Androgen receptor expression linked to lower immunotherapy response in ER-positive breast cancer

Researchers analyzed bulk transcriptomic data from five cohorts and single-cell data from two cohorts, covering 4,046 patients with breast cancer. The analysis assessed associations between AR expression, immune-cell signatures and response to immune checkpoint inhibitors (ICIs). The cohorts included 50 patients with ER-positive/HER2-negative disease in I-SPY2 who received neoadjuvant durvalumab-based treatment. A separate single-cell cohort included patients with triple-negative breast cancer treated with pembrolizumab, so it does not directly represent the target subtype.

Across ER-positive/HER2-negative cohorts, high AR expression was associated with lower transcriptome-derived immune-cell scores, including signatures for CD8-positive T cells, dendritic cells and M1 macrophages. In I-SPY2, AR-high tumors had significantly lower pathological complete response rates. AR expression predicted ICI response with an area under the curve of 0.82, compared with 0.73 for PD-1 and 0.60 for PD-L1. Enzalutamide exposure was associated with increased immune-cell signatures in a separate cohort.

The findings suggest AR may be a candidate biomarker and a target for further study, but they do not establish that AR inhibition improves ICI outcomes. The retrospective analyses rely partly on transcriptomic signatures, and the ICI response findings in ER-positive/HER2-negative disease came from a small cohort. Prospective studies are needed before these results can guide treatment decisions.