Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Response to CDK4/6 Inhibition in Metastatic HR+/HER2- Breast Cancer

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), combined with endocrine therapy, represent the standard treatment for metastatic HR+/HER2- breast cancer (mBC). Despite their established efficacy, intrinsic resistance affects approximately one-third of patients, posing a significant challenge and underscoring the importance of identifying reliable predictive biomarkers. This study utilizes single-cell RNA sequencing (scRNAseq) of metastatic site biopsies to unveil cellular and molecular biomarkers predictive of CDK4/6i response. Through this analysis, we have identified and validated the tumor-specific molecular biomarkers across two independent mBC patient cohorts using bulk RNAseq data from baseline fresh biopsies or FFPE slides of HR+/HER2- mBC patients prior to CDK4/6i treatment. Additionally, the data indicate that baseline predictors may include tumor-infiltrating cytotoxic NK and T lymphocytes, suggesting the potential utility of checkpoint inhibitors in CDK4/6i progressors. These potentially actionable insights underscore the importance of optimizing therapeutic strategies based on microenvironment-specific changes observed following disease progression.