Abstract
Background
The necessity of prostate biopsy in patients with a Prostate Imaging–Reporting and Data System (PI-RADS) score below 3 and prostate-specific antigen (PSA) levels of 4–10 ng/ml remains controversial. We tested the diagnostic performance of the free PSA ratio (%fPSA) in detecting clinically significant cancer (CSC) in patients with PI-RADS <3 and PSA ≤10 ng/ml.
Methods
We analyzed 1435 prostate biopsies performed by a single operator between April 2018 and January 2023 at a single institution. PSA and free PSA results on the day of biopsy or within 1 month were used, and all biopsies were performed after prostate magnetic resonance imaging (MRI). CSC was defined as Gleason grade group ≥2.
Results
Among 208 men with PI-RADS <3 and PSA ≤10 ng/ml, CSC was detected in 37 (17.8%) patients. The median age was 65 years (interquartile range [IQR] 61–71), with a median PSA level of 5.06 ng/ml (IQR 3.98–7.08) and a median %fPSA of 18.2% (IQR 13.7–22.0). The area under the curve was 0.757 (95% confidence interval, 0.674–0.841), with a %fPSA cutoff of 17.6%, sensitivity of 86.5%, specificity of 63.7%, positive likelihood ratio (LR) of 2.38, and negative LR of 0.21. CSC was diagnosed in 5 out of 114 patients (4%) with %fPSA >17.6%, compared to 32 out of 94 patients (34%) with %fPSA <17.6%.
Conclusions
In patients with PI-RADS <3 and PSA ≤10 ng/ml, %fPSA values < 17.6% may facilitate early prostate cancer diagnosis in those who might not undergo biopsy based on MRI results alone. Additionally, unnecessary biopsies could be avoided in patients with elevated PSA levels when %fPSA exceeds 17.6%.
Keywords: Clinically significant cancer, Free PSA, PI-RADS, Prostate cancer
1. Introduction
Recently, performing a prostate biopsy based on magnetic resonance image (MRI) results has become a standard protocol at most institutions. According to the MRI-based Prostate Imaging–Reporting and Data System (PI-RADS), a score of 4 or higher is associated with clinically significant cancer (CSC), a score of 3 is considered equivocal, and a score of 2 or lower indicates that CSC is unlikely to be present.1 CSC is defined as a Gleason grade group 2 or greater.2
In addition to MRI examination, serum prostate-specific antigen (PSA) detection is widely used in prostate cancer (PC) clinical screening due to its high diagnostic sensitivity. However, its low specificity leads to many patients undergoing unnecessary biopsies and being overtreated, especially those with PSA levels in the gray zone of 4–10 ng/ml.3,4 Previous studies have revealed that fewer than 30% of males with PSA levels in the gray zone have pathologically confirmed PC, leaving up to 70% with negative biopsy results.5,6
Although the likelihood of CSC is low in patients with a PI-RADS score <3 and PSA ≤10 ng/ml, additional biomarkers are needed to identify those who require a biopsy.3 One such biomarker is free PSA (fPSA), which is readily available, cost-effective, and has been associated with the overall diagnosis of PC. The free PSA ratio (%fPSA, free PSA/total PSA∗100) is recommended to help distinguish PC from benign prostatic hyperplasia when total serum PSA levels are between 4 and 10 ng/ml and the digital rectal examination (DRE) is negative.7 However, the optimal cutoff value for %fPSA remains unclear, with previous studies suggesting various thresholds.8, 9, 10, 11 Furthermore, the appropriate cutoff value for %fPSA when combined with the PI-RADS score has not yet been defined.
This study aimed to analyze the usefulness of %fPSA in diagnosing CSC in patients with a PI-RADS score <3 and PSA ≤10 ng/ml.
2. Materials and methods
We retrospectively analyzed 1435 prostate biopsies performed by a single operator between April 2018 and January 2023 at a single institution. This study was approved by the Institutional Review Board (IRB) of Yonsei University Severance Hospital (IRB number: 4-2024-0292), and the requirement for informed consent was waived due to the retrospective nature of the study.
Pre-biopsy prostate MRI scans were conducted using a 3.0-T scanner (Discovery MR750, GE Medical Systems; Intera Achieva, Philips Medical Systems; TrioTim, Siemens) at the same institution. The MRI sequences included T1-weighted, T2-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging. Three board-certified radiologists, each with over 15 years of experience in genitourinary imaging, interpreted the MRI results. For patients with PI-RADS <3 lesions, only systematic prostate biopsies were performed by a single urologist. Total and free PSA levels were measured on the day of biopsy or within 1 month, and %fPSA was calculated as the ratio of free PSA to total PSA, multiplied by 100. CSC was defined as a Gleason grade group 2 or higher based on the biopsy results.
