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 Table of Contents  
Year : 2021  |  Volume : 14  |  Issue : 1  |  Page : 22-30

Prostate-Specific antigen: An overview and its current status in the diagnosis of prostate cancer

Department of Urology, KLE Academy of Higher Education and Research (Deemed-to-be-University), Belagavi, Karnataka, India

Date of Submission06-May-2019
Date of Acceptance12-Mar-2020
Date of Web Publication09-Feb-2021

Correspondence Address:
Dr. Siddalingeshwar Neeli
Department of Urology, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus, Belagavi - 590 010, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kleuhsj.kleuhsj_97_19

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Prostate-Specific Antigen (PSA), which has high organ specificity and poor cancer specificity, has been widely utilized for the diagnosis and treatment of prostate cancer; though it is not an ideal tumor marker. Its extensive usage in screening programs has resulted in a large number of unwanted biopsies, over-diagnosis and over-treatment of indolent cancers as well. Hence, various PSA derivatives and PSA-based tests have evolved to improve the accuracy of prostate cancer diagnosis. This article provides an overview of PSA and PSA-based biomarkers and their current role in the screening and diagnosis of prostate cancer.

Keywords: Prostate cancer, prostate specific antigen, screening, tumor marker

How to cite this article:
Neeli S, Sharma M, Musale A. Prostate-Specific antigen: An overview and its current status in the diagnosis of prostate cancer. Indian J Health Sci Biomed Res 2021;14:22-30

How to cite this URL:
Neeli S, Sharma M, Musale A. Prostate-Specific antigen: An overview and its current status in the diagnosis of prostate cancer. Indian J Health Sci Biomed Res [serial online] 2021 [cited 2021 Apr 22];14:22-30. Available from: https://www.ijournalhs.org/text.asp?2021/14/1/22/308970

  Introduction Top

Carcinoma of prostate is primarily a disease of the elderly with more than 75% of the cases occurring in men aged more than 65 years.[1] It is the second most frequently diagnosed cancer in men worldwide and the fifth most common cancer overall.[2] It is also the sixth leading cause of cancer deaths in men.[3]

Prostate-Specific Antigen (PSA) has evolved as the most applicable tumor marker for carcinoma prostate. PSA-based testing has been widely used to aid prostate cancer detection since the late 1980s, and prostate cancer-specific mortality has decreased because of PSA-based screening programs in recent years.[4] However, there is a concern that this decline has come at the expense of overdiagnosis and overtreatment. This article provides an overview of PSA and emerging PSA-based biomarkers and their role in diagnosis and screening of prostate cancer.

  Discovery of Prostate-Specific Antigen Top

The search for a tumor marker for prostate cancer that is more sensitive and specific than prostatic acid phosphatase led to the discovery of several prostate antigens that subsequently became known as PSA. Today, PSA is recognized as the best tumor marker for prostate cancer.

Flocks et al., in 1960, were the first to experiment with antigens in the prostate, and later in 1970, Ablin et al. reported the presence of precipitation antigens in the prostate.[5],[6],[7] In 1971, Hara et al. in Japan, first described a protein isolated from seminal plasma and named it gamma-seminoprotein.[8] Li and Beling, in 1973, also identified and characterized an antigen from human seminal plasma, using a series of chromatographic techniques and named protein El based on its electrophoretic mobility.[9] In 1978, Sensabaugh identified an antigen in semen that he called p30 and later found that it was similar to E1 protein, and that prostate was the source.[10] Wang et al. (1973) purified a tissue-specific antigen from the prostate (”prostate antigen”) and it was seen to be present in normal, benign, and malignant prostate tissue. The findings were published in Investigative Urology in 1979, and because of its significance, it was republished in the Journal of Urology as a Milestone in Urology article in 2002.[11],[12] Papsidero et al., in 1980, showed that the PSA in serum was similar to the PSA identified in the prostate and that marked the beginning of the diagnosis of prostate cancer by a serum test.[13] In a landmark study from Stanford University, Stamey et al. reported that serum PSA levels of patients correlated well with advancing stage of prostate cancer.Serum PSA was proportional to the estimated tumor volume and it was a much better tumor marker that prostatic acid phosphatase..[14]

