Androgen Receptor Function and Targeted Therapeutics Across Breast Cancer Subtypes

Emily A. Kolyvas; Carlos Caldas; Kathleen Kelly; Saif S. Ahmad


Breast Cancer Res. 2022;24(79) 

In This Article


Breast cancer (BC) is the most common cancer in women with over 2.2 million estimated new cases and over 650,000 deaths each year worldwide.[1] While substantial improvements have been made over the years to reduce BC mortality, it remains a significant cause of death in women. BC is a heterogeneous disease with many subtypes with different molecular features. These subtypes are characterized by established biomarkers such as oestrogen receptor alpha (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2).[2] Molecular classification is important not only for patient prognosis but also to help predict therapy response and guide treatment strategies. To improve BC treatment, there remains a need to identify novel and alternative therapeutic targets for this disease, particularly in triple-negative breast cancer (TNBC) where systemic cytotoxic chemotherapy remains the primary pharmacological intervention. Although recent evidence has established a role for immunotherapy in metastatic TNBC, these benefits appear to be limited to patients with positive PD-L1 status.[3] In this respect, the androgen receptor (AR) is emerging as a new biomarker and a potential therapeutic target in BC.

AR is shown to be involved in all stages of BC development and is expressed in up to 30–80% of BC by immunohistochemistry (IHC), depending on subtype.[4] Notably, there is a wide range of reported AR+ samples in part due to a lack of standardization of cut-off levels to determine AR positivity. The exact mechanism of AR action in BC, however, remains elusive. The role of AR likely depends on the subtype of BC as well as levels of circulating hormones and tumour microenvironment. While data suggest that AR could be used as a potential biomarker, the degree of prognostic value remains unclear, making it difficult to identify which patients would benefit from therapeutics that exploit AR as a target. Furthermore, recent data suggest that AR is associated with radiation therapy (RT) resistance. Understanding the complex role of AR in BC subtypes would be useful in predicting which patients would benefit from targeted AR therapies.