Abstract
In recent years, several new biomarkers supplementing the role of prostate-specific antigen (PSA) have become available for men with prostate cancer. Although widely used in an ad hoc manner, the role of PSA in screening asymptomatic men for prostate cancer is controversial. Several expert panels, however, have recently recommended limited PSA screening following informed consent in average-risk men, aged 55–69 years. As a screening test for prostate cancer however, PSA has limited specificity and leads to overdiagnosis which in turn results in overtreatment. To increase specificity and reduce the number of unnecessary biopsies, biomarkers such as percent free PSA, prostate health index (PHI) or the 4K score may be used, while Progensa PCA3 may be measured to reduce the number of repeat biopsies in men with a previously negative biopsy. In addition to its role in screening, PSA is also widely used in the management of patients with diagnosed prostate cancer such as in surveillance following diagnosis, monitoring response to therapy and in combination with both clinical and histological criteria in risk stratification for recurrence. For determining aggressiveness and predicting outcome, especially in low- or intermediate-risk men, tissue-based multigene tests such as Decipher, Oncotype DX (Prostate), Prolaris and ProMark, may be used. Emerging therapy predictive biomarkers include AR-V7 for predicting lack of response to specific anti-androgens (enzalutamide, abiraterone), BRAC1/2 mutations for predicting benefit from PARP inhibitor and PORTOS for predicting benefit from radiotherapy. With the increased availability of multiple biomarkers, personalised treatment for men with prostate cancer is finally on the horizon.
Introduction
Although prostate-specific antigen (PSA) is the most widely used biomarker for prostate cancer [1], several other biomarkers have recently become available for this disease. As a blood-based cancer biomarker, PSA is unique in that it is used in all the main phases of prostate cancer detection and patient management, i.e. in screening, risk stratification for recurrence, surveillance following diagnosis and monitoring therapy [1], [2], [3]. To enhance the diagnostic accuracy of PSA for prostate cancer, several new biomarkers have become available in recent years. These newer biomarkers include prostate health index (PHI) and the 4K score which can help in reducing the number of biopsies performed in men with border-line low PSA levels and multigene signatures for helping to differentiate between indolent and aggressive prostate cancers [4], [5]. The aim of this article is to provide an updated and critical review on the role of PSA in prostate cancer screening, risk stratification, follow-up and monitoring therapy. In addition, I also discuss new and emerging blood, urine and tissue biomarkers for prostate cancer. Most of the emphasis, however, will be devoted to the use of PSA in screening asymptomatic men for prostate cancer.
Use of PSA in screening for prostate cancer
Three large randomized prospective trials have now evaluated the benefit of PSA screening in asymptomatic men for prostate cancer, i.e. the Prostate, Lung, Colorectal and Ovarian (PLCO) trial which was carried out in the US, the European Randomised Study for Screening of Prostate Cancer (ERSPC) trial which was performed in eight European countries and the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP) which was carried out at 573 primary care practices across the UK (Table 1) [6], [7], [8], [9], [10], [11], [12]. Two of these trials, i.e. PLCO and CAP found no benefit of screening for reducing mortality from prostate cancer [7], [12]. In contrast, the ERSPC found a significant benefit for screening in reducing prostate cancer-specific mortality in men aged 55–69 years [8], [9], [10], [11].
Key characteristics of major randomised trials addressing PSA screening.
| Parameter | PLCO | ERSPC | CAP |
|---|---|---|---|
| Location | USA | Europe | UK |
| No of participants | 77,000 | 162,000 | >400,000 |
| Age range | 55–74 years | 55–69 years | 50–69 years |
| Proportion tested in screening arma | 85% | 64% | 34% |
| Contamination in control groupb | >80% | 15% | 10%–15% |
| PSA test used | Beckman | Beckman | NS |
| PSA cut-off point used | 4 μg/L | 2–4 μg/L | 3 μg/L |
| fPSA used | No | Yes, at one site | No |
| Screening interval | Yearly for 6 years | Every 2–4 yearsc | One off |
| Mean follow-up | 13 years | 13 years | 10 years |
| PC mortality (RR) | 1.04 | 0.79 | 0.96 |
The impact of PSA screening on prostate cancer-specific mortality in the ERSPC trial has now been investigated after four different follow-up periods, i.e. after 9 years, 11 years, 13 years and 16 years. At each of these follow-up periods, screening with PSA resulted in a relative mortality reduction of 20% [8], [9], [10], [11]. However, the number of men needed to be invited (NNI) for screening in order to prevent one death declined with longer follow-up, i.e. it was 570 following 16 years of follow-up vs. 742 at 13 years [10], [11]. The number of men needed to be diagnosed (NND) to prevent one death was also reduced with the increased follow-up, i.e. 18 at 16 years vs. 23 at 13 years. In one of the pilot study arms of the ERSPC trial (Rotterdam Pilot 1) which randomised 1134 men to screening or no screening, analysis after 19 years of follow-up showed an overall relative risk of metastatic disease of 0.46 and a relative risk of prostate-specific deaths of 0.48, in favour of screening [13].
Although all the three trials mentioned mostly investigated asymptomatic men in their 50s and 60s, they differed widely in design (Table 1). Furthermore, all the trials had limitations, the most serious of which occurred in the PLCO trial. Indeed, the PLCO trial did not strictly compare screening with no screening, as up to 90% of men in the “control group” were estimated to having undergone PSA testing at least once, either prior to screening starting or during the screening period [14], [15]. This trial has thus been described as a comparison between frequent and sporadic PSA screening or between organised and opportunistic screening [16]. A further limitation of the PLCO trial was that only about 30%–35% of the men in the screening arm with a PSA concentration >4 μg/L, underwent a biopsy for confirmation of a definitive diagnosis [6].
A limitation of the ERSPC trial was the lack of a standardised screening strategy in the eight different countries in which the trial was performed. Thus, the strategies used in the different countries varied with respect to frequency of PSA testing, age-range of subject at entry to trial, follow-up tests and PSA cut-off concentrations [8]. These variations may have contributed to the different impacts of screening observed at the different sites, i.e. a decrease in mortality was found in only two of the countries in which the trial was carried out, i.e. in Sweden and the Netherlands [17].
The most recently reported randomised screening trial, i.e. CAP, investigated the effect of a single PSA measurement on prostate cancer-specific mortality [12]. This trial included 419,582 men aged 50–69 years and had a median follow-up of 10 years. As with the PLCO trial, men randomised to PSA screening had a similar outcome to the control group without screening. The key limitation of this trial was that only a single PSA measurement was performed which is unlikely to be the optimum screening strategy. A further limitation was that only 34% (64,436/189,386) of men randomised to the screening group underwent PSA testing with a valid result.
In an attempt to reconcile the different outcomes in the ERSPC and the PLCO trials, Tsodikov et al. [18] recently used mathematical modelling to correct for screening intensity in the two studies. After accounting for protocol adherence, contamination in control arms, and intensity of post-screening diagnostic procedures, the two trials were found to give essentially similar results, i.e. screening was found to be associated with a 25%–31% lower risk of death from prostate cancer in the European trial and a 27%–32% lower risk in the PLCO trial when compared to the respective control groups. In a further modelling study, de Koning et al. [19] concluded that if the PSA testing in the PLCO study had been performed as efficiently as in the ERSPC trial, the American trial would likely have resulted in a modest reduction in mortality (6%–8%). It is important to state that both of these screening trials included mostly White men. Thus, their conclusions may not applicable to non-White men.
Based on the available data, it would appear that if PSA screening reduces mortality from prostate cancer, the impact is likely to be modest and confined to men aged 55–69 years. However, as screening as well as any subsequent biopsies and treatments can also result in harms, it is not clear if the practice is beneficial overall [16]. Potential harms from the screening process include false positive results due to lack of specificity of PSA for prostate cancer. Thus, in the ERSPC trial which used a PSA cut-off concentration of 3 μg/L, approximately 75% of the men who underwent biopsy were not found to have cancer [10]. Furthermore, approximately 70% of the cancers detected were found to have low grade (i.e. likely to be indolent) [8]. Overall, the low specificity of PSA resulted in a biopsy being performed in approximately 20% of the men screened in the ERSPC trial [20], [21], [22].
Complications that may result from biopsy include infection, pain, bleeding, urinary retention and haematuria [23]. A positive biopsy may in turn result in overdiagnosis (i.e. detecting cancers that are unlikely to cause future morbidity and mortality) and overtreatment in men with indolent disease. Although it is difficult to determine the exact extent of overdiagnosis, it was estimated to occur in between 16% and 50% of cases in the randomised trials mentioned [24]. A positive biopsy can lead to treatment such as radical prostatectomy or radiotherapy, resulting in an increased risk of complications such as impotence, incontinence and bowel problems [25].
