSA ≥ 0.05ng/mL at one year, and lymph node involvement to predict BCR at 3 and 5years postoperatively. Our nomogram presented a higher c-index (0.89) than the CAPRA-S score (0.78; p = 0.001) and a positive net benefit at 3 and 5years postoperatively in the decision curve analyses. The 5-year conditional BCR-free survival increased with survival without BCR. The developed nomogram significantly improved the accuracy in predicting BCR-free survival after RARP.

Presence of cells in the polyaneuploid cancer cell (PACC) state predicts the risk of recurrence in prostate cancer.

The nonproliferating polyaneuploid cancer cell (PACC) state is associated with therapeutic resistance in cancer. A subset of cancer cells enters the PACC state by polyploidization and acts as cancer stem cells by undergoing depolyploidization and repopulating the tumor cell population after the therapeutic stress is relieved. Our aim was to systematically assess the presence and importance of this entity in men who underwent radical prostatectomy with curative intent to treat their presumed localized prostate cancer (PCa). Men with National Comprehensive Cancer Network intermediate- or high-risk PCa who underwent radical prostatectomy l from 2007 to 2015 and who did not receive neoadjuvant treatment were included. From the cohort of 2159 patients, the analysis focused on a subcohort of 209 patientsand 38 cases. Prostate tissue microarrays (TMAs) were prepared from formalin-fixed, paraffin-embedded blocks of the radical prostatectomy specimens. A total of 2807 tissue samples of matched normal/benign and cancer were arrayed in nineTMA blocks. The presence of PACCs and the number of PACCs on each core were noted. The total number of cells in the PACC state and the total number of cores with PACCs were significantly correlated with increasing Gleason score (p = 0.0004) and increasing Cancer of the Prostate Risk Assessment Postsurgical(CAPRA-S) (p = 0.004), but no other variables. In univariate proportional hazards models of metastasis-free survival, year of surgery, Gleason score (9-10 vs. 7-8), pathology stage, CAPRA-S, total PACCs, and cores positive for PACCs were all statistically significant. The multivariable models with PACCs that gave the best fit included CAPRA-S. Adding either total PACCs or cores positive for PACCs to CAPRA-S both significantly improved model fit compared to CAPRA-S alone. Our findings show that the number of PACCs and the number of cores positive for PACCs are statistically significant prognostic factors for metastasis-free survival, after adjusting for CAPRA-S, in a case-cohort of intermediate- or high-risk men who underwent radical prostatectomy. In addition, despite the small number of men with complete data to evaluate time to metastatic castration-resistant PCa (mCRPC), the total number of PACCs was a statistically significant predictor of mCRPC in univariate analysisand suggested a prognostic effect even after adjusting for CAPRA-S.

A novel nomogram provides improved accuracy for predicting biochemical recurrence after radical prostatectomy.

Background:Various prediction tools have been developed to predict biochemical recurrence (BCR) after radical prostatectomy (RP); however, few of the previous prediction tools used serum prostate-specific antigen (PSA) nadir after RP and maximum tumor diameter (MTD) at the same time. In this study, a nomogram incorporating MTD and PSA nadir was developed to predict BCR-free survival (BCRFS).Methods:A total of 337 patients who underwent RP between January 2010 and March 2017 were retrospectively enrolled in this study. The maximum diameter of the index lesion was measured on magnetic resonance imaging (MRI). Cox regression analysis was performed to evaluate independent predictors of BCR. A nomogram was subsequently developed for the prediction of BCRFS at 3 and 5 years after RP. Time-dependent receiver operating characteristic (ROC) curve and decision curve analyses were performed to identify the advantage of the new nomogram in comparison with the cancer of the prostate risk assessment post-surgical (CAPRA-S) score.Results:A novel nomogram was developed to predict BCR by including PSA nadir, MTD, Gleason score, surgical margin (SM), and seminal vesicle invasion (SVI), considering these variables were significantly associated with BCR in both univariate and multivariate analyses (P < 0.05). In addition, a basic model including Gleason score, SM, and SVI was developed and used as a control to assess the incremental predictive power of the new model. The concordance index of our model was slightly higher than CAPRA-S model (0.76 vs. 0.70, P = 0.02) and it was significantly higher than that of the basic model (0.76 vs. 0.66, P = 0.001). Time-dependent ROC curve and decision curve analyses also demonstrated the advantages of the new nomogram.Conclusions:PSA nadir after RP and MTD based on MRI before surgery are independent predictors of BCR. By incorporating PSA nadir and MTD into the conventional predictive model, our newly developed nomogram significantly improved the accuracy in predicting BCRFS after RP.

