Peripheral blood transcriptional profiling predicts tumor subtype and neoadjuvant chemoimmunotherapy outcomes in human breast cancer

Dynamic biomarkers of therapy response are critical for precision oncology but often rely on serial tissue biopsies, which are invasive and not always feasible. In contrast, peripheral blood offers a minimally invasive, dynamic window into the evolving systemic immune landscape. Leveraging this, we performed RNA sequencing on 546 peripheral blood samples from 160 patients with high-risk stage II/III human epidermal growth factor receptor 2 (HER2)-negative breast cancer treated with either chemotherapy alone or in combination with immunotherapy (chemoimmunotherapy). Our analysis uncovered immune correlates of tumor subtype and treatment response. For example, samples from patients with triple-negative breast cancer exhibited elevated T cell receptor clonality and robust immune activation profiles. Among patients receiving chemoimmunotherapy, early responders demonstrated high baseline T cell receptor diversity, followed by rapid clonal expansion and activation of T cells after just one treatment cycle. We developed a multiparametric peripheral immune biomarker that integrated baseline and early on-treatment features to predict response to pembrolizumab, which was successfully validated in an independent cohort of 59 patients with breast cancer treated with neoadjuvant dostarlimab. These findings reveal the potential of blood-based immune monitoring to predict immunotherapy benefit, offering an accessible tool for tailoring treatment strategies in breast cancer.