Luminal androgen receptor breast cancer subtype and investigation of the microenvironment and neoadjuvant chemotherapy response

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low overall survival rates and high molecular heterogeneity; therefore, few targeted therapies are available. The luminal androgen receptor (LAR) is the most consistently identified TNBC subtype, but the clinical utility has yet to be established. Here, we constructed a&nbsp;novel&nbsp;genomic classifier, LAR-Sig, that distinguishes the LAR subtype from other TNBC subtypes&nbsp;and provide&nbsp;evidence that it is a clinically distinct disease. A&nbsp;meta-analysis of&nbsp;seven TNBC&nbsp;datasets (<em>n</em> = 1086 samples) from neoadjuvant clinical trials demonstrated&nbsp;that LAR patients have significantly reduced response (pCR) rates than non-LAR TNBC&nbsp;patients (odds ratio = 2.11, 95% CI: 1.33, 2.89). Moreover, deconvolution of the tumor microenvironment confirmed an enrichment of luminal epithelium corresponding with a decrease in basal and myoepithelium in LAR TNBC tumors. Increased immunosuppression in LAR patients&nbsp;may&nbsp;lead to a decreased presence of cycling T-cells and plasma cells. While, an increased presence of myofibroblast-like cancer-associated cells may impede drug delivery and treatment.&nbsp;In summary, the lower levels of tumor infiltrating lymphocytes (TILs), reduced&nbsp;immune activity in the micro-environment, and lower pCR rates after NAC, suggest that new therapeutic strategies for the LAR TNBC subtype need to be developed.