Would you start fulvestrant plus CDK4/6 inhibitors in a patient with ESR1 mutation with metastatic breast cancer on liquid biopsy in a first-line setting?

Since the presence of ESR1 mutation is associated with a lack of benefit from aromatase inhibitors, I tend to start patients who have evidence of this mutation on fulvestrant in combination with a CDK 4/6 inhibitor (typically ribociclib). ESR1 mutation found on circulating tumor DNA suggests that a clone of malignant cells exists that would not be responsive to an aromatase inhibitor.

Yes. If a patient’s tumor has an ESR1mut in the first-line setting (presumably due to progressive disease while on an AI for early stage breast cancer), I would absolutely pursue fulvestrant with a CDK4/6 inhibitor. Several trials (including PADA-1 above) have demonstrated the efficacy of fulvestrant in the setting of an ESR1mut. In patients whose tumors harbored an ESR1mut in the EMERALD study, fulvestrant outperformed AIs (6 months PFS 19.1 months vs 20.75 months). In the phase III EFECT and s...

For patients with HR+/HER2- breast cancer who develop metastatic progression on (or shortly after receiving) aromatase inhibitor therapy, fulvestrant with a CDK4/6 inhibitor (CDK4/6i) is a widely utilized therapeutic option. Several new medications have recently been approved for patients with metastatic breast cancer based upon the presence of specific genomic alterations, including elacestrant for patients with ESR1 mutation (Bidard et al., PMID 35584336). ESR1, the gene that encodes the estro...