Imlunestrantin ER+ advanced breast cancer - bridging innovation and clinical reality - Introduction: breast cancer, heterogeneity, and the challenge of resistance

Sep 29, 2026

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Breast cancer remains a leading cause of cancer morbidity and mortality, with biological behavior shaped by receptor-defined subtypes such as ER, PR, and HER2. In HR+/HER2– disease, estrogen signaling drives tumor growth through ER-mediated transcription, while endocrine instability and progesterone/estrogen imbalance promote proliferation, DNA damage, and metastasis. Endocrine therapy is foundational, yet resistance emerges, particularly via ESR1 mutations that enable ligand-independent ER activation and reduce sensitivity to tamoxifen and SERDs. The article reviews ESR1 mutation/fusion mechanisms and the clinical rationale for imlunestrant, an oral SERD designed to degrade wild-type and mutant ER.

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Introduction: breast cancer, heterogeneity, and the challenge of resistance

ESR1 gene mutations, fusions, and endocrine resistance

Imlunestrant: pharmacology, preclinical rationale, and early development

EMBER-3: efficacy, safety, and patient-reported outcomes

Editorial # Imlunestrantin ER+ advanced breast cancer –bridging innovation and clinical reality Aleeza Khalid, MBBS, Momina Inayat, MBBS, Muddassir Khalid, MBBS* ## Introduction: breast cancer, heterogeneity, andthechallenge of resistance Globally, breast cancer continues to be a major cause of cancer -related morbidity and death. Itis responsible for about 15% offemale cancer deaths and nearly one-third of all cancers inwomen. Using immunohistochemistry, the biological and clin -ical behavior is further divided into subtypes according to theexpression of the human epidermal growth factor receptor-2(HER2), progesterone receptor (PR), and estrogen receptor(ER) . Approximately 70% of tumors are HER2-negative andhormone receptor-positive (HR+/HER2–), 15–20% are HER2+,and 15% are triple-negative (HR–/HER2–)[1] . Estrogen signaling plays a key role in the growth and survival oftumors in HR+ disease. By binding to the nuclear ER (encoded byESR1), estrogen controls transcription by interacting with growthfactor pathways and estrogen response elements. Exogenousestrogen exposure, endocrine instability, or dysregulation of theestrogen/progesterone balance can all promote uncontrolled pro -liferation, the buildup of DNA damage, and stromal remodeling,all of which favor metastasis and progression[2,3] . Endocrine therapy (ET) has been the backbone of ER+/HER2–breast cancer treatment, with agents such as tamoxifen (a selectiveestrogen receptor modulator) and aromatase inhibitors (AIs) form -ing mainstays in both early and advanced settings. Fulvestrant, aselective estrogen receptor degrader (SERD), was the first approvedagent that not only antagonizes ER but promotes its proteasomaldegradation. However, many patients eventually develop resis -tance, usually mediated by on-target ESR1 mutations[4] . ## ESR1 gene mutations, fusions, and endocrineresistance When treating advanced HR+ breast cancer, resistance to ET isan unavoidable hazard. The emergence of ESR1 ligand-binding Department of Medicine, Nishtar Medical University, Multan, PakistanSponsorships or competing interests that maybe relevant to content are disclosedatthe end of this article. *Corresponding author. Address: Nishtar Medical University, Nishtar Road, Multan60000, Pakistan. Tel.: +923330333544. E-mail: dr.muddassirkhalid@gmail.com(M. Khalid). Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is anopen access article distributed under the Creative Commons Attribution License 4.0(CCBY), which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly cited. Annals of Medicine & Surgery (2026) 88:29–31 Received 11 November 2025; Accepted 12 November 2025Published online 3 December 2025http://dx.doi.org/10.1097/MS9.0000000000004417 domain (LBD) point mutations, most commonly at codons 537and 538, is a major mechanism of acquired resistance. Thesemutations confer ligand-independent constitutive activation ofER, attenuate response to tamoxifen or AIs, and reduce sensi -tivity to wild-type-targeted SERDs (e.g., fulvestrant, giredes -trant) . Under the selective influence of previous ET, thesemutations are more prevalent in metastatic samples[5] . Another emerging mechanism is ESR1 fusion proteins. Thoughvery rare, ESR1 fusions may mark particularly aggressive, resistantphenotypesand represent an underexplored therapeutic target[6] . Because of the importance of ER signaling andthe ability ofcancer cells to adapt under endocrine pressure, the field haslooked for next-generationSERDs, and several other modalitiesto overcome LBD mutations and bypass resistance[7].Amongthese, imlunestrant (LY3484356) has drawn interest lately asa potentially effective oral SERD with brain-penetrant qualitiesand strength against mutant ER. Imlunestrant: pharmacology, preclinical rationale,and early development Imlunestrant is an oral, selective estrogen receptor antagonist/degrader designed

FAQs

Why is endocrine therapy resistance common in ER+/HER2– advanced breast cancer?

Resistance is driven by cancer cell adaptation under endocrine pressure, especially through ESR1 alterations that reactivate ER signaling despite treatment.

What role do ESR1 ligand-binding domain mutations play in acquired resistance?

Common LBD point mutations (notably codons 537 and 538) cause ligand-independent constitutive ER activation, weaken responses to tamoxifen or aromatase inhibitors, and reduce sensitivity to some SERDs.

How does imlunestrant work, and what was shown in early development?

Imlunestrant is an oral selective estrogen receptor antagonist/degrader that promotes ER breakdown and blocks transcription even when ESR1 is mutated; early development reported favorable pharmacokinetics, safety, and preliminary activity.

Sep 29, 2026

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