Although PSA was thought to be prostate specific, reports of its identification in extraprostatic tissue were published as early as 1984. However, until there are better markers for prostate cancer, prostate (not so)-specific antigen will continue to be the most widely used tumor marker in the world.[15]

  Prostate-Specific Antigen – The Molecule Top

PSA, a protease enzyme belonging to the kallikrein family, is a 33-kd protein consisting of a single-chain glycoprotein of 237 amino acid residues, 4 carbohydrate side chains, and multiple disulfide bonds. PSA is referred to as human glandular kallikrein (hK)-3 to distinguish it from hK-2, another prostate cancer marker with which it shares 80% homology. A third kallikrein, hK-1, is found mainly in pancreatic and renal tissue and shows 73% and 84% homology with PSA.[16],[17]

PSA is a neutral serine protease. It splits the seminal vesicle proteins seminogelin I and II, resulting in liquefaction of the seminal coagulum. The complete gene encoding PSA has been sequenced and localized to chromosome 19.[18],[19] PSA is produced under androgen regulation by the luminal cells of the prostate epithelium.[18],[19] The lumen of the prostate gland contains the highest concentration of PSA in the body. The basement membrane of the glands, the prostatic stroma, and the capillary endothelial cell act as barriers between the glandular lumen and the capillaries preventing entry of luminal PSA into the blood. Diseases such as infection, inflammation, and cancer may produce a breakdown in these barriers, allowing more PSA to enter the circulation.[13],[14]

Low concentrations of PSA have been identified in urethral glands, endometrium, normal breast tissue, breast milk, salivary gland tissue, and the urine of males and females.[20]

Like other serine proteases which are bound mostly to various serum proteins, the majority of serum PSA exists as complexed PSA and is bound to either alpha-2-macroglobulin (AMG) or alpha-1-antichymotrypsin (ACT), while a small percentage of it exists as free PSA (fPSA). Unlike serum, the ejaculate primarily contains fPSA. Immunoassays employed to detect PSA easily identify PSA-ACT complex as it has two unmasked epitopes and fails to measure PSA-AMG complex because it has no epitopes exposed for detection. As the levels of the PSA-AMG complex are insignificant, this complex is unlikely to play a significant biologic role in the serum.[21],[22],[23]

The half-life (t1/2) and metabolic clearance rate of PSA have been determined from studies of patients undergoing radical prostatectomy. Stamey et al. found the half-life to be 2.2 ± 0.8 days,[14] whereas Oesterling et al. determined it to be 3.2 ± 0.1 days.[24] Because of the relatively long half-life of PSA, a minimum of 2–3 weeks is required for the serum PSA to reach its nadir after radical prostatectomy and become undetectable.

  Factors influencing Prostate-Specific Antigen levels Top

Normal, hyperplastic, and neoplastic prostatic epithelial cells all make PSA, but the amount of PSA produced by cancer cells is 10 times higher per gram of tissue than the amount produced by normal or hyperplastic tissue.[14] A number of factors affect the normal PSA levels and should be known before making a decision on what is elevated.

