Individualizing Endocrine Therapy When Resistance Mutations Overlap

Rebecca Shatsky, MD, says her approach to co-mutations depends on the specific patient in front of her, citing a steep drop-off in response across oral selective estrogen receptor degraders that leaves a significant portion of patients without benefit. This pushes her toward dual-agent therapy more often, and she highlights the ELEVATE trial combination of elacestrant and capivasertib, citing a recent patient with both an ESR1 mutation and an RB1 mutation, which confers CDK4/6 inhibitor resistance. Dr. Shatsky adds that the duration of a patient's prior aromatase inhibitor and CDK4/6 inhibitor therapy, for example 4 years versus 12 months, shapes how she predicts ongoing endocrine sensitivity. Carol Tweed, MD, notes that second-line selective estrogen receptor degrader duration of response is short, reinforcing the case for earlier intervention rather than waiting for progression.