What would be your next line of therapy for a postmenopausal metastatic ER+/Her 2- BC, s/p anastrazole and palbociclib/fulvestrant who has progressive disease and ESR1 mutation on ctDNA?

For this postmenopausal metastatic ER+/HER2-negative breast cancer patient, progressing after anastrozole and palbociclib/fulvestrant with an ESR1 mutation, elacestrant, imlunestrant, or vepdegestrant monotherapy are all appropriate ESR1-directed options. Elacestrant has the longest track record and most mature data, while vepdegestrant showed a numerically longer median PFS in the ESR1-mutant subgroup (5.0 months) (Campone et al., PMID 40454645).

The prior fulvestrant exposure in this patient ca...

Given FDA approval of imlunestrant and vepdegestrant for patients with ESR1 mutation positive, hormone receptor positive, HER2 negative metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitor, these agents make up now additional treatment options for such patients.

The only other chemotherapy-free alternative I would consider in this scenario would be continuing fulvestrant but adding everolimus. This combination has shown efficacy in patients who progressed on AI by doubling median PFS from 5.1 to 10.3 months based on PrE0102 Phase II study. However, we don't know about magnitude of PFS benefit in patients who have progressed on fulvestrant and CDK 4-6 inhibitors.

The best treatment depends on the type of progression (aggressive/visceral vs indolent) and duration of prior CDK4/6i treatment.

For rather indolent progression with prior CDK4/6i duration of >6-12 months, I favor hormonal therapy. 3 medications are approved for ESR1 mutated breast cancer, and I tend to use elacestrant. Another attractive option is imlunestrant plus abemaciclib (not FDA approved), which seems to enhance activity even with prior CDK4/6i use (Jhaveri et al., PMID 39660834).

For aggr...