Evidence and Rationale for Prostate Cancer Screening - Takahashi - The Prostate - Wiley Online Library

Evidence and Rationale for Prostate Cancer Screening: Latest Research and Guidelines

Bottom Line Up Front: Current evidence strongly supports PSA-based screening for men aged 55-69, with new research showing promising advances in MRI-targeted biopsies, novel biomarkers, and risk-adapted screening strategies that may significantly reduce overdiagnosis while maintaining mortality benefits.

The Foundation: Why Screening Matters

PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened, according to the U.S. Preventive Services Task Force. At a follow-up of 16 years, the number of patients had dropped even further to 18 men needed to be treated to prevent one death from prostate cancer, demonstrating that screening benefits increase significantly with longer follow-up periods.

The mortality reduction is even more impressive in some studies. The Swedish part of the ERSPC trial (Göteborg trial) actually reported a 44% relative reduction of prostate cancer mortality in the screening group with a number needed to treat of only 12.

Current Professional Guidelines

American Urological Association (AUA) 2023 Guidelines

The AUA's latest evidence-based recommendations emphasize shared decision-making and risk stratification:

  • Clinicians should offer prostate cancer screening beginning at age 40 to 45 years for people at increased risk of developing prostate cancer based on the following factors: Black ancestry, germline mutations, strong family history of prostate cancer
  • Clinicians may begin prostate cancer screening and offer a baseline PSA test to people between ages 45 to 50 years
  • Clinicians should offer regular prostate cancer screening every 2 to 4 years to people aged 50 to 69 years

U.S. Preventive Services Task Force

Men who are 55 to 69 years old should make individual decisions about being screened for prostate cancer with a prostate specific antigen (PSA) test. Before deciding, men should talk to their doctor about the benefits and harms of screening for prostate cancer.

American Cancer Society

The discussion about screening should take place at: Age 50 for men who are at average risk of prostate cancer and are expected to live at least 10 more years · Age 45 for men at high risk of developing prostate cancer. This includes African American men and men who have a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than age 65).

Breakthrough Research: The PROBASE Trial

One of the most significant ongoing studies is the German PROBASE trial, which is revolutionizing our understanding of risk-adapted screening strategies. From February 2014 to December 2019 a randomized trial (PROBASE) recruited 46 642 men at age 45 to determine the efficacy of risk-adapted prostate-specific antigen-based (PSA) screening, starting at either 45 or 50 years.

Key PROBASE Findings

Men with a PSA level of under 1.5 nanograms per millilitre (ng/ml) are deemed low risk and followed up with a second test after five years. This approach could dramatically reduce screening burden while maintaining safety.

Recent PROBASE updates show that confirmatory second PSA reduced the group of men classified at 'high-risk' by nearly half, and thereby, reduced the number of MRIs and biopsies. Men with first of second PSA <1.5ng/ml and those with negative biopsy are at extremely low PCa risk and may need only re-testing every five years.

Revolutionary Advances in MRI-Guided Screening

STHLM3-MRI Trial Results

The STHLM3-MRI trial has provided landmark evidence for MRI's role in screening. In studies involving men referred for biopsy because of clinical suspicion of prostate cancer, targeted biopsy in men with positive findings on MRI (i.e., suggestive of prostate cancer) resulted in less detection of clinically insignificant cancers than standard biopsy while showing similar or better ability to detect clinically significant cancers.

MRI Performance in Young Men

However, challenges remain for younger screening populations. At a cutoff of PI-RADS 4, reference reading showed better performance for csPC detection (sensitivity 79%, NPV 91%, accuracy of 85%) than local reading (sensitivity 55%, NPV 80%, accuracy 68%). This highlights the critical importance of radiologist experience.

If PI-RADS ≥4 were to be used as a biopsy cutoff, mpMRI would reduce negative biopsies by 68% and avoid detection of nonsignificant PC in 71% of cases.

Game-Changing Technology: Micro-Ultrasound

A groundbreaking development was recently presented at the European Association of Urology Congress 2025. OPTIMUM is the first randomized trial to compare microultrasound (microUS)-guided biopsy with MRI-guided biopsy for prostate cancer detection. It included 677 men who underwent biopsy at 19 hospitals across Canada, the United States, and Europe.

The results are remarkable: MicroUS was able to identify prostate cancer as effectively as MRI-guided biopsy, with very similar rates of detection across all three arms of the trial. This technology could offer a one-stop shop, where patients are scanned [and] then biopsied immediately if required. There's no toxicity. There are no exclusions. It's much cheaper and more accessible.

