Plasma <i>ESR1</i> Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

Fribbens, Charlotte; O’Leary, Ben; Kilburn, Lucy; Hrebien, Sarah; García-Murillas, Isaac; Beaney, Matthew; Cristofanilli, Massimo; Varga, Andrea; Loi, Sherene; Loibl, Sibylle; Jiang, Jian-Tang; Bartlett, Cynthia Huang; Koehler, Maria; Dowsett, Mitchell; Bliss, Judith; Johnston, Stephen; Turner, Nicholas C.

doi:10.1200/jco.2016.67.3061

Cited by 624 publications

(565 citation statements)

References 22 publications

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“…It has been reported that patients treated with AIs are more likely to develop tumors harboring ESR1 mutations, resulting in ligand-independent transcriptional activity of ER (27,32). In addition, some ESR1 mutations can lead to conformational changes of ER, leading to decreased binding of tamoxifen, thereby potentially reducing its activity (29,31).…”

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

129

105

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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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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

129

105

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“…No difference in the primary endpoint of progression-free survival (PFS) was seen between the three arms. Subsequent prospective-retrospective analysis of ESR1 mutation status in archival plasma circulating tumor DNA (ctDNA) indicated improved outcomes with fulvestrant compared with exemestane among patients with ESR1 mutations, whereas no difference was seen in patients who were ESR1 wild type (Fribbens et al 2016). These results indicate a potential role for ESR1 mutation status in selecting endocrine therapy in patients with HR+ MBC, ideally with re-evaluation of mutation status at any new 'decision point' in the sequence of endocrine therapies.…”

Section: Fulvestrant Clinical Studiesmentioning

confidence: 94%

“…These mutations have clear therapeutic relevance, as functional analysis in both the Toy and Jeselsohn studies revealed relative resistance to tamoxifen and fulvestrant, which could be partially abrogated with increased dose. Analysis of ESR1 mutations has been performed on archival plasma samples of patients with HR+ MBC and prior nonsteroidal AI treatment participating in two large randomized phase II studies (Fribbens et al 2016). These analyses indicated mutation rates of 25% among patients with progression on endocrine therapy in the PALOMA3 study (rising to 29% in patients with prior AI therapy) and 39% among patients with prior AI sensitivity in the SoFEA study.…”

Section: Mechanisms Of Resistance: Esr1 Mutationsmentioning

confidence: 99%

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

Murphy¹,

Dickler²

2016

Endocrine-Related Cancer

107

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The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlying de novo and acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

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“…5 ESR1-status does not appear to determine response to selective oestrogen receptor downregulators. 58,59 However, preclinical studies revealed relative resistance of the mutations to tamoxifen and fulvestrant but effective inhibition with high doses. [60][61][62][63][64] Retrospective analyses of ESR1 mutations in baseline plasma circulating tumour DNA from completed clinical trials suggest that these mutations are prognostic and predictive of resistance to aromatase inhibitors in metastatic disease.…”

Section: Clinical Decisions For Treatment Strategymentioning

confidence: 99%

Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

Schmid¹

2017

European Oncology &Amp; Haematology

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Endocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity.

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Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

Abstract: ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Cited by 624 publications

References 22 publications

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

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

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

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