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Heterogeneous estrogen receptor expression in circulating tumor cells suggests diverse mechanisms of fulvestrant resistance.
- Source :
-
Molecular oncology [Mol Oncol] 2016 Aug; Vol. 10 (7), pp. 1078-85. Date of Electronic Publication: 2016 Apr 29. - Publication Year :
- 2016
-
Abstract
- Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch(®) system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B-cell lymphoma (BCL2) using the CellSearch(®) CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC-expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC-ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene (ESR1). All seven ER positive patients progressing on AIs had heterogeneous CTC-ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non-ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies.<br /> (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Aromatase Inhibitors pharmacology
Aromatase Inhibitors therapeutic use
Biomarkers, Tumor metabolism
Cell Line, Tumor
Estradiol pharmacology
Fulvestrant
Humans
Neoplastic Cells, Circulating drug effects
Neoplastic Cells, Circulating pathology
Treatment Outcome
Drug Resistance, Neoplasm drug effects
Estradiol analogs & derivatives
Neoplastic Cells, Circulating metabolism
Receptors, Estrogen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 27178224
- Full Text :
- https://doi.org/10.1016/j.molonc.2016.04.006