PRIME: Prototype-Driven Multimodal Pretraining for Cancer Prognosis with Missing Modalities

Multimodal survival models can combine complementary prognostic information from whole-slide images and genomic profiles, but effective fusion remains challenging amid external cohort shift and computational complexity. To address these challenges, we propose MIST, multimodal survival prediction with genomic-guided histology attention. MIST represents genomic features as tokens and allows them to query compact foundation-model-derived histology context tokens before survival prediction. This design enriches molecular information with histology context rather than merging separately encoded modalities only at the final stage. Training combines discrete-time survival prediction with genomic feature masking, WSI dropout, and paired WSI-genomics contrastive alignment. Across four external evaluations in colon, renal, lung, and glioblastoma cohorts, MIST improves external C-index over standard fusion baselines in the primary comparisons. These results support genomic-guided histology attention as a compact and effective strategy for multimodal oncology outcome prediction. Our code is available at https://github.com/samiyavuuz/MIST .

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.