Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer

Abstract

The androgen receptor (AR) has potential clinical relevance in metastatic breast cancer (mBC) since it might be a treatment target and has been associated with endocrine resistance. A minimal‐invasive way to determine AR expression on metastatic tumor cells is by characterization of circulating tumor cells (CTCs). Here, we assessed AR mRNA expression in CTCs (CTC‐AR) and in matched primary tumor samples from mBC patients representing different breast cancer subtypes. In addition, we explored CTC‐AR‐status in relation to outcome on endocrine therapy. AR, and 92 AR or estrogen receptor (ER) related genes, were measured in CellSearch‐enriched CTCs from 124 mBC patients and in 52 matched FFPE primary tissues using quantitative reverse‐transcriptase PCR. AR in CTCs was considered positive if the expression was 1 standard deviation higher than the expression measured in 11 healthy blood donors. A total of 31% of the mBC patients had AR‐positive (AR+) CTCs. 58% of the matched CTC and primary tumor samples were discordant with respect to AR status, observing both switches from AR+ to AR‐negative (AR‐) and vice versa. There was no statistically significant difference in progression‐free survival for patients treated with ER‐targeting drugs and CTC‐AR‐status (13 AR+/ 37 AR‐ cases, p = 0.28). Thus, AR can be determined in RNA isolated from CTCs, with in our set 31% AR‐positive samples. Given the discordance between AR status in CTC samples and corresponding primary tumors, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.

Circulating Tumor Cells Expressing the Prostate Specific Membrane Antigen (PSMA) Indicate Worse Outcome in Primary, Non-Metastatic Triple-Negative Breast Cancer

“…Up to now, only very few groups have addressed the expression of prostate cancer related genes on CTCs in BC (29)(30)(31)(32)(33)46). Most of these studies analyzed CTCs of metastatic HR+/HER2-BC patients for the expression of AR with a detection rate ranging from 20 to 43%, respectively (29,(31)(32)(33). Krujiff et al, further compared AR expression in primary tumor tissues and matched CTCs and observed switches from AR+ to AR-negative and vice versa with an overall disconcordance of 58% (32).…”

“…Most of these studies analyzed CTCs of metastatic HR+/HER2-BC patients for the expression of AR with a detection rate ranging from 20 to 43%, respectively (29,(31)(32)(33). Krujiff et al, further compared AR expression in primary tumor tissues and matched CTCs and observed switches from AR+ to AR-negative and vice versa with an overall disconcordance of 58% (32). In abiraterone/prednisone-treated postmenopausal ER+ advanced BC patients neither the analysis of biomarkers in serum, CTCs nor tumor tissue identified a subgroup a patients with significantly improved PFS, although dual expression of AR and ER in baseline CTCs were supposed to have an association with improved PFS (47).…”

“…Therefore, a few metastatic BC studies have analyzed AR expression on circulating tumor cells (CTCs) in blood as a minimal invasive approach to assess the real time AR status (29)(30)(31)(32)(33). Most of these studies were performed in HR+/HER2-BC, but AR+ CTCs could be detected in 13% of metastatic TNBC cases applying mRNA expression profiling for CellSearch enriched CTCs (32) and in 91% of metastatic TNBC cases using the Maintrac Assay (30).…”

“…Therefore, a few metastatic BC studies have analyzed AR expression on circulating tumor cells (CTCs) in blood as a minimal invasive approach to assess the real time AR status (29)(30)(31)(32)(33). Most of these studies were performed in HR+/HER2-BC, but AR+ CTCs could be detected in 13% of metastatic TNBC cases applying mRNA expression profiling for CellSearch enriched CTCs (32) and in 91% of metastatic TNBC cases using the Maintrac Assay (30). Performing comprehensive molecular CTC characterization in early TNBC patients after immunomagnetic CTC-selection, we recently demonstrated that TNBC-derived CTCs appeared to upregulate most of the analyzed 17 transcripts or kept their expression frequency on a high level after therapy except for AR which was detected in 33% of the patients before but rarely after therapy (34).…”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…The application of single cell analysis technologies to PDX models has shown that CTCs are continuously released by the primary tumour, however only a proportion of clones have the capacity to seed a metastatic deposit, and as such the utility of CTCs in predicting the characteristics of subsequent metastases may be limited [111]. Nevertheless, analysis of CTCs can capture phenotypic heterogeneity of the tumour of origin, for example in the expression of ER, HER2 and androgen receptors [112][113][114], and also of biological processes driving metastasis such as dynamic changes in epithelial and mesenchymal composition [115,116]. Clusters of CTCs, which may show intermediate epithelial/mesenchymal properties [115,117], demonstrate higher metastatic capacity than single cells [118][119][120][121].…”