Unraveling the clinicopathological features driving the emergence of ESR1 mutations in metastatic breast cancer

Abstract

<i>ESR1</i> mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ER + ) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the <i>ESR1</i> mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common <i>ESR1</i> mutations and <i>PIK3CA</i> mutations. Among the patients with ER + /HER2- disease, <i>ESR1</i> mutations were detected in 30% of the patients. There were no associations between the pathological features of the primary disease or time to distant recurrence and the emergence of <i>ESR1</i> mutations in metastatic disease. The prevalence of the <i>ESR1</i> mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the <i>ESR1</i> mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of <i>ESR1</i> mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of <i>PIK3CA</i> mutations. These results support the evolution of the <i>ESR1</i> mutations under the selective pressure of treatment with aromatase inhibitors in the adjuvant and metastatic settings and have important implications in the optimization of adjuvant and metastatic treatment in ER + breast cancer.