ESR1 Mutations in ER+ Breast Cancer Cells Found to Promote CDK4/6 Inhibitor Resistance

Mutations in the ESR1 gene drive resistance in estrogen receptor-positive (ER+) breast cancer to antiestrogen therapy, but it is not known if the ESR1 mutation conveys resistance to CDK4/6 inhibitors (CDK4/6i). A study was conducted to investigate this question using tumor samples from patients with ER+/HER2-negative (HER2–) metastatic breast cancer. Data were obtained from 1820 next-generation sequencing (NGS) tissue samples and 2108 circulating tissue (ct) DNA samples from 3958 patients. NGS had been performed using the Tempus xT tumor assay while the ctDNA had been performed using the Tempus xF liquid biopsy. The patients were stratified into 2 groups: treated and untreated. The treated group had been treated with CDK4/6i prior to biopsy while the untreated group was composed of patients who had biopsies within 30 days of diagnosis with metastatic breast cancer. The only gene that was found to have significant mutations after treatment with CDK4/6i was the ESR1 gene.

MCF-7 cells carrying ESR1 wild-type, Y537S, or D538G “hotspot” knock-in mutations were used to determine if ESR1 mutations are drivers of CDK4/6i mutations. The CDK4/6i palbociclib was used to treat the cells prior to cell proliferation assessment. The cells were then treated with palbociclib + fulvestrant or palbociclib + medium free of estrogen to mimic estrogen suppression in patients treated with aromatase inhibitors.


Chica-Parrado, Lin C-C, Jaeger E, et al. ESR1 mutations drive resistance to CDK4/6 inhibitors in ER+ breast cancer. Poster presented at: San Antonio Breast Cancer Symposium. December 7, 2023; San Antonio, TX. Abstract # PO3-23-09.

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