Dr Mouabbi on the Rationale for Early, Serial ESR1 Mutation Testing in HR+ Breast Cancer

"Detecting [an ESR1] mutation early is critical. If patients are kept on AIs without switching therapies, the resistant clone can expand, potentially leading to disease progression… The mutation can emerge at any time, making it important to assess for ESR1mutations early and perform serial testing over the course of treatment."

Jason A. Mouabbi, MD, an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the importance of testing for ESR1 mutations prior to radiographic progression in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

ESR1 mutations represent a clinically significant mechanism of resistance in HR-positive, HER2-negative breast cancer, Mouabbi began. These mutations are classified as therapy-selected alterations, commonly arising in response to prolonged exposure to endocrine therapies, particularly aromatase inhibitors (AIs), which are widely used in the first-line metastatic setting, he stated.

Functionally, ESR1 mutations result in a constitutively active estrogen receptor (ER), which no longer requires ligand binding for activation, he continued. Under healthy physiologic conditions, the ER remains inactive until bound by estrogen, at which point it promotes transcriptional activity leading to cell proliferation, Mouabbi detailed. However, in the presence of ESR1 mutations, the receptor remains in an active conformation independent of estrogen, according to Mouabbi. Consequently, AIs—which work by depleting estrogen—lose efficacy, allowing tumor proliferation to continue despite estrogen suppression, Mouabbi explained.

Early detection of ESR1 mutations is critical for optimizing treatment sequencing, Mouabbi reiterated. Continued use of AIs in patients harboring ESR1 mutations may enable clonal expansion of resistant subpopulations, resulting in more aggressive disease that is less responsive to subsequent therapies, he said. Because ESR1 mutations can arise dynamically throughout treatment, serial testing, such as with circulating tumor DNA, is essential to identify the emergence of resistance and guide timely therapeutic adjustments, Mouabbi added.

Data indicate that ESR1 mutations are uncommon at the time of initial metastatic diagnosis among patients previously treated with endocrine therapy in the early-stage setting, he reported. However, this frequency increases with continued exposure to anti-estrogen therapies, reaching approximately 20% to 30% in the first-line metastatic setting and approximately 40% in later-line settings, Mouabbi noted. These data underscore the cumulative selection pressure imposed by endocrine agents and highlight the importance of molecular monitoring to inform precision treatment strategies in advanced HR-positive, HER2-negative breast cancer, Mouabbi concluded.

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