Results: Patient with advanced breast cancer and a ctDNA ESR1 variant

A 64-year-old woman with metastatic oestrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer has been on first line therapy with letrozole and a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor for three years when she develops progressive disease in her liver. A circulating tumour DNA (ctDNA) blood test (liquid biopsy) indicates that there is an activating variant (mutation) in the ESR1 (oestrogen receptor 1) gene.

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

• Endocrine therapy with an aromatase inhibitor, with or without the use of a CDK4/6 inhibitor, is the standard treatment for patients with HR-positive, HER2-negative advanced 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 activating variants in ESR1 which cause ligand-independent activation of ER signalling.
• ESR1 variants result in oestrogen-independent ER activation and resistance to aromatase inhibitors but not ER inhibitors. The frequency of ESR1 variants is relatively low in primary breast cancer (0%–3%) but up to 55% in ER-positive metastatic breast cancers that have progressed on endocrine treatment.
• The EMERALD phase III trial randomised ER-positive, HER2-negative patients who had progressed on 1–2 lines of endocrine treatment and had previously been treated with a CDK inhibitor to receive elacestrant (an oral selective ER degrader) or standard-of-care endocrine monotherapy (fulvestrant or an aromatase inhibitor). 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% vs 8.2%).
• ESR1 variants are subclonal. Given spatial heterogeneity within tumours, such variants may be missed by a tissue biopsy. Blood-based ctDNA analysis is now considered the preferred testing methodology for identifying activating ESR1 variants in patients with advanced cancer.

Management of the current cancer

• Elacestrant is recommended by NICE as a treatment option for ER-positive, HER2-negative locally advanced or metastatic breast cancer with an activating ESR1 variant that has progressed after at least one line of endocrine therapy, plus a CDK4/6 inhibitor. The Cancer Drugs Fund eligibility criteria require at least 12 months treatment with endocrine therapy plus CDK4/6 inhibitor and no more than one previous line of chemotherapy.
• Testing for ESR1 variants using ctDNA is now available through the National Genomic Test Directory for cancer via test code M3.13 to guide treatment decisions in patients with ER-positive, HER2-negative advanced/metastatic breast cancer that are progressing on first-line treatment with endocrine therapy plus CDK 4/6 inhibitors (patients must have received at least 12 months of treatment). Please contact your Genomic Laboratory Hub (GLH) team for details about how to obtain the special blood bottles required and how to request this test in your geographical region.
• There are no constitutional (germline) implications from the identification of an ESR1 variant. Your patient may be eligible for constitutional genetic testing of other genes (such as BRCA1, BRCA2 and others) should they meet relevant eligibility criteria as outlined in the NHS Genomic Test Directory rare and inherited disease eligibility criteria.
• Variants of likely germline origin may incidentally be identified through analysis of tumour-derived DNA (including ctDNA), which is now standard in ER-positive breast cancer in this situation. Germline follow-up testing to confirm origin of a variant may be required, depending on variant allele frequency, associated clinical utility and actionability, as well as the patient’s personal and family history.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• NICE: Elacestrant for treating oestrogen receptor-positive, HER2-negative advanced breast cancer with an ESR1 mutation after endocrine treatment [ID6225]

References:

• 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
• Gennri 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

For patients

Breast Cancer Now: Elacestrant (Orserdu)