Endocrine resistance
What is endocrine resistance?
ET-based regimens are the therapeutic mainstay for HR+, HER2– BC;1 however, endocrine resistance can develop, leading to reduced clinical benefit and disease progression.2-5
* Secondary endocrine resistance definition also includes known ESR1 mutation (unaffected by therapy with CDK4/6i, mTOR/PI3Ki or other adjunctive drugs).6
1L/2L+, first/second line and beyond; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; PD, disease progression.
ESR1 mutations
One of the most well-documented mechanisms of endocrine resistance is the acquisition of mutations in the ESR1 gene encoding the oestrogen receptor α (ERα). These mutations develop over time under treatment pressure of aromatase inhibitors.2
ESR1 mutations stabilise the receptor in its active form. This leads to continuous ER signalling without the need for oestrogen.2
These mutations are rarely present in the eBC setting or in earlier treatment lines in mBC. Their frequency increases in later treatment lines, especially after aromatase inhibitor use.2,9,10 Patients with ESR1-mutated tumours generally have a poorer prognosis than those without these mutations.12-14
Other mechanisms of endocrine resistance
Other mechanisms of endocrine resistance include:
- Loss of ER expression, which leads to tumour cells becoming independent of ER-stimulated growth and proliferation, thereby becoming resistant to ETs acting through oestrogen deprivation or ER inhibition15
- Crosstalk between signalling pathways, for example via the PI3K/AKT/mTOR pathway, leading to phosphorylation and activation of ER and oestrogen-independent ER signalling16,17
References
- Clusan L, et al. Int J Mol Sci 2023; 24:6834;
- Brett JO, et al. Breast Cancer Res 2021; 23:85;
- Hartkopf AD, et al. Breast Care 2020; 15:347–354;
- Toy W, et al. Nat Genet 2013; 45:1439–1445;
- Razavi P, et al. Cancer Cell 2018; 34:427–438;
- Cardoso F, et al. Breast 2024; 76:103756;
- Gennari A, et al. Ann Oncol 2021; 32:1475–1495 {ESMO Metastatic Breast Cancer Living Guideline, v1.2 April 2025};
- Lambertini M, et al. eClinicalMedicine 2023; 59:101931;
- Bhave MA, et al. Breast Cancer Res Treat 2024; 207:599–609;
- Jeselsohn R, et al. ASCO 2023 (Poster 1062);
- Kinslow CJ, et al. JNCI Cancer Spectr 2022; 6:pkac060;
- Zhang X, et al. Adv Clin Exp Med 2024; 33:1069–1076;
- Cristofanilli M, et al. Clin Cancer Res 2022; 28:3433–3442;
- Chandarlapaty S, et al. JAMA Oncol 2016; 2:1310–1315;
- Zattarin E, et al. Cells 2020; 9:2644;
- Fan W, et al. Future Med Chem 2015; 7:1511–1519;
- Khatpe AS, et al. Cancers (Basel) 2021; 13:369.