The serum PSA levels are affected by the amount of benign prostate hyperplasia (BPH) tissue and the epithelial–stromal ratio. PSA is largely produced in the hyperplastic transitional zone of the prostate and only a relatively small amount is produced in the peripheral zone. While 80% of prostate cancers originate in the peripheral zone, cancers developing in the transitional zone tend to produce large amounts of PSA.[14],[25],[26] High-grade cancer cells tend to lose their ability to produce PSA.[26]

The serum PSA level can be influenced by various medications. Finasteride and dutasteride can produce a 50% decrease in total PSA (tPSA) levels within 6 months of therapy which persists as long as the drug is continued. A fresh PSA measurement obtained after 3–4 months of therapy establishes a new baseline. However, levels of fPSA are not altered by finasteride or dutasteride. PSA density (PSAD, that is, tPSA divided by prostate volume) also gets decreased by 5-alpha reductase medications because the major PSA-producing region of the prostate is reduced in volume.[27],[28],[29],[30],[31]

Other drugs which can lower the levels of PSA are nonsteroidal anti-inflammatory drugs, statins, and thiazide group of drugs.[32],[33],[34]

Alpha1-adrenergic antagonists and herbal products such as saw palmetto which are frequently used to treat the symptoms of BPH do not alter PSA levels. All medications that alter testosterone levels can affect the serum PSA level. Raising testosterone levels may increase PSA levels, but not to the same degree as reducing testosterone production.[30],[31]

Elevation of PSA levels has been demonstrated in noncancerous conditions such as acute prostatitis, subclinical or chronic prostatitis, and urinary retention.[12],[26]

Furthermore, some urologic manipulations are known to alter serum PSA levels. A digital rectal examination (DRE) causes no significant change in the PSA level, but a vigorous prostate massage can produce a short-term 2-fold increase. Cystoscopy, urethral catheterization, and transrectal ultrasonography (TRUS) of the prostate do not alter the PSA level. Needle biopsy of the prostate increases the PSA level by a median of 7.9 ng/mL (6.5 times the baseline value) within 5 min after the biopsy, and this level persists for 24 h.[35]

Men from different ethnic and racial groups have different average PSA concentrations. In particular, African-American men without prostate cancer tend to have higher PSA values than Caucasian men without prostate cancer.[36] Indian baseline values tend to be lower age-specific PSA and higher PSAD values than those quoted in Western literature. Among the Indian community, Ganpule et al. observed that the mean PSA values increased from 2.1 ng/mL in the age group of 40–49 years to 5.0 ng/mL in the age group of >70 years.[37] Similarly, the mean PSAD also increased from 0.15 to 0.2 ng/mL in the same age group of patients.[37]

PSA levels increase with age; this increase is related to rising prostate volume. As most PSA is produced in the transition zone of the prostate, and this region of the prostate increases in volume in men with BPH, higher levels of serum PSA are observed in the elderly.[38],[39]

  Prostate-Specific Antigen as a tumor marker - is it ideal? Top

A tumor marker is a substance produced by a tumor; measurable in body fluids; and useful for diagnosis, early detection, staging, prognosis, and follow-up after treatment. An ideal tumor marker should have 100% sensitivity and specificity. No currently available marker performs ideally in all settings; performance characteristics depend on specific aspects of each cancer such as prevalence, tumor heterogeneity, and response to therapy. PSA, which has high organ specificity, is an excellent tumor marker that has been widely accepted for the diagnosis and treatment of prostate cancer.

The American Cancer Society assessed PSA performance by systematically reviewing the literature.[40] In this pooled analysis, they reported that with a PSA cutoff of 4.0 ng/mL, the estimated sensitivity was 21% for detecting any prostate cancer and 51% for detecting high-grade cancers (Gleason ≥8). Lowering the cutoff to 3.0 ng/mL increased these sensitivities to 32% and 68%, respectively. The estimated specificity was 91% for a PSA cutoff of 4.0 ng/mL and 85% for a 3.0 ng/mL cutoff. As PSA is organ specific and not disease specific, it has poorer discriminating ability in men with symptomatic benign prostatic hyperplasia.[41]

The positive predictive value (PPV) for a PSA level >4.0 ng/mL is approximately 30%, implying that one in three men with an elevated PSA will have prostate cancer detected on biopsy.[42],[43],[44] The PPV is about 25% for PSA levels between 4.0 and 10.0 ng/mL. Most importantly, nearly 75% of cancers detected within the “gray zone” of PSA values between 4.0 and 10.0 ng/mL are organ confined and potentially curable.[43]

