ArticleBreast cancer research : BCR2019
Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours.
Article in Breast cancer research : BCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 50 citations in OpenAlex.
- Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.Cancer research · 2025Trial
- Trial
- Dormancy exit correlates with CREB1 reactivation that is a potential target to overcome endocrine therapy resistance in ERiScience · 2026Article
- Residual Breast Cancer Cells Co-opt SOX5-Driven Endochondral Ossification to Maintain Dormancy.Cancer discovery · 2026Article
- Estrogen receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer.The Journal of clinical investigation · 2026Article
- Article
- Microenvironmental Regulation of Dormancy in Breast Cancer Metastasis: "An Ally that Changes Allegiances".Advances in experimental medicine and biology · 2025Review
- Analyzing Hedgehog pathway-related genes: insights into breast cancer tumor microenvironment and prognostic implications.Frontiers in immunology · 2025Article
- DNA Methylation-Based Diagnosis and Treatment of Breast Cancer.Current cancer drug targets · 2025Review
- Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer.Current issues in molecular biology · 2024Article
- Comparative efficacy and safety of extended adjuvant endocrine therapy for hormone receptor-positive early breast cancer: a Bayesian network meta-analysis.Breast cancer research and treatment · 2024Review
- Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.Breast cancer research and treatment · 2023Article
- Frequent Upregulation Of HER2 Protein In Hormone Receptor-Positive HER2-Negative Breast Cancer After Short-Term Neoadjuvant Endocrine Therapy.Research square · 2023Article
- Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.Signal transduction and targeted therapy · 2023Review
- Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution.Cancer metastasis reviews · 2023Review
- Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor-positive Breast Cancers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Article
- Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Review
- G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.Cell reports · 2020Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundThe risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model.
methodsConsecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13-120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as "dormant", and the remaining 20 patients as "acquired resistant".
resultsChanges in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment.
conclusionsThis is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.
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Registered trials
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