Abstract
BackgroundESR1 mutations have attracted attention as a potentially important marker and treatment target in endocrine therapy-resistant breast cancer patients. The E380Q mutation, which is one of the ESR1 mutations, is associated with estradiol (E2) hypersensitivity, increased DNA binding to the estrogen response element, and E2-independent constitutive trans-activation activity, but its frequency in ESR1 mutations remains unknown. The present study aimed to investigate the E380Q mutation in comparison with the other representative ESR1 mutations.MethodsWe screened a total of 62 patients (66 tumor tissues and 69 plasma cell-free DNA (cfDNA)) to detect ESR1 mutations (E380Q, Y537S, Y537N, Y537C, and D538G) using droplet-digital polymerase chain reaction. Plasma was collected at more than two points of the clinical course, in whom changes of ESR1 mutations under treatment were investigated.ResultsWe detected ESR1 mutations in 21% (12/57) of MBCs. The E380Q ESR1 mutation was found in 16% (2/12) and the other ESR1 LBD mutations were five (41.6%) of Y537S, and four each (33.3%) of D538G, Y537N, and Y537C, in 12 ESR1 mutant breast cancer patients. Five tumors had multiple ESR1 mutations: three had double ESR1 mutations; Y537S/E380Q, Y37S/Y537C, and Y537S/D538G, and two had triple ESR1 mutations; Y537S/Y537N/D538G. In plasma cfDNA analysis, the E380Q mutation was not detected, but increases in other ESR1 mutations were detected in 46.2% (6/13) of MBC patients under treatment.ConclusionsWe have shown that there are distinct populations of ESR1 mutations in metastatic tissue and plasma. Each ESR1 mutation may have different clinical significance, and it will be necessary to investigate them all.
Highlights
ESR1 mutations have attracted attention as a potentially important marker and treatment target in endocrine therapy-resistant breast cancer patients
Fribbens and colleagues reported that the E380Q ESR1 mutation was found in 9.5% (6/63) in the SoFEA study for hormone receptor (HR)-positive breast cancer (BC) patients who had demonstrated prior sensitivity to aromatase inhibitor (AI), but it was found in 24.4% (22/91) in the PALOMA3 trial for HR–positive BC patients who had progressed during prior endocrine therapy (ET) [19]
These results suggest that E380Q ESR1 mutation may be a marker for screen of ET-resistant BC like the other representative ESR1 ligand-binding domain (LBD) mutations (Y537S, Y537N, Y537C, and D538G) [10,11,12, 20]
Summary
ESR1 mutations have attracted attention as a potentially important marker and treatment target in endocrine therapy-resistant breast cancer patients. Fribbens and colleagues reported that the E380Q ESR1 mutation was found in 9.5% (6/63) in the SoFEA study for hormone receptor (HR)-positive BC patients who had demonstrated prior sensitivity to AIs, but it was found in 24.4% (22/91) in the PALOMA3 trial for HR–positive BC patients who had progressed during prior ET [19] These results suggest that E380Q ESR1 mutation may be a marker for screen of ET-resistant BC like the other representative ESR1 LBD mutations (Y537S, Y537N, Y537C, and D538G) [10,11,12, 20]. The present study screened for the presence of the ESR1 E380Q mutation in ttDNA and plasma cfDNA of 62 ER-positive Japanese BC patients using droplet digital polymerase chain reaction (ddPCR) and compared the frequency with the representative ESR1 LBD mutations (Y537S, Y537N, Y537C, and D538G). This is the only precise study to use ddPCR to examine the presence of the E380Q ESR1 mutations in a series of tumor tissue and plasma samples of Japanese BC patients
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