Clearly, therefore, if population-based screening is to be introduced for prostate cancer, it must be implemented in a manner that maximises benefit and minimises overdiagnosis and overtreatment. Strategies that may achieve these ends include the use of baseline PSA testing during early mid-life [26] (see below), genetic testing to identify men at increased risk [27], reducing or eliminating screening in asymptomatic men >70 years or those with a life expectancy of <10 years, employing active surveillance for men diagnosed with indolent disease (assessed by clinical stage, tumour grade, PSA concentration and possibly a gene signature test), (see below for discussion of gene signatures) [28]. In addition, the employment of risk calculators [29], measurement of other biomarkers (Prostate Health Index, 4K score, genetic signature) [30], [31] and use of multiparametric magnetic resonance imaging (MRI) [32], could aid in differentiating between aggressive and indolent cancers, thus reducing the number of unnecessary biopsies performed.
Because of this close balance between potential good and harm, most published guidelines are opposed to mass screening but recommend screening in men 55–69 years of age following the practice of shared decision making and informed consent [33], [34], [35], [36], [37]. This shared decision making should include a discussion between the man and his health professional about the potential harms and benefits of the screening process and the likely ensuing impact on the man’s health and quality of life. Furthermore, most expert panels are opposed to or discourage screening in men with <10–15 years of life expectancy.
In a deviation from their original guidelines, the European Association of Urology (EAU) recently recommended that well-informed men with a life-expectancy of ≥10 years should have a baseline PSA measurement for risk stratification at 45 years of age [38]. It was suggested that men with a PSA concentration <1 μg/L might then undergo further testing at intervals up to 8 years. However, for men with a PSA level ≥1 μg/L, screening at intervals of 2–4 years was proposed [38]. The panel also suggested that multiparametric MRI as well as risk calculators based on family history, ethnicity, digital rectal examination and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis.
The Memorial Sloan Kettering Cancer Center guidelines also recommends that PSA screening should start at 45 years of age [39]. According to this organisation, if PSA levels are ≥3 μg/L, a biopsy should be considered. If PSA levels are ≥1 but <3 μg/L, a return for PSA testing every 2–4 years was recommended. If, however, PSA levels are <1 μg/L, a return for PSA testing at 6–10 years was recommended. Although these recommendations to begin screening at mid-life would appear to be a rational approach to reduce overdiagnosis, these is no published evidence that it would reduce mortality from prostate cancer.
Use of PSA in risk stratification (prognosis)
In addition to its use in screening, PSA levels in combination with specific clinical and pathological factors are widely used in assessing risk of recurrence (prognosis) in patients with newly diagnosed prostate cancer [40], [41], [42]. In general, an approximate linear relationship exists between PSA levels at initial diagnosis and outcome, i.e. the higher the PSA level, the worse the outcome [43], [44], [45], [46]. This relationship is especially found in patients with low or intermediate grade (i.e. Gleason score [GS] ≤7) disease. However, in some patients with high grade disease (GS, 8–10), low levels of PSA (≤2.5 μg/L) may predict a particularly poor outcome [43]. Overall, approximately 6% of men with high grade disease have low levels of PSA [43]. Although PSA levels at initial diagnosis broadly correlates with outcome, it has limited prognostic accuracy if used alone. In practice therefore, PSA levels are combined with clinical and tumour histological factors for predicting outcome [33], [47].
The cut-off concentrations used for PSA in assessing risk of recurrence are different from those used in the screening. For example, recent joint guidelines published by the American Urological Association, American Society for Radiation Oncology and Society of Urologic Oncology [33] state that men with PSA concentrations of <10 μg/L should be classified as very low or low risk. Men with PSA concentration 10−<20 μg/L should be regarded as being at intermediate risk of recurrence, while those with values ≥20 μg/L should be placed at high risk of recurrence. As mentioned, for each of these categories, PSA is not used alone but is combined with specific clinical and pathological features [33]. Essentially similar criteria are recommended by the National Comprehensive Cancer Network (NCCN) for risk stratification in patients with newly diagnosed prostate cancer [47]. However, the NCCN recommend use of the newer International Society of Urological Pathology (ISUP) grading system rather than the older Gleason grading system [47].
Use of PSA in follow-up following initial diagnosis
Management options for patients with newly diagnosed localised prostate cancer include radical prostatectomy, radiotherapy with or without androgen deprivation therapy (ADT), brachytherapy and active surveillance (the latter only for patients deemed to be at low risk of recurrence). Irrespective of the option chosen, serial concentrations of PSA are generally measured during follow-up. The optimum frequency for PSA testing in follow-up has not been established and indeed is likely to vary depending on aggressiveness of the primary cancer. Generally, however, following initial definitive therapy, measurement of PSA is recommended every 6–12 months for the first 5 years after diagnosis and annually thereafter [3]. For men at high risk for recurrence (i.e. ≥T3A disease or GR 8–10 or PSA >20 μg/L) PSA testing may be performed more frequently (e.g. every 3 months).
Rather than relying on static or absolute levels, the rate of change in serial PSA levels can also be used during follow-up. The rate of change in serial levels is usually determined by the PSA velocity (PSAV) (change in PSA concentration over time) or PSA doubling time (PSADT) (the time required for PSA levels to double their concentration). For follow-up after initial diagnosis, PSADT is more frequently used than PSAV. Although measurement of PSADT after radical prostatectomy, radiotherapy, following salvage therapy after PSA failure or during active surveillance has been found to correlate with patient outcome (for review, see Refs. [48], [49]), its determination has several problems. One of the main problems is the lack of standardised methodology for its measurements. Thus, the methods described to date varied in the number of samples used for calculation, frequency of measurement and the interval over which the measurements were made. In order to standardise methodology for the calculation of PSA-DT, the Prostate Specific Antigen Working Group published guidelines [50]. The main points in these guidelines are summarised:
All PSA concentrations used in calculating PSA-DT should be >0.2 μg/L and follow an increasing trend.
All values contained during a maximum period of 12 months should be included in the calculation.
The maximum period of the last 12 months is recommended to reflect the current disease status.
Minimum requirements for the PSA-DT calculation are 3 PSA results obtained during 3 months with a minimum of 4 weeks between measurements.
All PSA results must be obtained using the same method and preferable using the same laboratory.
PSA results should be recorded with a maximum of two significant digits after the decimal point.
Serum testosterone should be relatively stable during the period used for calculation.
Following successful radical prostatectomy for men with localised disease, PSA concentrations should decline to undetectable levels (<0.1 μg/L) within 2 months [3]. Biochemical recurrence (BCR) is then defined by two consecutive increasing PSA concentrations >0.2 μg/L [51]. In contrast, following radiotherapy or brachytherapy, PSA levels decrease slowly and generally reach concentrations <0.5 μg/L after about 6 months. However, in contrast to radical prostatectomy, they do not reach undetectable levels. Furthermore, with follow-up after radiotherapy, a transient increase or bounce may occur in up to 40% of treated patients. Transient increases generally occur within the first 3 years following treatment [52], [53]. According to an expert consensus group (Phoenix Consensus Conference), an increase in PSA concentration of 2 μg/L or more above the nadir (defined as the lowest PSA level achieved) should be regarded as a biochemical failure following radiotherapy with or without ADT [54]. However, this panel also suggested that an older definition of biochemical failure, i.e. three consecutive PSA increases above a nadir value could be used after radiotherapy or brachytherapy without ADT. Failure was then backdated to a date between the first increasing level and the nadir value.
Management of patients with biochemical recurrence
Although the presence of BCR indicates an increased risk of clinical recurrence, many such patients continue to remain free of symptoms. Thus, in one retrospective study in which 315 men experienced BCR, only 34% subsequently developed evidence of clinical recurrence [55]. The median time between the BCR and evidence of clinical recurrence was 8 years. The median time to death following clinical recurrence was then a further 5 years [55].
To identify factors associated with poor outcome following BCR, Van den Broeck et al. [56] carried out a systematic review of the published literature. Following radical prostatectomy, BCR was associated with poor outcome mostly in patients with a short PSA-DT and high final GS. Due to the heterogeneity in the PSA-DT used in the different studies, the authors were unable to select an optimum cut-off point. Most studies however, found that patients with a PSA-DT of <12 months had an increased risk of recurrence. After radiotherapy, a poor outcome was correlated with a short interval to BCR as well as a high biopsy GS [56]. As with the patients treated with radical prostatectomy, different studies used different cut-off points for PSA-DT in men treated with radiotherapy. Most however, found that an interval to BCR of <18 months was associated with the development of disease recurrence.
