title: A phase II trial of low-dose estradiol in postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibition.
abstract: BACKGROUND
  High-dose oestrogen (HDE) is effective but toxic in postmenopausal women with advanced breast cancer (ABC). Prolonged oestrogen deprivation sensitises BC cell lines to estrogen and we hypothesised that third-generation aromatase inhibitors (AIs) would sensitise BCs to low-dose estradiol (LDE).
  
  
  METHODS
  A single-arm phase II study of LDE (2 mg estradiol valerate daily) in postmenopausal women with estrogen receptor-positive (ER+) ABC. The primary end-point was clinical benefit (CB) rate. If LDE was ineffective, HDE was offered. If LDE was effective, retreatment with the pre-LDE AI was offered on progression.
  
  
  RESULTS
  Twenty-one patients were recruited before the trial was closed early due to slow accrual; 19 were assessable for efficacy and toxicity. CB was seen in 5 in 19 patients (26%; 95% confidence interval 9.1-51.2%), all with prolonged SD (median duration 16.8 months; range 11.0-29.6). Treatment was discontinued for toxicity in 4 in 19 patients (21%) and 8 in 11 women without hysterectomy experienced vaginal bleeding (VB). After primary LDE failure, three patients received HDE and one achieved a partial response (PR). Following CB on LDE, four patients restarted pre-LDE AI and three achieved CB including one PR. Those with CB to LDE had a significantly longer duration of first-line endocrine therapy for ABC than those without (54.9 versus 16.8 months; p < 0.01) CONCLUSION: LDE is an effective endocrine option in women with evidence of prolonged sensitivity to AI therapy. LDE is reasonably well tolerated although VB is an issue. Re-challenge with the pre-LDE AI following progression confirms re-sensitisation as a true phenomenon.
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: G
authors.initials: G
authors.lastname: Zucchini
authors.affiliation: The Christie NHS Foundation Trust, UK; The University of Manchester, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Armstrong
authors.affiliation: The Christie NHS Foundation Trust, UK; The University of Manchester, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Wardley
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: G
authors.initials: G
authors.lastname: Wilson
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: V
authors.initials: V
authors.lastname: Misra
authors.affiliation: Central Manchester NHS Foundation Trust, UK.
authors.forename: M
authors.initials: M
authors.lastname: Seif
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: W D
authors.initials: WD
authors.lastname: Ryder
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cope
authors.affiliation: The Christie NHS Foundation Trust, UK.
authors.forename: E
authors.initials: E
authors.lastname: Blowers
authors.affiliation: The Christie NHS Foundation Trust, UK; The University of Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Howell
authors.affiliation: The University of Liverpool, UK.
authors.forename: C
authors.initials: C
authors.lastname: Palmieri
authors.affiliation: The Christie NHS Foundation Trust, UK; The University of Manchester, UK. Electronic address: sacha.howell@christie.nhs.uk.
authors.forename: S J
authors.initials: SJ
authors.lastname: Howell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D057239:Early Termination of Clinical Trials; D004739:England; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018579:Patient Selection; D017698:Postmenopause; D011788:Quality of Life; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004958:Estradiol
keywords: Aromatase inhibitor; Breast cancer; Endocrine; Low dose; Oestrogen