PSA testing measures prostate-specific antigen levels in blood to screen for prostate cancer. While the test is highly sensitive, PSA’s limited specificity can lead to unnecessary biopsies since elevated levels may result from benign prostate conditions. Modern screening programs often combine PSA testing with digital rectal examinations and/or MRI imaging to improve diagnostic accuracy and reduce invasive procedures while emerging technologies such as at-home blood sampling are expanding testing options and personalizing screening approaches.

What is prostate-specific antigen (PSA)?

Prostate-specific antigen or PSA is a serine protease that is produced by healthy and cancerous cells within the prostate gland. Found predominantly in semen, PSA’s main function is to hydrolyze and liquefy the main components of the semen coagulum to facilitate sperm motility.

In healthy men, only small amounts of PSA leak into the bloodstream; this results in naturally low circulating concentrations that typically range from 0 to 3 nanograms per milliliter (ng/mL) or 3 micrograms per liter (µg/L) depending on age. However, when prostate cells become cancerous, more PSA can enter the bloodstream as a result of changes in the prostate tissue architecture. In advanced cases, PSA levels can rise dramatically, sometimes reaching hundreds of thousands of ng/mL or µg/L.

The threshold for a ‘normal’ PSA value may vary between countries. For example, in Sweden, the cut-offs over which a PSA score is considered abnormal are 3 µg/L (3 ng/mL) for men younger than 70 years, ≥5 µg/L (5 ng/mL) for men aged 70–80 years and ≥7 µg/L (7 ng/mL) for men older than 80 years (1).

While this difference provides the basis for using PSA as a biomarker for prostate cancer detection, elevated PSA levels aren’t specific to cancer alone. Several non-cancerous conditions, including benign prostatic hyperplasia, prostatitis, and even recent ejaculation, can also elevate PSA levels, creating challenges for accurate diagnosis and potentially leading to false positives.

The history and development of PSA testing

PSA’s journey from discovery to cancer biomarker spans several decades and involves researchers from various disciplines. In a review published in 2015, William J Catalona, Professor of Urology at Northwestern University, traces the history of PSA testing to the 1960s and 1970s (2). During this period, proteins specific to the prostate were first identified, with Japanese forensic scientist Mitsuwo Hara characterizing a protein he called ”gamma-seminoprotein” in 1966. He suggested its potential use as forensic evidence in rape cases since it could confirm the presence of semen. Other forensic scientists including George Sensabaugh at UC Berkeley continued this work, identifying proteins in semen that were later shown to have the same amino acid sequence as PSA.

According to Catalona’s review, the breakthrough occurred in 1979, when T. Ming Chu and his research group at Roswell Park Memorial Institute, and particularly Ming C. Wang, purified and characterized PSA and first suggested its potential clinical applications as a biomarker for prostate cancer. This team subsequently developed a sensitive ELISA immunoassay that could be used for blood testing and performed early studies exploring the clinical use of PSA in diagnosing prostate disease.

The significance of PSA testing for prostate cancer was formally recognized in 1986 when it became the first cancer marker approved by the U.S. FDA for prostate cancer screening. This regulatory milestone led to increased adoption of PSA testing in clinical practice, significantly influencing the landscape of prostate cancer detection and monitoring.

How is PSA testing done?

The standard PSA test for prostate cancer involves a conventional venous blood draw, typically taken from the arm by a phlebotomist or healthcare professional in a clinical setting. The blood sample is then sent to a laboratory and PSA levels are determined using standardized protocols with automated immunoassay using PSA-specific antibodies.

Interpreting the result of a PSA blood test requires context. PSA level typically rises naturally as men age due to gradual prostate enlargement. While a PSA level above 4.0 µg/L (4 ng/mL) is generally considered abnormal, age-specific reference ranges provide more accurate assessments than a one-size-fits-all cut-off. Significantly elevated levels strongly suggest prostate cancer, though confirmation requires additional testing.

Best practices dictate that PSA blood testing should be accompanied by a digital rectal examination (DRE), where a healthcare provider physically examines the prostate. This combined approach provides complementary information; while the PSA test offers a biochemical assessment, the DRE allows for physical evaluation of prostate size, shape, and texture. This approach helps healthcare providers to determine who really needs a prostate biopsy, helping to avoid unnecessary invasive procedures that can cause complications such as infection including sepsis, bleeding, impotence, and significant psychological distress.

Only when the PSA level is elevated and/or abnormalities are detected during the physical exam will healthcare providers typically recommend proceeding to a biopsy.

Recent innovations have expanded testing options to include microsampling technologies and at-home collection kits utilizing dried blood spot (DBS) technology. These emerging approaches aim to increase testing accessibility while maintaining clinical reliability.

Global burden of prostate cancer and impact of PSA screening

Prostate cancer represents a significant global health concern, with more than 1.4 million new cases diagnosed worldwide each year. According to a 2024 Lancet study, this number is projected to double to 2.9 million annual cases by 2040, meaning that approximately 330 men will be diagnosed with prostate cancer every hour. Deaths are expected to rise by 85% over this period, from 375,000 in 2020 to nearly 700,000 by 2040, with the true number likely higher due to underdiagnosis in low- and middle-income countries (3).

