Understanding ESR1 Mutations and the Role of Serial Testing After CDK4/6 Inhibition

In this segment, Dr. Jason Mouabbi and Dr. Bardia explore the growing importance of ESR1 mutations in the management of ER-positive, HER2-negative metastatic breast cancer, particularly after progression on CDK4/6 inhibitor–based therapy. Dr. Bardia explains that ESR1 mutations occur in the estrogen receptor itself and represent a key mechanism of resistance to AIs. Under selective pressure from estrogen-depleting therapies, tumor cells may acquire mutations that render the estrogen receptor constitutively active and estrogen-independent, leading to treatment resistance. In contrast, therapies that directly target the estrogen receptor, such as selective estrogen receptor degraders (SERDs), may remain effective in this setting.

The discussion addresses whether ESR1 mutations are pre-existing or acquired. Dr. Bardia notes that these mutations are rarely detected in primary breast tumors but are commonly identified in metastatic disease, particularly through plasma-based genotyping. Detection rates can reach 30–50% in advanced disease, supporting the concept that ESR1 mutations are largely acquired over time, even if present initially at extremely low, undetectable levels.

Both speakers emphasize the importance of routine testing for ESR1 mutations at baseline metastatic diagnosis and at every subsequent disease progression, as these alterations are actionable and can directly inform treatment selection. Liquid biopsy is highlighted as a practical and widely accessible tool, with increasing insurance coverage in the United States. The group also discusses emerging strategies such as molecular monitoring during therapy, exemplified by trials like SERENA-6, while acknowledging that this approach is not yet ready for routine clinical use and requires additional outcome data.

Finally, Dr. Bardia provides critical clarification on interpreting variant allelic frequency (VAF). He stresses that low VAF does not indicate a clinically irrelevant or subclonal mutation but rather reflects overall tumor burden in the blood. Clinicians are cautioned against dismissing ESR1 mutations based solely on low VAF values, reinforcing the principle that detection alone should guide therapeutic decision-making.