Usefulness of the Prostate Health Index in Predicting the Presence and Aggressiveness of Prostate Cancer Among Korean Men


 BackgroundWe aimed to evaluate the usefulness of the Beckman Coulter prostate health index (PHI) and compare it with total prostate specific antigen (PSA) and related derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in the Korean population.MethodsA total of 140 men who underwent their first prostate biopsy for suspected PCa were included in this prospective observational study. The diagnostic performance of total PSA, free PSA, %free PSA, [–2] proPSA (p2PSA), %p2PSA, and PHI in detecting and predicting the aggressiveness of PCa was estimated using the receiver operating characteristic curve (ROC) and logistic multivariate regression analyses.ResultsOf 140 patients, PCa was detected in 63 (45%), and 48 (76.2%) of them had significant cancer with a Gleason score (GS) ≥7. In the whole group, the area under the curve (AUC) for ROC analysis of tPSA, free PSA, %fPSA, p2PSA, %p2PSA, and PHI were 0.63, 0.57, 0.69, 0.69, 0.71, and 0.75, respectively, and the AUC was significantly greater in the PHI group than in the tPSA group (p = 0.005). For PCa with GS ≥7, the AUCs for tPSA, free PSA, %fPSA, p2PSA, %p2PSA, and PHI were 0.62, 0.58, 0.41, 0.79, 0.87, and 0.88, respectively, and the AUC was significantly greater in the PHI group than in the tPSA group (p < 0.001). In the subgroup with tPSA 4–10 ng/mL, both %p2PSA and PHI were strong independent predictors for PCa (p = 0.031, p = 0.027) and significantly improved the predictive accuracy of a base multivariable model including age, tPSA, and %fPSA, using multivariate logistic regression analysis. (p = 0.015, p = 0.010). Additionally, at a cutoff PHI value >33.4, unnecessary biopsy could be avoided in 22.9% (32/140) cases, with no aggressive cancer patients missed.ConclusionThis study shows that %p2PSA and PHI are superior to total PSA and %fPSA in predicting the presence and aggressiveness (GS≥7) of PCa among Korean men. Using PHI, a significant proportion of unnecessary biopsies can be avoided.


Abstract Background
We aimed to evaluate the usefulness of the Beckman Coulter prostate health index (PHI) and compare it with total prostate speci c antigen (PSA) and related derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in the Korean population.

Methods
A total of 140 men who underwent their rst prostate biopsy for suspected PCa were included in this prospective observational study. The diagnostic performance of total PSA, free PSA, %free PSA, [-2] proPSA (p2PSA), %p2PSA, and PHI in detecting and predicting the aggressiveness of PCa was estimated using the receiver operating characteristic curve (ROC) and logistic multivariate regression analyses.
Additionally, at a cutoff PHI value >33.4, unnecessary biopsy could be avoided in 22.9% (32/140) cases, with no aggressive cancer patients missed.

Conclusion
This study shows that %p2PSA and PHI are superior to total PSA and %fPSA in predicting the presence and aggressiveness (GS≥7) of PCa among Korean men. Using PHI, a signi cant proportion of unnecessary biopsies can be avoided.

Background
Prostate cancer (PCa) is the second most common cancer in the Western population [1].
In Korea, the incidence of PCa has steadily increased and is now the fth most frequent cause of cancer among men [2]. Several studies have demonstrated that PCa in Korean men shows worse disease characteristics [3]. Kang and colleagues demonstrated that Koreans had higher T stages than their American counterparts (p=0.021) and higher Gleason scores than Americans in all age groups. And Koreans also had higher Gleason scores than Americans for PSA >10 ng/mL (p<0.05) in their study.
A large proportion of PCa diagnosed in the Korean population shows poor differentiation compared to its American counterparts [4]. Therefore, the accuracy of diagnosis and risk strati cation of PCa using appropriate biomarkers may be more important for suitable treatment in the Korean population.
Total prostate-speci c antigen (tPSA) is a widely used tumor marker for the screening, diagnosis, monitoring, and prognosis of prostate cancer worldwide [5]. The introduction of tPSA has resulted in increased early detection of PCa and reduced mortality [6]. In the early diagnosis of PCa using tPSA, the main problem was that the low positive predictive value (PPV) of tPSA resulted in unnecessary biopsies [7]. The positive rate for cancer at biopsy was approximately 25% among the population with PSA levels of 2-10 μg/L.
In addition, PSA cannot accurately identify aggressive PCa, which has clinical signi cance for treatment. Consequently, the wide application of PSA in detecting PCa has increased concerns about over-diagnosis and over-treatment [8].
Therefore, the development of new biomarkers is needed to improve detection of PCa and to discriminate clinically signi cant and insigni cant PCa.
The aim of this prospective, observational study was to investigate the usefulness of p2PSA and its derived %p2PSA and PHI in the detection of PCa and to discriminate clinically signi cant PCa in Korean patients by estimating its ability to avoid unnecessary biopsies.

