Applying Precision Endocrine Therapy in ESR1-Mutant Breast Cancer: A Case-Based Treatment Decision

In this case-based segment, Drs. Mouabbi and Bardia apply prior discussions to a real-world clinical scenario involving a 56-year-old woman with ER-positive, HER2-negative metastatic breast cancer. After more than two years of disease control on first-line aromatase inhibitor plus palbociclib, the patient develops asymptomatic progression in bone and liver. She remains endocrine-sensitive, has an excellent performance status, and expresses strong preferences for oral therapy, flexibility, and avoidance of injections and frequent clinic visits.

Dr. Bardia begins by emphasizing the central role of patient preference and lifestyle in treatment selection. Given the patient’s active travel schedule, therapies associated with high rates of diarrhea or frequent clinic visits are viewed less favorably. Molecular profiling reveals both an ESR1 Y537S mutation and a PIK3CA mutation. Dr. Bardia highlights the clinical relevance of the Y537S alteration, noting its association with resistance to fulvestrant, further supporting avoidance of injectable endocrine therapy in this case.

Considering the patient’s prolonged benefit from prior CDK4/6 inhibition and moderate disease burden without visceral crisis, Dr. Bardia favors an oral SERD as the next line of therapy. Single-agent elacestrant or imlunestrant are identified as preferred options, balancing efficacy with tolerability and patient convenience. Combination approaches such as imlunestrant plus abemaciclib or fulvestrant-based doublets are deprioritized due to concerns about diarrhea, injections, and quality-of-life impact. If combination therapy were required, elacestrant plus everolimus is noted as a reasonable alternative, supported by data from ELEVATE and AVERA, and better aligned with the patient’s preferences.

The discussion then turns to monitoring strategy. Dr. Bardia recommends incorporating tumor markers when they have previously correlated with disease burden, performing early radiographic reassessment at approximately two months when using monotherapy, and considering serial circulating tumor DNA testing when feasible. In this context, trends in variant allelic fraction for ESR1 and PIK3CA mutations may function as dynamic biomarkers of treatment response, helping guide timely treatment adjustments while maintaining a patient-centered approach.