Sensitivity and specificity were calculated using receiver operating characteristic (ROC) curve analysis to determine the diagnostic performance of %fPSA in detecting CSC. The area under the curve (AUC) values were also determined. Statistical significance was set at 0.05, and all statistical analyses were performed using MedCalc® Statistical Software version 22.026 (MedCalc Software Ltd, Ostend, Belgium).
3. Results
Out of the 1435 patients included in this study, PC was diagnosed in 890 (62%), and CSC was detected in 699 (49%). Among the 1076 patients with PI-RADS ≥3, PC was diagnosed in 764 (71%), and CSC was detected in 625 (58%). Moreover, among the 349 patients with PI-RADS <3, PC was diagnosed in 126 (36%), and CSC was detected in 74 (21%).
A total of 208 patients with both PIRADS <3 and PSA≤10 ng/ml had available free PSA information. Baseline characteristics are shown in Table 1. The median age was 65 years old (interquartile range [IQR] 61–71), the median PSA was 5.1 ng/ml (IQR 4.0–7.1), and the median %fPSA was 18.2% (IQR 13.7–22.0). The cancer detection rate was 32.2%, with a CSC detection rate of 17.8%.
Table 1.
Patients’ characteristics.
| Variables | |
|---|---|
| No. of patients | 208 |
| Age, yr | 65 (61–71) |
| PSA, ng/ml | 5.06 (3.97–7.10) |
| Free PSA, ng/ml | 0.89 (0.63–1.23) |
| %fPSA, % | 18.16 (13.63–22.01) |
| PI-RADS, n (%) | |
| Score 1 | 138 (66.3) |
| Score 2 | 70 (33.7) |
| Pathology, n (%) | |
| Benign | 141 (67.8) |
| GGG1 | 30 (14.4) |
| GGG2 | 20 (9.6) |
| GGG3 | 9 (4.3) |
| GGG4 | 7 (3.4) |
| GGG5 | 1 (0.5) |
| Clinically significant cancer, n (%) | 37 (17.8) |
Data are expressed as median (interquartile range) unless otherwise specified.
%fPSA, free prostate-specific antigen ratio; GGG, Gleason grade group; PI-RADS, Prostate Imaging–Reporting and Data System; PSA, prostate-specific antigen.
Table 2 compares diagnostic performance for CSC by sensitivity, specificity, likelihood ratios, and ROC curve for various %fPSA cutoff values. A cutoff value of 17.6% yielded 86.5% sensitivity (95% confidence interval [CI] 71.2–95.5) and 63.7% specificity (95% CI 56.1–70.9) with AUC of %fPSA was 0.757 (95% CI 0.693–0.814, P < 0.001). In comparison, AUC for total PSA was 0.393 (95% CI 0.293-0.493, P = 0.041) and AUC for free PSA was 0.611 (95% CI 0.514-0.709, P = 0.050) (Fig. 1).
Table 2.
Sensitivity and specificity at various %fPSA cutoffs.
| %fPSA cutoff | Sensitivity (95% CI) | Specificity (95% CI) | Positive LR | Negative LR |
|---|---|---|---|---|
| 15.0% | 67.6 (50.2–82.0) | 75.4 (68.3–81.7) | 2.75 | 0.43 |
| 17.6% | 86.5 (71.2–95.5) | 63.7 (56.1–70.9) | 2.39 | 0.21 |
| 20.0% | 91.9 (78.1–98.3) | 46.8 (39.1–54.6) | 1.73 | 0.17 |
%fPSA, free prostate-specific antigen ratio; CI, confidential interval; LR, likelihood ratio.
Fig. 1.
ROC curve of free PSA ratio for detecting clinically significant cancer. PSA, prostate-specific antigen; ROC, receiver operating characteristic.
Table 3 presents the crosstab analysis using a %fPSA cutoff value of 17.6%. Among the 94 patients with %fPSA below 17.6%, 32 (34%) were diagnosed with CSC. Conversely, among the 114 patients with %fPSA above 17.6%, 5 (4%) had CSC.
Table 3.