The Prostate Cancer Prevention Trial (PCPT), which biopsied men with normal PSA levels, estimated a negative predictive value of 85% for a PSA value ≥4.0 ng/mL, meaning that 15% of men with PSA level less than 4 ng/ml harbor cancer.[45]

Among men with a PSA concentration between 2.1 and 4.0 ng/mL, 24.7% had prostate cancer, and 5.2% had prostate cancer with a Gleason score of 7 or higher. These findings lead to suggestion for using a lower PSA cutoff for doing a prostate biopsy.[46],[47],[48],[49]

The PCPT found that for biopsies performed during follow-up in the control group, even a PSA cutoff of 1.1 ng/mL would miss 17% of cancers, including 5% of poorly differentiated cancers.[50] Thus, any choice of PSA cutoff involves a trade-off between sensitivity and specificity. While lowering the PSA cutoff would improve test sensitivity, a lower PSA cutoff would also reduce specificity, leading to far more false-positive tests and unnecessary biopsies. However, if the PSA threshold was to be lowered to 2.5 ng/mL, the number of men with PSA level considered abnormal would double.[51] In addition, many of the cancers detected at these lower levels may never have become clinically evident, thereby leading to overdiagnosis and overtreatment.[52]

It is evident that there is no such thing as a normal PSA in terms of prostate cancer risk. Obviously, there is no PSA cutoff threshold below which the risk of detecting a prostate cancer on biopsy is zero.[45] As such, the choice of a PSA threshold at which a clinician might recommend a patient biopsy is controversial.[53],[54],[55] If the PSA threshold is set too high, clinically significant prostate cancers might be missed. Conversely, if it is set too low, an unacceptably high number of men without prostate cancer would be subjected to an unnecessary biopsy and thereby be exposed to the inherent risks and anxieties associated with this invasive procedure. Several PSA derivatives, such as PSAD, PSA velocity (PSAV), age-adjusted PSA, fPSA-to-tPSA ratio, and different molecular derivatives of PSA, have been described in an attempt to improve the sensitivity and specificity in detecting prostate cancer. Furthermore, efforts are on to identify prostate cancer biomarkers with better performance characteristics than PSA alone.

  Prostate-Specific Antigen as a screening tool Top

Screening for any disease refers to the diagnosis of preclinical cases of the disease at an early stage and to improve the outcomes for that condition. PSA-based screening for prostate cancer is widely adopted by health-care providers, even though some population-based prostate cancer screening programs using PSA have shown clear survival benefits?; it needs to justify several important requirements to be acceptable as the ideal screening tool.[56],[57]

An ideal screening program should focus on diseases with high clinical impact on public health; screen the population with a long life expectancy; be able to identify asymptomatic disease at a treatable stage during its natural course; have a high-accuracy, noninvasive, easy-to-apply, and low-cost diagnostic tests that do not detect latent tumors; and have a treatment capable of modifying the natural history of the disease and reducing the mortality without worsening quality of life.

Screening for prostate cancer with serum PSA aims to detect prostate cancer at an early stage amenable to curative treatment and reduce the overall and disease-specific mortality.[56],[57] The PSA screening has lowered the incidence of metastatic prostate cancer at presentation; however, it has failed to show survival advantage.[58],[59] Instead, it is associated with increased harms of overdiagnosis and complications of treatment for indolent disease that affect patient quality of life, such as urinary incontinence and erectile dysfunction.[60] Thus, screening for prostate cancer using PSA remains highly controversial.

The American Prostate Cancer Screening Trial (PLCO) study randomized 76,693 men aged 55–74 years for annual screening with PSA and rectal examination (n = 38,343) or control group with the “usual urological care,” that is, at the discretion of the urologist (n = 38,350). The PSA value used to indicate biopsy was ≥4.0 ng/mL. After 7 years of monitoring, mortality was similar between the two groups (P, nonsignificant).[61] It was found that almost half of the patients in the control group did PSA test compared to the randomized group and hence there was no difference between groups.

