Artificial intelligence-based histopathology image analysis identifies a novel subset of endometrial cancers with distinct genomic features and unfavourable outcome

Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employed artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identified a novel sub-group of NSMP EC patients that had markedly inferior progression-free and disease-specific survival (termed ‘p53abn-like NSMP’), in a discovery cohort of 368 patients and an independent validation cohort of 290 patients from another center. Shallow whole genome sequencing revealed a higher burden of copy number abnormalities in the ‘p53abn-like NSMP’ group compared to NSMP, suggesting that this new group is biologically distinct compared to other NSMP ECs. Our work demonstrates the power of AI to detect prognostically different and otherwise unrecognizable subsets of EC where conventional and standard molecular or pathologic criteria fall short, refining image-based tumor classification.