Estrogen Receptor Mutations in Breast Cancer—New Focus on an Old Target

Segal, Corrinne V.; Dowsett, Mitch

doi:10.1158/1078-0432.ccr-14-0067

Cited by 45 publications

(33 citation statements)

References 10 publications

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“…Primary ESR1 mutations are relatively rare in primary tissue, up to 7% of specimens analyzed with very low allele frequencies (0.07–0.2%), when compared to a much higher detection in patients with metastatic disease [11]. The first study on the detection of ESR1 mutations in patients that were exposed to endocrine therapy was conducted on metastatic biopsies and matched cfDNA samples [37].…”

Section: Discussionmentioning

confidence: 99%

“…Since ESR1 mutations are rare, occurring in only 1% of primary BC, their ability to confer endocrine resistance has been speculated for many years [10]. However, in metastatic tissues the incidence of such mutations is estimated at 20% [11]. In the last several years, 14 ESR1 point mutations have been reported, mainly localized in the ligand-binding domain (LBD) including 3-hot spot mutations in codons 380, 537 and 538.…”

Section: Introductionmentioning

confidence: 99%

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Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells

Paolillo

Rossi

et al. 2017

Clinical Cancer Research

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Purpose Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 (ESR1) gene mutations at the single circulating tumor cell (CTC) level in metastatic breast cancer (MBC). Experimental Design We used a CTC molecular characterization approach to investigate heterogeneity of 14 hot spot mutations in ESR1 and their correlation with endocrine resistance. Combining the CellSearch® and DEPArray™ technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. 40 CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing. Results Among 3 selected patients, 2 had an ESR1 mutation (Y537). One showed two different ESR1 variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in ESR1 (Y537S and T570I), which has not been reported previously. Conclusions CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity, and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of ESR1 mutations, the emergence of endocrine resistance and the choice of further target therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells

Paolillo

Rossi

et al. 2017

Clinical Cancer Research

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“…17 The use of dPCR for ctDNA analysis has been reported previously for MBC, but only after deep sequencing of the primary tumor to define the non-recurrent driver mutations of TP53, PI3KCA or PTEN. 13,17,20,21 For ESR1, few activating mutations confined to codons 537 and 538 in exon 8 represent 74% of the described mutations, limiting the number of contributing designs 8 and the requirement for sequencing metastases. A more complex and non-invasive method for the determination of the ESR1 mutational status using a culture of circulating tumor cells has been described previously.…”

Section: Short Reportmentioning

confidence: 99%

“…[5][6][7] Approximately 12 ESR1 point mutations have been described, with a hot spot confined to codons 537 and 538 in exon 8. 8 These mutations result in a ligand-independent estrogen receptor (ER) activity. In vitro and preclinical data suggest that ESR1 mutations lead to complete AI resistance and to partial resistance to ER agonists and antagonists.…”

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confidence: 99%

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

Sefrioui

Perdrix

Sarafan-Vasseur

et al. 2015

Intl Journal of Cancer

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Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.Nearly 70% of breast cancers are hormone receptor positive (HR1) and potentially sensitive to hormonal therapy. Aromatase inhibitors (AI) or tamoxifen is the recommended first line hormonal therapy in postmenopausal HR1 metastatic breast cancer (MBC).1,2 Nevertheless, disease progression is usually observed within a few months after treatment initiation.3,4 Acquired resistance to hormonal therapy may be based on activating mutations in the estrogen receptor gene (ESR1). These mutations have been detected in HR1 MBC patients previously exposed to hormonal therapy, including treatment with an AI in all cases. The frequencies of ESR1 mutations was 25% (nine of 36), 38% (five of 13) and 54% (six of 11) among these cohorts. [5][6][7] Approximately 12 ESR1 point mutations have been described, with a hot spot confined to codons 537 and 538 in exon 8. 8 These mutations result in a ligand-independent estrogen receptor (ER) activity. In vitro and preclinical data suggest that ESR1 mutations lead to complete AI resistance and to partial resistance to ER agonists and antagonists.9,10 The detection of ESR1-activating mutations may be relevant for guiding clinicians between endocrine and nonendocrine therapy.11 Thus far, ESR1 genotyping must be performed on metastases: this method is hardly compatible with repetitive sampling analyses for disease monitoring. Circulating tumor DNA (ctDNA) analysis is considered a promising tool for providing relevant prognostic and/or predictive information instead of tumor sampling. 12,13

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“…Most recently, however, frequent somatic mutations in ERa have been identified in metastases from ERC breast cancer. This is more frequently associated with metastases that occur during or following endocrine therapy (Zhang et al 1997, Robinson et al 2013, Jeselsohn et al 2014, Segal & Dowsett 2014. The most frequent mutation identified was at Y537 or the residue beside it, D538; therefore, affecting directly or indirectly a well-known phosphorylation site on ERa (Arnold et al 1995a, Nettles et al 2008, Skliris et al 2010b with known clinical relevance (Skliris et al 2010b).…”

Section: Kinases Known To Phosphorylate Eramentioning

confidence: 99%

The kinome associated with estrogen receptor-positive status in human breast cancer

Bruce

McAllister

Murphy

2014

Endocrine Related Cancer

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Estrogen receptor alpha (ERa) regulates and is regulated by kinases involved in several functions associated with the hallmarks of cancer. The following literature review strongly suggests that distinct kinomes exist for ERa-positive and -negative human breast cancers. Importantly, consistent with the known heterogeneity of ERa-positive cancers, different subgroups exist, which can be defined by different kinome signatures, which in turn are correlated with clinical outcome. Strong evidence supports the interplay of kinase networks, suggesting that targeting a single node may not be sufficient to inhibit the network. Therefore, identifying the important hubs/nodes associated with each clinically relevant kinome in ERC tumors could offer the ability to implement the best therapy options at diagnosis, either endocrine therapy alone or together with other targeted therapies, for improved overall outcome.

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Estrogen Receptor Mutations in Breast Cancer—New Focus on an Old Target

Cited by 45 publications

References 10 publications

Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells

Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

The kinome associated with estrogen receptor-positive status in human breast cancer

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