Multimodal Feature Prototype Learning for Interpretable and Discriminative Cancer Survival Prediction

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, $K$ learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype $\times$ pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.

Multimodal survival analysis aims to improve cancer prognosis using heterogeneous biomedical data, such as histopathology images and genomic profiles. A common strategy is to align representations across modalities so that shared signals can be captured. However, strong cross-modal alignment can also remove modality-specific evidence that is critical for survival prediction. In this paper, we revisit multimodal survival learning from a simple observation: effective models should first discover shared patterns across modalities, and then preserve modality-specific signals. This motivates a representation learning principle that we refer to as Together Then Apart. Based on this idea, we propose TTA, a framework that balances cross-modal alignment and representation distinctiveness. TTA first performs prototype-based alignment to capture shared survival-related structures between modalities. It then encourages modality-specific distinctiveness through an anchor-guided contrastive objective. To further account for modality imbalance and noisy correspondences, we model cross-modal interactions using unbalanced optimal transport. We evaluate the proposed approach on multiple TCGA cancer cohorts with paired histopathology and genomic data. TTA consistently improves survival prediction over recent multimodal survival models. Moreover, the learned prototype structures reveal interpretable cross-modal patterns associated with clinical outcomes.

Multimodal learning has significantly advanced survival prediction by integrating pathology images with genomic data. However, clinical information, despite its critical role in reflecting a patient' s overall health, remains underutilized due to its discrete, sparse, and low-dimensional nature. Furthermore, the inherent heterogeneity across these modalities pose significant challenges in modeling cross-modal interactions. In this paper, we propose CIGTSurv, a Clinical Information Guided Tri-modal framework for Survival prediction. Specifically, we first design a holistic text template and use pretrained foundation models to transform clinical tabular data into high-dimensional tokenized embeddings. Using clinical information as an anchor, we then introduce a dual-level interaction mechanism: 1) a local prototype association (LPA) module based on cross-attention to explicitly learn token-level correspondences between different modalities, and 2) a global feature alignment (GFA) loss based on Maximum Mean Discrepancy (MMD) to implicitly enhance cross-modal distribution consistency. Extensive experiments on five TCGA cancer cohorts demonstrate that CIGTSurv achieves state-of-the-art (SOTA) survival prediction performance. Our source code is publicly available at https://github.com/Daijing-ai/CIGT-Surv.git.