Validation of the four-miRNA biomarker panel MiCaP for prediction of long-term prostate cancer outcome

Improved prostate cancer prognostic biomarkers are urgently needed. We previously identified the four-miRNA prognostic biomarker panel MiCaP ((miR-23a-3p × miR-10b-5p)/(miR-133a-3p × miR-374b-5p)) for prediction of biochemical recurrence (BCR) after radical prostatectomy (RP). Here, we identified an optimal numerical cut-off for MiCaP dichotomisation using a training cohort of 475 RP patients and tested this in an independent cohort of 281 RP patients (PCA281). Kaplan–Meier, uni- and multivariate Cox regression analyses were conducted for multiple endpoints: BCR, metastatic-(mPC) and castration-resistant prostate cancer (CRPC), prostate cancer-specific (PCSS) and overall survival (OS). Functional effects of the four MiCaP miRNAs were assessed by overexpression and inhibition experiments in prostate cancer cell lines. We found the numerical value 5.709 optimal for MiCaP dichotomisation. This was independently validated in PCA281, where a high MiCaP score significantly [and independent of the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score] predicted BCR, progression to mPC and CRPC, and PCSS, but not OS. Harrell’s C-index increased upon addition of MiCaP to CAPRA-S for all endpoints. Inhibition of miR-23a-3p and miR-10b-5p, and overexpression of miR-133a-3p and miR-374b-5p significantly reduced cell survival. Our results may promote future implementation of a MiCaP-based test for improved prostate cancer risk stratification.

Ability of cell-cycle progression score to predict risk for progression to metastatic disease and disease-specific mortality in prostate cancer patients after prostatectomy.

5524 Background: Prostate cancer treatment aims to prevent metastatic disease (METS) and disease-specific mortality (DSM). A major challenge is to identify those at highest risk so additional intervention can be initiated earlier when it has a better chance of success. Pathologic parameters alone have limited ability to predict METS and DSM, but data suggests biomarkers can improve risk discrimination. Methods: Eligible patients had: (1) prostate cancer treated with radical prostatectomy (RP; 1988-1995); (2) available tissue for cell-cycle progression (CCP) testing that resulted in a valid score; (3) preoperative prostate-specific antigen (PSA); (4) no neoadjuvant therapy; and (5) clinical follow-up (N = 360). Cancer of the prostate risk assessment post-surgical (CAPRA-S) was combined with CCP into a combined cell-cycle risk score (CCR = 0.38 × CAPRA-S + 0.57 × CCP). Results: Median follow-up was 23.5 years for patients alive at last follow-up. Overall, 11% (41/360) developed METS and 9% (33/360) had DSM. CCP score added significant information to CAPRA-S when predicting METS (p = 0.001) and DSM (p = 0.001). CCR score was also a significant predictor of METS and DSM (p-values &lt; 1×10−8). CCP and CCR scores were prognostic of METS in patients with rising post-RP PSA. Of patients with biochemical recurrence (BCR), 25% (41/163) developed METS. CAPRA-S alone was predictive of these events (p = 0.01) but was significantly improved with the addition of CCP (Hazard Ratio [HR] = 1.69 [95% Confidence Interval (CI) 1.13, 2.52], p = 0.014). CCR was also highly prognostic (HR = 1.56 [95% CI 1.20, 2.03], p = 0.001). CCR score discriminated risk of METS both post-RP and after post-RP BCR (Table). Conclusions: Overall, the CCR score significantly predicted METS and DSM in prostate cancer post-RP and was also highly prognostic in those with a post-RP rising PSA. It is therefore a useful tool for determining who is at greatest risk of treatment failure and may benefit from earlier intervention. [Table: see text]