As many men with evidence of BCR never develop clinical evidence of recurrence, it is unclear if or when ADT should be administered, i.e. whether to administer it early or await clinical evidence of disease [57], [58], [59], [60]. A recent randomised phase III clinical trial however, suggested that the early administration of ADT may enhance outcome compared to waiting for clinical symptoms to develop [61]. In this trial involving men with evidence of BCR following surgery or radiotherapy or those not considered suitable for these treatments, Duchesne et al. [61] found that immediate administration of ADT improved survival compared with delayed treatment administration. Median follow-up in this trial, however, was relatively short (5 years). Furthermore, only 40 deaths were recorded, of which only 18 were due to prostate cancer. Quality of life was reported to decrease by a “small but clinically notable amount” in men receiving the immediate vs. men in the delayed treatment arm.
Although administration of ADT may be beneficial in some men with evidence of BCR, many receiving this treatment will develop disease progression as evidenced by increasing PSA levels. Despite the increasing PSA levels, some of these men will nevertheless show no evidence of metastasis using conventional imaging. Such men are referred to as having castrate-resistant prostate cancer (CRPC). Castrate-resistant disease is frequently defined as two consecutive PSA increases, at least 1 week apart, with testosterone levels <1.7 nmol/L (<50 ng/mL). Three prospective randomised trials have recently shown the administration of third-generation androgen receptor (AR) antagonists such as enzalutamide, apalutamide or darolutamide enhanced metastasis-free survival in men who had non-metastatic CRPC with PSA doubling times of ≤10 months [62], [63], [64].
Use of PSA in monitoring treatment in advanced disease
Although most patients diagnosed with localised prostate cancer do not die from the disease, a minority develop distant metastases which are generally incurable. The initial treatments for patients with metastatic prostate cancer is usually hormone therapy (ADT) [65]. Although, serial determinations of PSA are widely used to monitor response to ADT, validated definitions of response or progression have not been established. Most studies, however, have shown that patients with a PSA level ≤4 μg/L following approximately 6/7 months of ADT treatment tend to have a better outcome than those with PSA levels >4 μg/L. In a large prospective trial involving 1345 patients with advanced prostate cancer treated with ADT (goserelin and bicalutamide), median survival was 13 months for patients with a PSA >4 μg/L, 44 months for patients with a PSA of >0.2–≤4 μg/L, and 75 months for patients with a PSA of ≤0.2 μg/L [66]. Furthermore, after controlling for standard prognostic factors, patients with a PSA of >0.2 but ≤4 μg/L had less than one third the risk of death compared with those with a PSA of >4 μg/L, while patients with PSA levels of ≤0.2 ng/mL had less than one fifth the risk of death as patients with a PSA value of >4 μg/L. Other studies have also found that the PSA nadir value following ADT is prognostic of patient outcome [67], [68], i.e. the lower the PSA level following ADT, the better the outcome. One of the problems in using PSA to monitor response to ADT in patients with prostate cancer is that as PSA production is controlled by androgens, this therapy can lower PSA levels without necessarily impacting on tumour bulk.
As in the non-metastatic situation mentioned, resistance (CRPC) usually occurs following initial ADT in the metastatic situation. Potential treatments for CRPC include second line ADT (abiraterone plus prednisolone, enzalutamide), ADT plus chemotherapy (docetaxel, cabazitaxel), radium-223 and immunotherapy (sipuleucel-T) [69], [70]. Although PSA is used in assessing response to these therapies in patients with metastatic CRPC, changes in its levels are poor predictors of survival [71], [72]. Indeed, a recent report involving five randomised phase III clinical trials using different treatments showed that a decrease in the number of circulating tumour cells (CTC) from ≥1 to zero was superior to PSA for predicting survival [72]. It should be stated however, that unlike PSA, CTC are not believed to be directly under the control of androgens and thus should not be affected by ADT. Measurement of CTC, however, is more expensive than that of PSA and furthermore is not widely available.
Finally, although immunotherapy with sipuleucel-T or administration of the radiopharmaceutical, radium-223 have been shown to increase overall survival, this improvement was not found to correlate with alterations in PSA levels. [73], [74]. Changes in PSA levels are thus also of limited value for predicting outcome in patients with castrate-resistant metastatic prostate cancer undergoing treatment with sipuleucel-T or radium-223.
Biomarkers for improving the diagnostic accuracy of PSA
One of the main problems in using PSA to screen for prostate cancer is the lack of specificity, especially when values are <10 μg/L. The consequence of this poor specificity is that large numbers of men may undergo unnecessary biopsy to confirm or exclude malignancy. Thus, 65%–75% of men with a PSA level in the 3/4–10 μg/L range do not have biopsy-detectable prostate cancer [10]. To improve specificity and thus reduce the number of unnecessary biopsies/repeat biopsies, several additional or adjunct tests have been proposed (Table 2). These include percent free PSA, PHI, 4K score and PCA3.
Serum and urinary biomarkers that may be combined with PSA for enhancing the diagnostic accuracy of prostate cancer detection including high grade disease.
| Test | Analytes detected | Fluid | References |
|---|---|---|---|
| Per cent fPSA | PSA and fPSA | Serum | [75], [76], [77], [78], [79] |
| PHI | PSA, fPSA, -2ProPSA | Serum | [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90] |
| 4K Score | PSA, fPSA, iPSA, kK2 | Serum | [91], [92], [93], [94], [95], [96] |
| Progensa PCA3 | PCA3a, PSAa | Urine | [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107] |
| MiPS | PCA3a, TMPRSS2-ERGa | Urine | [108] |
| STHLM3 | PSA, fPSA, iPSA, HK2, β-microseminoprotein, macrophage inhibitory cytokine, 232 SNPb | Serum | [109], [110] |
| epiCaPture | Methylated GSTP1, SFRP2, IGFBP3, IGFBP7, APC, PTGS2 | Urine | [111] |
aMeasured at mRNA level. bThese variables are combined with clinical and histological criteria. PSA, total PSA; fPSA, free PSA; iPSA, intact PSA; HK2, human kallikrein 2; PCA3, prostate cancer antigen 3; MiPS, Mi-Prostate Score; TMPRRS2, transmembrane protease, serine 2.
The key to the development of many of these tests was the discovery that PSA can exist in multiple forms (for review, see Refs. [75], [76]). Early studies showed that PSA existed in different forms in blood. Seventy to ninety percent of the protein is complexed with serum protease inhibitors especially with α1-antichymotripsin. The remainder 10%–30% exists in a free or unbound state (75, 76). The free PSA in serum is composed of three major forms: pro-PSA, BPSA and intact PSA. The preform can in turn exist in multiple forms including the native proPSA form containing a 7-amino-acid pro-peptide leader [(-7)proPSA] as well as forms with various truncated pro-peptide leader sequences. These truncated proPSA forms consist mostly of proPSA with a 5-amino-acid (-5) proPSA, 4-amino-acid (-4)]proPSA or 2-amino-acid (-2)proPSA [112], [113].
Percent free PSA
One of the first adjunct tests developed to enhance the specificity of PSA was percent free PSA (free PSA/total PSA ratio). In general, men with prostate cancer have lower levels of percent free PSA when compared to men without prostate cancer. Although the absolute amount of free PSA in blood has no established clinical value, measurement of the percent free PSA has been shown to increase the specificity of PSA for prostate cancer detection, especially in men with total PSA levels between 2 and 4 and 10 μg/L [75], [76], [77]. Because of this enhanced specificity, measurement of percent free has the potential to reduce the number of biopsies performed in men with border-line total PSA levels.
In an early multicentre prospective study, carried out in men with total PSA levels between 4 and 10 μg/L, percent free PSA ranged from 2% to 52% [75]. Using a cut-off value of 25, the measurement of percent free PSA was found to detect 95% of cancers and avoid 20% of unnecessary biopsies [75]. The cancers detected in men with ≥25% free PSA tended to be of lower grade and smaller volume than those found in men with lower percent free PSA levels. The risk of cancer increased as the free PSA percentage decreased. Thus, for men with per cent free PSA values of 0–10, the risk of cancer was 55% or 56% (depending on man’s age) while at levels >25%, the risk of cancer was <10%. Using multivariate analysis that also included total PSA and patient age, percent free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2).
These early finding have been essentially confirmed in several subsequent reports [76], [77]. Furthermore, it has been shown that measurement of percent free PSA can increase diagnostic specificity not only in the total PSA range of 4–10 μg/L range but also in the 2–10 μg/L range [76]. However, the diagnostic accuracy of percent free PSA was found to be significantly better for men with total PSA levels of 4–10 μg/L compared to those with total PSA levels of 2–4 μg/L (p<0.01). At a sensitivity of 95%, specificity was 18% for men in the 4–10 μg/L total PSA range but only 6% in the 2–10 μg/L total PSA range.