Next-Generation Biomarkers

Research is rapidly advancing beyond PSA to more sophisticated biomarker panels:

Multi-Biomarker Tests

The Mi-prostate score (MiPS) is a predictive algorithm that includes serum PSA and the urinary biomarkers PCA3 and TMPRSS2:ERG. There is evidence suggesting that it is markedly superior to PSA for diagnostic purposes. The MiPS has demonstrated the capability not just of detecting the existence of PCa before a biopsy, resulting in a significant reduction of 35–47% in unnecessary biopsies and overdiagnoses, but also of predicting high-grade PCa on a biopsy.

Emerging Biomarkers

Biomarkers such as PCA3, TMPRSS2:ERG fusion genes, and the Prostate Health Index (PHI) have emerged as significant improvements over PSA, providing more accurate distinctions between benign conditions and malignant prostate alterations.

Liquid Biopsy Advances

Emerging biomarkers, including non-coding RNAs, circulating tumor DNA, and prostate-specific antigen (PSA) glycosylation, offer valuable insights into PCa biology, enabling personalized treatment.

Precision Medicine and Genetic Testing

Recent research at UC Davis demonstrates the potential of personalized approaches. A total of 11 men with high-risk prostate cancer and certain biomarkers, specifically gene mutations, took part in the study testing targeted therapy. Circulating tumor DNA (ctDNA) biomarker analysis proved useful in tracking tumor evolution and resistance mechanisms in real time.

Artificial Intelligence and Machine Learning

Emerging technologies, such as machine learning and nanodiagnostic techniques, are enhancing diagnostic precision and reducing overdiagnosis. The application of ML algorithms will accelerate the identification and discovery of novel molecular biomarkers and it will lead biomedical investigation towards artificial-intelligence-based precision medicine.

Addressing Screening Challenges

Overdiagnosis Concerns

Follow-up of large randomized trials suggests that 20% to 50% of men diagnosed with prostate cancer through screening may be overdiagnosed. However, new approaches are addressing this concern.

Today, instead of men immediately having their prostates biopsied when they get an elevated PSA test, he and an increasing number of prostate-cancer specialists recommend first getting an MRI and, when possible, watching and waiting.

Quality of Life Considerations

About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence requiring use of pads, and 2 in 3 men will experience long-term erectile dysfunction. These risks underscore the importance of accurate risk stratification and shared decision-making.

Looking Forward: The Future of Screening

Research is pointing toward increasingly personalized screening strategies. New tools have been integrated into the PCa diagnostic algorithm to reduce overdiagnosis. The main tools being stratification steps (e.g. risk calculators or additional biomarkers) with or without MRI, leading to updated recommendations from urological associations worldwide on PCa early detection.

The study will also assess anxiety and quality of life during screening. Additionally, a first comparison will be made between arm 2 (PSA cut off 3 for MRI and targeted biopsies only) and arm 3 (PSA cut off 1.8 with targeted biopsies only).

Recommendations for IPCSG Members

Based on current evidence, men should:

  1. Discuss screening with their healthcare provider starting at age 45-50 for average-risk men, and earlier for high-risk individuals
  2. Consider their family history, ethnicity, and genetic factors when making screening decisions
  3. Understand both benefits and risks of screening, including the possibility of overdiagnosis
  4. Ask about newer technologies like MRI-targeted biopsy and advanced biomarker tests
  5. Seek care from experienced providers when MRI is part of the diagnostic pathway

The landscape of prostate cancer screening continues to evolve rapidly, with promising developments that may soon provide more accurate, less invasive screening options while maintaining the proven mortality benefits of early detection.

Sources and Citations

  1. National Public Radio. (2025, May 21). PSA tests to screen for prostate cancer. What age makes sense to get one? Shots - Health News. https://www.npr.org/sections/shots-health-news/2025/05/21/nx-s1-5405613/prostate-cancer-psa-test-age
  2. European Association of Urology. (2025). Prostate Cancer Guidelines. Uroweb. https://uroweb.org/guidelines/prostate-cancer
  3. American Urological Association. (2023). Early Detection of Prostate Cancer: AUA/SUO Guideline. https://www.auanet.org/guidelines-and-quality/guidelines/early-detection-of-prostate-cancer-guidelines
  4. U.S. Preventive Services Task Force. (2018, May 8). Recommendation: Prostate Cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate-cancer-screening
  5. Jain, M. A., Leslie, S. W., & Sapra, A. (2023, October 26). Prostate Cancer Screening. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK556081/
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  19. Liu, Y., et al. (2025). Liquid Biomarkers in Prostate Cancer Diagnosis: Current Status and Emerging Prospects. PubMed. https://pubmed.ncbi.nlm.nih.gov/38772530/
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Evidence and Rationale for Prostate Cancer Screening - Takahashi - The Prostate - Wiley Online Library

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