Risk Stratification of Suspected Clinically Localized Prostate Cancer Using Multi-Indicator Functional Differentiation: A Predictive Model With fPSA/tPSA, PHI, PCA3, and MRI.

It remains unclear whether the Prostate Health Index (PHI) or the urinary Prostate-Cancer Antigen 3 (PCA-3) score is more accurate at screening for prostate cancer (PCa). The aim of this study was to prospectively compare the accuracy of PHI and PCA-3 scores to predict overall and significant PCa in men undergoing an initial prostate biopsy. Double-blind assessments of PHI and PCA-3 were conducted by referent physicians in 138 patients who subsequently underwent trans-rectal ultrasound-guided prostate biopsy according to a 12-core scheme. Predictive accuracies of PHI and PCA-3 were assessed using AUC and compared according to the DeLong method. Diagnostic performances with usual cut-off values for positivity (i.e., PHI >40 and PCA-3 >35) were calculated, and odds ratios associated with predicting PCa overall and significant PCa as defined by pathological updated Epstein criteria (i.e., Gleason score ≥7, more than three positive cores, or >50% cancer involvement in any core) were estimated using logistic regression. Prevalences of overall and significant PCa were 44.9% and 28.3%, respectively. PCA-3 (AUC = 0.71) was the most accurate predictor of PCa overall, and significantly outperformed PHI (AUC = 0.65; P = 0.03). However, PHI (AUC = 0.80) remained the most accurate predictor when screening exclusively for significant PCa and significantly outperformed PCA-3 (AUC = 0.55; P = 0.03). Furthermore, PCA-3 >35 had the best accuracy, and positive or negative predictive values when screening for PCa overall whereas these diagnostic performances were greater for PHI >40 when exclusively screening for significant PCa. PHI > 40 combined with PCA-3 > 35 was more specific in both cases. In multivariate analyses, PCA-3 >35 (OR = 5.68; 95%CI = [2.21-14.59]; P < 0.001) was significantly correlated with the presence of PCa overall, but PHI >40 (OR = 9.60; 95%CI = [1.72-91.32]; P = 0.001) was the only independent predictor for detecting significant PCa. Although PCA-3 score is the best predictor for PCa overall at initial biopsy, our findings strongly indicate that PHI should be used for population-based screening to avoid over-diagnosis of indolent tumors that are unlikely to cause death.

Background: Prostate cancer (PCa) an adenocarcinoma is the most common cancer diagnosed in African men today. At present, the only widely accepted screening tools for prostate cancer are prostate specific antigen (PSA) and digital rectal examination. There is controversy regarding the appropriate level of serum PSA that should trigger a biopsy. This study is aimed at finding a better marker/panel of markers for prostate cancer. Methods: 150 consented patients requiring a prostate biopsy and 100 age matched controls were recruited for this study. Genetic materials were found in 132 (88%) of the samples. Serum Total PSA (TPSA) , and free PSA were assayed using ELISA method, % free/total PSA(%f/tpsa) was obtained statistically, prostatic volume was determined using TRUS. In addition, selected urinary RNA’s were assayed; transmembrane serine protease (TMPRSS2:ERG and TMPRSS2:ETS) fusion genes, PSA gene and PCA3 (prostate cancer antigen 3) , using standard polymerase chain reaction (PCR) protocols. Results: TMPRSS2:ERG was detected in 9 (7 %) of the samples and limited to biopsy positive for PCa. Similarly, TMPRSS2:ETS was found in only 4 (3%) of the samples and also restricted to biopsy positive for PCa. PCA3 score had the best discriminatory accuracy in diagnosing PCa amongst patients with serum Total PSA in the range of 4 - 10 ng/ml with AUC of 0.705 compared to Total PSA, f/t PSA ratio, and PSA Density which were 0.365, 0.695, and 0.541 respectively. At the cut off value of 24.6, PCA3 score yielded its best sensitivity of 0.615 and specificity of 0.630. At the cutoff of 18, free/total PSA ratio (0.615, 0.77), at the cutoff of 0.14 PSAD yielded its best (0.538, 0.704.) respectively. Direct logistic regression was performed to access the predictability of PCa using different models comprising of three (3) covariates, the model comprising PCA3 Score, f/t PSA ratio and PSAD had the best discriminating accuracy in the subgroup with TPSA range of 4 - 10ng/ml, with the sensitivity, specificity, positive predictive value, and negative predictive values of 0.59, 0.93, 71.4% and 75.8% respectively, over models comprising PCA3 Score ,TPSA and %f/t PSA, and PCA3 Score, TPSA and PSAD with these values (0.23, 0.85, 42.9 % and 70.1%), (0.39, 0.89, 62.5%, and 75 %) and ( 0.15, 0.85,66.7% and 67.6%) respectively. Conclusions: In predicting PCa amongst patients with serum total PSA in the grey area of 4 - 10 ng/ml, the model comprising PCA3 Score, f/t PSA ratio and PSAD had the best discriminating accuracy. Note: This abstract was not presented at the meeting. Citation Format: Oluyemi Akinloye, Aniebietabasi S. Obot, Taiwo A. Adewole. Potentials of some serum proteins and urinary molecular biomarkers for early diagnosis of prostate cancer in Nigeria 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 732. doi:10.1158/1538-7445.AM2017-732