In practice, measurement of percent free PSA is most useful at its extreme concentration limits, i.e. at low and high levels. Thus, as mentioned above, for men with a total PSA level between 4 and 10 μg/L, those with percent free PSA concentrations lower than 10% have a >50% probability of being diagnosed with prostate cancer, whereas those with levels >25% have a <10% chance of having prostate cancer [75], [76], [77]. The latter however, may not be of much clinical value, as some men would consider a <10% probability of being diagnosed with prostate cancer to be insufficiently low not to undergo a biopsy.
Caution is advised when measuring and interpreting percent free PSA levels. Firstly, as increasing prostate volume produces a greater amount of percent free PSA, this parameter has been reported to provide reliable data only in men with a prostate volume <40 mL [78]. A further problem is selecting the optimum cut-off point. Indeed, there is no universally accepted cut-off point for percent free PSA, with values ranging from 8% to 25% described in the literature [79]. Most investigators, however, use cut-off values of between 15% and 20% [79]. A practical problem in determining percent free PSA is that the free PSA molecule is relatively unstable at room temperature [114]. According to the National Academy of Clinical Biochemistry (NACB) guidelines [34], serum for free PSA may be stored at refrigerated temperatures for up to 24 h. Samples not analysed within 24 h of collection should be stored frozen at −20 °C or lower. For long-term storage, freezing at −70 °C was recommended [34].
Currently, percent free PSA has no role in screening for prostate cancer but may be useful as a reflex test for men with total PSA levels between 2 and 10 μg/L. Thus, according to the NACB recommendations “the use of percent free PSA is recommended as an aid in distinguishing prostate cancer from benign prostate hyperplasia, when the total PSA levels in serum are between 4 and 10 μg/L and DRE is negative” [34].
Prostate Health Index (PHI)
The PHI involves measurement of -2proPSA, percent free PSA and total PSA. Levels of these three proteins are then combined using the formula (-2 proPSA/free PSA)×√total PSA (Beckman Coulter, Inc.) [80]. PHI has been shown to be superior to total PSA and percent free PSA in detecting prostate cancer including aggressive prostate cancer [80], [81], [82], [83]. Thus, following a meta-analysis of eight studies (n=2919 patients), the pooled sensitivity of PHI for the detection of prostate cancer was 90% while the pooled specificity was 31.6% [83]. In this meta-analysis, measurement of PHI was found to have superior accuracy for detecting prostate cancer than total or percent free PSA across the eight studies analysed. This superior accuracy was especially evident in men with PSA levels between 2 μg/L and 10 μg/L.
In addition to having superior accuracy for detecting prostate cancer in general, PHI also has higher predictive accuracy for clinically-significant/aggressive disease compared with PSA or percent free PSA [84], [85]. Thus, in a large multicentre study, PHI was found to be significantly associated with high grade disease (GR≥7) with an area under the curve (AUC) of 0.815 [85]. At 95% sensitivity, the PHI specificity was 36.0% compared to 17.2% for total PSA and 19.4% for percent free PSA. At 95% sensitivity for detecting aggressive prostate cancer, the optimal cut-off value for PHI was 24. At this cut-off point, measurement of PHI could potentially avoid 36%–41% of unnecessary biopsies and 17%–24% of overdiagnosed indolent cancers.
The main clinical use of PHI is in reducing the number of unnecessary biopsies in men with border-line PSA levels. Depending on the cut-off point used, this can vary from about 15% to 45% [86]. Avoiding biopsy, however, may result in missing a small number of cancers (usually <10% at a cut-off point of 25) [86].
In addition to reducing the number of unnecessary biopsies, other potential uses of PHI include predicting biochemical recurrence following radical prostatectomy [87], [88] and enhancing the predictive value of multi-parametric MRI [89], [90]. PHI at present is not recommended in primary screening for prostate cancer. However, in the future, its value in this setting should be considered for evaluation as a reflex test in patients with PSA values between 2 and 10 μg/L.
Finally, regarding the measurement of PHI levels, it is important to state that the optimum conditions for pre-analytical handling and storage of samples remain to be determined. Indeed, further studies are needed to assess whether plasma or serum is the best matrix for its measurement.
4K score
The 4K score tests measure total PSA, free PSA, intact PSA (a form of free PSA) and human kallikrein 2 (hK2) [91]. Levels of these biomarkers are combined in an algorithm together with patient age, digital rectal exam status and any prior biopsy findings for predicting the risk of a man having high grade prostate cancer. Similar to the situation with PHI, several studies have also shown that the 4K score provides superior diagnostic accuracy for detecting prostate cancers in general as well as high grade prostate cancer, compared to PSA or percent free PSA [92], [93], [94], [95], [96]. Thus, using 4765 patients participating in a prospective, randomised trial (ProtecT trial), the AUC for the 4K score was 0.719 compared with 0.634 for PSA for all cancers and 0.820 vs. 0.738 for high-grade cancers [92]. As regards comparison with PHI, a meta-analysis of published studies concluded that both tests had essentially similar diagnostic accuracy for high grade prostate cancer [96]. As with percent free PSA and PHI, one of the main clinical uses of the 4K score is its potential to reduce the number of unnecessary biopsies. Depending on the cut-off point selected, this has been reported to vary from 41% to 57% [86].
PCA3
PCA3 (prostate cancer gene 3) which is also known as DD3, is a prostate-specific non-coding mRNA. In an early study, 53/56 specimens of prostate cancer tissue investigated were found to contain 10–100-fold greater levels of PCA3 than that found in adjacent non-malignant prostate tissue [97]. Although PCA3 was also found in both normal prostate and benign prostate hypertrophy, expression was undetectable in several normal and malignant non-prostatic tissues [97]. These results when combined with the finding of PCA3 in prostate cells in urinary sediments [98] suggested that this molecule might be a new marker for prostate cancer.
The best characterised PCA3 assay (Progensa PCA3, Hologic Inc, Marlborough, MA, USA) detects mRNA for PCA3 and PSA in first-catch urine following digital rectal examination [99]. Measurement of PSA mRNA is necessary to control for the number of prostate epithelial cells in the urine. In one of the largest reports to evaluate the diagnostic potential of PCA3 for prostate cancer, Cui et al. [100] combined the data from 46 studies involving 12,295 men investigated for possible prostate cancer. Pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (−LR), diagnostic odds ratio (DOR) and AUC for prostate cancer were 0.65 (95% confidence interval [CI]: 0.63–0.66), 0.73 (95% CI: 0.72–0.74), 2.23 (95% CI: 1.91–2.62), 0.48 (95% CI: 0.44–0.52), 5.31 (95% CI: 4.19–6.73) and 0.75 (95% CI: 0.74–0.77), respectively.
In a large multicentre prospective validation study (n=859) published subsequent to the above meta-analysis, Wei et al. [101] reported that PCA3 had positive predictive value (PPV) of 80% (95% CI, 72%–86%) for men presenting for their initial biopsy. In those with a PCA3 score >60 units, the specificity for prostate cancer was 0.91 (95% CI, 0.87–0.94) and the sensitivity was 0.42 (0.36–0.48). For men presenting for a second biopsy, PCA3 had a negative predictive value (NPV) of 88% (95% CI, 81%–93%). For men with a PCA3 score of <20 units at repeat biopsy, the sensitivity for prostate cancer was 0.76 (95% CI, 0.64–0.86) and the specificity was 0.52 (95% CI, 0.45–0.58). Importantly, Wei et al. [101] found that adding of the PCA3 score to individual risk estimation models that included patient age, race/ethnicity, prior biopsy finding, PSA and digital rectal examination result, improved the stratification of any prostate cancer as well as high-grade cancer. Based on these findings, the authors concluded that measurement of PCA3 helps minimise underdetection of high grade disease in initial biopsies and overdetection of low grade malignancy in repeat biopsies [101]. Other studies have suggested that the diagnostic accuracy of PCA3 for prostate cancer was superior to that of the total PSA, percent free PSA and PSA velocity [102], [103]. However, PCA3 does not appear to add to PHI in predicting cancer at an initial or repeat biopsy [104]. Finally, conflicting data has been published regarding a possible role for PCA3 in predicting prostate cancer aggressiveness [105], [106].
Although PCA3 is unlikely to replace PSA as the frontline biomarker for prostate cancer, the combined measurement of both should result in enhanced specificity for prostate cancer diagnosis. Assaying of PCA3 however, may be of particular value in patients with elevated PSA levels but who have histologically-negative biopsies [107]. In this situation, PCA3 can provide information in deciding whether or not to repeat a biopsy. In 2012, The Food and Drug Administration (USA) approved the PROGENSA PCA3 assay for use in conjunction with other patient information to aid in the decision for repeat biopsy in men ≥50 years who have had one or more previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on the current standard of care.
