AI-powered interpretable imaging phenotypes noninvasively characterize tumor microenvironment associated with diverse molecular signatures and survival in breast cancer

Tumor microenvironment (TME) is a determining factor in decision-making and personalized treatment for breast cancer, which is highly intra-tumor heterogeneous (ITH). However, the noninvasive imaging phenotypes of TME are poorly understood, even invasive genotypes have been largely known in breast cancer. Here, we develop an artificial intelligence (AI)-driven approach for noninvasively characterizing TME by integrating the predictive power of deep learning with the explainability of human-interpretable imaging phenotypes (IMPs) derived from 4D dynamic imaging (DCE-MRI) of 342 breast tumors linked to genomic and clinical data, which connect cancer phenotypes to genotypes. An unsupervised dual-attention deep graph clustering model (DGCLM) is developed to divide bulk tumor into multiple spatially segregated and phenotypically consistent subclusters. The IMPs ranging from spatial heterogeneity to kinetic heterogeneity are leveraged to capture architecture, interaction, and proximity between intratumoral subclusters. We demonstrate that our IMPs correlate with well-known markers of TME and also can predict distinct molecular signatures, including expression of hormone receptor, epithelial growth factor receptor and immune checkpoint proteins, with the performance of accuracy, reliability and transparency superior to recent state-of-the-art radiomics and ‘black-box’ deep learning methods. Moreover, prognostic value is confirmed by survival analysis accounting for IMPs. Our approach provides an interpretable, quantitative, and comprehensive perspective to characterize TME in a noninvasive and clinically relevant manner.