The European Prostate Cancer Screening Trial (ERSPC) randomized a population of 162,243 men between 55 and 69 years for PSA screening (n = 81,816) or control without PSA (n = 99,184). A PSA value ≥3.0 ng/mL was set for prostate biopsy by most centers and PSA level was performed every 4 years. After monitoring for 11 years, screening reduced the risk of metastases by 41% and the chance of death from prostate cancer by 21% (P = 0.04). The point of concern was that of the total number of patients submitted to biopsy, 76% had benign tissue, indicating high false-positive results. Of the 781 patients who needed to be screened, 27 were diagnosed and treated to prevent tumor-related death.[57],[62]

In the study conducted at Gothenburg in Sweden, 20,000 men aging 50–64 years (mean 56 years) were randomized 1:1 for PSA screening every 2 years or control without PSA. The PSA value used to indicate the biopsy was between 3.0 and 4.0 ng/mL. Prostate cancer was diagnosed in 12.7% of the patients in the screening group and in 8.2% of those in the control group. After a 14-year follow-up, there was a relative decrease in prostate cancer mortality of 44%. In this study, 293 cases needed to be screened and 12 treated for prostate cancer to prevent one tumor-related death.[56]

Prostate biopsy indications have also changed over the years. After the PCPT study showed cancer in at least 15% of patients with PSA <4 ng/mL, prostate biopsy began to be recommended with lower PSA values of around 2.5 ng/mL, and this has contributed to the progressive finding of clinically insignificant tumors of lower biological aggressiveness.[45]

In the randomized Prostate Cancer Intervention versus Observation Trial (PIVOT Trial) comparing radical prostatectomy versus observation in the PSA era, it was shown that there was no benefit from radical surgery for patients with low-risk tumors, which are precisely the majority of cases found in screening programs. In this study, there was no difference in mortality after 20 years of monitoring for patients with prostate adenocarcinoma with a Gleason score of 6 between those who did and did not undergo surgery. There was only increased survival in the cases of more aggressive tumors.[63]

A major problem for prostate cancer screening with PSA is tumor hyperdetection or overdiagnosis, characterized by excessive diagnosis of clinically insignificant tumors. The ERSPC study reported the presence of low-risk tumors (PSA < 10 ng/mL and Gleason score ≥6) to be three times higher in the screened group than the control group.[57],[62]

Hence, it is reasonable to accept that universal screening of the male population, regardless of age and family history, may not be the best approach. On the other hand, there are many methodological flaws in the published studies that have not been correctly interpreted. Most studies evaluated only cancer-specific survival to measure the benefits of screening, whereas the chance of decreased metastases, quality of life, or other benefits that may result from an earlier diagnosis of the disease were not used as a primary parameter in any of the studies.[60]

Vickers et al. demonstrated that PSA levels around 45 years in patients with no family risk factors could provide data on the chance of developing aggressive prostate cancer and risk of death from the tumor in the coming decades. When the baseline PSA values were below the population median according to the different age ranges (up to 42 years, ≥0.6 ng/mL; up to 50 years, ≥0.7 ng/mL; and up to 55 years, ≥0.9 ng/mL), the chance of death from prostate cancer in 25 years was estimated at 0.1%, 0.5%, and 0.8%, respectively. These authors suggest that only three PSA measurements, the first performed at around 45 years, the second at the beginning of the fifth decade of life, and the third at 60 years, may be sufficient for a safe risk assessment for half of the population.[58]

In 2013, the American Urological Association (AUA) recommended PSA screening every 1–2 years for men aged 55–69 years after a decision shared between the doctor and the patient about the risks and benefits of the test. It further stated that, except for men with risk factors for prostate cancer, routine use of PSA is not recommended for other age groups or if life expectancy is <10–15 years.[64]