Prognostic value of mitotic checkpoint protein BUB3, cyclin B1, and pituitary tumor-transforming 1 expression in prostate cancer

The mitotic checkpoint protein BUB3, cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1) regulates cell division, and are sparsely studied in prostate cancer. Deregulation of these genes can lead to genomic instability, a characteristic of more aggressive tumors. We aimed to determine the expression levels of BUB3, CCNB1, and PTTG1 as potential prognostic markers of recurrence after radical prostatectomy. Protein levels were determined by immunohistochemistry on three formalin-fixed paraffin-embedded tissue sections from each of the 253 patients treated with radical prostatectomy. Immunohistochemistry scores were obtained by automated image analysis for CCNB1 and PTTG1. Recurrence, defined as locoregional recurrence, distant metastasis or death from prostate cancer, was used as endpoint for survival analysis. Tumors having both positive and negative tumor areas for cytoplasmic BUB3 (30%), CCNB1 (28%), or PTTG1 (35%) were considered heterogeneous. Patients with ≥1 positive tumor area had significantly increased risk of disease recurrence in univariable analysis compared with patients where all tumor areas were negative for cytoplasmic BUB3 (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.41–3.36), CCNB1 (HR = 2.98, 95% CI 1.93–4.61) and PTTG1 (HR = 1.91, 95% CI 1.23–2.97). Combining the scores of cytoplasmic BUB3 and CCNB1 improved risk stratification when integrated with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score (difference in concordance index = 0.024, 95% CI 0.001–0.05). In analysis of multiple tumor areas, prognostic value was observed for cytoplasmic BUB3, CCNB1, and PTTG1.

Cell cycle progression score improves risk stratification in prostate cancer patients with adverse pathology after radical prostatectomy.

To assess the use of the cell cycle progression (CCP) score versus actual risk stratification practice in making treatment decisions for prostate cancer patients with locally adverse pathology after radical prostatectomy (RP). Men with adverse pathologic features, pT3 or positive surgical margins who underwent RP in 2010-2014 at Renji hospital were retrospectively analyzed. The primary outcome was biochemical recurrence (BCR) after RP. RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. The prognostic utility of the CCP score was assessed using Kaplan-Meier analysis and multivariable Cox proportional hazards model. Among the 100 men identified, 5-year BCR-free survival for the low- (< 0), intermediate- (0-1) and high- (> 1) CCP score groups was 89.3%, 38.8%, and 12.9%, respectively. In multivariable models adjusting for clinical and pathological variables with the cancer of the prostate risk assessment post-surgical (CAPRA-S) score, both continuous CCP score [hazard ratio (HR) 1.373 per unit score, 95% confidence interval (CI) 1.006-1.874; p = 0.046) and the categorized CCP score (p < 0.001)were independent predictors of BCR. The present study provides insights into the role the CCP score plays in risk stratification of this cohort and in determining candidacy for deferred secondary treatment. From our perspective, the CCP score allows better stratification and can help identifying patients at lower risk of disease recurrence who could benefit from a wait-and-see policy.

The impact of birth parameters on pre-eclampsia in adulthood among women in a Swedish Birth Cohort

We aimed to validate GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate) as a novel copy number signature predictive of prostate cancer recurrence.We randomly selected patients who underwent radical prostatectomy at Cleveland Clinic or University of Rochester from 2000 to 2005. DNA isolated from the cancer region was extracted and subjected to high resolution array comparative genomic hybridization. A high GEMCaP score was defined as 20% or greater of genomic loci showing copy number gain or loss in a given tumor. Cox regression was used to evaluate associations between the GEMCaP score and the risk of biochemical recurrence.We report results in 140 patients. Overall 38% of patients experienced recurrence with a median time to recurrence of 45 months. Based on the CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score 39% of the patients were at low risk, 42% were at intermediate risk and 19% were at high risk. The GEMCaP score was high (20% or greater) in 31% of the cohort. A high GEMCaP score was associated with a higher risk of biochemical recurrence (HR 2.69, 95% CI 1.51–4.77) and it remained associated after adjusting for CAPRA-S score and age (HR 1.94, 95% CI 1.06–3.56). The C-index of GEMCaP alone was 0.64, which improved when combined with the CAPRA-S score and patient age (C-index = 0.75).A high GEMCaP score was associated with biochemical recurrence in 2 external cohorts. This remained true after adjusting for clinical and pathological factors. The GEMCaP biomarker could be an efficient and effective clinical risk assessment tool to identify patients with prostate cancer for early adjuvant therapy.

