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Updated: Jul 2, 2026
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Assessing endocrine resistance: monitoring circulating ESR1 mutations in Irosustat-treated ER positive breast cancer
Karen Page1, Luke J Martinson1, Robert K Hastings2
1Leicester Cancer Research Centre, Division of Cancer Sciences, University of Leicester, Leicester Royal Infirmary, Robert Kilpatrick Clinical Sciences Building, Leicester, LE2 7LX, UK.
Purpose:
We aimed to investigate the prevalence and spectrum of ESR1 mutations alongside cell-free DNA (cfDNA) dynamics in patients with estrogen receptor-positive metastatic breast cancer recruited to the phase II IRIS study who had progressed on first-line aromatase inhibitor (AI) therapy and then continued their AI in combination with Irusostat (40 mg), an irreversible steroid sulfatase inhibitor.
Methods:
cfDNA was isolated from 96 serial plasma samples from 24 patients, alongside primary tumour DNA (n = 16), and analysed by next-generation sequencing using a custom-designed mutation panel on the Illumina NovaSeq platform.
Results:
Thirteen of 16 tumour DNA samples harboured at least one somatic mutation across nine genes. Twenty one of the 24 patients (88%) had at least one somatic mutation in cfDNA (248 total mutations across 10 genes). Circulating tumour DNA ESR1 mutations (ctESR1m) were the most prevalent, present in 16 patients (76%) with both stable (SD) and progressive disease (PD), showing no clear association with disease progression. Eleven patients had polyclonal ctESR1m within the ligand-binding domain, six at baseline, while five harboured a single ctESR1m variant. Five other patients acquired polyclonal mutations over treatment.
Conclusions:
Analysis of serial plasma samples revealed highly dynamic ctESR1m during AI treatment and frequent detection of polyclonal ctESR1m in patients (both with SD and PD) recruited to the IRIS study. These findings, albeit in a limited sample size, underscore the challenge of targeting a single ESR1 mutation and emphasise the need for careful patient selection, specifically those with wild-type ESR1, in trials investigating sequential estrogen-lowering therapies.
Insights
Estrogen receptor 1 (ESR1) mutations are common in metastatic breast cancer treated with aromatase inhibitors (AIs). Polyclonal ESR1 mutations in cell-free DNA (cfDNA) are dynamic during AI therapy, complicating targeted treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic breast cancer (ER+) often progresses on aromatase inhibitor (AI) therapy.
- Estrogen receptor 1 (ESR1) mutations are a known resistance mechanism.
- Cell-free DNA (cfDNA) analysis offers a non-invasive method to track tumor evolution.
Purpose of the Study:
- To investigate ESR1 mutation prevalence and cfDNA dynamics in ER+ metastatic breast cancer patients progressing on first-line AI therapy.
- To assess the impact of combining AI with Irusostat, a steroid sulfatase inhibitor, on ESR1 mutations.
- To analyze cfDNA and tumor DNA for somatic mutations using next-generation sequencing.
Main Methods:
- Collected serial plasma samples (n=96) and primary tumor DNA (n=16) from 24 patients in the IRIS study.
- Utilized next-generation sequencing with a custom panel on the Illumina NovaSeq platform.
- Analyzed cfDNA for circulating tumor DNA (ctDNA) and ESR1 mutations (ctESR1m).
Main Results:
- Somatic mutations were found in 13/16 tumor DNA samples and 21/24 patients' cfDNA.
- ctESR1m were prevalent (76% of patients), detected in both stable and progressive disease.
- Polyclonal ctESR1m were common, with some present at baseline and others acquired during treatment.
Conclusions:
- Serial cfDNA analysis reveals dynamic ctESR1m during AI treatment in metastatic breast cancer.
- Frequent detection of polyclonal ctESR1m highlights challenges in targeting single mutations.
- Patient selection, particularly for ESR1 wild-type status, is crucial for trials involving sequential estrogen-lowering therapies.
