Prostate Cancer Screening

Abstract

Prostate cancer represents one of the most frequent cancers affecting men worldwide. Screening for prostate cancer remains an essential strategy in reducing mortality and morbidity and also in improving the quality of life of men affected by this pathology. On the other hand, there is a fine line between screening, diagnosis and treatment of prostate cancer and overdiagnosis with unnecessary biopsies. In this direction, many strategies have been carried out, the first evaluation stratifying men into low-risk and high-risk for prostate cancer. Low-risk male patients should undergo an evaluation every eight years, while high-risk male patients are recommended to be evaluated every two years. The aim of this paper is to describe the target population for prostate cancer screening, as well as different methods of prostate cancer assessment and monitoring, in order to ensure the optimum healthcare for male patients.

Introduction

Early detection of prostate cancer (PC) in the general population is defined as the systematic screening of asymptomatic men to identify individuals at risk, with the goals of reducing prostate cancer mortality and improving quality of life (QoL). Prostate cancer mortality has a great variation from country to country in the industrialized world [1]. In Western countries, cancer mortality prostate has decreased significantly, but the results differ between countries. Despite all these results, prostate cancer screening remains one of the most controversial topics in the literature [2]. Initially, an aggressive screening was carried out in the United States, which was associated with a decrease in mortality [3]. In 2012, a recommendation against performing PSA screening alone was initiated in the USA, which was adopted in 2013 in the American Urological Association (AUA) guidelines, which in the following years led to a reduction in the use of prostate-specific antigen (PSA) for the early detection of PC [4,5]. Along with the reduction in the use of PSA as a PC detection method, there has been an increase in cases of advanced neoplastic disease at the time of diagnosis. While PC mortality has decreased over the past 2 decades since the introduction of PSA testing, the incidence of advanced stages has increased slowly and progressively since 2008, with a significant decrease in 2012 [6,7]. Most authors emphasize the need and benefits of using PSA as a population-wide screening tool to reduce PC mortality [8,9]. An updated Cochrane review [10] published in 2013, outlines the principles of screening for PC, respectively screening is associated with an increased rate of PC diagnosis and screening is associated with more frequent diagnosis of localized disease and less advanced prostate cancer.

Risk factors

An individualized strategy for early detection may still be associated with a substantial risk of overdiagnosis. It is essential to remember that separating the diagnosis and the active treatment is the only way to reduce overtreatment while maintaining the potential benefit of early individual diagnosis for patients [11].

Table 1. Summary of the main characteristics of PC *.

Evidence summary	Level of evidence
PC represents a major health issue among men, its incidence depending on age	3
Genetic factors are associated with a high risk of PC (aggressive form)	3
A great variety of diet/exogenous/environmental factors have been associated with the PC incidence and prognosis	3
Selenium and vitamin E supplements do not provide a beneficial effect in preventing PC	2a
In men with hypogonadism, testosterone supplementation does not increase the risk of PC	2
There are no data in the literature supporting specific preventive or dietary measures to reduce the risk of developing PC	1a

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

Table 1. Summary of the main characteristics of PC *.

Evidence summary	Level of evidence
PC represents a major health issue among men, its incidence depending on age	3
Genetic factors are associated with a high risk of PC (aggressive form)	3
A great variety of diet/exogenous/environmental factors have been associated with the PC incidence and prognosis	3
Selenium and vitamin E supplements do not provide a beneficial effect in preventing PC	2a
In men with hypogonadism, testosterone supplementation does not increase the risk of PC	2
There are no data in the literature supporting specific preventive or dietary measures to reduce the risk of developing PC	1a

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

Male patients with the age over 50 years or over 45 years but with a family history of PC are at increased risk of developing PC [13,14]. Germline BRCA 2 mutations are associated with an increased risk of developing aggressive PC. Prostate-specific antigen screening in male BRCA1 and 2 germline mutation carriers managed to diagnose PC at a younger age compared to those without such germline mutations [15]. Men with an initial PSA < 1 ng/mL at age 40 and < 2 ng/mL at age 60 have a low risk of advanced metastatic disease or death from PC several decades later [16].

