{"product_id":"new-prostate-cancer-biomarkers-a-guide-for-patients-and-clinicians","title":"New Prostate Cancer Biomarkers: A Guide for Patients and Clinicians","description":"\u003cp\u003eThis review article explains how newer prostate cancer biomarkers can improve on the standard PSA blood test. The authors describe serum, urine, and tissue tests that help doctors decide whether to perform a prostate biopsy, whether to repeat a biopsy, and how to choose treatment. The article reports specific performance data for each test, including the Prostate Health Index (PHI) and the 4Kscore, and notes that professional guidelines now recommend considering these tests. The authors conclude that biomarkers are most useful when combined with MRI and risk calculators, but that optimal cutoff values and cost-effectiveness remain unresolved.\u003c\/p\u003e\n\n\u003ch1\u003eNew Prostate Cancer Biomarkers: A Guide for Patients and Clinicians\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Prostate Cancer Is Hard to Manage\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#psa-limits\"\u003eThe Limits of the PSA Test\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#prebiopsy\"\u003eBiomarkers for the Initial Diagnosis (Before Biopsy)\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#phi\"\u003eThe Prostate Health Index (PHI)\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#4kscore\"\u003eThe 4Kscore Test\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#other-tests\"\u003eOther Biomarkers and Tests\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#guidelines\"\u003eWhat Guidelines Recommend\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations and Open Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003ePSA alone is imperfect: at a cutoff of 4 ng\/mL, it detects 21% of any prostate cancer and 51% of clinically significant prostate cancer.\u003c\/li\u003e\n\u003cli\u003eGuidelines recommend considering additional biomarker tests before deciding on a prostate biopsy, especially for PSA in the unclear middle range.\u003c\/li\u003e\n\u003cli\u003eThe PHI and 4Kscore are serum tests with the most supporting evidence; both can reduce unnecessary biopsies while missing relatively few significant cancers.\u003c\/li\u003e\n\u003cli\u003eBiomarkers perform better when combined with MRI or risk calculators; for example, PHI plus MRI achieved an AUC of 0.84 for clinically significant cancer.\u003c\/li\u003e\n\u003cli\u003eNo optimal cutoff values are established, cost-effectiveness is unresolved, and many studies were retrospective and underpowered.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Prostate Cancer Is Hard to Manage\u003c\/h2\u003e\n\n\u003cp\u003eProstate cancer is the most commonly diagnosed cancer in urology practice. It is also the leading cause of cancer-related death in this patient population. Prostate cancer remains a major public health issue worldwide.\u003c\/p\u003e\n\n\u003cp\u003eDoctors have improved prognosis and cancer-specific survival in recent years. They have done this by introducing more treatment options and approving more therapeutic agents. Despite these advances, managing prostate cancer has become more challenging, not less.\u003c\/p\u003e\n\n\u003cp\u003eOne core problem is that current risk stratification systems have limitations. These systems group patients by risk, but they struggle to provide a personalized, patient-centered management strategy. Another problem is that prostate cancer behaves very differently from patient to patient.\u003c\/p\u003e\n\n\u003cp\u003ePatients in the same risk group can have very different outcomes. Some have indolent disease (a slow-growing cancer that will never progress and needs no treatment). Others have aggressive disease (a cancer likely to progress and cause death). This heterogeneity (wide variation in behavior) affects clinical decision-making and oncological outcomes, regardless of the treatment strategy chosen.\u003c\/p\u003e\n\n\u003cp\u003eSeveral biomarkers and available tests have been developed to help clinicians in difficult decision-making scenarios. This review article focuses on the scientific evidence that supports the clinical use of several biomarkers. Professional urological societies consider these biomarkers, and uro-oncological guidelines include them. The article covers the diagnosis process and specific difficult management strategies for clinically localized or advanced prostate cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"psa-limits\"\u003eThe Limits of the PSA Test\u003c\/h2\u003e\n\n\u003cp\u003eThe discovery of serum PSA (prostate-specific antigen, a protein measured in blood) revolutionized the diagnostic process and disease management of prostate cancer. To date, PSA is the only universally accepted biomarker in urological practice worldwide. Doctors use PSA for early diagnosis (screening), definitive diagnosis (prostate biopsy), prognosis, and therapeutic decisions.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the serum PSA test has only modest performance characteristics. It detects any prostate cancer or clinically significant prostate cancer (csPC, defined by a Gleason score of 7 or higher) imperfectly. This was true in both historical and contemporary patient cohorts.\u003c\/p\u003e\n\n\u003cp\u003eIn a systematic review, a PSA cutoff level of 4 ng\/mL had a sensitivity of 21% for detecting any prostate cancer. The same cutoff had a sensitivity of 51% for detecting clinically significant prostate cancer. Sensitivity means the test's ability to correctly identify patients who have the disease.\u003c\/p\u003e\n\n\u003cp\u003eSerum PSA is not a cancer-specific biomarker. Routine population-based screening using PSA testing was frequently associated with clinical harm. The main harms were an increased risk of overdiagnosis (finding cancers that would never cause problems) and overtreatment (treating cancers that did not need treatment).