Early Detection of Prostate Cancer: The Essential Serum Tumor Marker PSA Test
Since 1979, when prostate-specific antigen (PSA) was isolated and purified from prostate tissue and first used in clinical practice in 1986, the serum tumor marker PSA has gradually become a clinically valuable indicator for prostate cancer detection. over the past 30 years, it has been increasingly used in early screening, risk stratification, diagnosis and prognosis assessment of prostate cancer.
In a master class on tumor markers held in Beijing, Prof. Rafael Molina, Director of the Cancer Research Center of the Biochemistry Laboratory of the Hospital Clínico de Barcelona, Spain, discussed the development of PSA research, its medical value and its application to the management of prostate cancer.
Appropriate use of PSA testing to assist in prostate cancer diagnosis and risk assessment
As a member of the human tissue kinase-releasing enzyme gene family, PSA is a serine protease secreted by prostate epithelial cells. However, PSA is not specific to prostate tissue and is produced in prostate diseases such as benign prostatic hyperplasia (BPH), prostatitis and prostate cancer, as well as other non-prostate tissues.
PSA has also been found in some body fluids such as fetal amniotic fluid, bronchoalveolar lavage fluid, breast cysts, milk and ovarian cysts in women, and is present at very low levels in female serum.
The majority of PSA in blood is bound to a variety of endogenous protease inhibitors to form complex PSA, such as α1-anti-chymotrypsin (ACT) to form PSA-ACT, which is the major component of complex PSA in serum and is currently the main component detectable by immunological methods, as several other bound forms of the The antigenic determinants of the other binding forms are masked by human α-2 macroglobulin and are not recognized by the PSA detection antibody. The remaining small fraction of PSA is free in the serum and becomes free PSA (fPSA).
Therefore, the total PSA clinically detected (tPSA) is in fact only fPSA and PSA-ACT.
The half-life of tPSA and fPSA in serum is only a few hours and their stability decreases over time, especially for fPSA, which is more unstable, therefore, laboratory testing of PSA markers must take care of sample preservation to maintain PSA stability. The European Group for Tumor Markers (EGTM) has clearly defined the recommended practices for sample preservation in laboratory testing.
Blood specimens for tumor marker testing should be centrifuged and serum separated within 3 hours of collection and preserved under the correct conditions for the time of the test.
For tPSA, it is stable for a short period of 5 days at 2-8 °C and can be stored for 6 months at -20 °C. For fPSA, specimens intended to be tested within 24 hours should be stored at refrigerated temperatures to prevent PSA degradation, or at least frozen at -20 °C if specimen analysis is delayed beyond 24 hours, while samples for long-term storage should preferably be stored below -70 °C.
The stability of tPSA and fPSA in plasma is currently being studied clinically, and preliminary results indicate that they are stable for 60 hours at 2 to 8°C.
The World Health Organization (WHO) PSA calibration method (WHO 96 / 670) published in 1999 sets the cut-off value at 3.1 ng/mL, and the possibility of prostate cancer is generally considered above 10 ng/mL. However, it has been found that because serum PSA concentrations are elevated in both prostate enlargement and prostatitis, there is a crossover between benign prostate disease and prostate cancer at 2 to 10 ng/mL, resulting in a high percentage of false negative and false positive results.
If a false negative occurs at 2-4 ng/mL, it can lead to 15% of missed cancers; when a false positive occurs at 4-10 ng/mL, it is considered a gray area for determining prostate cancer, and 65% of benign disease will be wrongly diagnosed as cancer. In this case, the free prostate index (%fPSA) can be calculated by combining fPSA to improve the detection rate of prostate cancer. In patients with tPSA levels of 4 to 10 ng/mL, using %fPSA as a standard can reduce unnecessary biopsies by 35% and has a sensitivity of 94% for prostate cancer detection.
In addition, because PSA is closely related to the regulation of androgen levels, the use of anti-androgen therapy such as 5-alpha reductase inhibitors in the treatment of prostate enlargement can reduce PSA concentrations by 40% to 50%, and the effect can be maintained for up to 6 months after the end of treatment without affecting the f/tPSA index, and the evaluation of PSA levels in these patients needs to be adjusted accordingly.
