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Table 3 Open questions and relevant ongoing trials

From: ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

Open question 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?
  1. Shown are questions and relevant trials discussed in the text. Additional preclinical questions are listed at the bottom