Around 1 in 8 men will be diagnosed with prostate cancer in their lifetime, yet the current screening process isn’t working for patients, for families, or for an already overburdened healthcare system. So where do prostate cancer diagnostics go from here?
We spoke with Jason Hafron, Chief Medical Officer and Medical Director of Clinical Research at Michigan Institute of Urology, and Professor of Urology at the William Beaumont School of Medicine, Oakland University in Royal Oak, about his vision for the path forward.
What are the biggest problems with PSA testing as a screening tool?
The prostate-specific antigen (PSA) test is a valuable diagnostic tool, but it has important limitations. Before examining those, it’s worth noting why PSA screening became widespread in the first place. Two large trials – the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial – show that PSA screening can reduce prostate cancer mortality by up to 30 percent. While the studies differed in design and early outcomes, long-term data confirm that PSA testing has saved lives.
The main drawbacks are overdiagnosis and overtreatment. Elevated PSA can lead to unnecessary biopsies and treatments for slow-growing cancers that may never harm patients. The test’s specificity and sensitivity at the ≥4 ng/mL threshold are 20 percent and 93 percent, respectively. In other words, PSA is prostate-specific, not cancer-specific. An elevated result does not always mean cancer. In fact, up to 75 percent of prostate biopsies in the US are negative for high-grade disease. False positives cause anxiety and lead to invasive procedures, while false negatives risk missing aggressive cancers.
Even so, PSA remains a cost-effective, non-invasive first step in prostate cancer detection and has proven mortality benefits. The challenge lies in what comes next – how to act on an elevated result. Traditionally, physicians repeated the PSA test, then ordered imaging and biopsy. Today, newer tests can extract more information from the same blood sample. IsoPSA, for example, analyzes whether the PSA protein originated from cancer cells. Clinical studies show it can cut unnecessary biopsies by up to 55 percent.
How might demographics or family history change the way PSA results are interpreted?
Age, race, and family history all shape how PSA results are interpreted. Older men typically have higher baseline PSA levels, African American patients often show naturally higher scores, and those with a family history of prostate cancer face greater risk overall. These factors help urologists decide whether an elevated PSA warrants further testing, and if so, which kind.
If benign causes are likely, the next step might be a follow-up blood test. If cancer remains a concern, more aggressive measures – such as MRI imaging or biopsy – may be recommended.
What simple lab or reporting changes could improve the accuracy and usefulness of PSA results?
The commonly cited PSA threshold of 4 ng/mL comes from early studies that identified it as the highest level seen in men presumed free of prostate cancer. The ERSPC later suggested an alternative threshold of 3 ng/mL, showing reduced prostate cancer mortality among men aged 55-69 who underwent biopsy at that cutoff.
Because PSA levels naturally rise with age – even without cancer – most experts now recommend age-adjusted thresholds. The original 4 ng/mL standard is considered too high for men in their 40s and 50s, and too low for men in their 70s and 80s, where overdiagnosis becomes more likely.
The American Urological Association (AUA) guidelines commonly use the following age-based cutoffs:
2.5 ng/mL for men in their 40s
3.5 ng/mL for men in their 50s
4.5 ng/mL for men in their 60s
6.5 ng/mL for men in their 70s and older
What are the most promising biomarkers currently recommended in the guidelines, and how do they compare to conventional PSA?
While PSA remains an important first step, an elevated result does not always indicate high-grade cancer and can lead to unnecessary biopsies or overdiagnosis. The diagnostic process is becoming more refined, with greater focus on detecting clinically significant disease early. Both the AUA and the National Comprehensive Cancer Network (NCCN) now recommend biomarker testing for patients with elevated PSA. The NCCN also notes that MRI or other ancillary tests may be considered, listing six possible biomarkers: IsoPSA, Prostate Health Index (PHI), SelectDx, 4Kscore, ExoDx, and MyProstateScore (MPS) 2.0.
Importantly, clinicians never act on a single PSA result. When retested, PSA levels normalize in 25-40 percent of patients with a newly elevated reading. Using biomarkers and/or MRI before biopsy can help reduce unnecessary procedures while improving detection of high-grade cancers. Clear communication and shared decision-making with patients are essential, ensuring their values and preferences guide the next steps.
Current guidelines advocate for targeted approaches: patients with high PSA levels should undergo MRI, if available, or biomarker testing before biopsy to better assess the risk of clinically significant disease (grade group ≥2). However, widespread adoption of MRI is limited by resource constraints, variability in accuracy across readers, and reduced availability in many community settings.