Patients consulting for an early diagnosis should have a PSA test and a digital rectal examination. The use of rectal examination as the only tool in the diagnosis of PC had a sensitivity and specificity below 60%, possibly due to the lack of experience of the examiner and for this reason the exclusion of PC cannot be recommended. However, it should be taken into consideration that in 18% of cases, prostate cancer is detected during rectal examination, regardless of the serum PSA value [17]. Modifications identified during the rectal examination of the patient, in association with elevated serum PSA levels, double the risk of a positive biopsy [18]. Rectal palpation is of great importance in the screening, diagnosis and treatment of PC: an altered rectal palpation is associated with PC with a higher ISUP (International Society of Urological Pathology) grade, can predict progression to clinically significant PC in patients on active surveillance, and represents an indication for performing an MRI and prostate biopsy [18,19].

PSA and digital rectal examination should be repeated, but the optimal intervals for PSA testing and clinical reassessment are unknown, as different results have been published in several prospective studies. A risk-adjusted strategy could be considered based on baseline PSA level. Thus, we can perform this assessment every 2 years for those at initial increased risk or delayed up to 8 years in those at low risk, respectively patients with an initial PSA < 1 ng/mL at age 40 and a PSA < 2 ng/ mL at age 60 and a negative family history for prostate cancer [20].

Data from the literature support the recommendation for performing clinical and biological evaluation with a frequency of every 8 years in men with a baseline PSA concentration <1 μg/L, less than 1% of men with a baseline PSA concentration <1 ng/mL were found to have a PSA concentration above 3 ng/mL at a 4-year follow-up and the 8-year PC diagnosis rate was close to 1% [21].

Table 2. Current recommendations *.

Recommendation	Level of recommendation
Do not test men for PSA without counseling them regarding the risks and benefits of PSA testing	High
Adopting an adapted strategy to the individual risk for early detection PC in well-informed men with a life expectancy of at least 10-15 years	Low
PSA dosing should be performed on well-informed men with a high risk of developing PC: Men over the age of 50 Men over the age of 45 with a family history of PC Men with African descent, beginning with the age of 45 Men carrying BRCA2 gene mutation beginning with the age of 40	High
Approaching a risk-based strategy (based on the initial value of PSA dosing), with a 2-year reassessment for those initially at risk: Men with PSA>1 ng/mL at the age of 40 Men with PSA> 2ng/mL at the age of 60 An 8-year reassessment for those who are not initially at risk	Low
It is recommended to stop screening for PC men with a life expectancy less than 15 years or who present a reduced performance status (those will probably not present a benefit)	High

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

Table 2. Current recommendations *.

Recommendation	Level of recommendation
Do not test men for PSA without counseling them regarding the risks and benefits of PSA testing	High
Adopting an adapted strategy to the individual risk for early detection PC in well-informed men with a life expectancy of at least 10-15 years	Low
PSA dosing should be performed on well-informed men with a high risk of developing PC: Men over the age of 50 Men over the age of 45 with a family history of PC Men with African descent, beginning with the age of 45 Men carrying BRCA2 gene mutation beginning with the age of 40	High
Approaching a risk-based strategy (based on the initial value of PSA dosing), with a 2-year reassessment for those initially at risk: Men with PSA>1 ng/mL at the age of 40 Men with PSA> 2ng/mL at the age of 60 An 8-year reassessment for those who are not initially at risk	Low
It is recommended to stop screening for PC men with a life expectancy less than 15 years or who present a reduced performance status (those will probably not present a benefit)	High

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

Imaging

Traditionally, transrectal ultrasound (TRUS) represented a way to identify areas in the prostate suspected of being PC, which appear as hypoechoic areas; recent studies have shown that TRUS is not a reliable method of detecting PC, and biopsy hypoechoic areas does not increase the yield of PC diagnosis [22]. New ultrasonographic evaluation methods have been developed, such as HistoScanningTM, micro-doppler, contrast sonoelastography, high resolution micro-ultrasonography, but these have limited clinical utility, they have not been not been standardized or evaluated in large-scale studies [23].

