Abstract 737: Variation in prognostic value of Gleason score for lethal prostate cancer using time-varying area under the curve
Authors: Lin Zhike , Stopsack Konrad H. , Fiorentino Michelangelo , Vaselkiv Jane B. , Gerke Travis , Pettersson Andreas , Flanagan Sinead , Penney Kathryn L. , Finn Stephen P. , Loda Massimo , Mucci Lorelei A. 
Published: April 2023

Abstract
Background: Gleason score is one of the strongest prognostic factors for prostate cancer survival in patients with primary prostate cancer. However, its predictive accuracy is less clear during extended follow-up periods.
Methods: We included men diagnosed with prostate cancer in the Physicians’ Health Study (PHS) and Health Professionals Follow-up Study (HPFS) between 1982 and 2009. We included individuals with available radical prostatectomy tissue specimens and undertook a central standardized histopathologic re-review of H&E slides including Gleason score according to the 2014 International Society of Urological Pathology Consensus. Comparing pathologic Gleason score, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for lethal prostate cancer-free survival from the time of diagnosis using the Cox proportional hazards regression through 2018. Lethal prostate cancer was defined as development of distant metastases or prostate cancer-specific death. We assessed the time-dependent predictive accuracy of Gleason score over 10, 15, 20, and 25-years post-diagnosis with time-varying area under the curve (tAUC) using the Uno estimator.
Results: Among the 1,404 prostate cancer patients, 113 developed lethal prostate cancer during a follow-up of up to 30 years (median 17.1 years). There were 11% men with Gleason score of 9-10 (grade group 5), 7.1% with 8 (grade group 4), 23% with 4+3 (grade group 3), 36% with 3+4 (grade group 2), and 23% with 6 (grade group 1). Compared to Gleason score 6, the HRs for lethal disease were 5.6 (95% CI: 1.3 to 24) for score 3+4, 13 (95% CI: 3.1 to 55) for 4+3, 17 (95% CI: 3.8 to 75) for 8, and 27 (95% CI: 6.5 to 117) for 9-10, adjusting for pathological tumor stage, age at diagnosis, and prostate-specific antigen (PSA) level at diagnosis. The overall AUC over the entire follow-up was 0.71 (95% CI: 0.63 to 0.79) for Gleason score alone and 0.76 (95% CI: 0.68 to 0.83) with the addition of stage, PSA, and age. Discrimination for lethal prostate cancer based on Gleason score alone varied over follow-up, peaking at a tAUC of 0.81 (95% CI: 0.77 to 0.85) at 10 years, and slowly declined to 0.78 (95% CI: 0.74 to 0.83) at 15 years, 0.78 (95% CI: 0.74 to 0.81) at 20 years, and 0.74 (95% CI: 0.69 to 0.80) at 25 years post-diagnosis. The tAUC had a similar trend with the addition of stage, PSA, and age, with higher point estimates at each time point.
Conclusions: The prognostic value of Gleason score for lethal prostate cancer after prostatectomy, based on genitourinary pathologist re-review, remains high for decades after diagnosis, with only a modest decline over time. Given the long natural history of prostate cancer, an understanding of the factors that contribute to remaining metastasis-free is needed to inform clinical decisions.
Citation Format: Zhike Lin, Konrad H. Stopsack, Michelangelo Fiorentino, Jane B. Vaselkiv, Travis Gerke, Andreas Pettersson, Sinead Flanagan, Kathryn L. Penney, Stephen P. Finn, Massimo Loda, Lorelei A. Mucci. Variation in prognostic value of Gleason score for lethal prostate cancer using time-varying area under the curve [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 737.