Is the Androgen Receptor a Viable Target in Triple Negative Breast Cancer in 5 Years?

Triple negative breast cancer (TNBC) is characterized by high rates of disease recurrence after definitive therapy, and median survival of less than 18 months in the metastatic setting. Systemic therapy options for TNBC consist pr imar ily of cytotoxic chemotherapy-containing regimens, and while recently FDA-approved chemo-immunotherapy combinations and antibody-drug conjugates such as Sacituzumab govitecan have improved clinical outcomes, there remains an unmet need for more effective and less toxic therapies. A subset of TNBC expresses the androgen receptor (AR), a nuclear hormone steroid receptor that activates an androgen-responsive transcriptional program, and gene expression profiling has revealed a TNBC molecular subtype with AR expression and luminal and androgen responsive features. Both preclinical and clinical data suggest biologic similarities between luminal AR (LAR) TNBC and ER + luminal breast cancer, including lower proliferative activity, relative chemoresistance, and high rates of oncogenic activating mutations in the phosphatidylinositol-3-kinase (PI3K) pathway. Preclinical LAR-TNBC models are sensitive to androgen signaling inhibitors (ASIs), and particularly given the availability of FDA-approved ASIs with robust efficacy in prostate cancer, there has been great interest in targeting this pathway in AR + TNBC. Here, we review the underlying biology and completed and ongoing androgen-targeted therapy studies in early stage and metastatic AR + TNBC.

Automated summary

Triple negative breast cancer (TNBC) is a subtype of breast cancer with high recurrence rates and poor survival. Current treatment options for TNBC are limited to cytotoxic chemotherapy. However, a subset of TNBC expresses the androgen receptor (AR), which has similarities to ER+ luminal breast cancer. Targeting the androgen pathway has shown great potential in AR+ TNBC, especially with the availability of effective drugs used in prostate cancer.