Other biomarkers for enhancing the specificity of PSA
Other reflex biomarkers that may be used for enhancing decision making with respect to performing a biopsy in men with borderline PSA levels are listed in Table 2.
Tissue-based biomarkers for determining prognosis and clinical decision making
In recent years, several tissue biomarker tests have become available for determining aggressiveness and predicting outcome in patients with newly diagnosed prostate cancer (Table 3). Some of these are multi-analyte tests, measure multiple molecular species, especially mRNAs. Of the tests listed in Table 3, the best validated include Decipher, Oncotype DX (Prostate), Prolaris and ProMark. Although these tests have been evaluated in different settings and used different end points, they all essentially provide information on tumour aggressiveness and patient outcome.
Tissue-based assays reported to identify prostate cancer aggressiveness and/or predict patient outcome.
| Test | No. of analytes detected | Type of analyte | Outcome/endpoint provided by test | References |
|---|---|---|---|---|
| Confirm | 3 | Methylated genes | Deciding on repeat biopsy if PSA is high and initial biopsy is negative | [115], [116] |
| Decipher | 22 | mRNA | High-grade disease, metastasis, prostate-cancer-specific mortality | [117], [118] |
| Ki67 | 1 | Protein | Formation of metastasis | [119] |
| Oncotype DX | 17a | mRNA | Tumour aggressiveness and outcome | [120], [121] |
| Prolaris | 46b | mRNA | Tumour aggressiveness and prostate-specific mortality | [122], [123] |
| ProMark | 8 | Protein | Aggressive disease in patients with GS 3+3 and 3+4 | [124] |
| PTEN | 1 | Protein | Aggressive disease and patient outcome | [125] |
| Select MDX | 2 | mRNA | Tumour aggressiveness | [126] |
a12 test genes and five control genes; b31 test and 15 control genes. GS, Gleason score.
Although multigene signatures can potentially fulfil an unmet need in the management of patients with prostate cancer, several problems are currently limiting their use. Firstly, none have yet been prospectively validated for clinical utility using a randomised clinical trial. Secondly, compared to the blood biomarkers discussed above, tissue-based multigene signatures are expensive, costing $3000–$4000. Thirdly, it is unclear which test (if any) is best for predicting a specific endpoint or indeed how they compare with the simple and less expensive blood-based tests discussed above (PHI, 4K score). Finally, due the heterogeneity of prostate cancer tissue, different results can be found depending on the location of sample biopsied [127]. Despite these limitations, the current NCCN guidelines state that Decipher, Oncotype DX. Prolaris and ProMark may be considered for risk stratification in men with low or favourable intermediate-risk disease [47].
Therapy predictive biomarkers
The tissue-based multigene tests discussed are essentially prognostic and provide little information regarding response or resistance to different therapies. Recently, however, a small number of therapy predictive biomarkers for prostate cancer treatments have begun to emerge. These include the AR splice variant, AR-V7 measured in CTC for predicting resistance to enzalutamide and abiraterone [128], [129], [130], mutant BRCA1/2 in prostate cancer tissue for predicting response to the PARP inhibitor, olaparib [131], the PORTOS test (measured in prostate cancer tissue) for predicting response to radiotherapy [132] and circulating tumour DNA for predicting resistance to enzalutamide in castrate-resistant patients [133]. In 2016, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation (BTD) for olaparib for the treatment of BRCA1/2 (or ATM) gene mutated metastatic castrate-resistant prostate cancer patients who have received a prior taxane-based chemotherapy and abiraterone or enzalutamide (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm592357.htm).
Conclusions
Despite its limitations, PSA is likely to remain the only biomarker available for prostate cancer screening for the foreseeable future. Although traditionally, expert panels differed in their recommendations on whether or not to screen for prostate cancer, most currently recommend limited screening following a process of education and informed consent [33], [34], [35], [36], [37]. Although for the present, PSA is the best validated and most widely used prostate cancer biomarker, several other tests are likely to be increasingly used in the future. These will include PHI, the 4K score or multi-parametric MRI for enhancing the specificity of PSA for prostate cancer and reducing the number of men undergoing unnecessary biopsy. For determining tumour aggressiveness and predicting patient outcome, it is likely that multiple factors will be used such as blood biomarkers (e.g. PSA, PHI, 4K score, PCA3), gene expression profiles (in selected cases), histological and clinical criteria. With the increasing number of biomarkers becoming available and validated, we will finally be on the road to personalised management for men with suspected or diagnosed prostate cancer.
Author contributions: The author has accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Pinsky PF, Prorok PC, Kramer BS. Prostate cancer screening – a perspective on the current state of the evidence. N Engl J Med 2017;376:1285–9.10.1056/NEJMsb1616281Search in Google Scholar
2. Ilic D, Djulbegovic M, Jung JH, Hwang EC, Zhou Q, Cleves A, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. Br Med J 2018;362:k3519.10.1136/bmj.k3519Search in Google Scholar
3. Loblaw A, Souter LH, Canil C, Breau RH, Haider M, Jamnicky L, et al. follow-up care for survivors of prostate cancer – clinical management: A program in evidence-based care systematic review and clinical practice guideline. Clin Oncol (R Coll Radiol) 2017;29:711–7.10.1016/j.clon.2017.08.004Search in Google Scholar
4. Lamy PJ, Allory Y, Gauchez AS, Asselain B, Beuzeboc P, de Cremoux P, et al. Prognostic biomarkers used for localised prostate cancer management: a systematic review. Eur Urol Focus 2018;4:790–803.10.1016/j.euf.2017.02.017Search in Google Scholar
5. McGrath S, Christidis D, Perera M, Hong SK, Manning T, Vela I, et al. Prostate cancer biomarkers: are we hitting the mark? Prostate Int 2016;4:130–5.10.1016/j.prnil.2016.07.002Search in Google Scholar
6. Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310–9.10.1056/NEJMoa0810696Search in Google Scholar
7. Andriole GL, Crawford ED, Grubb 3rd RL, Buys SS, Chia D, Church TR, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012;104:125–32.10.1093/jnci/djr500Search in Google Scholar
8. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320–8.10.1056/NEJMoa0810084Search in Google Scholar
9. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012;366:981–90, Erratum in: N Engl J Med 2012;366:2137.10.1056/NEJMoa1113135Search in Google Scholar
10. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384:2027–35.10.1016/S0140-6736(14)60525-0Search in Google Scholar
11. Hugosson J, Roobol MJ, Månsson M, Tammela TL, Zappa M, Nelen V, et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol 2019;76:43–51.10.1016/j.eururo.2019.02.009Search in Google Scholar PubMed PubMed Central
12. Martin RM, Donovan JL, Turner EL, Metcalfe C, Young GJ, Walsh EI, et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. J Am Med Assoc 2018;319:883–95.10.1001/jama.2018.0154Search in Google Scholar PubMed PubMed Central
13. Osses DF, Remmers S, Schröder FH, van der Kwast T, Roobol MJ. Results of prostate cancer screening in a unique cohort at 19 yr of follow-up. Eur Urol 2019;75:374–7.10.1016/j.eururo.2018.10.053Search in Google Scholar PubMed
14. Shoag JE, Schlegel PN, Hu JC. Prostate-specific antigen screening: time to change the dominant forces on the pendulum. J Clin Oncol 2016;34:3499–501.10.1200/JCO.2016.67.8938Search in Google Scholar PubMed PubMed Central
15. Albers P. Re: Reevaluating PSA testing rates in the PLCO trial. Eur Urol 2017;71:300.10.1016/j.eururo.2016.10.039Search in Google Scholar PubMed
16. Duffy MJ. PSA in screening for prostate cancer: more good than harm or more harm than good? Adv Clin Chem 2014;66:1–23.10.1016/B978-0-12-801401-1.00001-3Search in Google Scholar
17. Wilt TJ, Ahmed HU. Prostate cancer screening and the management of clinically localized disease. Br Med J 2013;346:f325.10.1136/bmj.f325Search in Google Scholar PubMed PubMed Central
