ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients

Angus, Lindsay; Beije, Nick; Jager, Agnes; Martens, John W.M.; Sleijfer, Stefan

doi:10.1016/j.ctrv.2016.11.001

Cited by 81 publications

(63 citation statements)

References 52 publications

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“…One patient had co-mutations (PIK3CA mutations and AKT1 mutation). This finding agrees with previous studies in which PIK3CA mutations are particularly common, whereas AKT1 and ESR1 mutations occur less frequently in PBC patients [3][4][5]. The presence of plasma PIK3CA mutations were statistically associated with invasive lobular carcinoma (P = 0.036) and marginally associated with histological grade III carcinoma (P = 0.059) (Additional file 1: Table S3).…”

Section: Resultssupporting

confidence: 82%

“…A somatic mutation in the plekstrin homology domain of AKT1:p.Glu17Lys is found in approximately 4% of breast tumors [3]. Conversely, recent evidence describing next generation sequencing showed that another key potential mechanism of the failure of ET involves activating mutations in the ligand-binding domain of the ESR1 gene [4]. Those mutations cause ligand-independent estrogen receptor (ER) transcriptional activity that does not respond to endocrine manipulation.…”

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confidence: 99%

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Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

et al. 2018

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The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.Keywords: Estrogen receptor-positive breast cancer, Cell-free DNA, PIK3CA mutations, AKT1 mutation, ESR1 mutations Endocrine therapy (ET) resistance occasionally occurs during the treatment of primary breast cancer (PBC) and inevitably results in metastatic BC (MBC). Recently, the focused mechanisms of ET resistance include hyperactivation of PI3K/AKT pathway. Importantly, somatic activating mutations of PIK3CA and AKT1 affect the magnitude of PI3K/AKT activation [1]. Meta-analysis of the BC literature shows that the PIK3CA mutation is present in 20%-40% of all BCs, making this gene the second most frequently mutated in BC, with most mutations being expressed in 'hotspots' in the helical domain (exon (Ex) 9) or the catalytic domain (Ex20) [2]. A somatic mutation in the plekstrin homology domain of AKT1:p.Glu17Lys is found in approximately 4% of breast tumors [3]. Conversely, recent evidence describing next generation sequencing showed that another key potential mechanism of the failure of ET involves activating

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Section: Resultssupporting

confidence: 82%

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confidence: 99%

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

et al. 2018

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“…Among the patients with HER2 þ disease, HER2 alteration is the second most frequent. ESR1 mutation is another important alteration, with implications on treatment selection (37,38). It occurs in approximately 30% of patients exposed to endocrine therapies and may represent the driver of the endocrine resistance (3,9).…”

Section: Secondary Objectivesmentioning

confidence: 99%

Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer

Rossi

Rademaker

et al. 2018

Clinical Cancer Research

120

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Purpose: Liquid biopsy provides a real-time assessment of metastatic breast cancer (MBC). We evaluated the utility of combining circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) to predict prognosis in MBC.Experimental Design: We conducted a retrospective study of 91 patients with locally advanced breast cancer and MBC. CTCs were enumerated by CellSearch; the plasma-based assay was performed utilizing Guardant360 and the survival analysis using Kaplan-Meier curves.Results: Eighty-four patients had stage IV cancer, and 7 patients had no metastases. Eighty patients had CTC analysis: median number 2 (0-5,612). Blood samples [232 of 277 (84%)] had mutations. The average ctDNA fraction was 4.5% (0-88.2%) and number of alterations 3 (0-27); the most commonly mutated genes were TP53 (52%), PIK3CA (40%), and ERBB2 (20%). At the time of analysis, 36 patients (39.6%) were dead. The median follow-up for CTCs was 9 months; for ctDNA, it was 9.9 months. For CTCs and ctDNA, respectively, progression-free survival (PFS) was 4.2 and 5.2 months and overall survival (OS) was 18.7 and 21.5 months. There was a statistically significant difference in PFS and OS for baseline CTCs < 5 versus CTCs ! 5 (P ¼ 0.021 and P ¼ 0.0004, respectively); %ctDNA < 0.5 versus ! 0.5 (P ¼ 0.003 and P ¼ 0.012); number of alterations < 2 versus ! 2 (P ¼ 0.059 borderline and P ¼ 0.0015). A significant association by Fisher exact test was found between the number of alterations and the %ctDNA in the baseline sample (P < 0.0001).Conclusions: The study demonstrated that liquid biopsy is an effective prognostic tool. Clin Cancer Res; 24(3); 560-8. Ó2017 AACR.

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“…Aromatase inhibitor treatment in the metastatic setting rather than in the adjuvant setting induces ESR1 mutations. 28 The pan-phosphatidylinositol 3-kinase (PI3K) inhibitor pictilisib and the CDK4/6-inhibitor palbociclib do not seem to be effective in ESR1 mutated patients, 29 and ESR1 mutations did not indicate impaired survival on fulvestrant compared to ESR1 wildtype. On examestane, however, ESR1 mutations do seem to indicate worse prognosis.…”

Section: Esr1 Mutationsmentioning

confidence: 99%

Molecular Diagnostics in Breast Cancer Routine Practice

Hoeve¹,

Moelans²,

Schrijver³

et al. 2017

European Oncology &Amp; Haematology

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T he portfolio of adjuvant systemic treatment of breast cancer nowadays contains novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules that are only effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand, and costs and side effects on the other. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. KeywordsBreast cancer, pathology, molecular biomarkers Disclosure: Natalie D ter Hoeve, Cathy B Moelans, Willemijne AME Schrijver, Wendy de Leng and Paul J van Diest have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Adjuvant systemic treatment of breast cancer is moving away from the limited portfolio of traditional hormonal drugs and chemotherapy, towards a gamma of novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules. All these therapeutic approaches are unfortunately effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, the traditional "one size fits all" approach can no longer be upheld, and a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand and costs and side effects on the other.Over recent years, progress in molecular techniques has made it possible to analyse formalin fixed paraffin embedded (FFPE) tumour material of larger cohorts of patients. This has incentivised many translational studies relating molecular tumour biomarkers to diagnosis, prognosis and/or response to therapy, yielding many relevant molecular biomarkers that have rather quickly made it to clinical pathology practice. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. Diagnostic markers Hereditary breast cancersAbout 5-10% of breast cancer cases are due to a hereditary predisposition.1 In most of these cases, mutations are found in we...

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ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients

Cited by 81 publications

References 52 publications

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer

Molecular Diagnostics in Breast Cancer Routine Practice

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