Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [tissue]

This study addresses the critical need for predictive biomarkers in patients with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) who have been treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is). Using single-cell RNA sequencing, we reveal differential mechanisms of early versus late progression, enhancing our understanding of resistance to CDK4/6is. We identify and validate tumor-specific molecular biomarkers and demonstrate that tumor-infiltrating cytotoxic natural killer and CD8+ T cells are predictive of therapeutic response. Additionally, increased immune activity suppression in late progressing tumors suggests that combining CDK4/6is with checkpoint inhibitors could be beneficial against drug resistance. Validation across 2 independent cohorts confirms the robustness and clinical relevance of our findings. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, offering a personalized and effective approach to managing HR+/HER2- mBC and improving patient outcomes.