TRUST: Threshold-Recalibrated Uncertainty-Safe Training for Certified Dismissal in Breast Cancer Screening

Pathology foundation models have shown strong retrospective performance, but whether such systems can support clinically relevant use remains unclear. This challenge is particularly important in breast cancer, where pathological assessment serves as the gold standard for diagnosis and guides treatment planning, surgical decision-making and risk stratification across pre-, intra- and post-operative stages. Here we present \textbf{BRAVE}, a breast-adaptive pathology foundation model developed and evaluated using a total resource of 101,638 breast whole-slide images from 32 sources across Asia, Europe and North America. We assessed BRAVE across 34 tasks in 82 cohorts spanning pre-operative biopsy, intra-operative frozen section and post-operative resection, using an evidence chain comprising retrospective benchmarking, clinically challenging scenarios, workflow-oriented clinical impact simulations, prospective observational validation with the thresholds locked in the retrospective cohorts and crossover pathologist-AI interaction studies. Across these settings, BRAVE supported practical roles in the clinical workflow, including safe exclusion of low-risk cases from routine review, AI-assisted second-review rescue of initially missed positives and prioritization of cases for further assessment. In prospective validation across three centres, BRAVE excluded 76.9% of negative biopsy cases (NPV 0.953) and 70.1% of negative frozen-section cases (NPV 0.973), and triaged 78.8% of post-operative subtyping cases as high-confidence clear-cut cases (NPV 1.000). In reader studies, AI assistance improved balanced accuracy from 88.5% to 95.1% (OR 3.14, P<0.001), with better efficiency, confidence and inter-rater agreement. BRAVE-derived scores also independently predicted disease-free survival (adjusted HR 4.79, P<0.001) and overall survival (adjusted HR 8.14, P<0.001).

Breast cancer remains a leading cause of cancer-related mortality among women. Its clinical management requires multimodal reasoning across a clinical workflow that spans \textit{screening}, \textit{diagnosis} and \textit{treatment planning}, where each stage involves distinct imaging modalities, task objectives, and reasoning patterns. However, constrained by data scarcity and model versatility, existing medical MLLMs are typically evaluated on isolated modalities or narrow task families, limiting their ability to support workflow-level clinical reasoning. In this work, we first introduce \textbf{BreastStage}, a workflow-aligned breast imaging instruction corpus comprising 1.86M instruction-following pairs curated from 17 sub-datasets across 5 imaging modalities and 136 task templates. Its held-out split, \textbf{BreastStage-Bench}, provides a comprehensive benchmark for evaluating multimodal reasoning across the breast cancer care continuum. Building on this corpus, we propose \textbf{BreastGPT}, a unified MLLM equipped with a dual-branch visual encoder and concept-preserving token compression to bridge the scale gap between standard radiology and gigapixel pathology. On BreastStage-Bench, BreastGPT achieves 75.66% closed-ended accuracy and 89.92% open-ended score, outperforming both general-purpose and medical-specific MLLMs across clinical stages and task formats. These results suggest that workflow-aligned data and cross-scale visual modeling are critical for clinically grounded medical MLLMs. All data, code, and model checkpoints are released at https://yangyy-liu.github.io/BreastGPT.io.

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).