Crosstab analysis according to a free PSA ratio cutoff value of 17.6%.
| %fPSA <17.6 | %fPSA ≥17.6 | Total | |
|---|---|---|---|
| CSC (−) | 62 (66%) | 109 (96%) | 171 (82%) |
| Benign | 50 | 91 | |
| GGG1 | 12 | 18 | |
| CSC (+) | 32 (34%) | 5 (4%) | 37 (18%) |
| GGG2 | 17 | 3 | |
| GGG3 | 8 | 1 | |
| GGG4 | 6 | 1 | |
| GGG5 | 1 | 0 | |
| 94 | 114 | 208 |
%fPSA, free prostate-specific antigen ratio; CSC, clinically significant cancer; GGG, Gleason grade group; PSA, prostate-specific antigen.
4. Discussion
We found that in patients with PI-RADS <3 and PSA ≤10 ng/ml, CSC was diagnosed in 34% (32/94) of those with %fPSA lower than 17.6%, who might have otherwise faced a delayed biopsy based on MRI findings. Conversely, among patients with %fPSA higher than 17.6%, 96% (109/114) were diagnosed with either no cancer or insignificant cancer, suggesting that unnecessary biopsies could be reduced in patients with elevated PSA levels.
Detecting CSC is crucial for achieving high cure rates and local disease control. In the PSA screening era, only 22% of patients with PSA levels in the gray zone of 4–10 ng/ml had a positive prostate biopsy.6 To enhance CSC diagnosis in this gray zone and reduce unnecessary biopsies, various additional tests are being utilized.3 Multi-parametric MRI has demonstrated an improved detection rate of CSC, with 33.3% for targeted biopsy compared to 23.6% for systematic biopsy.12 Consequently, the American Urological Association (AUA) and European Association of Urology (EAU) guidelines now recommend performing an MRI before a biopsy.13,14 The diagnosis rate for CSC in PI-RADS 3 lesions is considered equivocal, ranging from 22–32% in men.15,16 However, for MRI-negative cases, categorized as PI-RADS 2 or lower, diagnosis rates vary significantly among studies, ranging from less than 10% to as high as 40%.17, 18, 19 Given the potential to miss CSC in patients with PSA levels in the gray zone or in MRI-negative cases if biopsies are omitted, molecular biomarkers may complement PSA and MRI for early CSC detection.
Most molecular biomarkers for PC utilize PSA derivatives.3 PSA exists in multiple forms in the blood, with 10–30% of the protein found in a free or unbound state. PSA that is not bound to plasma proteins constitutes fPSA, which accounts for 5–35% of total PSA.20 The ratio of fPSA to total PSA, referred to as %fPSA, has been shown to increase the specificity of PSA for detecting PC, especially in men with PSA levels between 4 and 10 ng/ml. Those with %fPSA levels <10% have over a 50% probability of having PC, whereas those with levels >25% have less than a 10% chance of being diagnosed with PC.11,20,21 However, the ideal %fPSA cutoff remains unclear, with literature suggesting values between 10% and 25%. Most investigators use cutoff values between 15% and 20%.9,22,23 The prostate health index (PHI) involves measurement of -2proPSA, %fPSA, and total PSA, showing particular accuracy in men with PSA levels between 2 and 10 ng/ml.24,25 The cutoff value for PHI ranges from 15–45%, and the risk of missing cancer is less than 10% when using a 25% threshold.26 The 4 K score test measures total PSA, fPSA, intact PSA (a form of fPSA), and human kallikrein 2,27 with reported cutoff points varying from 41–57%. A meta-analysis comparing PHI and 4K score concluded that both tests exhibit similar diagnostic accuracy for high-grade PC.26
Although these biomarkers are considered in both the EAU and NCCN guidelines,14,28 the lack of consensus on cutoff values limits their utility. A systematic review analyzing 22 qualified guidelines for PC diagnosis found that approximately half of them did not recommend the use of additional biomarkers.29 Even when recommended, most markers are not advised for initial screening purposes.30 For instance, the National Academy of Clinical Biochemistry guideline recommended %fPSA as an aid in distinguishing PC from benign prostate hyperplasia when total serum PSA levels are between 4 and 10 ng/ml and the DRE is negative.7 Although the %fPSA, PHI, 4K score, and other markers may further define the probability of clinically significant cancer (CSC), the optimal application of these tests in conjunction with MRI remains unclear. However, since its approval by the FDA, %fPSA has gained widespread clinical acceptance and is included in guidelines as an option before initial biopsy and for those with a prior negative biopsy.28
Although the accuracy of biomarkers is crucial, in cases where an expensive MRI (average $964.21 in the United Kingdom as of 2016) has already been performed alongside PSA testing, the additional cost of biomarkers may further increase the financial burden on the patient.31 In previous studies evaluating cost-effectiveness, the cost of the PHI test showed large differences across countries and regions. In the United States (US), the average cost was $71.95 (range: $50–94) as of 2009, whereas in Europe, it averaged €78 ($114.66) in 2008. In China, the cost ranged from $72 to $130 as of 2019.32, 33, 34 The cost of the %fPSA test in the US averaged $40 (range: $20–60) as of 2001, whereas in Europe, it averaged €19.14 ($21.75) in 2001, making it relatively less expensive than the PHI test.35,36
