Results: Patient with breast cancer and a somatic (tumour) ESR1 variant

A 58-year-old post-menopausal woman with metastatic ER-positive, HER2-negative breast cancer has been on a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and letrozole for two years and has developed progressive liver metastases. A liver biopsy confirms that the cancer is still ER-positive and HER2-negative. As part of screening investigations for a clinical trial, the liver biopsy is submitted for massively parallel sequencing (sometimes called next-generation sequencing) of a large panel of cancer-related genes. A somatic (tumour) variant in the ESR1 gene is reported.

ESR1 variants in ER-positive, HER2-negative breast cancer

• Endocrine therapy, with or without the use of a CDK4/6 inhibitor, is the standard treatment for patients with ER-positive, HER2-negative metastatic breast cancer; however, most patients will go on to develop treatment resistance.
• A common mechanism of acquired resistance to endocrine therapy in ER-positive breast cancers is the development of somatic (tumour) variants in ESR1. The frequency of ESR1 variants is relatively low in primary breast cancer (0%–3%) but between 6%–55% in ER-positive metastatic breast cancers that have progressed on endocrine treatment.
• ESR1 variants can result in oestrogen-independent ER activation and resistance to aromatase inhibitors, though not to ER inhibitors.
• The Emerald phase III trial enrolled patients with ER-positive, HER2-negative metastatic breast cancer who had progressed on one to two lines of endocrine treatment and had previously been treated with a CDK inhibitor. Patients were randomised to receive elacestrant, an oral selective ER degrader, or standard-of-care endocrine monotherapy (fulvestrant or an aromatase inhibitor). In total, 47.8% of the patients recruited had a tumour with an ESR1 variant. Progression-free survival (PFS) in the elacestrant arm was superior to the aromatase inhibitor arm in all patients (hazard ratio (HR) 0.70) but greater benefit was seen in patients with an ESR1 variant (HR 0.55; 12-month PFS 26.8% versus 8.2%).

Management of the current cancer

• The identification of an ESR1 variant may inform decisions about hormonal therapies for metastatic breast cancer. The presence of an ESR1 variant is associated with resistance to aromatase inhibitor monotherapy and comparatively better response to fulvestrant; however, fulvestrant is not currently approved by NICE as a monotherapy.
• The European Medicines Agency has approved elascestrant for use in post-menopausal women with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 variant who have disease progression following one or more line(s) of endocrine therapy, including a CDK inhibitor. This treatment is not currently available within the NHS.
• Access to novel endocrine therapies for metastatic breast cancer with ESR1 variants may be available in the context of clinical trials.
• ESR1 somatic (tumour) results do not have any implications for constitutional (germline) genomic testing of breast cancer patients.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

• Bidard FC, Kaklamani VG, Neven P and others. ‘Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial‘. Journal of Clinical Oncology 2022: volume 40, issue 28, pages 3,246–3,256. DOI: 10.1200/JCO.22.00338 (published correction appears in Journal of Clinical Oncology 2023: volume 41, issue 23, page 3,962, DOI: 10.1200/JCO.23.01239)
• Gennari A, André F, Barrios CH and others. ‘ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer‘. Annals of Oncology 2021: volume 32, issue 12, pages 1,475–1,495. DOI: 10.1016/j.annonc.2021.09.019
• Zundelevich A, Dadiani M, Kahana-Edwin S and others. ‘ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis‘. Breast Cancer Research 2020: volume 22, issue 1, page 16. DOI: 10.1186/s13058-020-1246-5