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Updated: Feb 20, 2026
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer
C Fribbens1,2, I Garcia Murillas1, M Beaney1
1Breast Cancer Now Research Centre, Institute of Cancer Research, London, UK.
Background:
Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer.
Patients And Methods:
Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI.
Results:
Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival.
Conclusions:
Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.
Insights
Endocrine resistance in advanced breast cancer is driven by genetic mutations like ESR1 and RAS. These sub-clonal mutations emerge early, potentially limiting future targeted therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Endocrine resistance is a significant challenge in advanced breast cancer treatment.
- Estrogen receptor 1 (ESR1) mutations are infrequent in primary tumors but common in advanced disease after aromatase inhibitor (AI) therapy.
- Investigating the genetic evolution of resistance is crucial for understanding treatment failure.
Purpose of the Study:
- To examine the emergence and evolution of genetic resistance mutations during first-line AI therapy for advanced breast cancer.
- To identify specific mutations, such as ESR1 and RAS, associated with AI resistance.
- To assess the clonal architecture and timing of resistance mutations using serial plasma sampling.
Main Methods:
- Prospective study of 83 patients with advanced breast cancer receiving first-line AI therapy.
- Serial plasma collection every 3 months for ctDNA analysis using digital droplet PCR and eTAm-Seq.
- Tracking of mutations identified at progression in earlier samples to understand their evolution.
- Validation of novel mutation frequencies in an independent cohort (SoFEA trial).
Main Results:
- ESR1 mutations were detected in 56.4% of patients at progression, often polyclonal and detectable months before clinical progression.
- Sub-clonal ESR1 mutations were prevalent (72.2% of cases analyzed).
- RAS gene mutations (KRAS, HRAS, NRAS) were found in 15.4% of progressing patients; KRAS mutations were frequent in an independent cohort but not prognostic.
Conclusions:
- AI-resistant advanced breast cancers exhibit significant genetic heterogeneity and frequent sub-clonal mutations.
- Sub-clonal KRAS mutations are common in this setting.
- The genetic diversity observed may pose challenges for subsequent targeted therapy strategies.
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