\u003c\/p\u003e\n\n\u003cp\u003eIn addition, there is no universally accepted serum PSA value that accurately indicates when to perform a prostate biopsy. Serum PSA also cannot differentiate between indolent and aggressive forms of prostate cancer.\u003c\/p\u003e\n\n\u003cp\u003eFor these reasons, urological associations and experts now recommend using serum PSA together with other tools. These tools help with screening, with assessing whether a prostate biopsy is appropriate, and with identifying aggressive cancer behavior.\u003c\/p\u003e\n\n\u003cp\u003eNumerous biomarkers and prognostic or predictive tools have been developed to improve the accuracy of serum PSA. Emphasis was placed on identifying clinically significant prostate cancer and helping clinicians in difficult decisions. These decisions include:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePrebiopsy: whether to perform a biopsy or not\u003c\/li\u003e\n\u003cli\u003ePre-treatment: identifying which patients will benefit most from active surveillance (AS, careful monitoring instead of immediate treatment), specific curative therapies, or a multimodal approach\u003c\/li\u003e\n\u003cli\u003ePost-treatment: choosing the most beneficial adjuvant treatment (treatment given after the main treatment)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAn ongoing concern among urologists is that prostate cancer has a recognized heterogeneous clinical and biological behavior. Patients in the same prognostic-risk group can still have very different disease courses. In daily uro-oncological practice, doctors must manage patients with localized, advanced, or progressive disease that behaves either indolently or aggressively, regardless of the initial disease stage or treatment strategy.\u003c\/p\u003e\n\n\u003cp\u003eTo date, despite improvements in prostate cancer staging, imaging, pathology, and risk stratification tools, there are no means to accurately differentiate indolent from aggressive forms of prostate cancer. There are also no means to predict the aggressiveness of the disease or the responsiveness to a specific therapy. Adequate characterization of each patient, from initial diagnosis and throughout the disease course, is crucial for establishing an appropriate therapeutic strategy and improving specific survival.\u003c\/p\u003e\n\n\u003ch2 id=\"prebiopsy\"\u003eBiomarkers for the Initial Diagnosis (Before Biopsy)\u003c\/h2\u003e\n\n\u003cp\u003eThere has been an increasing incidence of prostate cancer and metastatic forms among patients diagnosed after the 2012 USPSTF (U.S. Preventive Services Task Force) recommendation. In response, many urological associations strongly recommend using serum PSA together with other biomarkers, magnetic resonance imaging (MRI), or tools such as risk calculators (RC). This happens in a shared decision-making process.\u003c\/p\u003e\n\n\u003cp\u003eThe goals are to optimize the initial diagnosis process and increase the detection rate of clinically significant prostate cancer. The goals are also to reduce the potential harms related to biopsy procedures, such as overdiagnosis or overtreatment.\u003c\/p\u003e\n\n\u003cp\u003eIn 2021, the EAU (European Association of Urology) developed a risk-adapted strategy for early prostate cancer detection. The strategy starts with an initial serum PSA value in properly counselled patients aged 50 to 70 years. It then follows a step-by-step post-screening risk stratification algorithm for patients with a PSA value of 3 ng\/mL or higher.\u003c\/p\u003e\n\n\u003cp\u003eThis algorithm uses risk calculators based on family history, PSA density, PSA velocity, digital rectal examination (DRE), and subsequently MRI nomograms. A nomogram is a tool that combines several factors to estimate risk. The goal is to identify high-risk patients harboring clinically significant prostate cancer at systematic and targeted biopsy.\u003c\/p\u003e\n\n\u003cp\u003eIn the authors' opinion, this strategy will have a positive impact. It should reduce prostate cancer-specific mortality rates and the incidence of advanced-stage disease. It should also avoid the risks associated with overdiagnosis and overtreatment.\u003c\/p\u003e\n\n\u003cp\u003eTwo widely used risk calculators are the ERSPC-RC (the European Randomized Study of Screening for Prostate Cancer risk calculator) and the PCPT-RC (the Prostate Cancer Prevention Trial Risk Calculator). Both were developed and independently validated to estimate the risk of prostate cancer detection and high-grade prostate cancer (HGPC) when a prostate biopsy is performed.\u003c\/p\u003e\n\n\u003cp\u003eNotably, the diagnostic accuracy of these risk calculators can be improved by including a serum PHI (Prostate Health Index) score or urinary biomarkers. These urinary biomarkers include PCA3 (Prostate Cancer Antigen 3), MiPS (Michigan Prostate Score), and T2:ERG. The improvement is particularly relevant for detecting clinically significant prostate cancer.\u003c\/p\u003e\n\n\u003cp\u003eSeveral serum, urinary, and tissue biomarkers have been developed to help urologists and their patients in the initial diagnosis process. They help particularly with the decision to perform a prostate biopsy or re-biopsy, to avoid unnecessary biopsies, and to increase specificity without missing a substantial number of clinically significant cancers. They also help limit the risks associated with prostate biopsies, mainly for serum PSA in the gray zone (an unclear middle range of values).\u003c\/p\u003e\n\n\u003cp\u003eTable 1 of the original article lists biomarkers recommended by experts to improve the probability of detecting clinically significant prostate cancer. The recommendations differ between initial biopsy and repeat biopsy settings.\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eNCCN v2.2023 prostate cancer early detection guidelines: for initial biopsy, %fPSA, PHI, 4K, SelectMDX, EXODx (EPI), MyProstateScore (MPS), and IsoPSA. For repeat biopsy, %fPSA, PHI, 4K, EXODx (EPI), PCA3, ConfirmMDX, MPS, and IsoPSA.