Methods
The study included consecutive men who underwent their rst prostate biopsy between April 2016 and July 2019. The indications for prostate biopsies were any one of the following: serum tPSA > 3.0 ng/mL, presence of palpable nodule on prostate digital rectal examination, and observation of hypoechoic ndings on transrectal prostate ultrasonography. Exclusion criteria were medical therapies or procedures that might affect PSA levels, acute prostate in ammation, or urinary tract infection in the 3 months prior to biopsy. Patients who underwent prostate biopsy or were treated with any 5-alpha-reductase inhibitors were excluded.
Blood samples were collected to measure the pre-biopsy tPSA, fPSA, and p2PSA levels prior to prostate biopsy. The blood was processed to clot for 1 h at room temperature, followed by centrifugation for 15 min. The sera were aliquoted and frozen at -80° C and processed on an Access 2 immunoassay system (Beckman Coulter, Brea, CA, USA) using dedicated Access tPSA, fPSA, and p2PSA reagents. %p2PSA was calculated using the formula [(p2PSA pg/mL)/ (fPSA ng/mL × 1000)] × 100, and PHI using the formula [(p2PSA pg/ mL)/(fPSA ng/mL] × √tPSA.
The patients then underwent transrectal ultrasound-guided prostate biopsies following a standardized extended scheme with at least 12 biopsy cores obtained from the prostate gland and additional cores taken when other areas were suspected. The specimens were inspected by a genitourinary pathologist who was blinded to the results of the blood test. PCa was con rmed and graded according to the de nitions of the International Society of Urological Pathology.
The primary endpoint was comparison of accuracy of the diagnostic performance of %p2PSA and PHI with that of tPSA 0 %fPSA, which are currently widely used biomarkers in detecting PCa at biopsy. The secondary endpoint was the predictive ability of these biomarkers to discriminate aggressive PCa with a Gleason score (GS) ≥ 7.
Quantitative data are presented as median (interquartile range) and categorical data as numbers (n) and percentages. The normal distribution of variables was assessed using the Kolmogorov-Smirnov test.
Student's t-test was used for comparisons of parametric variables, and the Mann-Whitney U-test for nonparametric continuous variables. Bivariate and multivariate logistic regression analyses were used to determine the association between the biomarkers and the presence of PCa in the whole group and subgroup with PSA 4-10 and PCa with GS ≥ 7 at biopsy.
These markers were added to the base multivariate model including age, tPSA, and %fPSA to evaluate the usefulness of %p2PSA and PHI in predicting the presence of PCa. The improvement in predictive accuracy was measured as the area under the curve (AUC) of the receiver operating characteristic (ROC) analysis. The DeLong method was used to compare the statistical differences between the AUCs. Odds ratios (ORs) with 95% con dence intervals were determined.
The study protocol was approved by the Institutional Review Board (IRB) of the Sanngye Paik Hospital, Inje University. All participants provided written informed consent before participation in the study. All methods were carried out in accordance with relevant guidelines and regulations.

Results
A total of 140 men who underwent their rst prostate biopsy with positive or negative prostate biopsy between April 2016 and July 2019 were included in this study. The demographic and clinical characteristics of the study participants are summarized in Table 1. Among all patients, 77 men had a tPSA level between 4 and 10 ng/mL. PCa at the initial biopsy was detected in 45% (63/140) of the patients. Among 63 patients diagnosed with PCa, 15 (23.8%) had GS 6 disease, 18 (28.6%) had GS 7 disease, and 30 (47.6%) had GS ≥8 disease.
Patients with PCa showed signi cantly higher age, tPSA, %p2PSA, and PHI than those without PCa at biopsy. Conversely, %fPSA levels were signi cantly higher in patients without PCa. However, the fPSA concentration did not differ between the two groups.
In 77 patients with a tPSA level between 4 and 10 ng/mL, %p2PSA and PHI were signi cantly different between groups with and without PCa (Table 2). However, the median tPSA, %fPSA, and p2PSA levels did not differ between the two groups.
Using tPSA as a standard, the AUC was signi cantly greater in the PHI group (p = 0.005). Both %p2PSA and PHI were strong independent predictive markers (p <0.001, p <0.001) and signi cantly increased the predictive accuracy of a base multivariable model including age, tPSA, and %fPSA using multivariate logistic regression analysis (Table 4).
Similarly, in the subgroup of patients with tPSA 4-10 ng/mL, both %p2PSA and PHI were strong independent predictors (p =0.031, p =0.027) and showed signi cantly improved predictive accuracy in addition to a base multivariable model using multivariate logistic regression analysis. (p = 0.015, p = 0.010, Table 5).
In Table 6, the results of univariate and multivariable logistic regression analyses identifying the predictors of PCa with a Gleason score ≥7 are presented. %p2PSA and PHI signi cantly improved the predictive accuracy of a base multivariable model. (p <0.001, p <0.001). Table 7 shows the number of patients in whom unnecessary biopsies could be avoided and the number and pathologic characteristics of cancers that would be missed using %fPSA, p2PSA, %p2PSA, and PHI at a cutoff level with 90% sensitivity in the subgroup with tPSA 4-10 ng/mL and the entire population, respectively.
Patients with aggressive cancers had higher PHI scores. The median values of the PHI score showed a stepwise increase along the Gleason score more obviously compared to the other markers (Fig. 2).