MRI (magnetic resonance imaging) is an imaging evaluation method that shows increased sensitivity for the detection and localization of PC lesions with ISUP grade ≥2, especially if the diameter of the lesion is over 10 mm [24]. In a Cochrane meta-analysis, MRI had a sensitivity of 0.91 (95% CI: 0.83–0.95) and a specificity of 0.37 (95% CI: 0.29–0.46) for ISUP≥2 cancers [25]. For ISUP 1 lesions, MRI shows lower sensitivity, identifying less than 30% of cysts with a volume of less than 0.5 cc [24]. MRI evaluation of the prostate was standardized by creating the PI-RADS (Prostate Imaging Reporting and Data System) score, reaching the PI-RADS v2.1 version. A PI-RADS score ≥ 3 shows an increased suspicion of the lesion being malignant and is an indication to perform a prostate biopsy [26].

Despite its usefulness, MRI is not recommended by the European Urological Association Guidelines as a screening method for prostate cancer [12].

Other tools useful in the diagnosis of PC are now available to determine the need for a prostate biopsy to establish the diagnosis of PC.

Biomarkers

Prostate cancer can produce elevated PSA levels per tissue volume compared to benign prostatic hyperplasia. To account for prostate volume, Benson et al. introduced PSA density (PSAD) in the early 1990s [27]. This was done to improve the accuracy of serum PSA testing to differentiate localized PC from benign prostatic hypertrophy. PSAD was calculated by dividing serum PSA by prostate volume, which was measured by transrectal ultrasonography or MRI. Several studies have demonstrated that PSAD has the potential to influence the decision to perform a prostate biopsy by helping to identify men with clinically significant PC. Thus, the PSAD represents a simple to use and inexpensive diagnostic tool allowing a better orientation towards patients who need prostate biopsy and those who do not [27,28].

The alteration of certain PSA parameters, such as the doubling time (PSADT- the time interval in which the PSA doubles its value) and the PSA velocity (PSAV- the rate of change of PSA/year), provide additional information. Evidence indicates that PSAV has better value in post-treatment monitoring rather than in the pre-treatment setting. PSADT has been a promising element used as a predictive biomarker for the detection of PC in a repeated biopsy, thus demonstrating its potential in avoiding unnecessary prostate biopsies [29]. In the monitoring process of the recurrence or progression of PC after undergoing curative therapy, PSADT can be useful, for example, the presence of a doubling time <3 months revealing a reduced survival. PSADT can also predict the occurrence of metastases [30,31]. The formula used to calculate PSADT is [log(2 )*T2-T1(time difference)]/[log PSA2/logPSA1]. PSADT is considered to be more useful when regarding the treatment phases of PC and also in monitoring the recurrence of prostate cancer, rather than in diagnosis process [32]. PSAV is defined by the absolute annual increase, measured in ng/mL/year. At a cut-off point of 0.3–0.5 ng/mL/year, the specificity of PSAV was 90% in monitoring patients with prostate cancer, compared with 60% if total PSA was used [33].

Prostate-specific antigen is found in the blood in several forms and is classified as free PSA (fPSA) or complexed PSA (cPSA). fPSA does not bind to proteins or carrier molecules, cPSA binds to protease inhibitors (α1-antichymotrypsin, α2 macroglobulin or α1-antitrypsin). fPSA levels are generally expressed as a percentage of total PSA (%fPSA). In general, men with PC have low %fPSA levels compared to men without PC, the fPSA level tends to decrease in association with PC, and clinicians can distinguish PC from benign prostatic hyperplasia [34]. In addition, maneuvers that stimulate the prostate, such as digital rectal examination and prostatic puncture, lead to an increase in the amount of fPSA; also, the increase in prostate volume influences %fPSA, thus %fPSA provides meaningful data only in patients with prostate volume <40 cm³ [35].

The PHI (prostatic health index) test was initially established to aid in the clinically significant detection of PC. The PHI test represents a score calculated from the total PSA, fPSA and proPSA values with the help of the formula (proPSA/fPSA) × √PSA total. ProPSA is a preferentially produced in cancerous cells peptide precursor of mature PSA. Its main advantage is the fact that it permits clinicians to assess individual PSA parameters in association with the overall score. The leading utility of PHI is to diminish the number of unnecessary biopsies performed on patients with borderline PSA serum levels, keeping the detection capacity of aggressive prostatic tumors, thus avoiding unnecessary prostate biopsies performed in male patients with PSA serum levels in the "gray zone", respectively 4-10 nl/mL [36].

