title: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.
abstract: OBJECTIVE
  Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs).
  
  
  METHODS
  This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned.
  
  
  RESULTS
  The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%).
  
  
  CONCLUSIONS
  This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.
authors.affiliation: Département de Cancérologie Médicale et Unité INSERM U590, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon cedex 08, France. thomas.bachelot@lyon.unicancer.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Céline
authors.initials: C
authors.lastname: Bourgier
authors.forename: Claire
authors.initials: C
authors.lastname: Cropet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Sophie
authors.initials: S
authors.lastname: Abadie-Lacourtoisie
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Eymard
authors.forename: Marc
authors.initials: M
authors.lastname: Debled
authors.forename: Dominique
authors.initials: D
authors.lastname: Spaëth
authors.forename: Eric
authors.initials: E
authors.lastname: Legouffe
authors.forename: Djelila
authors.initials: D
authors.lastname: Allouache
authors.forename: Claude
authors.initials: C
authors.lastname: El Kouri
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000068338:Everolimus; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D047072:Aromatase Inhibitors; D000068338:Everolimus; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020123:Sirolimus; D013629:Tamoxifen; C508053:ERBB2 protein, human