HR+, HER2- Metastatic Breast Cancer
ESR1m
Multiple mechanisms lead to resistance to endocrine therapy (ET) ± cyclin-dependent kinase 4/6 inhibitors (CDK4/6i)1-5; up to 50% of patients with endocrine resistance harbor the ESR1 mutation.6
- Approximately 20-40% of patients who have received an aromatase inhibitor (AI) for advanced breast cancer (ABC) develop ESR1 mutations6
- ESR1 mutations induce ligand-independent activation, causing resistance to ET6
- All ESR1 mutations form in the ligand-binding domain and decrease the binding affinity for selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs)6
- Constitutive activity is a method by which ESR1 mutations produce resistance. The ESR1-mutated estrogen receptor (ER) auto activates, even in the absence of estrogen, leading to constitutive ER signaling6
- In addition to constitutive activity, ESR1 mutations may also gain neomorphic and hypermorphic activity6
ESR1-mutated ER auto activates even in the absence of estrogen, leading to constitutive ER signaling.6
When and How to Test for ESR1 Mutations
Guidelines recommend routine testing for emerging ESR1 mutations at recurrence or progression on ET in ER-positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) ABC to help identify the appropriate next line of therapy.1,7,8 Upon disease recurrence in the adjuvant setting, patients should be tested for ESR1 mutations.7 Patients who still have ESR1 wildtype on second-line and greater treatment should be retested at subsequent disease progression(s).7
Test at disease recurrence
Test at disease progression
Retest at subsequent disease progression(s) in patients who remain ESR1 wildtype
ESR1 mutations emerge while on treatment (typically AI) and are not usually detected before treatment.1,7,8 ESR1 mutations are best detected by blood-based, circulating-tumor DNA analyses, which have greater sensitivity and are less invasive than tissue-based testing.1,7-9
As healthcare providers, understanding when and how to test for ESR1 mutations may help identify the appropriate next line of therapy for patients with metastatic disease. See resources below for more information on ESR1 mutations in the ABC setting.
References
- Al-Qasem AJ, et al. Cancers (Basel). 2021;13(21):5397.
- Lindstrom LS, et al. J Clin Oncol. 2012;30(21):2601-2608.
- Hanker AB, et al. Cancer Cell. 2020;37(4):496-513.
- Clarke R, et al. Mol Cell Endocrinol. 2015;418(03):220-234.
- Patel HK, Bihani T. Pharmacol Ther. 2018;186:1-24.
- Brett JO, et al. Breast Cancer Res. 2021;23(1):85.
- Burstein HJ, et al. J Clin Oncol. 2023;31(18):3423-3425.
- Clatot F, et al. Oncotarget. 2016;7(46):74448-74459.
- Lone SN, et al. Mol Cancer. 2022;18;21(1):79.
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