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

• Published in: British journal of cancer Vol. 126; no. 2; pp. 174 - 186
• Main Authors: Herzog, Sarah K., Fuqua, Suzanne A. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2022; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/1347; 631/67/322; 692/308/575; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Clinical trials; Drug Resistance; Drug Resistance, Neoplasm; Endocrine therapy; Epidemiology; ESR1 protein; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Humans; Metastases; Metastasis; Molecular Medicine; Molecular Targeted Therapy - methods; Mutants; Mutation; Neoplasm Metastasis; Oncology; Review; Review Article; Transcription
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-021-01564-x

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.