Table 3 Open questions and relevant ongoing trials

How do different ESR1 mutations (D538G, Y537S, others) differentially affect resistance?

NCT03250676: Phase 2 trial (~ 150 patients) of H3B-6545 for patients after progression on ET + CDK4/6i, with plan to analyze outcomes by different ESR1 mutations

How does selecting treatment based on the detection of ESR1-MUT in cfDNA affect clinical outcomes?

PADA-1 (NCT03079011): Phase 3 trial (~ 1000 patients) of randomizing patients on AI + palbociclib to continuing versus changing to fulvestrant + palbociclib after detection of ESR1-MUT in surveillance cfDNA

ELAINE-2 (NCT04432454): Phase 2 trial (~ 25 patients) of lasofoxifene + abemaciclib for patients who progressed on ET and have ESR1-MUT

ELAINE (NCT03781063): Phase 2 trial (~ 100 patients) of lasofoxifene versus fulvestrant for patients who progressed on AI + CDK4/6i and have ESR1-MUT

Are novel SERM/SERCA/SERD drugs superior to tamoxifen/fulvestrant for ESR1-MUT?

ELAINE (NCT03781063): Phase 2 trial (~ 100 patients) of lasofoxifene versus fulvestrant for patients who progressed on AI + CDK4/6i and have ESR1-MUT

EMERALD (NCT03778931): Phase 3 trial (~ 500 patients) of elacestrant versus AI/fulvestrant for patients who progressed on ET + CDK4/6i

AMEERA-3 (NCT04059484): Phase 2 trial (~ 400 patients) of amcenestrant versus AI/fulvestrant/tamoxifen for patients who progressed on ET

SERENA-2 (NCT04214288): Phase 2 trial (~ 250 patients) of camizestrant versus fulvestrant for patients who progressed on ET

acelERA (NCT04576455): Phase 2 trial (~ 300 patients) of giredestrant versus fulvestrant/AI for patients who progressed on ET

How can neomorphic/hypermorphic activities of ESR1-MUT be targeted?

How does ESR1-MUT interact with PI3K-AKT-mTORC1 signaling?

Why does AI in the adjuvant setting (as opposed to the metastatic setting) fail to select for ESR1-MUT?

How does ESR1-MUT VAF reflect total tumor burden and progression?

What are effective treatments for ESR1 fusions that lack the LBD?

How can combinatorial resistance be modeled in experiments?