There are biomarkers other than PSA that have a role in the pre-diagnosis setting. The ideal biomarker here should have the ability to increase the probability of identifying clinically significant PC on biopsied tissues, while avoiding performing biopsies in men who do not require one, due to the absence of clinically significant PC. These types of biomarkers can be classified into those used to decide which patients have an indication for prostate biopsy (SelectMDX, TMPRSS2-ERG score) and those used to choose when a re-biopsy should be performed (prostate cancer antigen 3 [PCA3]).

SelectMDx represents a urine test designed to identify PC after performing a biopsy. SelectMDx is performed after the prostate massage, measuring mRNA levels of the DLX1 respectively HOXC6 genes (genes that have gained their reputation for being accurate predictors for the identification of high-grade prostate cancer, quantified in urine using qRT-PCR. Further, DLX1 and HOXC6 gene expression levels are assessed alongside clinical parameters (PSA density, rectal palpation, age, and family history information). SelectMDx presents a 98% negative predictive value for a patient with a Gleason score disease ≥ 7 while it presents a 99% negative predictive value for a male patient with a Gleason score disease of 8, while diminishing the number of unnecessary biopsies with up to 53% [37].

Another biomarker involved in determining the necessity for a prostate biopsy is represented by the TMPRSS2-ERG score, which implies chromosomal translocations directing to the fusion of the TMPRSS2 (androgen-regulated transmembrane protease serine 2 gene) and ETS transcription factors (predominantly the ETS-regulated gene - ERG), also known as TMPRSS2-ERG [38]. In order to measure TMPRSS2-ERG mRNA a real-time quantitative polymerase chain reaction (qRT-PCR) is the method used to evaluate urine samples after prostate massage. Concurrently, the PSA mRNA assessment provides the TMPRSS2-ERG score generation as a result of the TMPRSS2-ERG mRNA/PSA mRNA ratio. In the literature, there has been demonstrated the fact that the assessment of the TMPRSS2-ERG gene fusions evaluated in the urine, can predict the PC diagnosis from urine samples performed immediately after prostate biopsy [39].

Prostate cancer antigen 3 (PCA3) or DD3 (Differential Display Code 3) is a non-coding RNA produced almost exclusively in prostate tissue [40]. Bussemakers et al., who first identified and described it in 1999, also demonstrated that the PCA3 gene is significantly overexpressed in malignant tissue compared with normal prostate [41]. Like the other genetic tests, PCA3 is performed from the urine after prostate massage and aims to analyze a real-time quantitative polymerase chain reaction (qRT-PCR). This method is used because digital rectal examination induces pressure inside the prostate, causing prostate cells to be released through the prostate ducts and into the urethra. The most appropriate cut-off for the FDA-recommended PCA3 score is less than 25 and is associated with a low probability of a positive biopsy [41].

Table 3. Screening for prostate cancer recommendation *.

Recommendation	Level of recommendation
For asymptomatic men with a low PSA serum value between 3-10ng/mL and a normal digital rectal examination, it is necessary to repeat PSA before any other investigation	Low
For asymptomatic men with a low PSA serum value between 2-10 ng/mL and a normal digital rectal examination, we can use the following tools in order to evaluate the necessity of a prostate biopsy - risk calculators - prostate MRI	High
- a serum, urine or tissue biomarker test	Low

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

Table 3. Screening for prostate cancer recommendation *.

Recommendation	Level of recommendation
For asymptomatic men with a low PSA serum value between 3-10ng/mL and a normal digital rectal examination, it is necessary to repeat PSA before any other investigation	Low
For asymptomatic men with a low PSA serum value between 2-10 ng/mL and a normal digital rectal examination, we can use the following tools in order to evaluate the necessity of a prostate biopsy - risk calculators - prostate MRI	High
- a serum, urine or tissue biomarker test	Low

*Adapted after the European Association of Urology guidelines on PC (2022) [12].

In conclusion, screening for PC should be performed in patients at risk, because screening tests can help detect prostate cancer in early stages, before the appearance of any symptoms. In addition, discovered early, the disease can be successfully treated.