Elevated miR-615-3p Expression Predicts Adverse Clinical Outcome and Promotes Proliferation and Migration of Prostate Cancer Cells

miR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P<0.05, log-rank test). In addition, high miR-615-3p expression was a significant predictor of PC-specific survival in univariate (hazard ratio, 3.75; P<0.001) and multivariate (hazard ratio, 2.66; P=0.008) analysis after adjustment for the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) nomogram in a merged RP cohort (n = 734). Moreover, overexpression of miR-615-3p in PC cells (PC3M) significantly increased cell viability, proliferation, apoptosis, and migration. Together, our results suggest that miR-615-3p is a significant predictor of postoperative BCR and PC-specific survival and has oncogenic functions in PC cells.

Accuracy of CAPRA-S Score for Predicting Long-Term Biochemical Progression After Radical Prostatectomy.

The Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score is a tool to stratify patients into groups according to their risk for biochemical recurrence after radical prostatectomy. The aim of this study was to assess the accuracy of the CAPRA-S score for predicting biochemical progression at 5 and 10 years in our cohort of patients after radical prostatectomy. Between June 2004 and December 2015, radical prostatectomy was performed as the main treatment option for patients with localized prostate cancer. Patients who had received adjuvant or neoadjuvant treatment were excluded from this study. Biochemical progression after radical prostatectomy was considered in patients by prostate-specific antigen (PSA) > 0.1 ng/mL after surgery (biochemical persistence) and by at least 2 determinations of PSA > 0.2 ng/mL in those patients with initial undetectable postoperative PSA any time during their follow-up (biochemical failure). Cox proportional hazard model and Kaplan-Meier analysis were used for the statistical analysis. Of 531 patients who underwent radical prostatectomy, 479 met the inclusion criteria. Mean follow-up was 85 months (min-max, 13-153 months). The rate of biochemical progression-free survival at 10 years was 84.2%, 55.1%, and 32.8%, respectively, for high-, intermediate-, and low-risk patients according to the CAPRA-S score. The concordance index for CAPRA-S predicting biochemical progression at 5 years was 0.71 and at 10 years was 0.70. The CAPRA-S score is a useful and easy-to-use tool in patients after radical prostatectomy to classify their risk for biochemical progression, thus helping decide if adjuvant treatment should be required.

Tristetraprolin Is a Prognostic Biomarker for Poor Outcomes among Patients with Low-Grade Prostate Cancer.

Background: We studied the utility of the tumor suppressor Tristetraprolin (TTP, ZFP36) as a clinically relevant biomarker of aggressive disease in prostate cancer patients after radical prostatectomy (RP).Methods: TTP RNA expression was measured in an RP cohort of patients treated at Moffitt Cancer Center (MCC) and obtained from six publically available RP datasets with biochemical recurrence (BCR; total n = 1,394) and/or metastatic outcome data (total n = 1,222). TTP protein expression was measured by immunohistochemistry in a tissue microarray of 153 MCC RP samples. The time to BCR or metastasis based on TTP RNA or protein levels was calculated using the Kaplan-Meier analysis. Univariable and multivariable Cox proportional hazard models were performed on multiple cohorts to evaluate if TTP is a clinically relevant biomarker and to assess if TTP improves upon the Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score for predicting clinical outcomes.Results: In all of the RP patient cohorts, prostate cancer with low TTP RNA or protein levels had decreased time to BCR or metastasis versus TTP-high tumors. Further, the decreased time to BCR in TTP-low prostate cancer was more pronounced in low-grade tumors. Finally, pooled survival analysis suggests that TTP RNA expression provides independent information beyond CAPRA-S to predict BCR.Conclusions: TTP is a promising prostate cancer biomarker for predicting which RP patients will have poor outcomes, especially for low-grade prostate cancer patients.Impact: This study suggests that TTP RNA expression can be used to enhance the accuracy of CAPRA-S to predict outcomes in patients treated with RP. Cancer Epidemiol Biomarkers Prev; 27(11); 1376-83. ©2018 AACR.