The Gleason score was promulgated by the International Society of Urological Pathology in 2005 and is now the standard for grading prostate cancer pathology.
The Gleason score is a constant for grading cancerous tissues, which fluctuates from 2 to 10, with a score of 2 indicating the least aggressive and 10 the most aggressive.
When Gleason score ≤ 6 and PSA < 10ng/mL and clinical stage ≤ T2a, it is judged as low risk; if Gleason score ≤ 7 or PSA is 10-20ng/mL or clinical stage ≤ T2b, it belongs to the intermediate risk group; if Gleason score > 7 or PSA > 20ng/mL or clinical stage is T2c, it indicates the high risk group.
Active surveillance has become a conservative treatment strategy recommended by international PSA treatment guidelines
Currently, international organizations such as EGTM, the European Association of Urology (EAU), the American Academy of Clinical Biochemistry (NACB), and the American Urological Association (AUA) have issued guidelines related to prostate cancer to guide clinical management.
The American Cancer Society (ACS) recommends annual PSA testing and rectal examinations (DRE) for all men over the age of 50, especially for high-risk men under the age of 65 who are of African descent and have a family history of prostate cancer, starting at age 45, and for men at high risk who have a family history of prostate cancer, starting at age 40. For men with a family history of prostate cancer, two tests are required every year starting at age 40. PSA levels <2.5 ng/mL need to be retested only every 2 years, but above 2.5 ng/mL, annual retesting is required. For patients with an expected survival of less than 10 years, screening is of little benefit.
In addition, Prof. Molina presented the European Randomized Screening Study for Prostate Cancer (ERSPC), which covered eight European countries and enrolled men aged 50 to 74 years. The study randomized the population into a group with regular PSA screening and a control group with no restriction on PSA screening, with a 4-year interval between PSA screening in the screening group, to account for prostate cancer mortality in subjects in the core age group of 55 to 69 years.
The ratio of prostate cancer mortality in the core age group with regular screening to the control group was found to be 0.85 at year 9 and 0.78 at year 11. A recent 13-year follow-up published in The Lancet showed that PSA screening reduced prostate cancer mortality by 21% in men aged 55 to 69 years and that this benefit was increasing compared to the results at 9 and 11 years of follow-up. This benefit tended to increase compared to the 9- and 11-year follow-up results.
Nevertheless, the EGTM guidelines note that PSA screening has potential harms, including overdiagnosis and subsequent overtreatment. Further quantitative assessment of its deficiencies and reduction in mortality remains a prerequisite for deciding whether to screen for PSA in a population.
To reduce the rate of overtreatment in patients with a clinical diagnosis of low-grade risk prostate cancer, active surveillance by means of regular DRE and PSA testing as well as periodic biopsies has become the current main strategy for conservative treatment, with the option of delaying interventional treatment options for patients in the low-risk group by watching and waiting for progression.
The EAU 2011 guidelines recommend patient indications for active surveillance, which include patients with well-differentiated prostate cancer at clinical stage T1 to T2 and low-risk patients with a Gleason score ≤ 6, PSA < 10 ng/mL, ≤ 3 positive biopsies or ≤ 50% tumor per puncture specimen.
Before screening, it is recommended that physicians and patients discuss the choice of test, benefits and possible side effects so that patients can make their own choices based on the situation, and PSA screening should not be denied to those with early diagnostic requirements,” said Prof. Molina.
However, because of the variety of tPSA assays, the level of variation between reagents and assays from different manufacturers ranges from 10% to 40%, and Professor Molina notes, “The inconsistency of PSA assays has long made their value controversial. Because different assays produce different results, PSA loses its important diagnostic and prognostic value.
To improve the specificity and value of PSA testing, clinicians need to combine age-specific reference ranges, PSA antigen density (PSA/D), rate (PSAV), free to total PSA ratio (f/t), and peripheral zone PSA (PSA-TZD) testing with additional indicators.
Although there is still a large variation between different PSA assays, the accuracy of PSA assays is increasing with the improvement of diagnostic techniques. The Roche Diagnostics Elecsys? PSA and fPSA tests have WHO standard traceability and provide accurate results and high medical value information in just one tube of blood in 18 minutes, while providing a reliable basis for long-term patient follow-up, contributing to the efficient management of prostate cancer.