Efficient AI-Driven Multi-Section Whole Slide Image Analysis for Biochemical Recurrence Prediction in Prostate Cancer

Accurate prediction of biochemical recurrence (BCR) after radical prostatectomy is critical for guiding adjuvant treatment and surveillance decisions in prostate cancer. However, existing clinicopathological risk models reduce complex morphology to relatively coarse descriptors, leaving substantial prognostic information embedded in routine histopathology underexplored. We present a deep learning-based biomarker that predicts continuous, patient-specific risk of BCR directly from H&E-stained whole-slide prostatectomy specimens. Trained end-to-end on time-to-event outcomes and evaluated across four independent international cohorts, our model demonstrates robust generalization across institutions and patient populations. When integrated with the CAPRA-S clinical risk score, the deep learning risk score consistently improved discrimination for BCR, increasing concordance indices from 0.725-0.772 to 0.749-0.788 across cohorts. To support clinical interpretability, outcome-grounded analyses revealed subtle histomorphological patterns associated with recurrence risk that are not captured by conventional clinicopathological risk scores. This multicohort study demonstrates that deep learning applied to routine prostate histopathology can deliver reproducible and clinically generalizable biomarkers that augment postoperative risk stratification, with potential to support personalized management of prostate cancer in real-world clinical settings.

Biochemical recurrence (BCR) after radical prostatectomy is a critical endpoint in prostate cancer, yet risk stratification relies almost entirely on variables dominated by Gleason grade. Whether H&E whole slide images (WSIs) carry prognostic signal beyond grade, and whether multiple instance learning (MIL) can recover it, remains unsettled. A key obstacle is that many pipelines select model checkpoints on the evaluation fold, artificially inflating concordance. We construct a rigorous benchmark on TCGA-PRAD (487 patients, 101 BCR events) using strict out-of-fold scoring over five-fold cross-validation repeated across five seeds. The choice of MIL aggregator (ABMIL, CLAM, TransMIL, PatchGCN) has little effect (C-index 0.61-0.64 with UNI2-h), while the feature extractor is the dominant factor (ResNet50 0.566 versus pathology foundation models up to 0.639). A clinical Cox model on grade, stage, and age reaches 0.687; no imaging-only model significantly outperforms it (p > 0.10). We introduce Grade-Disentangled MIL (GD-MIL), a gated-attention MIL encoder trained with a gradient-reversal grade adversary that encourages the slide representation to be invariant to Gleason grade before late fusion with clinical variables. GD-MIL achieves C-index 0.704, significantly outperforming both the clinical baseline (delta-c = +0.029, p = 0.0005) and the best imaging-only model (delta-c = +0.062, p = 0.039), suggesting H&E morphology contains prognostic information complementary to grade. A median risk split yields log-rank p < 0.0001 separation in BCR-free survival (~20% vs ~70% at five years).

Biochemical recurrence (BCR), defined as any detectable prostate-specific antigen level after prostatectomy with confirmatory elevation, is widely used as a surrogate endpoint and typically assessed using clinical and pathological variables. Currently, no standardized benchmark exists for multimodal prognostic modeling in urological cancers, partly because curating heterogeneous multimodal data remains challenging. We developed the CHIMERA Challenge, a multimodal benchmark integrating preoperative mpMRI, post-prostatectomy histopathology, patient characteristics, and clinician-derived variables from 267 patients across two institutions. The dataset comprises 801 MRI sequences, 13 clinical variables per case, and 942 WSIs. Training (n=95), validation (n=23), and test (n=149) splits were established and hosted on the Grand Challenge platform. Baseline clinical and pathological characteristics did not differ significantly across splits. Models were evaluated on predicting time to BCR using the C-index. Post-challenge analyses tested how each model type performed when clinician-derived variables were withheld or randomized. Unimodal clinical models achieved the highest test C-index of 0.7402 but proved sensitive to the integrity of these variables, with performance collapsing toward chance (C approximately 0.50) when they were randomized. Multimodal models retained near-baseline performance when these variables were withheld (delta C at most 0.04), indicating their ability to recover prognostic signal directly from imaging data. CHIMERA is the first public, standardized multimodal benchmark for prostate cancer prognosis. Although models using only patient characteristics and clinician-derived variables yielded the highest leaderboard performance, multimodal models demonstrated greater robustness in clinically realistic scenarios where complete expert annotation is not guaranteed.