\u003c\/li\u003e\n\u003cli\u003eEAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer 2023: for initial biopsy, PHI, 4K, PCA3, SelectMDX, MiPS, EXODx (EPI), and IsoPSA; for repeat biopsy, PHI, 4K, PCA3, SelectMDX, and ConfirmMDX\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eTable 2 of the original article summarizes the potential clinical utility of each recommended biomarker. The table covers the assay and company, the biomarkers used, the output, how to interpret the result, and the potential clinical use.\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003ePHI (Beckman Coulter Inc., Brea, CA, USA):\u003c\/strong\u003e uses free PSA, [-2] proPSA, and total PSA. The output is a PHI score ranging from 0 to 100. A cutoff of 27 applies when a prior multiparametric MRI was negative. Biopsy is recommended at a PHI score of 36 or higher. A higher score is associated with a greater risk of detecting prostate cancer, a higher pathological Gleason score, and a higher stage. It is a stronger predictor in combination with the ERSPC risk calculator, MRI, or the 4Kscore. Potential use: screening and active surveillance to improve biopsy decisions in patients with suspicious PSA levels and a normal digital rectal examination.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e4K (OPKO Lab, Nashville, TN, USA):\u003c\/strong\u003e uses total PSA, free PSA, intact PSA, and human kallikrein protein 2. The output is a 4Kscore ranging from 0 to 100. Low risk is 1 to 7.5; high risk is 20 or higher. A higher risk is associated with a higher probability of detecting clinically significant prostate cancer, aggressive pathology, or progression to metastasis or death. Potential use: screening and active surveillance, prediction of developing prostate cancer and metastasis, and better predictive performance in combination with the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and MRI.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePCA3 (Progensa PCA3 assay; Gen-Probe, San Diego, CA, USA):\u003c\/strong\u003e uses mRNA PCA3 and mRNA PSA. The output is a PCA3 score. Cutoff stratification is below 20, 20 to 60, and above 60 for predicting a positive biopsy. Increasing PCA3 scores were associated with a high probability of detecting any prostate cancer and high-grade prostate cancer. Potential use: re-biopsy decision-making in patients with suspicious PSA levels and a normal digital rectal examination. Potential use: better predictive performance in combination with risk calculators (PCPT-RC, ERSPC-RC) and among patients with low suspicion scores on MRI at a PCA3 score above 35.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMiPS (MiPS, Mlabs, Ann Arbor, MI, USA):\u003c\/strong\u003e uses serum PSA and two urinary biomarkers (PCA3 and TMPRSS2:ERG). The output is a MiScore ranging from 0 to 100%. A MiScore of 10 or less could exclude Gleason grade group 2 or higher cancer. The higher the score, the greater the risk of aggressive cancer. Potential use: prediction of clinically significant prostate cancer in patients with suspicious PSA levels, and better predictive performance of MiPS with PSA, PCA3, or a risk calculator (PCPT-RC).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSelectMDX (MDxHealth, Inc., Irvine, CA, USA):\u003c\/strong\u003e uses mRNA of the HOXC6 gene (a proliferation gene) and the DLX1 gene (a progression gene). The output is a risk score ranging from minus 6 to 6, with a cutoff of minus 2.8. A positive test is a risk score of minus 2.8 or higher. The higher the score, the greater the risk of aggressive cancer. Potential use: prediction of clinically significant prostate cancer in patients with suspicious PSA levels with or without an abnormal digital rectal examination. Potential use: to be considered in combination with an MRI-based strategy (PSA above 3 ng\/mL and PIRADS score 4 to 5, or PIRADS score 1 to 3 followed by a positive SelectMDX).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eExoDx Prostate (INTELLISCORE) (EPI; Exosome Diagnostics, Cambridge, MA, USA):\u003c\/strong\u003e uses three urinary exosomal RNAs (ERG and PCA3 normalized to SPDEF). The output is a risk score ranging from 0 to 100, with a cutoff of 15.6. A score above 15.6 indicates a high risk of prostate cancer with a Gleason score above 7. Potential use: prediction of clinically significant prostate cancer among patients with suspicious serum PSA levels or digital rectal examination. Potential use: better when combined with standard-of-care clinical variables (PSA level, age, race, and family history).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eConfirmMDX (MDxHealth, Inc., Irvine, CA, USA):\u003c\/strong\u003e uses DNA methylation of the GSTP1, APC, and RASSF1 genes. The output is a DNA methylation result. A positive assay means the doctor should consider re-biopsy. Potential use: prediction of prostate cancer in repeat biopsy settings. Data regarding its clinical utility in predicting clinically significant prostate cancer are expected.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThere are many issues regarding the clinical utility and cost-effectiveness of these biomarkers. These issues include insufficient and inconsistent results, numerous retrospective and underpowered studies, a lack of clinical validation and comparative studies, and no established optimal cutoff test value.\u003c\/p\u003e\n\n\u003cp\u003eDespite these issues, current uro-oncological guidelines for early detection of prostate cancer recommend considering such additional testing before making the decision to perform a biopsy. Multiparametric MRI (mpMRI) now provides significant clinical benefit and is widely used in the initial diagnosis process of prostate cancer. In this context, it is important to reevaluate the role of these biomarkers. It is also important to establish which patients are most likely to benefit from MRI or biomarker use, and in which diagnostic setting and sequence.