Prognostic RNA-splicing archetypes in breast cancer identified by extended pre-training of histopathology foundation models.

Recently, histopathology foundation models (hFM) have rapidly advanced in size and complexity, achieving excellent performance in cancer diagnosis and biomarker discovery. Here, we specialise pre-trained hFMs to invasive tumour tissue and present three key contributions. First, we systematically evaluate the biological concepts encoded in hFM representations across multiple biological scales. Second, we demonstrate that informed extended pre-training transforms generalist models into tumour-specialised ones encoding richer semantic information, enabling discovery of recurrent tumour archetypes with consistent morphological and molecular identities across patients. Third, we identify dominant tumour archetypes with aberrant gene-expression programs coexisting within tumours and recurring across heterogeneous epithelial cancers, including HER2-positive and triple-negative breast cancer. Crucially, these archetypes exhibit prognostic value, with RNA splicing-associated archetypes consistently predicting poorer outcomes. Our work shows that tumour-specialised hFMs unlock rich molecular and morphological information from routine H&E slides, providing computationally efficient and biologically informed solutions for biological discovery and patient stratification.