Prostate health index (phi) and prostate cancer antigen 3 (PCA3) have been recently proposed as novel biomarkers for prostate cancer (PCa). We assessed the diagnostic performance of these biomarkers, alone or in combination, in men undergoing first prostate biopsy for suspicion of PCa. One hundred sixty male subjects were enrolled in this prospective observational study. PSA molecular forms, phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay), and other established biomarkers (tPSA, fPSA, and %fPSA) were assessed before patients underwent a 18-core first prostate biopsy. The discriminating ability between PCa-negative and PCa-positive biopsies of Beckman coulter phi and PCA3 score and other used biomarkers were determined. One hundred sixty patients met inclusion criteria. %p2PSA (p2PSA/fPSA × 100), phi and PCA3 were significantly higher in patients with PCa compared to PCa-negative group (median values: 1.92 vs. 1.55, 49.97 vs. 36.84, and 50 vs. 32, respectively, P ≤ 0.001). ROC curve analysis showed that %p2PSA, phi, and PCA3 are good indicator of malignancy (AUCs = 0.68, 0.71, and 0.66, respectively). A multivariable logistic regression model consisting of both the phi index and PCA3 score allowed to reach an overall diagnostic accuracy of 0.77. Decision curve analysis revealed that this "combined" marker achieved the highest net benefit over the examined range of the threshold probability. phi and PCA3 showed no significant difference in the ability to predict PCa diagnosis in men undergoing first prostate biopsy. However, diagnostic performance is significantly improved by combining phi and PCA3.

To assess prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG scores in patients with advanced and metastatic prostate cancer at baseline and after 6 months of treatment with triptorelin 22.5 mg, and analyse these scores in patient-groups defined by different disease characteristics. The Triptocare study was a prospective, open-label, multicentre, single-arm, Phase III study of triptorelin 22.5 mg in men with locally advanced or metastatic prostate cancer, who were naïve to androgen-deprivation therapy (ADT). The primary objective was to model the urinary PCA3 change at 6 months, according to baseline variables. Other outcome measures included urinary PCA3 and TMPRSS2-ERG scores and statuses, and serum testosterone and prostate-specific antigen (PSA) levels at baseline and at 1, 3 and 6 months after initiation of ADT. Safety was assessed by recording adverse events and changes in laboratory parameters. The intent-to-treat population comprised 322 patients; 39 (12.1%) had non-assessable PCA3 scores at baseline, and 109/322 (33.9%), 215/313 (68.7%) and 232/298 (77.9%) had non-assessable PCA3 scores at 1, 3 and 6 months, respectively. Baseline Gleason score was the only variable associated with non-assessability of PCA3 score at 6 months (P = 0.017) - the hazard of having a non-assessable PCA3 score at 6 months was 1.824-fold higher (95% confidence interval 1.186-2.805) in patients with a Gleason score ≥8 vs those with a Gleason score ≤6. The median PCA3 scores at baseline were significantly higher in patients aged ≥65 years vs those aged <65 years and in patients with a serum PSA level <100 ng/mL vs those with serum PSA level of >200 ng/mL. The median PCA3 score was significantly lower in patients with metastasis than in patients with no metastasis or unknown metastasis status. TMPRSS2-ERG scores ≥35 were considered positive (n = 149 [51.6%]). Age, presence of metastasis, PSA level and Gleason score at baseline were not associated with a significant difference in the proportion of TMPRSS2-ERG-positive scores. The median serum PSA levels decreased from 45.5 ng/mL at baseline to 1.2 ng/mL after 6 months, and as expected, >90% of patients achieved castrate levels of testosterone (<50 ng/dL) at 1, 3, and 6 months during triptorelin treatment. The safety profile reported from this study is consistent with the known safety profile of triptorelin. These data from the Triptocare study suggest that urinary PCA3 or TMPRSS2-ERG score are not reliable markers of cancer stage in advanced prostate cancer. Urinary PCA3 and TMPRSS2-ERG scores do not appear to be useful in assessing response to ADT in advanced prostate cancer, with most patients having non-assessable scores after 6 months of treatment.