\u003c\/p\u003e\n\n\u003ch2 id=\"phi\"\u003eThe Prostate Health Index (PHI)\u003c\/h2\u003e\n\n\u003cp\u003ePHI is an FDA-approved test. It uses the serum values of free PSA, [-2] proPSA, and total PSA to calculate a prognostic score called the PHI score. The formula is ([-2] proPSA\/free PSA) multiplied by the square root of total serum PSA. The test detects prostate cancer and distinguishes benign from tumor lesions in patients over 50 years with a serum PSA level between 4 and 10 ng\/mL and a normal digital rectal examination.\u003c\/p\u003e\n\n\u003cp\u003eSeveral clinical studies have shown that the PHI test is a stronger predictor of a positive biopsy compared to serum PSA or its individual components. This applies to the detection of any prostate cancer and clinically significant prostate cancer, particularly in patients with total PSA levels between 4 and 10 ng\/mL.\u003c\/p\u003e\n\n\u003cp\u003eIn a meta-analysis of 28 studies including 16,762 patients, the PHI test showed a pooled sensitivity and specificity of 89% and 34% for detecting prostate cancer. For detecting high-grade prostate cancer, the pooled sensitivity and specificity were 93% and 34%.\u003c\/p\u003e\n\n\u003cp\u003eIt is clinically important to note that the PHI test improves diagnostic accuracy over serum PSA, depending on the cutoff value used. It helps reduce unnecessary biopsies by 15% to 45% and reduces detection of insignificant prostate cancer. However, it also misses a substantial number of prostate cancers, up to 10% at a cutoff of 25.\u003c\/p\u003e\n\n\u003cp\u003eTwo studies addressed the potential clinical utility of the PHI test in helping urologists decide whether to perform a prostate biopsy. The studies involved patients with serum PSA between 4 and 10 ng\/mL and a normal digital rectal examination.\u003c\/p\u003e\n\n\u003cp\u003eIn the single-center prospective study conducted by Tosoian and colleagues, using the PHI test in clinical assessment was associated with a 9% decrease in prostate biopsies. The rate of high-grade prostate cancer was unchanged. No patient with a PHI score below 21.2 had clinically significant prostate cancer. In contrast, 76% of patients with a PHI score of 55 or higher were diagnosed with a Gleason score of 7 or higher.\u003c\/p\u003e\n\n\u003cp\u003eA cutoff value of 27 discriminated between clinically significant prostate cancer and insignificant prostate cancer for patients with a prior mpMRI and PIRADS scores of 3 or lower. The authors also showed that the PHI score increased with higher pathological Gleason score (p = 0.002) and pathological stage (p = 0.001). They found that PHI density, calculated using the formula PHI score divided by prostate volume, is a promising biomarker for detecting clinically significant prostate cancer. A cutoff value of 0.43 had a sensitivity of 0.98 and a specificity of 0.38.\u003c\/p\u003e\n\n\u003cp\u003eIn the other recently published multicenter prospective study conducted by White and colleagues, the PHI test was significantly associated with a 23.9% reduction in prostate biopsies. It influenced the urologist's biopsy decision management plan in 72.5% of cases. The study used a questionnaire to assess whether the PHI test impacted the biopsy decision compared with the same urologist's previous management plan based on routine TRUS-guided biopsy. Urologists were more likely to recommend a biopsy based on an intermediate-to-high-risk PHI score (PHI of 36 or higher).\u003c\/p\u003e\n\n\u003cp\u003eAdditionally, the predictive role of the PHI test for a positive biopsy was shown in combination with the ERSPC risk calculator, MRI, or other biomarkers. PHI-based ERSPC calculators outperformed PSA-based risk calculators for predicting prostate cancer and clinically significant prostate cancer in several studies.\u003c\/p\u003e\n\n\u003cp\u003eThe studies of Gnanapragasam and colleagues demonstrated that the PHI test was not only a stronger predictor of a positive MRI. The combination of PHI with MRI also improved the prediction of clinically significant prostate cancer, with an AUC (area under the curve, a measure of test accuracy) of 0.84.\u003c\/p\u003e\n\n\u003cp\u003eAt a cutoff value of 30, the PHI test reduced the rate of biopsies performed in patients with suspicious mpMRI lesions by 25%, while missing 6% of clinically significant prostate cancers. The rate of biopsies performed after using the combined results from both the PHI test and MRI was reduced by 40%.\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, the combination of the PHI test and MRI in the re-biopsy setting missed only 1 of 21 clinically significant prostate cancers. At a PHI test cutoff value of 35, it had a sensitivity of 0.99 (range 0.94 to 1). It had a specificity of 0.17 (range 0.12 to 0.23). It had a positive predictive value (PPV) of 0.38 (range 0.32 to 0.44). It had a negative predictive value (NPV) of 0.97 (range 0.84 to 1).\u003c\/p\u003e\n\n\u003cp\u003eTherefore, these studies provide scientific evidence that the PHI test and MRI are complementary before performing a prostate biopsy.\u003c\/p\u003e\n\n\u003cp\u003eIn a prospective study performed on 177 patients with prostate cancer treated by radical prostatectomy (RP, surgical removal of the prostate), Francesco Gentile and colleagues showed something. An artificial neural network-based approach combining mpMRI and PHI could predict clinically significant prostate cancer at initial diagnosis. It had a sensitivity of 80% and a specificity of 68%. This method could be helpful in the individualized management of these patients.\u003c\/p\u003e\n\n\u003cp\u003eIn another study, the combination of PHI and Proclarix (a risk score based on thrombospondin-1, cathepsin D, total PSA, free PSA, and patient age) was evaluated. The combination had a significantly higher diagnostic accuracy for clinically significant prostate cancer compared to the individual tests alone. The AUC for the biopsy grade endpoint was 0.82 (95% confidence interval: 0.77 to 0.87). The AUC for the pathological grade endpoint was 0.84 (95% confidence interval: 0.80 to 0.88).\u003c\/p\u003e\n\n\u003cp\u003eSome studies documented the role of the PHI test as a predictor of unfavorable pathological findings in radical prostatectomy specimens. The PHI test predicted a pT3 stage or a pathological Gleason score of 7 or higher. However, it did not improve clinical decision-making.