Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
Ingeborg Elisabeth de Kruijff , Anieta M. Sieuwerts , Wendy Onstenk , A. Jager , Paul Hamberg , Felix De Jongh , Marcel Smid , Mieke A. Timmermans , John W.M. Martens , Stefan Sleijfer
Background: The androgen receptor (AR) is of clinical relevance in metastatic breast cancer (mBC): AR has been associated with resistance to endocrine therapy and could be a potential target for therapy, especially in the triple negative (TN) subtype. A minimal-invasive way to determine AR expression is by characterization of circulating tumor cells (CTCs). We therefore assessed AR mRNA expression in CTCs (CTC-AR) from mBC patients representing different breast cancer subtypes in relation to outcome on endocrine therapy and 25 genes related to the ER and AR pathways. Furthermore, we assessed AR in matched primary tumors and CTC samples taken at advanced disease. Methods:AR and AR- and ER-related gene expression levels were measured in CellSearch-enriched CTCs from 133 mBC patients with ≥5 CTCs and in 48 matched formalin-fixed paraffin embedded primary tissues using quantitative reverse-transcriptase PCR. AR was considered positive if the expression was 1 standard deviation higher than the expression measured in 12 healthy blood donors. mBC subtypes were established based on ER, PR and HER2-status of the primary tumor (9 unknowns). Results: 31% of the CTC samples were AR-positive (AR+). The HER2+ subtype had most frequently AR+ CTCs (4/8, 50%), which was significantly higher than observed in the TN subtype (2/16, 13%) (p = 0.046). The ER+/HER2- subtype had 35% (27/78) AR+ samples and the ER+/HER2+ 23% (5/22). There was no significant difference between PFS in ER-targeting treated patients and CTC-AR-status (17 AR+ / 41 AR-negative (AR-) cases, p = 0.991). 65% of the matched CTC samples and primary tissues were discordant with respect to AR, observing both switches from AR+ to AR- and vice versa. Conclusions:AR can be determined in RNA isolated from CTCs from different mBC subtypes, with in our set 31% AR-positive samples. Because there was a 65% discordancy between AR in CTC samples and the primary tumor, it seems that AR should be determined in CTCs, but more research should be conducted in a larger set. In our current analysis patients had similar outcome on ER-targeting therapy regardless of their CTC-AR status. Thus, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.
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