Comparing Gleason Pattern 4 Measurement Approaches on Prostate Biopsy Using Machine Learning: A Proof-of-Principle Study

Objective: To demonstrate the proof of principle that machine learning (ML) can be used to quantify Gleason Pattern (GP) 4 on digitized biopsy slides using multiple measurement approaches, allowing direct comparison of their prognostic performance. Methods: We assembled a convenience sample of 726 patients with grade group 2-4 prostate cancer on systematic biopsy who underwent radical prostatectomy between 2014 and 2023. Digitized biopsy slides were analyzed using a machine-learning algorithm (PAIGE-AI) to quantify GP4 using multiple measurement approaches, particularly with respect to how gaps between cancer foci ("interfocal stroma") were handled. GP4 extent was quantified using linear measurements or a pixel-based area metric. Discrimination of each GP4 quantification approach, along with Grade Group (GG), was assessed for adverse radical prostatectomy pathology and biochemical recurrence. Results: We identified 15 different quantification approaches and observed differences between their discrimination. The highest discrimination was in the pixel-countingmethod (AUC 0.648). GP4 quantification outperformed GG for predicting adverse pathology (AUC 0.627 vs 0.608). Amount of GP3 was non-predictive once GP4 was known. These findings were consistent for BCR. Conclusions: We were able to measure slides using 15 distinct measurement approaches and replicated prior findings using ML to quantify GP4. Our findings support the use of ML as a research tool to compare different GP4 quantification approaches. We intend to use our method on larger cohorts to determine with which measurement approach best predicts oncologic outcome.