\u003c\/p\u003e\n\n\u003cp\u003eThe use of the PHI test in clinical practice is limited by several factors. These include the lack of an appropriate cutoff value based on strong scientific evidence for biopsy decision-making. These include its use in particular settings (prebiopsy or re-biopsy settings, with or without mpMRI, before or after mpMRI), and its cost-effectiveness. Although current guidelines mention the PHI test to improve the strategy of prostate cancer management, its role remains to be fully determined. Its role remains to be fully determined in conjunction with patient cancer history, risk calculators, and MRI.\u003c\/p\u003e\n\n\u003ch2 id=\"4kscore\"\u003eThe 4Kscore Test\u003c\/h2\u003e\n\n\u003cp\u003eThe 4Kscore combines serum levels from a panel of four kallikrein prostate-specific biomarkers. These are total PSA, free PSA, intact PSA, and human kallikrein protein 2 (hK2). It combines these with clinical parameters (age, prior biopsy status, and digital rectal examination) in an algorithm called the OPKO algorithm.\u003c\/p\u003e\n\n\u003cp\u003eThe test predicts aggressive forms of prostate cancer (Gleason score of 7 or higher). It discriminates between indolent disease (low-risk 4Kscore between 1 and 7.5) and clinically significant prostate cancer (high-risk 4Kscore of 20 or higher). This discrimination is in patients with suspicious PSA levels or digital rectal examination at the initial or repeat set of biopsy.\u003c\/p\u003e\n\n\u003cp\u003eIn fact, the 4Kscore gives an individualized risk prediction score. This is a probability of detecting aggressive prostate cancer from 1 to 100. It helps urologists in biopsy clinical decision-making. For example, urologists can consider biopsying a younger man with or without additional prostate cancer risk factors at a cutoff value below 7.5. They can consider biopsying an older man with significant comorbidities at higher cutoff values.\u003c\/p\u003e\n\n\u003cp\u003eThe clinical usefulness of the 4Kscore in the initial diagnosis process of prostate cancer has been demonstrated in numerous trials and clinical utility studies. This applies particularly to the decision to perform a prostate biopsy or re-biopsy in patients (unscreened or prior screened) thought to harbor aggressive prostate cancer (Gleason score of 7 or higher). Its additional impact in avoiding unnecessary biopsies has also been demonstrated.\u003c\/p\u003e\n\n\u003cp\u003eA systematic review and meta-analysis conducted by Zappala and colleagues in 2017 evaluated its predictive accuracy for detecting aggressive prostate cancer. It showed a pooled discrimination (AUC) value above 0.8 across multiple US and European studies. This was compared with standard-of-care models based on age, PSA, and digital rectal examination. It was also compared with respect to changes in the algorithm and contemporary guidelines, reflecting changes in biopsy procedure or the Gleason grading report system.\u003c\/p\u003e\n\n\u003cp\u003eIn the first prospective US study, which enrolled 1,012 patients in the validation phase, the authors reported a predictive accuracy of 0.82. For clinical utility purposes, they showed that using a 4Kscore cutoff value of 7.5 for predicting a Gleason score of 7 or higher could avoid 36% of prostate biopsies. Only 1.7% of diagnoses of clinically significant prostate cancer would be delayed (the majority were Gleason 3+4 and none were Gleason 8 or higher). Overall, this represented a 30% to 58% reduction in unnecessary biopsies, while only 1.3% to 4.7% of Gleason score 7 or higher cancers were missed.\u003c\/p\u003e\n\n\u003cp\u003eThe decision curve analysis performed to investigate the net clinical benefit showed a higher AUC compared with the commonly used PCPT-RC v2.0 across all risk cutoffs. Net clinical benefit was defined by benefit due to true positive results versus harm due to false negative results.\u003c\/p\u003e\n\n\u003cp\u003eIn another prospective clinical trial conducted in 6,129 patients with PSA of 3 ng\/mL or higher undergoing 10 core biopsies, the 4Kscore showed higher predictive accuracy for any prostate cancer or high-grade prostate cancer compared with a model based on PSA or age. Moreover, the authors showed that a cutoff of 6 for predicting high-grade prostate cancer would avoid 428 unnecessary biopsies from 1,000 screened patients. It would detect 119 high-grade prostate cancers from 1,000 patients and delay diagnosis in 14 patients out of 133.\u003c\/p\u003e\n\n\u003cp\u003eA meta-analysis performed by Voigt and colleagues in 2014 using data from more than 8,500 patients showed a statistically significant improvement. The improvement was of 10% to 13% in the urologist's ability to correctly identify any prostate cancer. It also showed an 8% to 10% improvement in correctly identifying any high-grade prostate cancer. This was based on the discrimination accuracy of the 4Kscore compared with any of its individual parameters.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, this meta-analysis showed that 48% to 56% of prostate biopsies performed for PSA of 3 ng\/mL or higher could be avoided. The rate of delayed diagnosis of high-grade prostate cancer or any prostate cancer was 0.63% to 0.70% and approximately 7%, respectively.\u003c\/p\u003e\n\n\u003cp\u003eIn another clinical utility study, Konety and colleagues showed that performing a 4Kscore test in urological practice before a patient's referral to a biopsy procedure (prebiopsy settings) influenced the biopsy decision. The biopsy decision was influenced in 88.7% of cases. Stratifying patients into low (below 7.5%), intermediate, and high risk (20% or higher) groups led to a 64.6% reduction in prostate biopsies. Also in this study, the 4Kscore risk groups were associated with biopsy findings on pathological specimens.