New perspectives on endocrine therapy suitability for hormone receptor-positive metastatic breast cancer in clinical practice.

Hormone receptor-positive/HER2-negative advanced breast cancer (ABC) is a heterogeneous and dynamic disease. Endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors remain the standard-of-care first-line therapy for ABC. However, the treatment landscape is rapidly evolving as our understanding of the complex biology underlying this common subtype advances. Predicting how a patient's cancer might respond to ET across lines of therapy and understanding optimal sequencing in clinical practice are key unmet needs. A range of established and emerging clinical characteristics and biomarkers, including endocrine receptor expression, presence of specific mutations (e.g., ESR1, PIK3CA), and visceral disease, are currently used to guide treatment decisions. However, international guidelines have variable definitions of ET resistance and sensitivity, making delivery of individualized care in clinical practice challenging. Considering this unmet need and leveraging the existing evidence for both prognostic and predictive markers of therapeutic response, we propose that idea of ET suitability be used as a complement to ET resistance and sensitivity. We consider ET suitability to be the clinical assessment of whether a patient could benefit from ET, where benefit is defined not solely by tumor response but by a clinically relevant constellation of characteristics and markers possibly predicting the durability of disease response and symptom control. Several unresolved questions remain regarding issues such as disease heterogeneity, optimal treatment sequencing, and biomarker precision, but further work and ongoing studies will help to support the evolution of guidelines and provide clarity around the effective application of this quickly developing field to daily clinical practice.