In 2017, the United Stated Preventive Services Task Force (USPSTF) upgraded its recommendation for PSA screening of prostate cancer from Grade D to Grade C.[65] It suggested that there is a benefit to the use of PSA, but that the test should be used selectively based on the professional judgment and patient preferences, recommendations similar to those proposed by the AUA in 2013. The USPSTF concludes that there is a small overall benefit after a decade with the use of PSA, but continues to note that damages may occur during this screening period. Furthermore, the new USPSTF will not recommend PSA for men over 70 years and for those under 55 years, which seems inadequate, given that it does not take into account clinical characteristics nor individual volition.[65]

  Prostate-Specific Antigen Screening in India Top

The actual incidence of prostate cancer in India is lower than that in the Western populations as is also true for the nonresident Indians.[1] However, the incidence of the disease is increasing in various parts of India due to the changes in the diagnostic modalities, increased awareness among the public, and changing lifestyles.

The age-specific PSA ranges for men in the Indian population belonging to Gujarat state are on the lower side and the PSAD on the higher side.[37] Malati et al. found that the PSA level was significantly high in BPH patients and adenocarcinoma prostate patients when compared to healthy males in Andhra Pradesh of South India.[66]

Although PSA has been regarded as a useful tool for the early detection of prostate cancer, Dubey seriously doubted the utility of this tool for screening prostate cancer in Indian males due to the low incidence of this particular disease.[67] Agnihotri et al. reported that the PPV of PSA in the range of 4–10 ng/ml is 15.2, and in patients with PSA 4–20 ng/ml is 24% among Indians, whereas in Western population, the PPV of PSA in the range of 4–10 ng/ml is around 32%, which increases to more than 60% at PSA level >10 ng/ml.[68] They suggested that the PSA threshold for TRUS-guided biopsy in Indian men with LUTS and negative DRE may be raised to 5.4 ng/ml. This would still detect 95% of cancers and avoid unwarranted biopsy in 10% of men.[68]

Meticulous implementation of registration and reporting mechanisms may improve knowledge regarding prostate cancer in India and formulate guidelines for PSA screening and prostate biopsy.

  Prostate-Specific Antigen based tests to improve screening Top

Although PSA has been widely used for the detection of prostate cancer, it is not a perfect tumor marker because it cannot discriminate BPH from prostate cancer. Using a cutoff of 4 ng/ml, the sensitivity of PSA to detect prostate cancer varies from 68% to 80% and its specificity varies from 49% to 90%. This lack of accuracy is more strikingly seen in patients with PSA values between 4 and 10 ng/ml. Various PSA derivatives and PSA-based tests have been described to improve the accuracy and avoid unnecessary biopsy and its associated complications.

Prostate-Specific Antigen Density

Prostate-Specific Antigen Density (PSAD) is calculated by dividing serum PSA by prostate volume as determined by transrectal ultrasound. A higher PSAD value (>0.15 ng/mL) is more suggestive of prostate cancer, whereas the lower values are suggestive of benign hypertrophy.[69],[70] Although use of PSAD was found promising in the early studies, subsequent studies found that almost 50% of cancer would have been missed using 0.15 ng/ml as cutoff for biopsy.[71]

Prostate-Specific Antigen Velocity

Prostate-Specific Antigen Velocity (PSAV) is the rate of PSA change over time.. An elevated serum PSA that continues to rise over time is more likely to reflect prostate cancer than one that is consistently stable.[72] Carter et al. reported that a PSAV cutoff of 0.75 ng/mL/year distinguished patients with prostate cancer from those with either BPH or no prostate disease with a specificity of 90% and 100%, respectively.[73] They also found that when PSA was <4 ng/mL, a PSAV >0.35 ng/mL/year measured over several years was associated with a high risk of death from prostate cancer 15 years later.[74] In reality, the usefulness of PSAV is limited by the variability in the serum PSA levels at different times in the same patient, irrespective of the presence or absence of cancer. If one uses a 0.75 ng/ml/year cutoff point as a marker for prostate cancer, at least 1.5–2 years is necessary for the evaluation of PSAV to maintain sensitivity and specificity.[75]