\u003c\/p\u003e\n\n\u003cp\u003eA meta-analysis was conducted to compare the accuracy in the diagnosis of prostate cancer and clinical usefulness of the 4Kscore and PHI tests. The meta-analysis revealed that both tests performed similarly in detecting overall prostate cancer and high-grade prostate cancer (Gleason score of 7 or higher). The AUC was 0.82 for PHI and 0.81 for 4Kscore. For high-grade prostate cancer, the pooled sensitivity was 0.93 for PHI and 0.87 for 4Kscore. The pooled specificity was 0.34 for PHI and 0.61 for 4Kscore.\u003c\/p\u003e\n\n\u003cp\u003eThe clinical utility of the 4Kscore has also been demonstrated in treatment decision-making. Examples include predicting the reclassification of prostate cancer patients on active surveillance or predicting unfavorable pathological findings on radical prostatectomy specimens.\u003c\/p\u003e\n\n\u003cp\u003eIn a cohort of 392 screened patients who were diagnosed with prostate cancer at PSA of 3 ng\/mL or higher and underwent radical prostatectomy, the 4Kscore showed a higher predictive accuracy for detecting aggressive pathology compared to a clinical model based on age, stage, PSA, and biopsy Gleason. Aggressive pathology was defined by pT3-T4, extracapsular extension, tumor volume above 0.5 cmc, or Gleason grade of 4 or higher. The AUC was 0.84 versus 0.81. In addition, the authors reported that using the 4Kscore would avoid 14% of unnecessary surgeries.\u003c\/p\u003e\n\n\u003cp\u003eOther authors showed the usefulness of the 4Kscore in predicting more significant clinical outcomes, such as the risk of progression to metastasis or death from prostate cancer. In a population-based case-control study that included 40,379 patients, Stattin and colleagues showed that the 4Kscore improves the prediction of distant prostate cancer metastases occurring 10 and 20 years later.\u003c\/p\u003e\n\n\u003cp\u003eThe study revealed that in 50- and 60-year-old patients with a PSA above 2 ng\/mL, the AUC for distant metastasis was improved with the 4Kscore compared with PSA alone. At age 50, the AUC was 0.75 for total PSA alone versus 0.86 for the 4Kscore. At age 60, the AUC was 0.805 versus 0.875.\u003c\/p\u003e\n\n\u003cp\u003eMoreover, a low-risk 4Kscore predicted a low risk of developing prostate cancer metastasis. For example, a 60-year-old patient with a PSA of 3 ng\/mL or higher and a 4Kscore below 7.5% has a risk of 0.2% and 1.8% of developing distant metastasis by 10 or 15 years later. These data support a risk-based adapted strategy for prostate cancer screening and early detection based on using the 4Kscore, similar to recommendations proposed recently by EAU experts.\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, to improve the biopsy decision-making protocol and facilitate the detection of clinically significant prostate cancer, the 4Kscore was investigated in combination with a risk calculator or MRI.\u003c\/p\u003e\n\n\u003cp\u003eA recent prospective study enrolled 2,872 men who underwent an initial prostate biopsy for a PSA level of 3.0 ng\/mL or higher. It showed a significant improvement in the predictive performance of clinically significant prostate cancer. This improvement was for the combination of the 4Kscore with the Rotterdam Prostate Cancer Risk Calculator (RPCRC, including age, PSA value, digital rectal examination abnormalities, and DRE-based prostate volume estimates). The combination had an AUC of 0.89, with a sensitivity of 88% and a specificity of 71% at a 5% risk cutoff. This compared to an AUC of 0.88 for the 4Kscore alone (p \u0026lt; 0.01) and an AUC of 0.87 for the RPCRC alone (p \u0026lt; 0.01).\u003c\/p\u003e\n\n\u003cp\u003eIn addition, depending on the cutoff used, the combined 4Kscore-RPCRC model reduced the number of unnecessary prostate biopsies by 60% to 80%. It missed only 1% to 2% of clinically significant prostate cancers, with an additional net reduction of 3.3 to 7.2 biopsies per 100 patients. However, the clinical benefit must be weighed against additional costs associated with this model.\u003c\/p\u003e\n\n\u003cp\u003eThe clinical utility of the 4Kscore in combination with MRI was reported in a recently published study of 574 patients. These patients underwent systematic or combined MRI\/TRUS fusion biopsy for a 4Kscore test above 7%, an abnormal digital rectal examination, or a PI-RADS score of 3 or higher. This was according to PIRADS version 2.\u003c\/p\u003e\n\n\u003cp\u003eThe authors developed and validated a nomogram incorporating age, prostate volume, prior negative biopsy, digital rectal examination findings, 4Kscore, and PI-RADS score. The nomogram showed an AUC of 0.88 for predicting clinically significant prostate cancer. When a prediction model with a threshold of 30 was used, the authors found that 30% of overall biopsies, 41% of benign biopsies, and 19% of indolent prostate cancers could be avoided. The authors also found that 9% of clinically significant prostate cancers could be missed.\u003c\/p\u003e\n\n\u003ch2 id=\"other-tests\"\u003eOther Biomarkers and Tests\u003c\/h2\u003e\n\n\u003cp\u003eThe original article also describes several other tests that guidelines recommend. These include urinary and tissue biomarkers used in both initial and repeat biopsy settings.\u003c\/p\u003e\n\n\u003cp\u003ePCA3 is a urinary biomarker measured by the Progensa PCA3 assay. Doctors use cutoff stratification (below 20, 20 to 60, and above 60) to predict a positive biopsy. Increasing PCA3 scores were associated with a high probability of detecting any prostate cancer and high-grade prostate cancer. The test is used for re-biopsy decision-making in patients with suspicious PSA levels and a normal digital rectal examination. It performs better in combination with risk calculators (PCPT-RC and ERSPC-RC) and among patients with low suspicion scores on MRI at a PCA3 score above 35.\u003c\/p\u003e\n\n\u003cp\u003eMiPS (Michigan Prostate Score) uses serum PSA and two urinary biomarkers (PCA3 and TMPRSS2:ERG). A MiScore of 10 or less could exclude Gleason grade group 2 or higher cancer. The higher the score, the greater the risk of aggressive cancer. The test predicts clinically significant prostate cancer in patients with suspicious PSA levels. MiPS performs better in combination with PSA, PCA3, or a risk calculator (PCPT-RC).