Defining a Cohort that May Not Require Repeat Prostate Biopsy Based on PCA3 Score and Magnetic Resonance Imaging: The Dual Negative Effect

To assess the performance capabilities of multiparametric magnetic resonance imaging (mpMRI), the prostate health index (PHI) and prostate cancer antigen 3 (PCA3) in predicting the presence of pathologically confirmed significant prostate cancer (PCSPCa), according to the European Randomized Study of Screening Prostate Cancer definition, in a single cohort of patients who underwent radical prostatectomy (RP) but who were eligible for active surveillance (AS). An observational retrospective study was performed in 120 patients with prostate cancer (PCa), treated with robot-assisted RP but eligible for AS according to Prostate Cancer Research International: Active Surveillance criteria. Blood and urine specimens were collected before initial prostate biopsy for PHI and PCA3 measurements, respectively. In addition, all patients underwent mpMRI, preoperatively and 6-8 weeks after biopsy, with a 1.5T scanner using a four-to-five-channel phase array coil combined with an endorectal coin. mpMRI images were assessed and diagrams showing the prostate sextants were used to designate regions of abnormality within the prostate. Prostate findings were assigned to one of five categories according to Prostate Imaging-Reporting and Data System guidelines (PI-RADS) and considered positive for PCa if final PI-RADS score was >3 and negative if ≤3. Pathologically confirmed reclassification was observed in 55 patients (45.8%). mpMRI showed good specificity and negative predictive value (0.61 and 0.73, respectively) for excluding PCSPCa compared with the PHI and PCA3. On multivariate analyses and after 1 000 bootstrapping resampling, the inclusion of both mpMRI and the PHI significantly increased the accuracy of the base model in predicting PCSPCa. For the prediction of PCSPCa, in particular, the base model had an area under the curve (AUC) of 0.71 which significantly increased by 4% with the addition of the PHI (AUC = 0.75; P < 0.01) and by 7% with the addition of mpMRI (AUC = 0.78; P < 0.01). Decision-curve analysis showed that the multivariable model with mpMRI had the highest net benefit. In a single cohort of patients who underwent RP but who were eligible for AS, mpMRI and, to a lesser extent, the PHI, had an important role in discriminating the presence of PCSPCa; both measures could therefore be useful in the selection and monitoring of patients undergoing AS.

Critical Assessment of Preoperative Urinary Prostate Cancer Antigen 3 on the Accuracy of Prostate Cancer Staging

Performance of Prostate Cancer Antigen 3 (PCA3) and Prostate-Specific Antigen in Prescreened Men: Reproducibility and Detection Characteristics for Prostate Cancer Patients with High PCA3 Scores (≥100)

Predicting prostate biopsy outcome: prostate health index (phi) and prostate cancer antigen 3 (PCA3) are useful biomarkers

Prostate cancer antigen 3 (PCA3) encodes a prostate-specific messenger ribonucleic acid (mRNA) that serves as the target for a novel urinary molecular assay for prostate cancer detection. The objective of the current study was to evaluate the ability of PCA3, added to measurements of serum prostate-specific antigen (PSA), to predict cancer detection by extended template biopsy. Between September 2006 and December 2007, whole urine samples were collected after attentive digital rectal examinations from 187 men before they underwent ultrasound-guided, 12-core prostate biopsy in a urology outpatient clinic. Urine PCA3/PSA mRNA ratio scores were measured within 1 month, and serum PSA was measured within 6 months prior to biopsy. Those measurements were related to cancer-positive biopsies. Overall, 87 of 187 biopsies (46.5%) were positive for cancer. The sensitivity and specificity of a PCA3 score > or =35 for positive biopsy were 52.9% and 80%, respectively, and the positive and negative predictive values were 69.7% and 66.1%, respectively. By using receiver operating characteristic curve analysis, PSA alone resulted in an area under the curve (AUC) of 0.63 for prostate cancer detection; whereas a combined PSA and PCA3 score resulted in an AUC of 0.71. The likelihood of prostate cancer detection rose with increasing PCA3 score ranges (P > .0001), providing possible PCA3 score parameters for stratification into groups at low risk, moderate risk, high risk, and very high risk for a positive biopsy. Adding PCA3 to serum PSA improved prostate cancer prediction. The use of PCA3 in a clinical setting may help to stratify patients according to their risk for biopsy and cancer detection, although a large-scale validation study will be needed to address assay standardization, optimal cutoff values, and appropriate patient populations.

