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ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges

Abstract

Breast cancer accounts for 25% of the cancers in women worldwide. The most common subtype of breast cancer diagnosed is hormone receptor positive, which expresses the oestrogen receptor (ER). Targeting of the ER with endocrine therapy (ET) is the current standard of care for ER-positive (ER+) breast cancer, reducing the mortality by up to 40%. Resistance to ET, however, remains a major issue for ER + breast cancer, leading to recurrence and metastasis. One major driver of ET resistance is mutations in the ER gene (ESR1) leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly detrimental in metastatic breast cancer (MBC) as they are present in as high as 36% of the patients. This review summarises the pre-clinical characterisation of ESR1 mutations and their association with clinical outcomes in MBC and primary disease. The clinically approved and investigational therapeutic options for ESR1 mutant breast cancer and the current clinical trials evaluating ESR1 mutations and ET resistance are also discussed. Finally, this review addresses pre-clinical models and multi-‘omics’ approaches for developing the next generation of therapeutics for ESR1 mutant and ET-resistant breast cancer.

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Fig. 1: Potential therapeutic targets identified in clinical and pre-clinical studies for ESR1 mutant breast cancer.

Data availability

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Funding

This study is supported by BCRF 19-055, NIH R01 CA207270, NIH R01 CA072038, CPRIT MIRA RP180712 (Kelly Hunt, PI), and T32 CA203690-02 to SAWF. SKH received training support from the National Institute of Health (NIH) Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (F31CA260983) and the NIH Training Program in Cell and Molecular Biology (T32GM008231).

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Concept and design of review: SKH and SAWF. Writing and review of the paper: SKH and SAWF.

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Correspondence to Suzanne A. W. Fuqua.

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SAWF is a subject editor, member of the Editorial Board of BJC and guest editor of the special issue on metastasis.

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Herzog, S.K., Fuqua, S.A.W. ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01564-x

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