\u003c\/p\u003e\n\n\u003cp\u003eSelectMDX uses mRNA of the HOXC6 gene (a proliferation gene) and the DLX1 gene (a progression gene). A positive test is a risk score of minus 2.8 or higher. The higher the score, the greater the risk of aggressive cancer. The test predicts clinically significant prostate cancer in patients with suspicious PSA levels with or without an abnormal digital rectal examination. Doctors consider it in combination with an MRI-based strategy (PSA above 3 ng\/mL and PIRADS score 4 to 5, or PIRADS score 1 to 3 followed by a positive SelectMDX).\u003c\/p\u003e\n\n\u003cp\u003eExoDx Prostate (INTELLISCORE) uses three urinary exosomal RNAs (ERG and PCA3 normalized to SPDEF). A score above 15.6 indicates a high risk of prostate cancer with a Gleason score above 7. The test predicts clinically significant prostate cancer among patients with suspicious serum PSA levels or digital rectal examination. It performs better when combined with standard-of-care clinical variables (PSA level, age, race, and family history).\u003c\/p\u003e\n\n\u003cp\u003eConfirmMDX uses DNA methylation of the GSTP1, APC, and RASSF1 genes. A positive assay means the doctor should consider re-biopsy. The test predicts prostate cancer in repeat biopsy settings. Data regarding its clinical utility in predicting clinically significant prostate cancer are expected.\u003c\/p\u003e\n\n\u003ch2 id=\"guidelines\"\u003eWhat Guidelines Recommend\u003c\/h2\u003e\n\n\u003cp\u003eCurrent uro-oncological guidelines for early detection of prostate cancer recommend considering additional testing before making the decision to perform a biopsy. This recommendation stands despite many issues regarding the clinical utility and cost-effectiveness of these biomarkers.\u003c\/p\u003e\n\n\u003cp\u003eThe issues include insufficient and inconsistent results, numerous retrospective and underpowered studies, a lack of clinical validation and comparative studies, and no established optimal cutoff test value.\u003c\/p\u003e\n\n\u003cp\u003eIn the present context, efforts focus on changing the prostate cancer screening strategy. The goals are to increase detection of clinically significant prostate cancer while missing as few cases as possible. Multiparametric MRI provides significant clinical benefit and is widely used in the initial diagnosis process of prostate cancer.\u003c\/p\u003e\n\n\u003cp\u003eTherefore, it is important to reevaluate the role of these biomarkers. It is also important to establish which patients are most likely to benefit from MRI or biomarker use, and in which diagnostic setting and sequence.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eIf you have a PSA level in the unclear middle range, your doctor may now discuss additional tests with you before recommending a biopsy. These tests can help estimate your personal risk of having a clinically significant prostate cancer.\u003c\/p\u003e\n\n\u003cp\u003eThe PHI test and the 4Kscore are the two serum tests with the most supporting evidence. Both can reduce the number of unnecessary biopsies while missing relatively few significant cancers. For example, the PHI test reduced biopsies by 9% in one study and by 23.9% in another. The 4Kscore reduced biopsies by 64.6% in one clinical utility study.\u003c\/p\u003e\n\n\u003cp\u003eThese tests perform best when combined with other information. Combining a biomarker with MRI, a risk calculator, or both improves accuracy. For example, combining the PHI test with MRI improved the prediction of clinically significant prostate cancer to an AUC of 0.84. Combining the 4Kscore with the Rotterdam risk calculator achieved an AUC of 0.89.\u003c\/p\u003e\n\n\u003cp\u003eBiomarkers can also help in treatment decisions, not only in biopsy decisions. The 4Kscore helped predict aggressive pathology at surgery and the risk of distant metastasis many years later. A low-risk 4Kscore predicted a low risk of developing prostate cancer metastasis.\u003c\/p\u003e\n\n\u003cp\u003eAsk your urologist whether a biomarker test is appropriate for your situation. The answer depends on your PSA level, your prior biopsy history, your MRI results, and your personal risk factors.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations and Open Questions\u003c\/h2\u003e\n\n\u003cp\u003eThe authors are clear that important questions remain unanswered. There is no optimal cutoff value for the PHI test that is based on strong scientific evidence. The same uncertainty applies to other biomarkers.\u003c\/p\u003e\n\n\u003cp\u003eMany studies of these biomarkers were retrospective (looking back at existing data) and underpowered (too small to give reliable answers). There is a lack of clinical validation and comparative studies. There is also no established optimal cutoff test value.\u003c\/p\u003e\n\n\u003cp\u003eThe cost-effectiveness of these tests is not fully established. Adding a biomarker test increases costs. The clinical benefit must be weighed against these additional costs.\u003c\/p\u003e\n\n\u003cp\u003eThe role of the PHI test remains to be fully determined in conjunction with patient cancer history, risk calculators, and MRI. The authors also note that the PHI test predicted a pT3 stage or a pathological Gleason score of 7 or higher, but it did not improve clinical decision-making.\u003c\/p\u003e\n\n\u003cp\u003eFor ConfirmMDX, data regarding its clinical utility in predicting clinically significant prostate cancer are still expected.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations\u003c\/h2\u003e\n\n\u003cp\u003eBased on this review, patients and clinicians can consider the following points:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003eDo not rely on a single PSA value alone to decide about a prostate biopsy. Guidelines now recommend combining PSA with other tools.\u003c\/li\u003e\n\u003cli\u003eDiscuss biomarker testing with your urologist if your PSA is in the unclear middle range (for example, 4 to 10 ng\/mL) and your digital rectal examination is normal.