Abstract PD6-4: Heterogeneity of expression of estrogen receptor by circulating tumor cells suggests diverse mechanisms of resistance to fulvestrant in metastatic breast cancer patients
Authors: Paoletti C , Muñiz MC , Aung K , Larios J , Thomas DG , Tokudome N , Brown ME , Connelly MC , Chianese DA , Schott AF , Henry NL , Rae JM , Hayes DF 
Published: August 2014

Introduction: Fulvestrant is a selective estrogen receptor down-regulator (SERD). Recent studies have shown that the efficacy of fulvestrant is dose-related. However, at the higher dose (500 mg/month) most cancers develop resistance and progress. We previously reported expression of several markers, including estrogen receptor (ER) and BCL-2, on breast cancer circulating tumor cells (CTC) using CellSearch®. We now report pilot data showing inter-patient heterogeneity of these markers on CTC in patients with known ER positive breast cancer whose disease is progressing on fulvestrant.

Methods: We conducted a pilot trial to determine the analytical validity of measuring expression of markers of endocrine sensitivity (ER, BCL-2) or resistance (HER-2, Ki-67) with fluorescent-labeled antibodies using the CellSearch® system. Patients with ER positive metastatic breast cancer (MBC) whose disease was progressing on any type of therapy were eligible after signed informed consent. This report is limited to the subjects who were progressing on fulvestrant. Whole blood (WB) was characterized for CTC counts and each of the four molecular markers using the CXC CellSearch® kit.

Results: Of 50 enrolled patients, seven were progressing on fulvestrant. Two patients had no detectable CTC, while five patients had an average of ≥5 CTC/7.5 mL WB. Results are shown in a table below:

   CTC-ERCTC-BCL-2Patient #Fulvestrant dose (mg/month)Days since last doseN CTC/7.5 mL of WB% of CTC-ER+N CTC/7.5 mL of WB% of CTC-BCL-2+295002880%110%4550028170%170%2250341010%714%850031812%1735%172507728%367%

These exploratory data suggest widely different mechanisms of resistance to fulvestrant in different patients with ER positive MBC. In two of the patients (29, 45) treated with 500 mg/month, both CTC-ER and CTC-BCL-2 expression were absent, suggesting no signaling through the ER pathway. We hypothesize either that fulvestrant was actively down-regulating ER, but the cancers had adopted other growth and survival pathways, or that ER negative, hormone-independent clones had evolved. In the other three cases, ER was clearly present with evidence of signaling, based on BCL-2 expression. Two of these patients (2, 17) were on the lower dose of fulvestrant, now considered to be less effective. However, the third (8) was on the higher dose and yet still had evidence of ER signaling. This observation suggests that some patients may benefit from even higher doses of SERD therapy.

Conclusions: These pilot results suggest heterogeneous biological or pharmacological mechanisms of resistance to SERD therapy. These data suggest that CTC-ER and CTC-BCL-2 expression could serve as pharmacodynamic monitoring tools for dose escalation of fulvestrant or other SERDs. Further molecular analysis might provide biological bases for resistance to fulvestrant.

Supported by Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-4.