According to the American Cancer Society’s data from men diagnosed between 2014-2020, early detection dramatically impacts survival rates. The current 5-year relative survival rate for localized prostate cancer exceeds 99%, compared to 37% for distant metastatic disease, with an overall survival rate of 97% for all stages combined. These survival benefits highlight the importance of effective screening tools, with PSA testing being the primary method currently available.

Evolving approaches to improve PSA testing for prostate cancer

What makes PSA attractive is its high sensitivity. The PSA test can detect even minute amounts of the protein in blood samples. This sensitivity allows for early detection of potential prostate issues, often before physical symptoms appear. However, this sensitivity comes at the cost of specificity as mentioned previously. Consequently, countries around the world have developed varying approaches to balance the benefits and limitations of PSA testing (reviewed in 4).

In Sweden’s Organized Prostate Cancer Testing (OPT) program, healthcare providers incorporate MRI as an intermediate step to reduce unnecessary biopsies for men with elevated PSA levels above the typical 3 µg/L (3 ng/mL) threshold. The addition of MRI not only reduces the number of unnecessary biopsies but also results in a more complete picture of the prostate and enables targeted biopsies in specific areas where potentially pathological changes are detected by MRI. This increases the value of the biopsy by finding the ‘right’ tissue while excluding possible false positives based on a random biopsy and thereby reduces unnecessary prostatectomies with the associated side effects of this surgery.

Similar risk-adapted strategies have been implemented in Norway and Austria, following guidelines from the European Association of Urology. Meanwhile, recently published European expert guidelines recommended a stepwise approach to prostate cancer screening across EU member states, combining PSA testing with additional MRI scanning as a follow-up test (summarized in 5). These evolving approaches reflect the growing international consensus that PSA testing, when used as part of a structured protocol rather than opportunistically, can effectively balance early detection benefits against potential drawbacks including harmful side effects.

The scientific community has also responded to these challenges, with several promising advances. For instance, research into epigenetic markers associated with prostate cancer has yielded tests that analyze DNA methylation patterns and other modifications, potentially offering improved specificity (reviewed in 6). Simultaneously, risk calculators have been developed that incorporate multiple factors including age, family history, previous PSA results, and ethnicity; these are designed to offer more personalized screening approaches than one-size-fits-all PSA thresholds (reviewed in 7).

Advancing prostate cancer screening: Innovative technologies and patient-centered approaches

Since 2018, Sweden’s OPT program has been working to standardize and optimize PSA testing across most healthcare regions in Sweden. Despite the program’s established infrastructure and national coordination, participation remains a significant challenge, with only 35% of invited men currently participating in screening. This persistent low participation rate has driven newer approaches to improve access and engagement.

The OPT program, which targets men 50 years and older, has consistently demonstrated the potential to reduce prostate cancer mortality. Preliminary analyses suggest that increasing participation to 50% could prevent 18 deaths from prostate cancer in the northern region alone, potentially extending life expectancy by an average of 8 years after just one year of testing.

Building on this foundation, newer sampling options such as Capitainer’s quantitative dried blood spot (qDBS) devices offer promising solutions to increase participation rates in screening programs, particularly for men in rural areas or those with limited mobility. Their volumetric devices allows precise blood volume collection via a simple finger prick at home, directly addressing key challenges such as geographic distance and the time constraints faced by working-aged men.

Conclusion

PSA testing remains a critical tool in prostate cancer detection and monitoring, despite its limitations. As medical technologies advance, the focus is on creating more precise, personalized, and accessible screening methods. Newer approaches like microsampling and sophisticated imaging techniques demonstrate the medical community’s commitment to balancing early detection benefits with the risks of overdiagnosis and overtreatment.

The ongoing evolution of PSA testing reflects a broader trend towards more patient-centered, technologically advanced healthcare, offering hope for earlier detection, more informed decision-making, and ultimately, improved patient outcomes.

References

1. Bratt O, Carlsson S, Fransson P, et al. Swedish National Prostate Cancer Guidelines Group. The Swedish national guidelines on prostate cancer, part 1: early detection, diagnostics, staging, patient support and primary management of non-metastatic disease. Scand J Urol. 2022 Aug;56(4):265-273.
2. Catalona WJ. History of the discovery and clinical translation of prostate-specific antigen. Asian J Urol. 2014 Oct;1(1):12-14.
3. James ND, Tannock I, N’Dow J, et al. The Lancet Commission on prostate cancer: planning for the surge in cases. Lancet. 2024 Apr 27;403(10437):1683-1722.
4. Denijs FB, Van Poppel H, Stenzl A, et al. PSA testing in primary care: is it time to change our practice? BMC Prim Care. 2024 Dec 26;25(1):436.
5. Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2024 Aug;86(2):148-163.
6. Conteduca V, Hess J, Yamada Y, et al. Epigenetics in prostate cancer: clinical implications. Transl Androl Urol. 2021 Jul;10(7):3104-3116.
7. Denijs FB, van Harten MJ, Meenderink JJL, et al. Risk calculators for the detection of prostate cancer: a systematic review. Prostate Cancer Prostatic Dis. 2024 Sep;27(3):544-557.