\u003c\/li\u003e\n\u003cli\u003eAsk whether MRI should be part of your evaluation. Biomarkers and MRI are complementary, and combining them improves accuracy.\u003c\/li\u003e\n\u003cli\u003eUnderstand that a biomarker test can reduce the chance of an unnecessary biopsy, but no test is perfect. Some significant cancers can still be missed.\u003c\/li\u003e\n\u003cli\u003eAsk how your personal risk factors (age, family history, prior biopsy, prostate volume) affect the interpretation of any test result.\u003c\/li\u003e\n\u003cli\u003eRecognize that biomarker tests are most useful in specific settings. These settings include before a first biopsy, before a repeat biopsy, and when choosing between active surveillance and treatment.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eMy PSA is in the unclear middle range. What tests might my doctor discuss before recommending a biopsy?\u003c\/h3\u003e\n\u003cp\u003eIf your PSA is in the unclear middle range, such as 4 to 10 ng\/mL, and your digital rectal examination is normal, your doctor may discuss additional tests before recommending a biopsy. These include serum tests like the Prostate Health Index (PHI) and the 4Kscore, as well as urine and tissue biomarkers. Guidelines now recommend considering such tests to help estimate your personal risk of clinically significant prostate cancer.\u003c\/p\u003e\n\u003ch3\u003eHow much can the PHI test reduce unnecessary biopsies, and what are the risks?\u003c\/h3\u003e\n\u003cp\u003eIn one single-center study, using the PHI test was linked to a 9% decrease in prostate biopsies, and in a multicenter study, a 23.9% reduction. However, the PHI test can miss some cancers; at a cutoff of 25, it may miss up to 10%. No test is perfect, so discuss the benefits and risks with your urologist.\u003c\/p\u003e\n\u003ch3\u003eWhat does a 4Kscore result mean for my risk of aggressive prostate cancer?\u003c\/h3\u003e\n\u003cp\u003eThe 4Kscore gives a risk score from 0 to 100. A low-risk score is 1 to 7.5, and a high-risk score is 20 or higher. A higher score is associated with a higher probability of detecting clinically significant prostate cancer, aggressive pathology, or progression to metastasis or death. Your doctor can use this score to help decide whether a biopsy is needed.\u003c\/p\u003e\n\u003ch3\u003eCan combining a biomarker test with an MRI improve accuracy?\u003c\/h3\u003e\n\u003cp\u003eYes. Combining the PHI test with MRI improved the prediction of clinically significant prostate cancer to an area under the curve (AUC) of 0.84. Combining the 4Kscore with the Rotterdam Prostate Cancer Risk Calculator achieved an AUC of 0.89. These combinations can help reduce unnecessary biopsies while missing relatively few significant cancers, but they may also increase costs.\u003c\/p\u003e\n\u003ch3\u003eI've already had a biopsy. Can these biomarkers help decide about a repeat biopsy?\u003c\/h3\u003e\n\u003cp\u003eYes. Some biomarkers are specifically used in repeat biopsy settings. For example, PCA3 is used for re-biopsy decision-making in patients with suspicious PSA levels and a normal digital rectal examination. ConfirmMDX, a tissue test, can indicate whether a repeat biopsy should be considered. Guidelines list several tests for repeat biopsy, including PHI, 4K, PCA3, SelectMDX, and ConfirmMDX.\u003c\/p\u003e\n\u003ch3\u003eWhat are the main limitations of these newer prostate cancer biomarkers?\u003c\/h3\u003e\n\u003cp\u003eImportant questions remain. There is no optimal cutoff value for the PHI test based on strong scientific evidence, and the same uncertainty applies to other biomarkers. Many studies were retrospective and underpowered, and there is a lack of clinical validation and comparative studies. The cost-effectiveness is not fully established. Also, the PHI test predicted unfavorable pathology but did not improve clinical decision-making.\u003c\/p\u003e\n\u003ch3\u003eMy PSA is in the 4 to 10 ng\/mL range and my urologist wants to do a biopsy — when should I get a second opinion about biomarker testing first?\u003c\/h3\u003e\n\u003cp\u003eWhen your PSA falls in the unclear middle range, such as 4 to 10 ng\/mL, with a normal digital rectal examination, guidelines recommend considering additional testing before deciding on a biopsy. The Prostate Health Index and 4Kscore are the two serum tests with the most supporting evidence; both can reduce unnecessary biopsies while missing relatively few significant cancers. These tests perform better combined with MRI or a risk calculator. A second opinion can help clarify whether biomarker testing, MRI, or biopsy is appropriate for your PSA level, prior biopsy history, and personal risk factors. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e How to Integrate Prostate Cancer Biomarkers in Urology Clinical Practice: An Update.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Baston C, Preda A, Iordache A, Olaru V, Surcel C, Sinescu I, Gingu C.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Department of Nephrology, Urology, Immunology and Immunology of Transplant, Dermatology, Allergology, Faculty of Medicine, \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania; and Center of Uronephrology and Kidney Transplantation, Fundeni Clinical Institute, Bucharest, Romania\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Cancers 2024, volume 16, article 316. Published 11 January 2024. DOI: 10.3390\/cancers16020316\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eArticle type:\u003c\/strong\u003e Review article. Academic editor: Fred Saad.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. It restructures one published review article for a patient audience. All numbers, study results, and conclusions come from that original article.\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47816823668892,"sku":null,"price":0.0,"currency_code":"KRW","in_stock":true}],"url":"https:\/\/diagnosticdetectives.kr\/products\/new-prostate-cancer-biomarkers-a-guide-for-patients-and-clinicians","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}