18. Tsodikov A, Gulati R, Heijnsdijk EA, Pinsky PF, Moss SM, Qiu S, et al. Reconciling the effects of screening on prostate cancer mortality in the ERSPC and PLCO Trials. Ann Intern Med 2017;167:449–55.10.7326/M16-2586Search in Google Scholar PubMed PubMed Central
19. de Koning HJ, Gulati R, Moss SM, Hugosson J, Pinsky PF, Berg CD, et al. The efficacy of prostate-specific antigen screening: impact of key components in the ERSPC and PLCO trials. Cancer 2018;124:1197–206.10.1002/cncr.31178Search in Google Scholar PubMed PubMed Central
20. Kilpeläinen TP, Tammela TL, Roobol M, Hugosson J, Ciatto S, Nelen V, et al. False-positive screening results in the European randomized study of screening for prostate cancer. Eur J Cancer 2011;47:2698–705.10.1016/j.ejca.2011.06.055Search in Google Scholar PubMed
21. Bul M, van den Bergh RC, Zhu X, Rannikko A, Vasarainen H, Bangma CH, et al. Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int 2012;110:1672–7.10.1111/j.1464-410X.2012.11434.xSearch in Google Scholar PubMed
22. van den Bergh RC, Vasarainen H, van der Poel HG, Vis-Maters JJ, Rietbergen JB, Pickles T, et al. Short-term outcomes of the prospective multicentre Prostate Cancer Research International: Active Surveillance’ study. Br J Urol Int 2010;105:956–62.10.1111/j.1464-410X.2009.08887.xSearch in Google Scholar PubMed
23. Pinsky PF, Parnes HL, Andriole G. Mortality and complications after prostate biopsy in the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) trial. Br J Urol Int 2014;113:254–9.10.1111/bju.12368Search in Google Scholar PubMed PubMed Central
24. Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow J. Prostate-specific antigen-based screening for prostate cancer: evidence report and systematic review for the US Preventive Services Task Force. J Am Med Assoc 2018;319:1914–31.10.1001/jama.2018.3712Search in Google Scholar PubMed
25. Donovan JL, Hamdy FC, Lane JA, Mason M, Metcalfe C, Walsh E, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425–37.10.1056/NEJMoa1606221Search in Google Scholar PubMed PubMed Central
26. Loeb S. Evidence-based versus personalized prostate cancer screening: using baseline prostate-specific antigen measurements to individualize screening. J Clin Oncol 2016;34:2684–6.10.1200/JCO.2016.68.2138Search in Google Scholar PubMed PubMed Central
27. Seibert TM, Fan CC, Wang Y, Zuber V, Karunamuni R, Parsons JK, et al. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. Br Med J 2018;360:j5757.10.1136/bmj.j5757Search in Google Scholar PubMed PubMed Central
28. Donovan JL, Hamdy FC. Time for a “radical” change to active surveillance for prostate cancer? Eur Urol 2018;74:281–2.10.1016/j.eururo.2018.05.009Search in Google Scholar PubMed
29. Louie KS, Seigneurin A, Cathcart P, Sasieni P. Do prostate cancer risk models improve the predictive accuracy of PSA screening? A meta-analysis. Ann Oncol 2015;26:848–64.10.1093/annonc/mdu525Search in Google Scholar PubMed
30. Filella X, Fernández-Galan E, Fernández Bonifacio R, Foj L. Emerging biomarkers in the diagnosis of prostate cancer. Pharmgenomics Pers Med 2018;11:83–94.10.2147/PGPM.S136026Search in Google Scholar PubMed PubMed Central
31. Kretschmer A, Tilki D. Biomarkers in prostate cancer – current clinical utility and future perspectives. Crit Rev Oncol Hematol 2017;120:180–93.10.1016/j.critrevonc.2017.11.007Search in Google Scholar
32. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017;389:815–22.10.1016/S0140-6736(16)32401-1Search in Google Scholar
33. Sanda MG, Cadeddu JA, Kirkby E, Chen RC, Crispino T, Fontanarosa J, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and care options. J Urol 2018;199:683–90.10.1016/j.juro.2017.11.095Search in Google Scholar PubMed
34. Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008;54:e11–79.10.1373/clinchem.2008.105601Search in Google Scholar PubMed
35. US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. J Am Med Assoc 2018;319:1901–13. Erratum in: JAMA 2018;319:2443.10.1001/jama.2018.3710Search in Google Scholar
36. Smith RA, Andrews KS, Brooks D, Fedewa SA, Manassaram- Baptiste D, Saslow D, et al. Cancer screening in the United States, 2018: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin 2018;68:297–316.10.3322/caac.21446Search in Google Scholar PubMed
37. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2017;71:618–29.10.1016/j.eururo.2016.08.003Search in Google Scholar PubMed
38. Gandaglia G, Albers P, Abrahamsson PA, Briganti A, Catto JW, Chapple CR, et al. Structured population-based prostate-specific antigen screening for prostate cancer: the European Association of Urology position in 2019. Eur Urol 2019;76:142–50.10.1016/j.eururo.2019.04.033Search in Google Scholar PubMed
39. Vickers AJ, Eastham JA, Scardino PT, Lilja H. The Memorial Sloan Kettering Cancer Center Recommendations for prostate cancer screening. Urology 2016;91:12–8.10.1016/j.urology.2015.12.054Search in Google Scholar PubMed PubMed Central
40. Cooperberg MR, Broering JM, Carroll PR. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J Natl Cancer Inst 2009;101:878–87.10.1093/jnci/djp122Search in Google Scholar PubMed PubMed Central
41. Kattan MW, Eastham JA, Stapleton AM, Wheeler TM, Scardino PT. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90: 766–71.10.1093/jnci/90.10.766Search in Google Scholar PubMed
42. Stephenson AJ, Scardino PT, Eastham JA, Bianco FJ Jr, Dotan ZA, Fearn PA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006;98:715–7.10.1093/jnci/djj190Search in Google Scholar
43. Mahal BA, Yang DD, Wang NQ, Alshalalfa M, Davicioni E, Choeurng V, et al. Clinical and genomic characterization of low-prostate- specific antigen, high-grade prostate cancer. Eur Urol 2018;74: 146–54.10.1016/j.eururo.2018.01.043Search in Google Scholar
44. Cooperberg MR, Broering JM, Carroll PR. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J Natl Cancer Inst 2009;101:878–87.10.1093/jnci/djp122Search in Google Scholar
45. Gasinska A, Jaszczynski J, Rychlik U, Łuczynska E, Pogodzinski M, Palaczynski M. Prognostic significance of serum PSA level and telomerase, VEGF and GLUT-1 protein expression for the biochemical recurrence in prostate cancer patients after radical prostatectomy. Pathol Oncol Res 2019 Apr 15. doi: 10.1007/s12253-019-00659-4 [Epub ahead of print].10.1007/s12253-019-00659-4Search in Google Scholar
46. Stephenson AJ, Scardino PT, Eastham JA, Bianco FJ Jr, Dotan ZA, Fearn PA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006;98:715–7.10.1093/jnci/djj190Search in Google Scholar
47. NCCN Clinical practice Guidelines in Oncology, Prostate Cancer Version 2.2019. Available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed: 5 June 2019.Search in Google Scholar
48. Colloca G. Prostate-specific antigen kinetics as a surrogate endpoint in clinical trials of metastatic castration-resistant prostate cancer: a review. Cancer Treat Rev 2012;38:1020–6.10.1016/j.ctrv.2012.03.008Search in Google Scholar
49. Maffezzini M, Bossi A, Collette L. Implications of prostate-specific antigen doubling time as indicator of failure after surgery or radiation therapy for prostate cancer. Eur Urol 2007;51:605–13.10.1016/j.eururo.2006.10.062Search in Google Scholar
50. Arlen PM, Bianco F, Dahut WL, D’Amico A, Figg WD, Freedland SJ, et al. Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time. J Urol 2008;179:2181–5.10.1016/j.juro.2008.01.099Search in Google Scholar
51. Amling CL, Bergstralh EJ, Blute ML, Slezak JM, Zincke H. Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001;165:1146–51.10.1016/S0022-5347(05)66452-XSearch in Google Scholar
52. Zietman AL, Christodouleas JP, Shipley WU. PSA bounces after neoadjuvant androgen deprivation and external beam radiation: impact on definitions of failure. Int J Radiat Oncol Biol Phys 2005;62:714–8.10.1016/j.ijrobp.2004.11.020Search in Google Scholar PubMed
53. Hanlon AL, Pinover WH, Horwitz EM, Hanks GE. Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol Biol Phys 2001;50:845–9.10.1016/S0360-3016(01)01557-7Search in Google Scholar
54. Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965–74.10.1016/j.ijrobp.2006.04.029Search in Google Scholar
55. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. J Am Med Assoc 1999;281:1591–7.10.1001/jama.281.17.1591Search in Google Scholar
56. Van den Broeck T, van den Bergh RC, Arfi N, Gross T, Moris L, Briers E, et al. Prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: a systematic review. Eur Urol 2019;75:967–87.10.1016/j.eururo.2018.10.011Search in Google Scholar
