Peripheral blood gene expression signatures of systemic immunity predict tumor microenvironment biology and therapeutic response in breast cancer.

This study investigates the association between peripheral blood immunological features and immunotherapy response in breast cancer. We generated and analyzed RNAseq data from 546 blood samples of patients with high-risk stage II/III HER2-negative breast cancer enrolled in the I-SPY2 trial and identified peripheral immune signatures associated with tumor characteristics and immunotherapy response. Triple negative breast cancer (TNBC) patients showed higher T cell receptor (TCR) clonality and immune activation signatures. Responders to the chemotherapy + pembrolizumab regimen had high baseline TCR diversity, with TNBC responders experiencing T cell clonal expansion and activation after treatment. A logistic regression model based on immunological features before and early-on-treatment predicted response to pembrolizumab. The model was validated in an independent cohort of patients treated with dostarlimab in the neoadjuvant setting. We report the potential of peripheral blood-derived gene expression tests to predict immunotherapy benefit, guiding personalized treatment in breast cancer with a minimally invasive approach.