Modeling the novel SERD elacestrant in cultured fulvestrant-refractory HR-positive breast circulating tumor cells

Sep 24, 2026

Uploaded by Jake

Purpose: Metastatic HR+ breast cancer initially responds to sequential endocrine therapy, but commonly becomes refractory. Elacestrant, an FDA-approved oral SERD and antagonist, shows benefit in some patients, yet patient-derived models are limited for capturing effects across diverse treatment histories and acquired mutations. Methods: Clinical outcomes with elacestrant versus endocrine therapy were analyzed in women previously treated with fulvestrant-containing regimens from the EMERALD Study. Preclinical modeling used PDX and ex vivo cultured CTCs to test sensitivity versus fulvestrant. Results: Patients receiving elacestrant had improved progression-free survival versus standard endocrine therapy, independent of ESR1 mutations. Both CTC and PDX models were fulvestrant-refractory yet elacestrant-sensitive, regardless of ESR1 and PIK3CA gene mutations. Conclusion: Elacestrant may treat HR+/HER2- breast cancer with resistance to current ER-targeting therapies.

LanguageEnglish

CategoryHealthcare

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Pages14

Reading Time35 min

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Breast Cancer Research and Treatment (2023) 201:43–56 [https://doi.org/10.1007/s10549-023-06998-w](https://doi.org/10.1007/s10549-023-06998-w) Modeling the novel SERD elacestrant in cultured fulvestrant‑refractory HR‑positive breast circulating tumor cells Taronish D. Dubash · Aditya Bardia · Brian Chirn · Brittany A. Reeves · Joseph A. LiCausi · Risa Burr, et al. [full author details at the end of the article] Received: 22 March 2023 / Accepted: 26 May 2023 / Published online: 15 June 2023 © The Author(s) 2023 Abstract Purpose Metastatic hormone receptor-positive (HR+) breast cancer initially responds to serial courses of endocrine therapy, but ultimately becomes refractory. Elacestrant, a new generation FDA-approved oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+breast cancer, but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations. Methods We analyzed clinical outcomes with elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study. We further modeled sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant in patient-derived xenograft (PDX) models and cultured circulating tumor cells (CTCs) . Results Analysis of the subset of breast cancer patients enrolled in the EMERALD study who had previously received afulvestrant-containing regimen indicates that they had better progression-free survival with elacestrant than with standardof-care endocrine therapy, a finding that was independent estrogen receptor (ESR1) gene mutations. We modeled elacestrant responsiveness using patient-derived xenograft (PDX) models and in ex vivo cultured CTCs derived from patients with HR+breast cancer extensively treated with multiple endocrine therapies, including fulvestrant. Both CTCs and PDX models are refractory to fulvestrant but sensitive to elacestrant, independent of mutations in ESR1 and Phosphatidylinositol- 4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes. Conclusion Elacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER targeting therapies. Elacestrant may be an option for patients with HR+/HER2-breast cancer whose disease progressed on fulvestrantin the metastatic setting. Translational Relevance. Serial endocrine therapy is the mainstay of management for metastatic HR+breast cancer, but acquisition of drug resistance highlights the need for better therapies. Elacestrant is a recently FDA-approved novel oral selective estrogen receptor degrader (SERD), with demonstrated efficacy in the EMERALD phase 3 clinical trial of refractory HR+breast cancer. Subgroup analysis of the EMERALD clinical trial identifies clinical benefit with elacestrant in patients who had received prior fulvestrant independent of the mutational status of the ESR1 gene, supporting its potential utility in treating refractory HR+breast cancer. Here, we use pre-clinical models, including ex vivo cultures of circulating tumor cells and patient-derived xenografts, to demonstrate the efficacy of elacestrant in breast cancer cells with acquired resistance to fulvestrant. Keywords ER +metastatic breast cancer · Selective estrogen receptor degrader (SERD) · Fulvestrant resistance · Circulating tumor cells (CTCs) · Elacestrant Introduction Taronish D. Dubash and Aditya Bardia have contributed equally to this work. Metastatic Hormone Receptor-positive (HR+) breast cancer remains the predominant cause of breast cancer mortality in women, despite advances in targeted therapies [1] . Breast cancers expressing Estrogen Receptor alpha (ERα, encoded by the ESR1 gene) are dependent on estrogen-induced signaling for proliferation, and they are highly susceptible to an array of hormonal in

FAQs

What clinical question does the study address regarding elacestrant?

It evaluates whether elacestrant provides better outcomes than standard endocrine therapy in women with metastatic HR+ breast cancer who previously received fulvestrant-containing regimens.

How were patient-derived models used to study response to elacestrant versus fulvestrant?

Sensitivity was modeled using patient-derived xenograft (PDX) models and ex vivo cultured circulating tumor cells (CTCs) derived from extensively treated HR+ breast cancer patients.

Is elacestrant effectiveness dependent on specific genetic mutations?

The results indicate elacestrant benefit and model sensitivity were independent of ESR1 mutations, and responses in CTC and PDX models were also independent of ESR1 and PIK3CA mutations.

Sep 24, 2026

Uploaded by Jake