Free Prostate-Specific Antigen

Prostate cancer is associated with a lower percentage of free Prostate-Specific Antigen (fPSA) in the serum as compared with benign conditions. The percentage of fPSA (fPSA/tPSA) has been used to improve the sensitivity of cancer detection when tPSA is in the normal range (<4 ng/mL) and to increase the specificity of cancer detection when tPSA in the “gray zone” (4.1–10 ng/mL). In a study of men with PSA between 4 and 10 ng/ml and normal DRE, prostate cancer was found in 56% of men with percentage PSA less than 10%, in contrast to 8% cancer among men with percentage PSA more than 25%.[76] The data published from San Antonio Center of Biomarkers of Risk for Prostate Cancer (SABOR) showed that percentage fPSA as a reflex test could avoid 2/3rd of unnecessary biopsies.[77]

Prostate Health Index

The prostate health index (PHI) is a Food and Drug Administration (FDA)-approved test to be used in men over the age of 50 years with a PSA in the range of 2–10 ng/ml and negative DRE. PHI is calculated using the following formula: ([-2] proPSA/fPSA) × vPSA. As compared to BPH, prostate cancer releases more proPSA and fPSA. Hence, PHI is used as a secondary aid to PSA to distinguish between the two pathologies. NCCN considers a PHI more than 35 as potentially informative in men who have never undergone biopsy.[78] Calle et al., in a multicenter study, reported that a PHI cutoff of at least 25 could avoid 36%–41% of unnecessary biopsies and 17%–24% of overdiagnosis, while missing 5% of tumors with Gleason score 7 or higher.[79]

4-kallikrein score

The 4-kallikrein (4K) score test is a blood test that accurately determines the risk of aggressive prostate cancer and significantly reduces prostate biopsies and associated overdiagnosis and overtreatment of indolent cancer. It is not FDA approved, but is included in the 2016 NCCN guideline as a second option after PSA and prior to initial or repeat biopsy.[78]

Stattin et al.[9] found that men with an elevated PSA level and a low 4K score test (<7.5%) have a very low 20-year risk of developing metastatic PCa and thus could safely avoid a prostate biopsy.[80] In a validation study by Parekh et al., 4K score test decreased unnecessary biopsies by 30%–58%, without delaying an undue number of high-grade cancers.[81]

In a cohort of 392 men who were diagnosed with prostate cancer and underwent radical prostatectomy in the Rotterdam arm of the ERSPC trial, the addition of the 4K panel improved the prediction of aggressive histopathology from 0.81 to 0.84 compared with a clinical model of age, stage, PSA, and biopsy Gleason and cores data.[34] The authors reported that adding the use of the 4K panel in a clinical prediction model would allow a reduction of 135 (14%) unnecessary surgeries per 1000 men.[82]

A high-risk 4K score test result may be used to select men with a high probability of aggressive prostate cancer who would benefit from a biopsy of the prostate to prevent an adverse and potentially lethal outcome from prostate cancer. Men with a low 4K score test result may safely defer biopsy.[83]

  Summary Top

Although PSA has revolutionized the detection and treatment of prostate cancer, there remains considerable scope for both improvements in the use of variations of the PSA test and the development of novel biomarkers. An improved screening test may dramatically reduce the number of men undergoing an unnecessary biopsy when maintaining the ability to detect high-risk cases of this common malignancy. Such an approach has the potential to reduce the overdiagnosis and overtreatment of prostate cancer when enabling clinicians to focus on high-risk cases of localized prostate cancer in a population of men likely to benefit from radical intervention.

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Conflicts of interest

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