A Multimodal Foundation Model for Longitudinal Patient Representation and Scalable Insight Generation in Oncology

Precision oncology necessitates a longitudinal model of patient state that captures cancer evolution and treatment over time, integrating multimodal observations. We introduce the oFM, a foundation model developed on a real-world oncology cohort of 1.67 million cancer patients that integrates clinical trajectories with DNA, RNA, and H&E pathology. Patient-level partitions were reserved for training, validation, and testing, with over one million patients used for training. The oFM encodes daily clinical and molecular episodes and, along with pathology images, integrates them over time to produce a patient state embedding. We evaluate frozen oFM embeddings against expert-curated clinical and molecular baseline features. In prognostic benchmarks, the oFM improved AUC for treatment response, progression-free survival, and overall survival (0.774 vs. 0.563 for overall survival). Across 11 comparative-treatment cohorts, the oFM embeddings achieved a three-fold higher pooled and scale-normalized treatment-benefit AUTOC than baseline features with improved benefit ranking in 9 of 11 cohorts, and provided stronger prognostic discrimination within both treatment arms. We also evaluated a mechanism discovery framework that interprets downstream models built on oFM embeddings by linking their predicted outcomes to clinically and biologically grounded mechanisms through an evidence-grounded temporal graph, enabling evaluation in clinical and drug-development applications.

CHIMERA Challenge: Biochemical Recurrence Prediction in Prostate Cancer Patients using multimodal datasets

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.

JASPR: Joint Spatial Representation learning of histology and spatial genomics for improved virtual genomic screening and clinical prognostication

Recent studies have shown that spatial properties of tumors are critical for understanding disease biology and predicting patient outcomes. These spatial properties are increasingly uncovered through complementary modalities: spatial transcriptomics (ST) captures spatially-resolved molecular states, while hematoxylin and eosin-stained whole slide images (HE) reveal tissue morphology. While approaches are emerging to fuse these modalities, effective methods that learn not only joint representations but also incorporate spatial context across modalities are lacking. Here, we present JASPR (Joint Spatial Representation learning), a self-supervised deep learning framework that integrates HE images and ST data through a cross-modal reconstruction objective that incorporates spatial context within HE images and ST profiles. It employs shared modules to capture universal spatial properties across modalities, while modality-specific experts encode features unique to morphological and genomic data. We train and validate JASPR on breast cancer datasets, demonstrating that its learned joint representation substantially improves HE-based prediction of 9,248 genes and provides prognostic value for breast cancer outcomes.

Multi-FRuGaL: Multimodal Flexible Redundancy-aware Decomposed Gated Learning for Cancer Diagnosis and Prognosis

Modern medicine relies on heterogeneous data sources spanning radiology, pathology, text reports, and structured clinical information. However, real-world patient data are frequently incomplete, with missing or sparsely acquired modalities, limiting the effectiveness of standard multimodal fusion approaches. To this end, we propose the Multimodal Flexible Redundancy-aware decomposed GAted Learning (Multi-FRuGaL) framework, a decomposition-aware, adaptive gated intermediate-fusion framework that performs modality-level representation learning under missing data. Multi-FRuGaL integrates per-modality encoders with a signal decomposition layer, an input-conditioned gating network, and an information-aware fusion objective to separate redundant from modality-specific complementary signals, selectively upweighting informative modalities and suppressing redundant or noisy inputs, and remaining well-defined even when multiple modalities are absent. We evaluate Multi-FRuGaL on two multimodal head and neck cancer cohorts: the HANCOCK challenge dataset (N = 763) comprising five modalities and two prognostic endpoints (5-year survival and 2-year recurrence), and the HECKTOR challenge dataset (N = 588) comprising three modalities for human papillomavirus (HPV) status classification. Multi-FRuGaL consistently achieves higher mean performance than the evaluated baselines across multiple tasks, improving AUC from 0.601 to 0.8496 for survival, from 0.672 to 0.8102 for recurrence, and achieving 0.975 AUC for HPV prediction on HECKTOR. For survival analysis, it further achieves a concordance index of 0.6814 for overall survival, 0.7421 for recurrence-free survival, and 0.7143 for progression-free survival on HANCOCK, and 0.7203 for recurrence-free survival on HECKTOR. Qualitative analyses further show that Multi-FRuGaL learns discriminative and robust multimodal representations, even under severe missing-modality conditions.

Hierarchical Prototype-based Domain Priors for Multiple Instance Learning in Multimodal Histopathology Analysis

Digital pathology has fundamentally altered diagnostic workflows by enabling the computational analysis of gigapixel Whole Slide Images (WSIs), yet effectively deciphering their complex tumor microenvironments remains a formidable challenge. Existing Multiple Instance Learning (MIL) frameworks typically treat Whole Slide Images as unstructured bags of patches, discarding critical morphological semantics and spatial geometry. This lack of inductive bias often leads to overfitting on background noise and fails to align visual features with high-level diagnostic knowledge. To overcome these limitations, we propose the Hierarchical Prototype-based Domain Priors (HPDP) framework, a unified multimodal approach for joint histopathology diagnosis and prognosis. HPDP mitigates the data-driven "black box" issue by introducing a Morphologically Anchored Prototype System (MAPS), which anchors learning to interpretable morphological clusters, and a Sinusoidal Positional Encoder (SPE) to explicitly model tissue architecture. Furthermore, we bridge the semantic gap via a Hierarchical Cross-Modal Alignment (HCMA) module, using Large Language Model (LLM)-generated descriptions to contextually refine visual representations. Extensive experiments across seven cancer cohorts demonstrate that HPDP consistently achieves state-of-the-art performance with superior robustness and interpretability.