Discussion
This study evaluated the usefulness of %p2PSA and PHI in 140 subjects, and our ndings support previous results regarding both biomarkers. %p2PSA and PHI showed higher predictive performance in the detection of PCa than standard reference methods and the ability to distinguish aggressive (GS ≥7) from clinically indolent state of PCa. Thus, their use could avoid unnecessary biopsies without missing clinically signi cant cancers.
Currently, PSA is widely used for PCa screening, but the limitations of PSA as a biomarker for PCa detection have been well demonstrated. It is necessary to distinguish PCa from benign prostatic disease and to clarify the aggressiveness of cancers, but PSA cannot completely predict the presence and biological behavior of PCa [13]. The early detection of PCa using PSA results in a large number of negative biopsies and a high proportion of patients diagnosed with clinically low aggressive tumors (over-diagnosis) followed by unnecessary treatment (over-treatment) and morbidity related to complications [14,15]. Thus, a more speci c biomarker that could increase predictive accuracy and risk strati cation properties is needed to identify patients who may have PCa and reduce morbidity due to unnecessary diagnosis and treatment.
The usefulness of %p2PSA and PHI in the detection of PCa has been studied extensively in recent years. The biomarkers improve the speci city of tPSA for PCa detection and are associated with a more aggressive state of disease [5,13].
Catalona et al. demonstrated that high PHI level was associated with increased detection rate of PCa in subjects with a tPSA level between 2 and 10 ng/ml in a prospective multi-institutional study [16]. Jansen et al. showed that PHI showed signi cantly superior performance than PSA and %fPSA for PCa prediction, and the involvement of p2PSA in a base multivariable model signi cantly improved the predictive value and speci city of PCa [17].
Several studies have also validated the usefulness of PHI in Asian countries. Chiu  both in subjects with a PSA level between 2.1 and 10 ng/mL and in those with a PSA level > 10 ng/mL [19].
One meta-analysis showed that %p2PSA and PHI improved diagnostic performance compared to tPSA and %fPSA consistently in detecting PCa and can reduce unnecessary biopsies [20]. In addition, a European prospective study showed that PHI showed improved predictive performance for GS ≥ 7 PCa [21]. The European Association of Urology as per the 2016 guidelines suggested that the PHI could be considered as an additional diagnostic method for patients with PSA levels of 2-10 ng/mL and a negative DRE [22].
In the current study, the addition of %p2PSA or PHI to a predictive base multivariate regression model signi cantly increased its predictive accuracy. Moreover, %p2PSA and PHI were associated with aggressiveness of PCa and could improve the predictive performance of the base model for detecting GS ≥7 PCa. The European population had a fourfold higher incidence of PCa than the Asian population, while age and PSA level showed a tendency to be higher among Asians in a previous study [25]. Korean men also have a lower incidence rate of PCa than the Western population, but PCa in the Korean population shows worse characteristics of the disease compared to Western men [3,4]. Most of the previously reported data regarding %p2PSA and PHI have been collected mainly in Western groups; therefore, it is necessary to verify the usefulness of these biomarkers in Korean groups. . PHI is a blood test that can be performed simply and is ordered by general practitioners, and there is no need for radiologic interpretation. In the future, as the cost of a blood test will probably decrease, PHI will be widely used as a screening tool for PCa.
This study has several limitations. First, it was performed in a single tertiary center and had a relatively small sample size. Second, not all patients in our study underwent radical prostatectomy; therefore, we could not inspect the occurrence of Gleason upgrading after prostatectomy. In addition, we did not inspect the percentage of tumor involvement in each biopsy core and tumor size. Finally, we did not use multiparametric MRI. MRI could help guide more accurate localization for biopsy and increase the performance for detecting signi cant PCa.

Conclusions
Our ndings suggest that the diagnostic performance of %p2PSA and PHI to predict the presence and aggressiveness of PCa was superior to that of PSA and %fPSA in the Korean population. Using PHI, a high proportion of unnecessary biopsies could be avoided. Further research is needed to support these results.

Consent for publication
Written informed consent was obtained from every patient for publication of this research report.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.