Abstract
ESR1 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 ESR1 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 ESR1 mutations and PIK3CA mutations. Among the patients with ER + /HER2- disease, ESR1 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 ESR1 mutations in metastatic disease. The prevalence of the ESR1 mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the ESR1 mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of ESR1 mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of PIK3CA mutations. These results support the evolution of the ESR1 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.
Highlights
The ESR1 ligand-binding domain (LBD) mutations were unveiled in recent years as an important mechanism of acquired endocrine resistance that evolves under the selective pressure of endocrine treatments
Results of clinical ER, progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) testing on an archival metastatic biopsy specimen were available in 147 (95%) of the 155 patients included in this study
Previous studies have shown that the ESR1 endocrine resistance mutations are rarely detected in primary treatment naive tumors and evolve predominantly in metastatic disease under the selective pressure of endocrine treatment. cfDNA analysis using droplet digital PCR (ddPCR) is emerging as a non-invasive highly sensitive test that can capture the heterogeneity of the mutational landscape from multiple metastatic sites
Summary
The ESR1 ligand-binding domain (LBD) mutations were unveiled in recent years as an important mechanism of acquired endocrine resistance that evolves under the selective pressure of endocrine treatments. These mutations are rarely found in primary estrogen receptor-positive (ER + ) breast cancers but have a high prevalence in metastatic disease and lead to constitutive ligand independent activity.[1,2,3] The most prevalent mutations as detected in a number of studies are the Y537S and D538G mutations. Patients with metastatic ER + breast cancer with detectable cfDNA ESR1 mutations had decreased progression free survival on subsequent treatment with an aromatase AI.[6]
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