Self Study 2024 Release II: ESR1 Mutations in Metastatic Breast Cancer

Endocrine therapy is the backbone of treatment in hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative, metastatic breast cancer (mBC), but resistance universally develops. Our understanding of the role of mutations in the gene that encodes for the estrogen receptor, ESR1, in resistance to endocrine therapies has grown in the last 5 years. Patients acquire mutations in the ligand binding domain for ESR1 after treatment with endocrine therapy, leading to resistance to aromatase inhibitors. Retrospective review of studies of aromatase inhibitors with and without other agents suggest that those with ESR1 alterations have decreased benefit. Blood-based circulating tumor DNA (ctDNA) testing appears to be as reliable as tissue-based testing to identify ESR1 mutations and is being evaluated as a means to identify those who will progress on therapies sooner, such that interventions can occur. The use of selective estrogen down-regulators (SERDs) appears to overcome the biologic resistance caused by the ESR1 alterations and efforts to develop novel agents in this class are ongoing, with the FDA-approval of the first oral SERD, elacestrant, occurring in January 2023.