e12540 Background: Denosumab, a RANK ligand inhibitor, has been shown to improve disease free survival when given adjuvantly with an aromatase inhibitor to hormone receptor-positive breast cancer (BC) patients. Preclinical models have suggested that RANK signaling plays a crucial role in regulation of the tumor immune microenvironment. Methods: 31 pts with early stage BC were enrolled on window of opportunity study receiving 1 dose of denosumab, with paired biopsy and surgical specimens assessed by immunohistochemistry (RANK, RANKL, CD3, CD8, CD68, FOXP3, CD163, CD33, CSF1R, HLADR) and transcriptomic (NanoString BC-360 panel) methods. A cohort matched for menopausal status and BC subtype of untreated pts were included for comparative purposes. Results: Immune subset analysis by immunohistochemistry demonstrated lower CD68 expression in the surgical specimens of denosumab-treated patients as compared to untreated control patients (p = 0.0099). Multivariate DEG analysis did not demonstrate any statistically significant differences in single gene expression. However, differences in gene set enrichment analysis were detected on univariate analysis including an increase in antigen presenting signature (log fold change 1.61, p = 0.03), PD-L1 (logFC 1.1, p = 0.01) and TGF-Beta (logFC 1.5, p = 0.01) in the denosumab treated cohort. Conclusions: This presurgical study allowed for evaluation of the mechanism of denosumab’s antitumor effect, which suggests a more favorable switch in the immune profile of patients treated with this agent in the early stage setting. Denosumab-treated patients had different expressions of several gene signatures known to affect the tumor immune microenvironment including APM, PD-L1 and TGF-beta and suggests a potential role for denosumab in early-stage breast cancer as an immune-sensitizing agent.
Kucharczyk et al. (Thu,) studied this question.