From the Guidelines
ESR1 mutations are a significant factor in guiding treatment decisions for metastatic breast cancer patients, particularly those who have received prior endocrine therapy, and fulvestrant is recommended over aromatase inhibitors for patients with ESR1 mutations, as it has shown improved progression-free survival in this population. The presence of ESR1 mutations in metastatic hormone receptor-positive breast cancer is associated with reduced efficacy of aromatase inhibitors, and therefore, alternative treatments such as fulvestrant, a selective estrogen receptor degrader, are recommended 1. Some key points to consider in the management of ESR1-mutated breast cancer include:
- ESR1 mutations are more commonly detected in tumor biopsies from patients with metastatic breast cancer who have had at least one line of endocrine therapy in the metastatic setting 1
- Fulvestrant has shown improved progression-free survival compared to exemestane in patients with ESR1 mutations detected in baseline ctDNA analysis, particularly in those who have previously progressed on a nonsteroidal aromatase inhibitor 1
- CDK4/6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, are often combined with endocrine therapy to enhance effectiveness in patients with ESR1-mutated breast cancer
- Regular monitoring with imaging studies every 2-3 months and assessment of treatment response is essential in patients with ESR1-mutated breast cancer
- ESR1 mutation testing is becoming increasingly important in guiding treatment decisions for metastatic breast cancer patients, as identifying these mutations can help select more effective therapies and avoid treatments likely to be ineffective due to resistance mechanisms 1.
From the Research
Significance of ESR1 Mutation in Breast Cancer
- ESR1 mutations are associated with a worse prognosis, including faster progression and poorer survival, in patients with ER+/HER2- metastatic breast cancer 2.
- The presence of ESR1 mutations is a common mechanism of hormonal therapy resistance, and these mutations can preexist in primary tumors and be enriched during metastasis 3.
- ESR1 mutations can be detected in plasma using sensitive methods, such as multiplex digital polymerase chain reaction, and may help direct the choice of further endocrine-based therapy 4.
Prevalence and Detection of ESR1 Mutations
- ESR1 mutations are found in approximately 40% of patients with ER+/HER2- metastatic breast cancer, with more than 90% of these mutations developing in response to therapy 2.
- The detection of ESR1 mutations in plasma may become a prognostic and predictive biomarker in the future, used in clinical practice for hormone-receptor breast cancer, especially in the metastatic setting 5.
- Liquid biopsy, using digital-PCR or next-generation sequencing, may be used to assess ESR1 mutations, similar to other prognostic or predictive biomarkers, such as EGFR mutations in lung cancer 5.
Clinical Implications and Treatment Options
- Patients with ESR1 mutations may derive clinical benefit from treatment with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies is needed to overcome the endocrine-resistant phenotype of ESR1 mutant-bearing tumors 3.
- ESR1 mutation analysis in plasma after progression on prior aromatase inhibitor therapy may help direct the choice of further endocrine-based therapy, with fulvestrant plus palbociclib improving progression-free survival compared to fulvestrant plus placebo in both ESR1 mutant and wild-type patients 4.
- The development of targeted therapy directed to ESR1-mutated clones is an appealing concept, and preclinical and clinical works are in progress 6.