Association of Androgen Receptor Expression With Tumor Immune Landscape and Treatment Outcomes of Patients With Breast Cancer.

Abstract

Although estrogen receptor is well studied in breast cancer (BC), the role of androgen receptor (AR) in prognosis and therapy response is less understood. Here, we characterized the clinicopathologic and molecular features of <i>AR</i> gene expression in BC subtypes. Ten thousand seven hundred twenty-eight BC samples were tested by next-generation DNA sequencing, whole-transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Tumors with <i>AR</i>-high and <i>AR</i>-low RNA expression were stratified by top and bottom quartiles, respectively. Treatment-associated survival was obtained from insurance claims and calculated from treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney <i>U</i> test with <i>P</i> values adjusted for multiple comparisons (<i>q</i> < .05). <i>AR</i>-low was associated with basal-like tumors. <i>AR</i>-high tumors were associated with increased mutation rates in several genes-namely <i>PIK3CA</i> and <i>CDH1</i>-across all subtypes, while other associations such as <i>RB1</i> and <i>MAP3K1</i> were subtype-dependent. The immune landscape was differentially affected by <i>AR</i> expression in each subtype, but these differences did not correspond to differential responses to immune checkpoint blockade. Patients with <i>AR</i>-high tumors had a longer therapy response for most subtypes, but those with <i>AR</i>-high tumors that were human epidermal growth factor receptor 2-enriched and luminal B trended toward worse chemotherapy or hormone therapy response, respectively. Our data suggest a unique molecular profile of <i>AR</i>-high BC that is subtype-specific and generally associated with improved outcomes. Exploration of specific mutations and immune-oncology markers associated with <i>AR-</i>high may aid in molecularly selected clinical trial design for patients with advanced BC.