Validation of GEMCaP as a DNA Based Biomarker to Predict Prostate Cancer Recurrence after Radical Prostatectomy

We aimed to validate GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate) as a novel copy number signature predictive of prostate cancer recurrence. We randomly selected patients who underwent radical prostatectomy at Cleveland Clinic or University of Rochester from 2000 to 2005. DNA isolated from the cancer region was extracted and subjected to high resolution array comparative genomic hybridization. A high GEMCaP score was defined as 20% or greater of genomic loci showing copy number gain or loss in a given tumor. Cox regression was used to evaluate associations between the GEMCaP score and the risk of biochemical recurrence. We report results in 140 patients. Overall 38% of patients experienced recurrence with a median time to recurrence of 45 months. Based on the CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score 39% of the patients were at low risk, 42% were at intermediate risk and 19% were at high risk. The GEMCaP score was high (20% or greater) in 31% of the cohort. A high GEMCaP score was associated with a higher risk of biochemical recurrence (HR 2.69, 95% CI 1.51-4.77) and it remained associated after adjusting for CAPRA-S score and age (HR 1.94, 95% CI 1.06-3.56). The C-index of GEMCaP alone was 0.64, which improved when combined with the CAPRA-S score and patient age (C-index = 0.75). A high GEMCaP score was associated with biochemical recurrence in 2 external cohorts. This remained true after adjusting for clinical and pathological factors. The GEMCaP biomarker could be an efficient and effective clinical risk assessment tool to identify patients with prostate cancer for early adjuvant therapy.

Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States.

To analyze how prostate-specific antigen (PSA) screening and practice patterns has affected trends in tumor characteristics in men undergoing radical prostatectomy (RP) in the United States and Denmark. Unlike in the United States, PSA screening has not been recommended in Denmark. We performed an observational register study using pre- and postoperative data on 2168 Danish patients from Rigshospitalet, Copenhagen, Denmark, and 2236 patients from Stanford University Hospital, Stanford, CA, who underwent RP between 1995 and 2013. Patients were stratified according to Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) risk groups and D'Amico risk classification and were clustered into 4 time periods (1995-1999, 2000-2004, 2005-2009, and 2010-2013). Temporal trends in the proportions of patients of a given variable at the 2 institutions were evaluated with Cochran-Armitage test for trends and chi-square testing. A total of 4404 patients were included. Temporal changes in preoperative PSA, age, grade, and stage was found in both cohorts. Median preoperative PSA declined in both cohorts, while median age increased, with the Danish cohort showing the greatest changes in both PSA and age. In both cohorts, there was a trend for higher-risk preoperative features before RP over time. In 2010-2013, 27.7% and 21.8% of the patients were in the D'Amico high-risk group at Copenhagen and Stanford, respectively. Despite recommendation against PSA screening in Denmark, Danish men undergoing RP at Rigshospitalet to a considerable extent now resemble American men undergoing RP at Stanford. At both sites, there is continued trend to reduce the number of men undergoing RP for low-risk prostate cancer.

