title: Targeting Estrogen Receptor Beta in a Phase 2 Study of High-Dose Estradiol in Metastatic Triple-Negative Breast Cancer: A Wisconsin Oncology Network Study.
abstract: Estrogen receptor beta (ERβ) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ERβ has antiproliferative effects in TNBC cells expressing ERβ. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC.
  
  
  
  Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ERβ status were also examined.
  
  
  
  Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ERβ expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERβ-positive patients and 0% (0 of 4) in ERβ-negative patients (P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ERβ-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients.
  
  
  
  In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ERβ selective agonists in TNBC selected by ERβ expression may be warranted.
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; School of Medicine and Public Health, University of Wisconsin, Madison, WI. Electronic address: kbwisinski@medicine.wisc.edu.
authors.forename: Kari B
authors.initials: KB
authors.lastname: Wisinski
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; School of Medicine and Public Health, University of Wisconsin, Madison, WI.
authors.forename: Amye J
authors.initials: AJ
authors.lastname: Tevaarwerk
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saha
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI.
authors.forename: KyungMann
authors.initials: K
authors.lastname: Kim
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; School of Medicine and Public Health, University of Wisconsin, Madison, WI.
authors.forename: Anne
authors.initials: A
authors.lastname: Traynor
authors.affiliation: Gundersen Lutheran Health System, Lacrosse, WI.
authors.forename: Leah
authors.initials: L
authors.lastname: Dietrich
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; School of Medicine and Public Health, University of Wisconsin, Madison, WI.
authors.forename: Robert
authors.initials: R
authors.lastname: Hegeman
authors.affiliation: Vince Lombardi Cancer Clinic, Aurora HealthCare Network, Green Bay, WI.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Patel
authors.affiliation: St Vincent Regional Cancer Center, Green Bay, WI.
authors.forename: Jules
authors.initials: J
authors.lastname: Blank
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI.
authors.forename: Josephine
authors.initials: J
authors.lastname: Harter
authors.affiliation: Carbone Cancer Center, University of Wisconsin, Madison, WI; School of Medicine and Public Health, University of Wisconsin, Madison, WI.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burkard
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D004958:Estradiol / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D011446:Prospective Studies; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014922:Wisconsin
chemical_list: C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D004967:Estrogens; D004958:Estradiol
keywords: Estradiol; Estrogen receptor beta; Triple-negative breast cancer