Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Spoerke, Jill M.; Gendreau, Steven; Walter, Kimberly; Qiu, Jack Linchuan; Wilson, Timothy R.; Savage, Heidi; Aimi, Junko; Derynck, Mika K.; Chen, Meng; Chan, Iris T.; Amler, Lukas C.; Hampton, Garret M.; Johnston, Stephen; Krop, Ian E.; Schmid, Peter; Lackner, Mark R.

doi:10.1038/ncomms11579

Cited by 250 publications

(232 citation statements)

References 37 publications

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“…Gain-of-function mutations in ESR1, the gene encoding the ER, are a relatively rare event in primary breast cancer (Cancer Genome Atlas Network 2012), but can be detected using next-generation sequencing in approximately 20% of patients with metastatic ER-positive disease who had received prior endocrine therapies , Toy et al 2013, Jeselsohn et al 2015. A higher prevalence (up to 55%) of ESR1 mutations has been reported in circulating free DNA (cfDNA) in metastatic ER-positive breast cancers with prior AI therapy when using digital droplet PCR to increase mutation detection sensitivity (Chandarlapaty et al 2016, Fribbens et al 2016, Spoerke et al 2016. These mutations cluster in the ligand-binding domain of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy and potentially enhanced metastatic capacity.…”

Section: Endocrine-related Cancer (2016) 23 T227-t241mentioning

confidence: 99%

Pushing estrogen receptor around in breast cancer

Lim

Tarulli

Portman

et al. 2016

Endocrine-Related Cancer

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The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

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Section: Endocrine-related Cancer (2016) 23 T227-t241mentioning

confidence: 99%

Pushing estrogen receptor around in breast cancer

Lim

Tarulli

Portman

et al. 2016

Endocrine-Related Cancer

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show abstract

“…These findings highlight the need for a novel SERD that can bind and inhibit both wild-type and mutant forms of ER in order to more effectively treat this patient population. Recent clinical data have demonstrated that while the presence of ESR1 mutations can be a prognostic indicator of AI resistance, the extent of fulvestrant efficacy is not influenced by ESR1 status (32,33) …”

Section: Introductionmentioning

confidence: 99%

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Bihani

Patel

Arlt

et al. 2017

Clinical Cancer Research

116

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Purpose: Estrogen receptor-positive (ER þ ) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER þ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER þ breast cancer models, including several patientderived xenograft models.

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“…It has also been shown that patients with advanced breast cancer with ESR1 mutations at baseline have better survival when treated with fulvestrant [47]. Contradictory results have been published in a retrospective study, where ERS1 mutations detected by ctDNA did not change progression-free survival [48]. In addition, tumor volume in responders to neoadjuvant chemotherapy was shown to be related to the methylation of five genes (BRCA1, MGMT, GSTP1, stratifin, and MDR1) [49].…”

Section: Clinical Applications Of Liquid Biopsies In Breast Cancermentioning

confidence: 67%

Potential of Liquid Biopsies for Breast Cancer Screening, Diagnosis, and Response to Treatment

2019

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Cancer therapy decisions are often made according to the histopathological-molecular profile of tumor tissue obtained from surgery or biopsy. It has been shown that tumor profiles change with time and treatment, and that tumor tissue is heterogeneous. Thus, other approaches that are easily accessible and less invasive than surgery or biopsy to monitor responses to treatment and predict relapses are urgently needed. In the last few years, the term “liquid biopsies” has been introduced to represent multifunctional circulating biomarkers in the peripheral blood and other physiological fluids of patients with cancer. Liquid biopsies are a noninvasive alternative to tissue biopsies, but they have not been implemented in routine clinical practice for breast cancer. In addition, liquid biopsies seem to be a promising approach for personalized medicine, which enables the prediction, monitoring, and rational selection of appropriate therapy for individual patients. In this review, we outline recent progress and current challenges with liquid biopsies in clinical practice for breast cancer diagnosis, treatment choices, and responses to therapy from a clinician’s perspective.

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Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Cited by 250 publications

References 37 publications

Pushing estrogen receptor around in breast cancer

Pushing estrogen receptor around in breast cancer

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Potential of Liquid Biopsies for Breast Cancer Screening, Diagnosis, and Response to Treatment

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