The recently published largest prospective study examining %fPSA and PC outcomes with a 20-year follow-up has underscored the significance of %fPSA. The study compared patients with baseline PSA levels of 2–10 ng/ml, assessing the predictive ability for CSC when using PSA alone versus PSA combined with %fPSA. In younger men aged 55–64 years, the predictive ability, as indicated by the C index, improved from 0.56 to 0.60 for CSC. For older men aged 65–74 years, the C index for CSC improved from 0.60 to 0.66. Moreover, %fPSA showed a significant correlation with CSC (hazard ratio [HR] 1.05, P < 0.001) for each 1% decrease. Additionally, it improved CSC prediction across all racial groups. The authors confirmed that incorporating %fPSA in men with baseline PSA levels of ≥2 ng/ml improved the prediction of CSC, and they recommended using %fPSA to risk-stratify screening.9
In this study, we evaluated the diagnostic performance of the 17.6% %fPSA cutoff value identified through ROC analysis, comparing it to the conventional cutoffs of 15% and 20%.9,22,23 The results indicated that the 17.6% cutoff offered enhanced sensitivity, suggesting a greater ability to identify true positive cases of CSC. However, this increase in sensitivity was accompanied by a decrease in specificity compared to the 15% cutoff, raising concerns about the potential for false positives. Similarly, the 20% cutoff also showed a trade-off, showing higher sensitivity and lower specificity. While selecting an optimal %fPSA cutoff that balances sensitivity and specificity, we also considered the LRs. Given that a higher positive LR indicates a more convincing positive result and a lower negative LR indicates a more convincing negative result, we found that the 17.6% value determined through ROC analysis was the most informative among the three values.
The limitation of this study was that it represented a single-center retrospective analysis. Despite this limitation, several strengths enhanced the validity of the findings. All biopsies were performed by a single experienced surgeon using the same PSA assay, which minimized variability associated with surgeon factors and laboratory environments. Variations in these factors may exist across different institutions, potentially influencing the results. Additionally, using %fPSA in conjunction with PSA and MRI as a triage method provided a more accurate identification of patients with CSC, particularly those with negative MRI results. Further validation studies are required to strengthen our findings and support the integration of these biomarkers into clinical practice.
In conclusion, in patients with PI-RADS <3 and PSA ≤10 ng/ml, %fPSA values < 17.6% may facilitate early PC diagnosis in those who might not undergo biopsy based on MRI results alone. Additionally, unnecessary biopsies could be avoided in patients with elevated PSA levels when %fPSA exceeds 17.6%.
Authors’ contribution
Research conception and design: Ji Eun Heo, Jongsoo Lee.
Data acquisition: Hyun Ho Han, Won Sik Jang.
Statistical analysis and interpretation: Jongsoo Lee, Won Sik Ham.
Drafting of the manuscript: Ji Eun Heo, Jongsoo Lee.
Critical revision of the manuscript: Woong Kyu Han, Young Deuk Choi.
Supervision: Jongsoo Lee.
Approval of the final manuscript: all authors.
Ethics statement
This study was approved by the Institutional Review Board (IRB) of Yonsei University Severance Hospital (IRB number: 4-2024-0292), and the requirement for informed consent was waived due to the retrospective nature of the study.
Availability of data and materials
As this study covers an extremely specific population, our data set is potentially identifying patient information even after proper de-identification. Still, our data can be shared upon request. Contact for our data can be made through the institutional review board (Yonsei-IRB, irb@yuhs.ac).
Funding
This study was supported by a new faculty research seed money grant of Yonsei University College of Medicine for 2024 (2024-32-0065) and National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1A2C3005586).
Conflicts of interest
The authors have no financial conflicts of interest to declare.
Acknowledgments
None.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
As this study covers an extremely specific population, our data set is potentially identifying patient information even after proper de-identification. Still, our data can be shared upon request. Contact for our data can be made through the institutional review board (Yonsei-IRB, irb@yuhs.ac).