Sequencing analysis reveals evidence of immune activation in advanced HER2 negative breast cancer responders treated with the combination of entinostat

Sequencing analysis reveals evidence of immune activation in advanced HER2 negative breast cancer responders treated with the combination of entinostat, nivolumab, and ipilimumab. Download PDF Abstract Background Advanced HER2-negative breast cancer remains difficult to treat, and mechanisms associated with response to immunotherapy-based combinations are not fully understood. This study aimed to characterize therapeutic response pathways in patients treated with entinostat and dual immune checkpoint inhibitors (nivolumab and ipilimumab).

Methods We analyzed 37 tumor biopsies from 19 patients enrolled in a Phase Ib trial (NCT02453620). Samples from six metastatic sites were collected at baseline, post-entinostat run-in (C1D1), and post-triplet therapy (week 8). Using bulk RNA-seq, T-cell receptor repertoire (TCR), and neoantigen data, we evaluated gene expression changes and immune-related features associated with clinical response.

Results Here we show that differential gene expression revealed immune-related pathway changes, including interferon responses, IL6/JAK/STAT3, and IL2/STAT5 signaling. Responders show baseline enrichment of inflammatory and interferon pathways, suggesting a more immune-active tumor microenvironment (TME). Post-entinostat, responders show a trend toward increased expression of CD8 + T-cell and plasma cell markers, suggesting partial TME modulation.

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