Abstract 5716: Tristetraprolin is a prognostic biomarker for biochemical recurrence in low Gleason score patients

Abstract PURPOSE: Most prostate cancer patients currently classified as having a low-risk of disease-specific death are overtreated in the United States, resulting in hundreds of thousands of men to have debilitating side effects from unnecessary treatment. However, ~30% of low-risk patients on active surveillance are later reclassified and require therapeutic intervention. Thus, there is a dire need for biomarkers that can discriminate which prostate tumors currently classified as low-risk will progress into aggressive disease. EXPERIMENTAL DESIGN: Retrospective analyses of two independent prostate cancer expression datasets were performed to determine the relationship between the expression levels of the tumor suppressor Tristetraprolin (TTP, ZFP36) and biochemical recurrence (BCR). Further, TTP expression levels were measured by quantitative real-time PCR (qRT-PCR) in a cohort of prostate tumors from Moffitt Cancer Center patients having long-term follow-up (n=382), and will be correlated to associated clinical data, including BCR. Finally, the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) scores, a clinical tool used to predict prostate cancer outcomes following radical prostatectomy, were calculated along with BCR for the patients in one of the prostate cancer datasets. RESULTS: Analysis of The Cancer Genome Atlas (TCGA) prostate adenocarcinoma dataset revealed that tumors with low TTP expression have an increased rate of BCR compared to those with high TTP levels (p=0.0096). Further, assessment of the GEO dataset GSE21034 (Taylor et al., Cancer Cell, 2010) established that prostate cancer patients with low Gleason scores (6 and 3+4) have an increased chance of BCR if their tumors express low levels of TTP compared to men with high TTP expressing tumors (p=0.0001). To validate these findings, patients with low Gleason score tumors and decreased levels of TTP in the Moffitt Cancer Center cohort are being analyzed to determine their rate of BCR. In contrast, CAPRA-S scores for low Gleason score tumors in the GSE20134 dataset failed to distinguish if a patient would have BCR (p=0.0511). CONCLUSIONS: Prostate cancer patients with Gleason score 6 or 3+4, which are currently classified as having a low-risk of dying from prostate cancer, have an increased risk of BCR if their tumor expresses low levels of the tumor suppressor TTP. Our data suggests that TTP may be a biomarker that clearly discriminates which low Gleason score tumors will progress into aggressive disease. Citation Format: Anders E. Berglund, Travis Gerke, Shivanshu Awasthi, G. Daniel Grass, Hyun Y. Park, John L. Cleveland, Jong Y. Park, Kosj Yamoah, Robert J. Rounbehler. Tristetraprolin is a prognostic biomarker for biochemical recurrence in low Gleason score patients [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 5716. doi:10.1158/1538-7445.AM2017-5716

Australian validation of the Cancer of the Prostate Risk Assessment Post-Surgical score to predict biochemical recurrence after radical prostatectomy.

The Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) score is a simple post-operative risk assessment tool predicting disease recurrence after radical prostatectomy, which is easily calculated using available clinical data. To be widely useful, risk tools require multiple external validations. We aimed to validate the CAPRA-S score in an Australian multi-institutional population, including private and public settings and reflecting community practice. The study population were all men on the South Australian Prostate Cancer Clinical Outcomes Collaborative Database with localized prostate cancer diagnosed during 1998-2013, who underwent radical prostatectomy without adjuvant therapy (n = 1664). Predictive performance was assessed via Kaplan-Meier and Cox proportional regression analyses, Harrell's Concordance index, calibration plots and decision curve analysis. Biochemical recurrence occurred in 342 (21%) cases. Five-year recurrence-free probabilities for CAPRA-S scores indicating low (0-2), intermediate (3-5) and high risk were 95, 79 and 46%, respectively. The hazard ratio for CAPRA-S score increments was 1.56 (95% confidence interval 1.49-1.64). The Concordance index for 5-year recurrence-free survival was 0.77. The calibration plot showed good correlation between predicted and observed recurrence-free survival across scores. Limitations include the retrospective nature and small numbers with higher CAPRA-S scores. The CAPRA-S score is an accurate predictor of recurrence after radical prostatectomy in our cohort, supporting its utility in the Australian setting. This simple tool can assist in post-surgical selection of patients who would benefit from adjuvant therapy while avoiding morbidity among those less likely to benefit.

Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology

BackgroundApproximately 4–25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. ObjectiveTo identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Design, setting, and participantsUnsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Outcome measurements and statistical analysisMolecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. Results and limitationsA molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13–2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76–5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90–3.75]; p<0.0001 and HR=7.53 [4.13–13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. ConclusionsThe metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. Patient summaryThe metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

Background:To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF).Methods:422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2–0.49 and ⩾0.5 ng ml−1, respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical–genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome.Results:During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical–genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20–15.47) and 5.42 (95% confidence interval, 1.59–18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high.Conclusions:The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical–genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Low Other Cause Mortality Rates Reflect Good Patient Selection in Patients with Prostate Cancer Treated with Radical Prostatectomy

Treatment decisions in patients with prostate cancer are affected by patient age regardless of higher life expectancy compared to the baseline population. Our aim was to quantify cancer specific and other cause mortality rates after radical prostatectomy. A total of 8,741 patients with prostate cancer underwent radical prostatectomy between 1992 and 2009 at a European center.Ten-year other cause and cancer specific mortality rates were determined byage and comorbidities, and age and Cancer of the Prostate RiskAssessment Post-Surgical (CAPRA-S) risk groups. Competing risk regression was used for risk factor analyses including clinical and pathological variables. Ten-year other cause mortality rates increased with patient age, including 4.8%, 9.8%, 13.6% and 16.5% in men younger than 60, 60 to 64, 65 to 69 and 70 years or older, respectively. Cancer specific mortality was the leading cause of death in CAPRA-S high risk cases regardless of age. On multivariate analyses age groups achieved independent predictor status for other cause mortality (ages 60 to 64 years HR 1.81, 95% CI 1.26-2.62, 65 to 69 years HR 2.48, 95% CI 1.73-3.56 and 70 years or greater HR 3.02, 95% CI 1.97-4.62) as well as Charlson comorbidity indexes 1 (HR 1.45, 95% CI 1.00-2.09) and 3 or greater (HR 3.99, 95% CI 1.57-10.1). Gleason score 3 + 4 and 4 + 3 or greater, pT3b stage, lymph node invasion and positive margin status achieved independent predictor status when the end point was cancer specific mortality. The CAPRA-S high risk constellation increased cancer specific mortality risk in multifold fashion (HR 26, 95% CI 16-56). In patients with the CAPRA-S high risk constellation the rate of cancer specific mortality increased in multifold fashion and contributed to most deaths regardless of patient age. Low other cause mortality rates in all age groups showed reasonable patient selection.

Validation of a Genomic Classifier for Predicting Post-Prostatectomy Recurrence in a Community Based Health Care Setting

We determined the value of Decipher®, a genomic classifier, to predict prostate cancer outcomes among patients after prostatectomy in a community health care setting. We examined the experience of 224 men treated with radical prostatectomy from 1997 to 2009 at Kaiser Permanente Northwest, a large prepaid health plan in Portland, Oregon. Study subjects had aggressive prostate cancer with at least 1 of several criteria such as preoperative prostate specific antigen 20 ng/ml or greater, pathological Gleason score 8 or greater, stage pT3 disease or positive surgical margins at prostatectomy. The primary end point was clinical recurrence or metastasis after surgery evaluated using a time dependent c-index. Secondary end points were biochemical recurrence and salvage treatment failure. We compared the performance of Decipher alone to the widely used CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score, and assessed the independent contributions of Decipher, CAPRA-S and their combination for the prediction of recurrence and treatment failure. Of the 224 patients treated 12 experienced clinical recurrence, 68 had biochemical recurrence and 34 experienced salvage treatment failure. At 10 years after prostatectomy the recurrence rate was 2.6% among patients with low Decipher scores but 13.6% among those with high Decipher scores (p=0.02). When CAPRA-S and Decipher scores were considered together, the discrimination accuracy of the ROC curve was increased by 0.11 compared to the CAPRA-S score alone (combined c-index 0.84 at 10 years after radical prostatectomy) for clinical recurrence. Decipher improves our ability to predict clinical recurrence in prostate cancer and adds precision to conventional pathological prognostic measures.