57. Frydenberg M, Woo HH. Early androgen deprivation therapy improves survival, but how do we determine in whom? Eur Urol 2018;73:519–20.10.1016/j.eururo.2018.01.004Search in Google Scholar
58. Brand D, Parker C. Management of men with prostate-specific antigen failure after prostate radiotherapy: the case against early androgen deprivation. Eur Urol 2018;73:521–3.10.1016/j.eururo.2017.12.021Search in Google Scholar
59. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006;24:1868–76.10.1200/JCO.2005.04.7423Search in Google Scholar
60. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997;79:235–46.10.1046/j.1464-410X.1997.d01-6840.xSearch in Google Scholar
61. Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D’Este C,Frydenberg M, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016;17:727–37. Erratum in: Lancet Oncol 2016;17:e223.10.1016/S1470-2045(16)00107-8Search in Google Scholar
62. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378:2465–74.10.1056/NEJMoa1800536Search in Google Scholar PubMed PubMed Central
63. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378:1408–18.10.1056/NEJMoa1715546Search in Google Scholar PubMed
64. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019;380:1235–46.10.1056/NEJMoa1815671Search in Google Scholar PubMed
65. Morris MJ, Rumble RB, Basch E, Hotte SJ, Loblaw A, Rathkopf D, et al. Optimizing anticancer therapy in metastatic non-castrate prostate cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1521–39.10.1200/JCO.2018.78.0619Search in Google Scholar PubMed
66. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford ED, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24:3984–90.10.1200/JCO.2006.06.4246Search in Google Scholar PubMed
67. Harshman LC, Chen YH, Liu G, Carducci MA, Jarrard D, Dreicer R, et al. Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive prostate cancer treated with androgen deprivation with or without docetaxel. J Clin Oncol 2018;36:376–82.10.1200/JCO.2017.75.3921Search in Google Scholar PubMed PubMed Central
68. Crawford ED, Bennett CL, Andriole GL, Garnick MB, Petrylak DP. The utility of prostate-specific antigen in the management of advanced prostate cancer. Br J Urol Int 2013;112:548–60.10.1111/bju.12061Search in Google Scholar PubMed
69. Gillessen S, Attard G, Beer TM, Beltran H, Bossi A, Bristow R, et al. Management of patients with advanced prostate cancer: the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 2018;73:178–211.10.1016/j.eururo.2017.06.002Search in Google Scholar PubMed
70. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 2017;71:630–42.10.1016/j.eururo.2016.08.002Search in Google Scholar PubMed
71. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34:1402–18.10.1200/JCO.2015.64.2702Search in Google Scholar PubMed PubMed Central
72. Heller G, McCormack R, Kheoh T, Molina A, Smith MR, Dreicer R, et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: a comparison with prostate-specific antigen across five randomized phase III clinical trials. J Clin Oncol 2018;36:572–80.10.1200/JCO.2017.75.2998Search in Google Scholar PubMed PubMed Central
73. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006;24:3089–94.10.1200/JCO.2005.04.5252Search in Google Scholar
74. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213–23.10.1056/NEJMoa1213755Search in Google Scholar
75. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. J Am Med Assoc 1998;279:1542–7.10.1001/jama.279.19.1542Search in Google Scholar
76. Roddam AW, Duffy MJ, Hamdy FC, Ward AM, Patnick J, Price CP, et al. Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2–10 ng/mL: systematic review and meta-analysis. Eur Urol 2005;48:386–99.10.1016/j.eururo.2005.04.015Search in Google Scholar
77. Huang Y, Li ZZ, Huang YL, Song HJ, Wang YJ. Value of free/total prostate-specific antigen (f/t PSA) ratios for prostate cancer detection in patients with total serum prostate-specific antigen between 4 and 10 ng/mL. A meta-analysis. Medicine (Baltimore) 2018;97:e0249.10.1097/MD.0000000000010249Search in Google Scholar
78. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia. Cancer 1997;79:104–9.10.1002/(SICI)1097-0142(19970101)79:1<104::AID-CNCR15>3.0.CO;2-8Search in Google Scholar
79. Hoffman RM, Clanon DL, Littenberg B, Frank JJ, Peirce JC. Using the free-to-total prostate-specific antigen ratio to detect prostate cancer in men with nonspecific elevations of prostate-specific antigen levels. J Gen Intern Med 2000;15:739–48.10.1046/j.1525-1497.2000.90907.xSearch in Google Scholar
80. Jansen FH, van Schaik RH, Kurstjens J, Horninger W, Klocker H, Bektic J, et al. Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol 2010;57:921–7.10.1016/j.eururo.2010.02.003Search in Google Scholar
81. Lazzeri M, Haese A, de la Taille A, Palou Redorta J, McNicholas T, Lughezzani G, et al. Serum Isoform [-2]proPSA derivatives significantly improve prediction of prostate cancer at initial biopsy in a total PSA range of 2–10 ng/mL: a multicentric European study. Eur Urol 2013;63:986–94.10.1016/j.eururo.2013.01.011Search in Google Scholar
82. Stephan C, Vincendeau S, Houlgatte A, Cammann H, Jung K, Semjonow A. Multicenter evaluation of [-2]proprostate-specific antigen and the prostate health index for detecting prostate cancer. Clin Chem 2013;59:306–14.10.1373/clinchem.2012.195784Search in Google Scholar
83. Filella X, Giménez N. Evaluation of [-2] proPSA and Prostate Health Index (PHI) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013;51:729–39.10.1515/cclm-2012-0410Search in Google Scholar PubMed
84. Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol 2015;193:1163–9.10.1016/j.juro.2014.10.121Search in Google Scholar PubMed PubMed Central
85. de la Calle C, Patil D, Wei JT, Scherr DS, Sokoll L, Chan DW, et al. Multicenter Evaluation of the Prostate Health Index to detect aggressive prostate cancer in biopsy naïve men. J Urol 2015;194:65–72.10.1016/j.juro.2015.01.091Search in Google Scholar PubMed PubMed Central
86. Olleik G, Kassouf W, Aprikian A, Hu J, Vanhuyse M, Cury F, et al. Evaluation of new tests and interventions for prostate cancer management: a systematic review. J Natl Compr Canc Netw 2018;16:1340–51.10.6004/jnccn.2018.7055Search in Google Scholar PubMed
87. Lughezzani G, Lazzeri M, Buffi NM, Abrate A, Mistretta FA, Hurle R, et al. Preoperative prostate health index is an independent predictor of early biochemical recurrence after radical prostatectomy: results from a prospective single-center study. Urol Oncol 2015;33:337.e7–14.10.1016/j.urolonc.2015.05.007Search in Google Scholar PubMed
88. Maxeiner A, Kilic E, Matalon J, Friedersdorff F, Miller K, Jung K, et al. The prostate health index PHI predicts oncological outcome and biochemical recurrence after radical prostatectomy – analysis in 437 patients. Oncotarget 2017;8:79279–88.10.18632/oncotarget.17476Search in Google Scholar PubMed PubMed Central
89. Gnanapragasam VJ, Burling K, George A, Stearn S, Warren A, Barrett T, et al. The Prostate Health Index adds predictive value to multi-parametric MRI in detecting significant prostate cancers in a repeat biopsy population. Sci Rep 2016;6:35364.10.1038/srep35364Search in Google Scholar PubMed PubMed Central
90. Hsieh PF, Li WJ, Lin WC, Chang H, Chang CH, Huang CP, et al. Combining prostate health index and multiparametric magnetic resonance imaging in the diagnosis of clinically significant prostate cancer in an Asian population. World J Urol 2019. doi: 10.1007/s00345-019-02889-2 [Epub ahead of print].Search in Google Scholar PubMed PubMed Central
91. Vickers AJ, Cronin AM, Aus G, Pihl CG, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med 2008;6:19.10.1186/1741-7015-6-19Search in Google Scholar PubMed PubMed Central
92. Bryant RJ, Sjoberg DD, Vickers AJ, Robinson MC, Kumar R, Marsden L, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst 2015;107:3497–509.10.1093/jnci/djv095Search in Google Scholar PubMed PubMed Central
93. Vickers AJ, Gupta A, Savage CJ, Pettersson K, Dahlin A, Bjartell A, et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev 2011;20:255–61.10.1158/1055-9965.EPI-10-1003Search in Google Scholar
94. Vickers A, Cronin A, Roobol M, Savage C, Peltola M, Pettersson K, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol 2010;28:2493–8.10.1200/JCO.2009.24.1968Search in Google Scholar
95. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A four-kallikrein panel predicts high-grade cancer on biopsy: independent validation in a community cohort. Eur Urol 2016;69:505–11.10.1016/j.eururo.2015.04.028Search in Google Scholar
