Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast&amp;nbsp;cancer patients

Niu, Jiaxin; Andres, Grant; Krämer, Kim; Kundranda, Madappa N.; Álvarez, Ricardo H.; Klimant, Eiko; Parikh, Ankur R.; Tan, Bradford A.; Staren, Edgar D.; Markman, Maurie

doi:10.2147/ott.s92443

Cited by 45 publications

(43 citation statements)

References 22 publications

(37 reference statements)

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“…An ESR1 mutation rate of 25.8% was identified in the MBC patients who had a history of AI treatment, which was close to the average rate of 23% reported in previous studies. 11,12,15,31 Meanwhile, the ESR1 mutation rate was 0% in MBC patients without a history of AI treatment. In addition, the ESR1 mutation rate was higher in MBC patients who had AI treatment for over 12 months than in those whose treatment was shorter than 12 months.…”

Section: Discussionmentioning

confidence: 98%

<p>Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer</p>

Zhu

Ren

Wang

et al. 2020

OTT

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Background: ESR1 mutation and its possible relation to endocrine therapy resistance in ERpositive breast cancers have been studied with respect to genetic sequencing data from Western patients but rarely from Chinese patients. This study aimed to investigate the prevalence of ESR1 mutation in Chinese primary and metastatic ER-positive breast cancer. Methods: Tumor samples from 297 primary breast cancer (PBC) patients and blood samples from 43 metastatic breast cancer (MBC) patients were obtained to perform whole exon sequencing of the ESR1 gene through next-generation sequencing (NGS). Clinicopathological features of MBC patients were listed and grouped to explore potential factors in ESR1 mutations. Results: A total of 15 ESR1 variations, including 11 point mutations, 1 in-frame deletion mutation, 1 synonymous mutation, and 2 amplifications were identified in 13 patients. The ESR1 mutation rate was 1% (3/297) in PBC patients and 18.6% (8/43) in MBC patients. All ESR1 point mutations occurred in the estrogen receptor ligand-binding domain. Six (54.5%) of the 11 point mutations were hotspot mutations. Among all MBC patients, the ESR1 mutation rate in those who had a treatment history using aromatase inhibitors (AI) was significantly higher than those who did not (25.8% versus 0%, P=0.015). Moreover, the ESR1 mutation rate in those who received AI treatment over a period of 12 months was significantly higher than in those whose treatment lasted less than 12 months [36.3% versus 0%, P<0.001]. Conclusion: ESR1 mutations were more frequently observed in the circulating cell-free DNA of MBC patients than in PBC patients among the Chinese cohort, and higher among those pretreated with AI, suggesting that such mutations may undergo selection during AI treatment.

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Section: Discussionmentioning

confidence: 98%

<p>Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer</p>

Zhu

Ren

Wang

et al. 2020

OTT

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“…In other published series, the prevalence of ESR1 mutations has varied from 11 to 54%, mostly because of differences in patient profiles (see Table 1). Most recent studies analyzing ESR1 mutations in liquid biopsies in cohorts of clinical trials in AI-refractory HR+ advanced breast cancer suggest a prevalence ranging from 11 to 39% (21–26). In contrast, ESR1 mutations have been rarely detected in treatment-naïve primary tumors, suggesting that these mutations arise either through clonal selection of very low abundance resistant clones or are acquired later in the disease course under the selective pressure of ET.…”

Section: Esr1 Mutationsmentioning

confidence: 99%

Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

Reinert

Saad²,

Barrios

et al. 2017

Front. Oncol.

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Hormone receptor-positive breast cancer is the most frequent breast cancer subtype. Endocrine therapy (ET) targeting the estrogen receptor (ER) pathway represents the main initial therapeutic approach. The major strategies include estrogen deprivation and the use of selective estrogen modulators or degraders, which show efficacy in the management of metastatic and early-stage disease. However, clinical resistance associated with progression of disease remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes the ER, have been increasingly recognized as an important mechanism of ET resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition. ESR1 mutations, most often detected from liquid biopsies, have been consistently associated with a worse outcome and are being currently evaluated as a potential biomarker to guide therapeutic decisions. At the same time, targeted therapy directed to ESR1-mutated clones is an appealing concept with preclinical and clinical work in progress.

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“…The mutations occurring in the ligand binding domain (LBD) of ERα create ligand-independent constitutively active estrogen receptors and maintain ER signaling. The incidence of these mutations in breast cancers has been reported to be as low as less than 1% in primary cancers, but as high as 11% - 55% in metastatic ER + tumors ( 15 - 17 ).…”

Section: Resultsmentioning

confidence: 99%

“…Niu et al analyzed 341 advanced breast cancer patients with targeted next generation sequencing ( 17 ). The inclusion criterion was a recurrent breast cancer which had not responded to or had progressed on two lines of standard therapy.…”

Section: Resultsmentioning

confidence: 99%

Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer?

2016

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ContextBreast cancer is the most common cancer in women worldwide. Estrogen receptor (ER) positive breast cancer constitutes the majority of these cancers. Hormone therapy has significantly improved clinical outcomes for early- and late-stage hormone receptor positive breast cancer. Although most patients with early stage breast cancer are treated with curative intent, approximately 20% - 30% of patients eventually experience a recurrence. During the last two decades, there have been tremendous efforts to understand the biological mechanisms of hormone therapy resistance, with the ultimate goal of implementing new therapeutic strategies to improve the current treatments for ER positive breast cancer. Several mechanisms of hormone therapy resistance have been proposed, including genetic alterations that lead to altered ER expression or ERs with changed protein sequence.Evidence AcquisitionA Pubmed search was performed utilizing various related terms. Articles over the past 20 years were analyzed and selected for review.ResultsOn the basis of published studies, the frequencies of ESR1 (the gene encoding ER) mutations in ER positive metastatic breast cancer range from 11% to 55%. Future larger prospective studies with standardized mutation detection methods may be necessary to determine the true incidence of ESR1 mutations. ESR1 amplification in breast cancer remains a controversial issue, with numerous studies either confirmed or challenged the reports of ESR1 amplification. The combination of intra-tumor heterogeneity regarding ESR1 copy number alterations and low level ESR1 copy number increase may account for these discrepancies.ConclusionsWhile numerous unknown issues on the role of ESR1 mutations in advanced breast cancer remain, these new findings will certainly deepen current knowledge on molecular evolution of breast cancer and acquired resistance to hormone therapy.

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Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients

Cited by 45 publications

References 22 publications

<p>Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer</p>

<p>Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer</p>

Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer?

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