One of the most promising tools is IsoPSA, a blood test that evaluates cancer-specific structural changes in PSA proteins rather than simply measuring concentration. IsoPSA has demonstrated superior accuracy compared with conventional PSA and percent-free PSA for predicting high-grade prostate cancer (Gleason score ≥7).
IsoPSA is included in the NCCN guidelines and is gaining recognition as a valuable tool in routine practice. Patients should discuss its benefits and limitations with their physicians to determine whether it is an appropriate next step after an elevated PSA.
How do these biomarkers fit with MRI in guiding who really needs a biopsy?
A 2023 single-center retrospective study published in Urology examined patients who underwent IsoPSA, Multi-Parametric Magnetic Resonance Imaging (mpMRI), and biopsy. The goal was to determine whether combining IsoPSA with MRI could improve biopsy decision-making.
Findings showed that combining PI-RADS 1–3 – categories indicating a low to moderate likelihood of clinically significant prostate cancer – with IsoPSA ≤6 increased the negative predictive value compared to either method alone, helping to reassure clinicians when the likelihood of clinically significant prostate cancer was low. Conversely, using IsoPSA >6 with MRI extended high-grade cancer risk assessment across PI-RADS 1-2 and PI-RADS 3 cases – settings where cancers may be missed – supporting the need for biopsy. This simple decision tree helps clarify which PI-RADS 1-3 patients should proceed to biopsy, showing that IsoPSA adds useful information beyond PSA alone.
Additional support comes from the initial screening phase of the ProScreen trial, which used PSA, the Kallikrein Panel, and MRI. Compared with early outcomes from the European Randomized Study of Screening for Prostate Cancer, ProScreen achieved similar detection of high-grade cancer (1.7 percent vs 1.8 percent) but significantly reduced detection of low-grade disease (0.4 percent vs 3.2 percent). This improvement reflects better biopsy selection with biomarkers and MRI, highlighting the clinical benefits of these advanced diagnostic tools over PSA testing alone.
What barriers are stopping wider adoption of better testing options?
Some tests remain difficult for clinicians to adopt because they have not gained regulatory approval, disrupt diagnostic workflows, or lack comprehensive insurance coverage. The encouraging news is that prostate cancer diagnostics are advancing rapidly, and these barriers are steadily improving.
How do you address conflicting guidelines around PSA screening when talking to patients?
PSA screening guidelines for prostate cancer have shifted over time, creating confusion for both patients and physicians. In 2008, the US Preventive Services Task Force (USPSTF) recommended against screening men aged 75 and older. By 2012, that recommendation was extended to all men, assigning PSA screening a grade D.
Following these changes, PSA screening rates in the US declined by 3-10 percent across age groups and regions. Biopsies and prostate cancer diagnoses also fell, but the cancers detected tended to be more advanced and higher grade. Analysis of SEER data (2004-2018) shows a significant rise in metastatic prostate cancer during the period when USPSTF discouraged screening, a trend seen across age and racial groups.
For patients, the shifting recommendations have been confusing. Having open, honest discussions about the purpose of PSA screening, how the guidelines have evolved, and what those changes mean for them is the best way to decide on a personalized approach moving forward.
When do genomic tests on biopsy tissue add real value, especially for active surveillance decisions?
Clinical criteria alone are not enough to decide which men with prostate cancer can safely choose active surveillance. For many patients, it is unclear whether active surveillance or definitive treatment is the better path. Genomic tests add an important layer of information, helping to reassess risk and giving patients and physicians greater confidence when active surveillance is appropriate. In this way, they act as a molecular safety net, ensuring that higher-risk cancers are not overlooked.
What should clinicians be telling patients so they know to ask for better testing options?
Instead of focusing only on what clinicians should tell patients, we should focus on what information clinicians need to guide shared decision-making, which depends on each patient’s risk tolerance. To lead meaningful discussions, urologists need to understand how biomarkers perform and the local accuracy of MRI interpretation within their own clinical setting. Only then can they have quality shared decision-making conversations that leave patients informed and empowered to request different or better testing options if they choose.
Looking ahead, what is the ideal diagnostic pathway for prostate cancer detection?
The pathway begins with a comprehensive risk assessment that goes beyond the traditional PSA test and incorporates multimodal artificial intelligence. This AI-driven model combines genetics, demographics, imaging, and biomarker results to generate a personalized risk score for clinically significant prostate cancer.
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