Abstract
PurposeAndrogen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.MethodsBlood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.ResultsOf 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.ConclusionsCTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.
Highlights
Androgen receptor (AR) is a nuclear transcription factor in the steroid hormone receptor superfamily
The heterogeneity of intrapatient AR expression in Circulating tumor cells (CTCs) leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers
Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity
Summary
Androgen receptor (AR) is a nuclear transcription factor in the steroid hormone receptor superfamily. Some studies showed that in hormone receptor (HR)-positive (HR+) breast cancers, AR expression is associated with resistance to anti-estrogen therapies [16, 17]. Recent studies showed the heterogeneity of AR expression depending especially on ER positivity and the ER positivity in the context of AR seems to be important to predict survival or hormonal therapy sensitivity [15, 18, 20]. AR-targeting drugs such as bicalutamide and enzalutamide have been tested in clinical trials in breast cancer patients [9, 10]. Despite these emerging data, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood
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