96. Russo GI, Regis F, Castelli T, Favilla V, Privitera S, Giardina R, et al. A systematic review and meta-analysis of the diagnostic accuracy of prostate health index and 4-kallikrein panel score in predicting overall and high-grade prostate cancer. Clin Genitourin Cancer 2017;15:429–39.10.1016/j.clgc.2016.12.022Search in Google Scholar
97. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999;59:5975–9.Search in Google Scholar
98. Hessels D, Klein Gunnewick MT, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, et al. DD3PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44:8–16.10.1016/S0302-2838(03)00201-XSearch in Google Scholar
99. Groskopf J, Aubin SM, Deras IL, Blase A, Bodrug S, Clark C, et al. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem 2006;52:1089–95.10.1373/clinchem.2005.063289Search in Google Scholar PubMed
100. Cui Y, Cao W, Li Q, Shen H, Liu C, Deng J, et al. Evaluation of prostate cancer antigen 3 for detecting prostate cancer: a systematic review and meta-analysis. Sci Rep 2016;6:25776.10.1038/srep25776Search in Google Scholar PubMed PubMed Central
101. Wei JT, Feng Z, Partin AW, Brown E, Thompson I, Sokoll L, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014;32:4066–72.10.1200/JCO.2013.52.8505Search in Google Scholar PubMed PubMed Central
102. Auprich M, Augustin H, Budäus L, Kluth L, Mannweiler S, Shariat SF, et al. A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy. Br J Urol Int 2012;109:1627–35.10.1111/j.1464-410X.2011.10584.xSearch in Google Scholar PubMed
103. Merola R, Tomao L, Antenucci A, Sperduti I, Sentinelli S, Masi S, et al. PCA3 in prostate cancer and tumor aggressiveness detection on 407 high-risk patients: a National Cancer Institute experience. J Exp Clin Cancer Res 2015;34:15.10.1186/s13046-015-0127-8Search in Google Scholar PubMed PubMed Central
104. Scattoni V, Lazzeri M, Lughezzani G, De Luca S, Passera R, Bollito E, et al. Head-to-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy. J Urol 2013;190:496–501.10.1016/j.juro.2013.02.3184Search in Google Scholar
105. Hessels D, van Gils MP, van Hooij O, Jannink SA, Witjes JA, Verhaegh GW, et al. Predictive value of PCA3 in urinary sediments in determining clinico-pathological characteristics of prostate cancer. Prostate 2010;70:10–6.10.1002/pros.21032Search in Google Scholar
106. Auprich M, Chun FK, Ward JF, Pummer K, Babaian R, Augustin H, et al. Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. Eur Urol 2011;59:96–105.10.1016/j.eururo.2010.10.024Search in Google Scholar
107. Sidaway P. Prostate cancer: urinary PCA3 and TMPRSS2: ERG reduce the need for repeat biopsy. Nat Rev Urol 2015;12:536.10.1038/nrurol.2015.221Search in Google Scholar
108. Tomlins SA, Day JR, Lonigro RJ, Hovelson DH, Siddiqui J, Kunju LP, et al. Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2016;70:45–53.10.1016/j.eururo.2015.04.039Search in Google Scholar
109. Grönberg H, Adolfsson J, Aly M, Nordström T, Wiklund P, Brandberg Y, et al. Prostate cancer screening in men aged 50–69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol 2015;16:1667–76.10.1016/S1470-2045(15)00361-7Search in Google Scholar
110. Eklund M, Nordström T, Aly M, Adolfsson J, Wiklund P, Brandberg Y, et al. The Stockholm-3 (STHLM3) model can improve prostate cancer diagnostics in men aged 50–69 yr compared with current prostate cancer testing. Eur Urol Focus 2018;4:707–10.10.1016/j.euf.2016.10.009Search in Google Scholar PubMed
111. O’Reilly E, Tuzova AV, Walsh AL, Russell NM, O’Brien O, Kelly S, et al. epiCaPture: a urine methylation test for early detection of aggressive prostate cancer. JCO Precis Oncol 2019;2019. doi: 10.1200/PO.18.00134.Search in Google Scholar PubMed PubMed Central
112. Stenman UH. Biomarker development, from bench to bedside. Crit Rev Clin Lab Sci 2016;53:69–86. Erratum in: Crit Rev Clin Lab Sci 2016;53(2):i.10.3109/10408363.2015.1075468Search in Google Scholar PubMed
113. Mikolajczyk SD, Song Y, Wong JR, Matson RS, Rittenhouse HG. Are multiple markers the future of prostate cancer diagnostics? Clin Biochem 2004;37:519–28.10.1016/j.clinbiochem.2004.05.016Search in Google Scholar PubMed
114. Paus E, Nilsson O, Børmer OP, Fosså SD, Otnes B, Skovlund E. Stability of free and total prostate specific antigen in serum from patients with prostate carcinoma and benign hyperplasia. J Urol 1998;159:1599–605.10.1097/00005392-199805000-00051Search in Google Scholar PubMed
115. Wojno KJ, Costa FJ, Cornell RJ, Small JD, Pasin E, Van Criekinge W, et al. Reduced rate of repeated prostate biopsies observed in ConfirmMDx clinical utility field study. Am Health Drug Benefits 2014;7:129–34.Search in Google Scholar
116. Partin AW, Van Neste L, Klein EA, Marks LS, Gee JR, Troyer DA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol 2014;192:1081–7.10.1016/j.juro.2014.04.013Search in Google Scholar PubMed PubMed Central
117. Gore JL, du Plessis M, Santiago-Jiménez M, Yousefi K, Thompson DJ, Karsh L, et al. Decipher test impacts decision making among patients considering adjuvant and salvage treatment after radical prostatectomy: interim results from the multicenter prospective PRO-IMPACT study. Cancer 2017;123:2850–9.10.1002/cncr.30665Search in Google Scholar PubMed PubMed Central
118. Spratt DE, Yousefi K, Deheshi S, Ross AE, Den RB, Schaeffer EM, et al. Individual patient-level meta-analysis of the performance of the Decipher genomic classifier in high-risk men after prostatectomy to predict development of metastatic disease. J Clin Oncol 2017;35:1991–8.10.1200/JCO.2016.70.2811Search in Google Scholar PubMed PubMed Central
119. Berlin A, Castro-Mesta JF, Rodriguez-Romo L, Hernandez-Barajas D, González-Guerrero JF, Rodríguez-Fernández IA, et al. Prognostic role of Ki-67 score in localized prostate cancer: a systematic review and meta-analysis. Urol Oncol 2017;35:499–506.10.1016/j.urolonc.2017.05.004Search in Google Scholar PubMed
120. Klein EA, Cooperberg MR, Magi-Galluzzi C, Simko JP, Falzarano SM, Maddala T, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol 2014;66:550–60.10.1016/j.eururo.2014.05.004Search in Google Scholar PubMed
121. Cullen J, Rosner IL, Brand TC, Zhang N, Tsiatis AC, Moncur J, et al. A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol 2015;68:123–31.10.1016/j.eururo.2014.11.030Search in Google Scholar PubMed
122. Cuzick J, Stone S, Fisher G, Yang ZH, North BV, Berney DM, et al. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer 2015;113:382–9.10.1038/bjc.2015.223Search in Google Scholar PubMed PubMed Central
123. Health Quality Ontario. Prolaris cell cycle progression test for localized prostate cancer: a health technology assessment. Ont Health Technol Assess Ser 2017;17:1–75.Search in Google Scholar
124. Blume-Jensen P, Berman DM, Rimm DL, Shipitsin M, Putzi M, Nifong TP, et al. Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clin Cancer Res 2015;21:2591–600.10.1158/1078-0432.CCR-14-2603Search in Google Scholar PubMed
125. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018;15:222–34.10.1038/nrurol.2018.9Search in Google Scholar PubMed PubMed Central
126. Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol 2016;70:740–8.10.1016/j.eururo.2016.04.012Search in Google Scholar
127. Wei L, Wang J, Lampert E, Schlanger S, DePriest AD, Hu Q, et al. Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and genomic prognosticators. Eur Urol 2017;71:183–92.10.1016/j.eururo.2016.07.008Search in Google Scholar
128. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–38.10.1056/NEJMoa1315815Search in Google Scholar
129. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Zhu Y, et al. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol 2017;35:2149–56.10.1200/JCO.2016.70.1961Search in Google Scholar
130. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J Clin Oncol 2019;37:1120–9.10.1200/JCO.18.01731Search in Google Scholar
131. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708.10.1056/NEJMoa1506859Search in Google Scholar
132. Zhao SG, Chang SL, Spratt DE, Erho N, Yu M, Ashab HA, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol 2016;17:1612–20.10.1016/S1470-2045(16)30491-0Search in Google Scholar
133. Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol 2016;2:1598–606.10.1001/jamaoncol.2016.0494Search in Google Scholar PubMed PubMed Central
©2020 Walter de Gruyter GmbH, Berlin/Boston
