Prostate Screening

We appreciate the opportunity to clarify our positions regarding randomized prostate cancer screening trials and how implementation would be impacted in contemporary primary care practice that was reviewed in our recent publication. ¹

First, the 2 anchor trial narratives are often interpreted in ways that do not reflect their methodological realities. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), the control arm underwent substantial opportunistic PSA testing (>80% had 1 or more PSA tests during the study period), which markedly limits the trial’s ability to estimate the effect of screening versus no screening. ² Extended follow up studies and modeling work have demonstrated that PLCO more correctly reflects organized annual screening versus background screening and not screening for prostate cancer versus none.^3,4 In the UK CAP trial, which was a pragmatic cluster randomized design, the intervention was a single invitation to PSA testing with approximately 36% uptake, making it a low intensity exposure. ⁵ This study demonstrated that a 1 time, low uptake intervention for screening would be expected to have limited impact on prostate cancer mortality.

In addition to evaluating the practical implications of those 2 studies, a third trial, the European Randomized Study of Screening for Prostate Cancer (ERSPC), demonstrated a reduction in prostate cancer specific mortality with PSA testing. ⁶ ERSPC had a longer follow up and also illustrated key limitations relevant to policy translation, including heterogeneity across centers, evolving background opportunistic screening, and historical diagnostic and treatment pathways that differ meaningfully from today.

Second, we proposed an early baseline PSA with risk stratified, de-intensified follow-up and shared decision making, to avoid the historical harms that fueled backlash against PSA caused by indiscriminate annual PSA screening. We acknowledge no study has evaluated this specific screening regimen, yet our suggestion, representing the collaboration of experts in primary care and urology, factors in what is known about screening while minimizing the drawbacks of annual PSA testing. A blood test is not inherently good or bad; the net benefit depends on how the information is used. Modern downstream pathways, including repeat PSA confirmation, judicious biopsy selection, MRI integration where appropriate, and critically expanded use of active surveillance for low-risk disease, are designed to preserve benefit through earlier detection of lethal disease while minimizing overdiagnosis and overtreatment.

Third, the clinically meaningful endpoint for many patients is not only overall survival but also avoiding the morbidity of metastatic progression and prolonged systemic therapy. Late presentation with metastatic disease frequently commits patients to long courses of androgen deprivation therapy, which carries metabolic, skeletal, and cardiovascular consequences resulting in a well described quality of life decrease, as well as cost burden. ⁷ Consistent with this, multiple population based analyses report that the post 2012 decline in PSA screening in the United States coincided temporally with an increased incidence of metastatic prostate cancer at presentation.^8,9 Furthermore, a Veterans Administration study showed lower rates of metastatic prostate disease in facilities with higher rates of PSA testing. ¹⁰ While observational data cannot prove causality, it is clinically concerning and reinforces the importance of appropriately targeted early detection.

Finally, we emphasized the patient’s central role. PSA screening is a preference sensitive decision. Patients deserve clear, balanced counseling on benefits and harms so they can decide whether to obtain the test, and if elevated, how to proceed. Our intent is not to screen everyone, but to support primary care clinicians in offering an evidence based, individualized strategy that respects patient values while incorporating modern risk stratification and reduced morbidity within management paradigms.

Mahnoor Ashraf, Daniel Frendl, and Jack R. Andrews
Mayo Clinic, Phoenix, AZ, USA

Gregory M. Garrison and Nathaniel E. Miller
Mayo Clinic, Rochester, MN, USA