Luminal androgen receptor breast cancer subtype and investigation of the microenvironment and neoadjuvant chemotherapy response
Kevin J. Thompson, Roberto A. Leon‐Ferre, Jason P. Sinnwell, David Zahrieh, Vera J. Suman, Filho Otto Metzger, Sarah Asad, Daniel G. Stover, Lisa A. Carey, William M. Sikov, James N. Ingle, Minetta C. Liu, Jodi M. Carter, Eric W. Klee, Richard M. Weinshilboum, Judy C. Boughey, Liewei Wang, Fergus J. Couch, Matthew P. Goetz, Krishna R. Kalari
Abstract
Abstract 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 novel genomic classifier, LAR-Sig, that distinguishes the LAR subtype from other TNBC subtypes and provide evidence that it is a clinically distinct disease. A meta-analysis of seven TNBC datasets (n = 1086 samples) from neoadjuvant clinical trials demonstrated that LAR patients have significantly reduced response (pCR) rates than non-LAR TNBC 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 may 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. In summary, the lower levels of tumor infiltrating lymphocytes (TILs), reduced 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.