The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20–40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the ‘evolvability’ of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers.
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J.L. and C.M. are both Genentech/Roche employees and own shares of Roche. C.M. is a named co-inventor on patent 11081236 entitled ‘Diagnostic and therapeutic methods for the treatment of breast cancer’. S.C. reports research grants from NIH/NCI and Breast Cancer Research Foundation during the conduct of the study; personal fees from Novartis, AstraZeneca, Nuvalent, Boxer Capital, Effector and Neogenomics; equity/leadership in Totus Medicines and Odyssey Biosciences and grants from Daiichi Sankyo and AstraZeneca outside the submitted work; and a patent for CDK4/CDK6 degraders is also pending. M.W. has no competing interest.
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A class of drugs that combine monoclonal antibodies with cytotoxic agents to specifically target cells expressing the antigens recognized by those antibodies.
- Aromatase inhibitors
A class of drugs that block the synthesis of oestrogens by the aromatase enzyme in non-ovarian tissues.
The C-terminal ligand-binding domain of ER, responsible for the binding of oestrogen ligand.
- Liquid biopsies
A technology that allows sampling of body fluids such as blood for molecular profiling, allowing for a less-invasive way of tumour monitoring, detection and characterization than traditional tissue-based biopsies.
A class of anti-oestrogen agents that bind covalently to the LBD of ER and prevent recruitment of co-activators.
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Will, M., Liang, J., Metcalfe, C. et al. Therapeutic resistance to anti-oestrogen therapy in breast cancer. Nat Rev Cancer 23, 673–685 (2023). https://doi.org/10.1038/s41568-023-00604-3