Long-term prediction of metastatic and fatal prostate cancer: reaffirming the Gleason score

In their paper “Long-term performance of the Gleason score in predicting metastatic and fatal prostate cancer” (1), the authors make a useful contribution to the literature regarding prostate cancer prognosis. In an era increasingly driven by artificial intelligence platforms and genomic biomarkers, this study presents arguments for the sustained prognostic value of the Gleason score, particularly over extended follow-up periods. The study also addresses the challenges of time-dependent prognostic accuracy, providing results with clinical implications for future patient management and research.

The study design is noteworthy. With a “cumulative/dynamic” time-varying area under the curve (tAUC), the authors discuss a challenge in cancer epidemiology: the description of prognostic capacity across various time horizons, with particular application to long natural history diseases like prostate cancer. Differing from traditional hazard-based AUCs, which focus on a point in time, risk-based tAUC provides a more clinically meaningful indication of how well a prognostic factor can forecast whether or not a patient will be free of a specific outcome (e.g., metastasis) within a period of time. This shift in focus allows for more interpretable prognostic accuracy of direct interest to patient and clinician expectations.

The evidence focuses on the fact that while the relative prognostic value of the Gleason score is highest during the first 10 years following radical prostatectomy, discriminant power remains very high even at 25 years. Such predictive capacity in terms of lethal prostate cancer in the event of patients undergoing radical prostatectomy reaffirms its qualitative status in clinical oncology. The data show that high Gleason scores define a high absolute excess risk, even decades after surgery, a pattern different from other solid cancers.

The work elucidates the time-dependent dynamics of lethal prostate cancer progression across different Gleason scores. For patients with high Gleason scores (e.g., 9–10), the fatal disease risk is estimated predominantly early, with a significant fraction of events in the initial 10 years. On the other hand, lower Gleason scores (e.g., 3+4) feature an initially low risk with the potential of a slow accumulation of events that may be fatal over decades. This more nuanced appreciation of the risk trajectory has far-reaching implications for tailoring surveillance strategies.

As an example, current guidelines (2) encourage intensive prostate-specific antigen testing in the early years following surgery. However, the evidence from this study suggests a discrepancy for patients with low-grade cancer. For them, less frequent initial monitoring might be sufficient, with later requirement for vigilance many years post-diagnosis, and possibly sharing some of the later follow-up burden with primary care. Conversely, high-grade cancer might require more intense early follow-up based on its increased risk in the first few years.

These results have implications for the broader context of precision medicine. The fact that the Gleason score, even alone, provides strong prognostication suggests that for many patients additional genomic or molecular data often may not meaningfully reclassify their intrinsic risk. That is not intended to diminish the value of such advanced testing; rather, it highlights the long precedent and often sufficient predictive power of a meticulously assessed Gleason score.

Furthermore, the authors report an interesting opportunity: the “somewhat lower prognostic performance of Gleason score among long-term metastasis-free survivors”. This group represents a cohort with which to develop and validate new prognostic biomarkers. Among these long-term metastasis-free survivors, the identification of subtle biological markers of extremely late-onset lethal disease may make a significant difference in individualized surveillance and intervention. This underscores the ongoing necessity for investment in studies focused on later-stage risk assessments.

The increase in tAUC when PSA and pathologic tumor-node-metastasis (pTNM) stage are added to the Gleason score is another demonstration of the synergistic effect of combining known clinical predictors. The particularly good discrimination of young patients (diagnosed at age <60 years) when added is a sign of the utility of overall risk assessment in this age group.

The use in this study of two large, established prospective cohorts [Physicians’ Health Study (3) and Health Professionals Follow-up Study (4)] with up to 35 years of follow-up and centralized histopathologic re-review by experienced genitourinary pathologists enhances the validity and generalizability of findings. The careful re-review process decreases the influence of interobserver variability and temporal drift in Gleason grading criteria, yielding a high-quality and standardized evaluation of tumor pathology. This degree of specificity renders the findings most applicable to prediction after radical prostatectomy in patients following expert histopathologic evaluation.

While this study makes an important contribution, it also points towards future research. The authors comment that the findings of their investigation are generalizable, to a large extent, to men following prostatectomy. Future studies must be aimed at observing time-dependent patterns of Gleason scores after pre-treatment biopsies in men undergoing active surveillance or primary radiotherapy. These investigations would further broaden our understanding of the Gleason score in the entire spectrum of prostate cancer management.

Additionally, examination of the interaction between Gleason score and newer genomic classifiers following long-term follow-up will establish whether or not such newer tools provide complementary prognostic information, particularly for the subgroup of long-term survivors with lower grade disease. How they interact to enhance risk prediction—particularly in accounting for risks of death from other causes—will be essential.

In conclusion, the authors have provided a study that reinforces the enduring and dynamic predictive power of the Gleason score in prostate cancer. Their work not only strengthens the foundation of our current prognostic models but also highlights critical directions for future epidemiological and clinical research aimed at optimizing personalized patient care over a lifetime. This research reminds us that simple pathological analysis, when rigorously applied and interpreted through innovative epidemiological methods, continues to be an indispensable tool in the fight against prostate cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2025-8/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2025-8/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Lin Z, Stopsack KH, Fiorentino M, et al. Long-term performance of the Gleason score in predicting metastatic and fatal prostate cancer. Am J Epidemiol 2026;195:919-26. [Crossref] [PubMed]
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer Version 2.2025. Available online: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (Cited 2025 August 13).
3. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-35. [Crossref] [PubMed]
4. Harvard T.H. Chan School of Public Health. Health Professionals Follow-up Study. Available online: https://hsph.harvard.edu/research/health-professionals (Cited 2025 Aug 13).