Objective. The aim of this study was to test the ability of prostate cancer antigen-3 (PCA3) and Hansen’s PCA3-based nomogram to predict prostate cancer (PCa) probability in a Norwegian cohort, with the goal of reducing unnecessary biopsies. Material and methods. Altogether, 127 consecutive patients were recruited to this study at Haukeland University Hospital, Norway. Prostate-specific antigen (PSA), PCA3 score, digital rectal examination (DRE), prostate volume (Pvol) and age were determined. All patients had an extended 10-core biopsy. The performance of PCA3 score and Hansen’s nomogram was tested. Results. There were 124 evaluable patients. Among these, 59 patients had PCa on the initial biopsies. Mean PSA, PCA3 score and age were significantly higher and Pvol was significantly lower in patients with PCa. PCA3 scores of 35 and 21 led to a sensitivity of 71% and 81% and specificity of 72% and 55%, respectively. Hansen’s nomogram gave an area under the curve (AUC) of 0.806. The intraclass correlation was 0.959 (Cronbach’s alpha). Applied to this material, PCa would be missed in 15.2% of patients when applying the suggested threshold probability of 30%, among whom 66.7% had high-grade PCa. With a threshold probability of 20% only one patient had PCa and this was low grade. Conclusions. Hansen’s PCA3-based nomogram is valid for this cohort. A threshold probability of 20% seems more adequate than 30% for this less screened cohort. PCA3 score only affects the biopsy indication in some patients and is recommended only for this subset. The results need to be confirmed in a larger study.

The days of using one PSA threshold to trigger a biopsy for all men are over, and the field has moved toward a more individualized approach to prostate biopsy decisions, taking into account each patient's specific set of risk factors. Foley et al. 1 provide compelling evidence supporting the use of the Prostate Health Index (PHI) as part of this multivariable approach to prostate biopsy decisions. There is now a large body of evidence showing that the PHI is more specific for prostate cancer than total PSA and percent free PSA, as was concluded in a 2014 systematic review 2. Moreover, several recent studies have confirmed the superiority of the PHI over its individual components 3, 4 and compared with other markers such as PCA3 5, for predicting clinically significant prostate cancer. The present new study by Foley et al. 1 builds on this literature by providing clinically useful data on the role of the PHI in prostate biopsy decisions. Specifically, they examined 250 men with elevated age-specific PSA and/or abnormal DRE who were referred for ≥12-core prostate biopsy as part of the Irish Rapid Access Clinic. The median PHI was 48.6 in men with prostate cancer, vs 33.4 in men without prostate cancer on biopsy. On receiver-operating characteristic analysis, the PHI had a higher area under the curve (AUC) for overall prostate cancer compared with total and percent free PSA (AUCs 0.71, 0.62 and 0.64, respectively), as well as for high grade prostate cancer (AUC 0.78, 0.70 and 0.67, respectively). Compared with the PHI, even the combination of total and percent free PSA had a lower AUC of 0.67 for overall prostate cancer and 0.75 for high grade prostate cancer. Next, the authors developed a multivariable prediction model incorporating age, family history, DRE and previous biopsy history, along with either PSA or the PHI. Using the PHI in this model rather than total PSA resulted in greater predictive accuracy for the detection of overall and Gleason ≥7 disease. The PHI-based model also showed superior net benefit to the PSA-based multivariable models on decision curve analysis. These findings are exactly what we would expect, as studies have consistently shown that the PHI outperforms PSA 2, 6. Other groups from the European Randomized Study of Screening for Prostate Cancer (ERSPC) have also integrated the PHI into multivariable risk prediction through the development of a user-friendly smartphone app called the Rotterdam Risk Calculator 7. Because our goal is to provide each patient with the best information from which to make decisions about biopsy, it only makes sense to use the best possible combination of markers that we have. The author reports personal fees and other from Sanofi, personal fees and other from Bayer, outside the submitted work.

MP15-09 BASELINE AND LONGITUDINAL PCA3 PREDICT MORE EXTENSIVE CANCER IN AN ACTIVE SURVEILLANCE POPULATION

Development and Internal Validation of a Prostate Health Index Based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Objective: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [–2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer.Materials and methods: The subjects were 50 consecutive men with a PSA level of 2.0–10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer.Results: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%).Conclusion: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer.