Understanding ESR1-Mediated Endocrine Resistance in HR-Positive, HER2-Negative Advanced Breast Cancer

Dr. Jason Mouabbi and Dr. Seth Wander discuss the biological role of ESR1 mutations and their impact on endocrine resistance in HR-positive, HER2-negative advanced breast cancer. Dr. Wander explains how ESR1 mutations commonly emerge following prolonged exposure to aromatase inhibitor therapy and represent an evolutionary adaptation that allows estrogen receptor signaling to continue despite estrogen deprivation. The experts highlight that ESR1 mutations primarily drive resistance to aromatase inhibitors rather than directly causing resistance to CDK4/6 inhibitors, emphasizing the importance of maintaining effective estrogen receptor pathway inhibition. Dr. Mouabbi and Dr. Wander discuss how understanding mechanisms of acquired resistance can help guide future treatment strategies, including approaches that modify the endocrine therapy backbone while continuing to target additional pathways. The conversation reinforces the importance of recognizing ESR1 mutations as markers of evolving endocrine resistance in advanced breast cancer management.