Addressing ESR1 Mutation: A Key Factor in Hormone Therapy Resistance in Breast Cancer

Breast cancer is a prevalent and heterogeneous disease, particularly the hormone receptor (HR)-positive/HER2-negative subtype. Historically, endocrine therapy (ET) was the primary approach for HR-positive/HER2-negative advanced breast cancer (ABC). Despite its efficacy, about 20% develop resistance. Biologically directed therapies, including cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), have gained prominence. Understanding ET resistance mechanisms, particularly ESR1 mutations, is crucial for effective HR-positive/HER2-negative ABC treatment. ESR1 mutations play a pivotal role in ET resistance in HR-positive/HER2-negative ABC. These mutations confer constitutive, neomorphic, and hypermorphic activity to ESR1, contributing to resistance mechanisms. Liquid biopsy, particularly circulating cell-free DNA analysis, has emerged as a noninvasive method for assessing ESR1 mutations, overcoming challenges associated with tumor tissue analysis. ESR1 mutations, detected in 20–40% of ABC cases undergoing aromatase inhibition, significantly impact prognosis and therapeutic responses. Strategic management of ESR1 mutations involves monitoring and adjusting treatment approaches, such as transitioning to fulvestrant in the presence of mutations during aromatase inhibitors plus cycline-dependent kinase 4/6 inhibitors therapy. The importance of assessing other genetic mutations, like PIK3CA, in predicting response to fulvestrant is also highlighted. This chapter explores ESR1 mutations in HR-positive/HER2-negative ABC, focusing on their prevalence, clinical implications, and role in therapy resistance. Strategic management involves vigilant monitoring and tailored treatments, emphasizing the clinical potential of liquid biopsy.