Long-term follow-up from the STHLM3 trial suggests that a multi-marker risk model can identify aggressive prostate cancers missed by PSA thresholds while potentially reducing unnecessary biopsies.
Context: The Limits of PSA-Based Screening
For more than three decades, prostate cancer screening has relied primarily on prostate-specific antigen (PSA). While PSA testing has contributed to reductions in prostate cancer mortality, it has important limitations. PSA lacks specificity, leading to unnecessary biopsies and overdiagnosis of indolent disease. At the same time, PSA also has limited sensitivity for clinically significant prostate cancer when conventional thresholds are used, meaning that aggressive cancers may occur in men with PSA levels below commonly used cutoffs.
These limitations have prompted increasing interest in precision screening strategies that move beyond a single biomarker and incorporate multiple biological signals to better identify men at risk for aggressive disease.
The Stockholm3 Approach
The STHLM3 trial evaluated one such strategy using the Stockholm3 test, a multivariable risk prediction model that integrates plasma protein biomarkers, a polygenic risk score, and clinical variables into a single algorithm-generated risk estimate. By combining these markers, Stockholm3 aims to improve the detection of clinically significant prostate cancer while reducing unnecessary biopsies and overdiagnosis.
While previous analyses from the STHLM3 trial demonstrated improved diagnostic performance compared with PSA alone, the recently published nine-year outcomes provide important insight into the long-term biological significance of cancers detected through this approach.
Rather than focusing solely on initial detection rates, the current analysis examined long-term oncologic outcomes, including biochemical recurrence after curative treatment, which serves as a surrogate marker for aggressive tumor biology.
Key Findings
A central finding from this study is that clinically significant prostate cancer frequently occurs in men with PSA levels below traditional biopsy thresholds. Men with PSA <3 ng/mL, but an elevated Stockholm3 score (≥11) was found to have a substantially increased risk of aggressive disease. In contrast, men with PSA ≥3 ng/mL but a negative Stockholm3 result experienced no cases of high-risk biochemical recurrence during follow-up. The difference between these groups was striking. Men with PSA <3 ng/mL, but elevated Stockholm3 scores were nearly nine times more likely to experience high-risk biochemical recurrence compared with men who had PSA ≥3 ng/mL but a negative Stockholm3 test (Hazard Ratio 8.8, 95% CI: 1.06–72; p = 0.044).
These findings illustrate an important limitation of PSA-based screening thresholds: clinically meaningful cancers may be missed when screening relies on PSA alone. By incorporating additional biological information, including protein biomarkers and inherited genetic risk, the Stockholm3 model provides a more refined assessment of prostate cancer risk and helps identify aggressive disease that PSA may fail to detect.
Reducing Unnecessary Biopsies
Equally important, the study demonstrated that deferring biopsy in men with PSA ≥3 ng/mL but a low Stockholm3 score rarely resulted in missed aggressive cancers. This suggests that Stockholm3 may serve a dual role in prostate cancer screening:
- Identifying aggressive cancers in men with PSA levels below traditional biopsy thresholds
- Reducing unnecessary biopsies among men with elevated PSA but low predicted cancer risk.
Implications for Modern Screening Pathways
Prostate cancer screening strategies are increasingly evolving toward precision pathways that incorporate biomarkers, imaging, and targeted biopsy. Within this framework, Stockholm3 can function as an upstream risk stratification tool, helping identify which men should proceed to prostate MRI and biopsy. By detecting aggressive cancers in men with lower PSA levels while avoiding unnecessary procedures among men with benign PSA elevations, precision screening approaches may improve the balance between early detection and overdiagnosis.
The Importance of Long-Term Evidence
Screening strategies must ultimately be evaluated over long time horizons. While short-term diagnostic accuracy studies are informative, long-term outcomes help determine whether screening preferentially identifies cancers with aggressive biological potential. The nine-year results from the STHLM3 trial demonstrate that elevated Stockholm3 risk scores are strongly associated with subsequent aggressive disease, supporting the biological relevance of the cancers detected through this approach.
Clinical Takeaways
Several practical insights emerge from these findings:
- PSA alone has limited sensitivity for aggressive prostate cancer. Clinically significant cancers may occur at PSA levels below traditional biopsy thresholds.
- Multi-marker risk models improve risk stratification. Stockholm3 integrates protein biomarkers, genetic risk, and clinical variables to refine prostate cancer risk assessment.
- Biopsy decisions can be improved. Men with elevated PSA but low Stockholm3 scores may safely avoid unnecessary biopsies.
- Precision screening may improve the balance between early detection and overdiagnosis. Risk-adapted approaches can focus diagnostic efforts on men most likely to harbor clinically significant disease.
As prostate cancer screening continues to evolve, the central challenge remains unchanged: detect cancers that matter while minimizing unnecessary interventions. The long-term findings from the STHLM3 trial suggest that multi-marker precision screening strategies such as Stockholm3 may play an important role in achieving this balance.
Written by: Hari T. Vigneswaran,1 Thorgerdur Palsdottir,2 Chiara Micoli,2 Derya Tilki,3 Daniel Lin,4 Matthew Cooperberg,5 Scott Eggener,6 Ugo Giovanni Falagario,7 Axel Möller,7 Markus Aly,7 Olof Akre,7 Peter Wiklund,7 Lars Egevad,8 Henrik Grönberg,2 Tobias Nordström,9 Martin Eklund2
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Martini-Klinik Prostate Cancer Center, University Hospital Hamburg Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, Koc University Hospital, Istanbul, Turkey.
- Department of Urology, University of Washington Medical Center and Fred Hutchinson Cancer Center, Seattle, WA, USA.
- Department of Urology, University of California San Francisco, San Francisco, CA, USA.
- Department of Surgery, University of Chicago, Chicago, IL, USA.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.