title: A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer.
abstract: BACKGROUND
  We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for four weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10 mg per week (w)) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model.
  
  
  METHODS
  Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery. The primary endpoint was tissue change of Ki-67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers.
  
  
  RESULTS
  Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and antithrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki-67 and a marked increase of sex hormone-binding globulin (SHBG) were observed in the active phenotype.
  
  
  CONCLUSIONS
  A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki-67 expression, in premenopausal BC patients. However, in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation.
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.forename: Matteo
authors.initials: M
authors.lastname: Lazzeroni
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gjerde
authors.forename: Ernst
authors.initials: E
authors.lastname: Lien
authors.forename: Irene
authors.initials: I
authors.lastname: Feroce
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Maria
authors.initials: M
authors.lastname: Sandri
authors.forename: Fabio
authors.initials: F
authors.lastname: Bassi
authors.forename: Fabricio
authors.initials: F
authors.lastname: Brenelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Clara
authors.initials: C
authors.lastname: Varricchio
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Andrea
authors.initials: A
authors.lastname: DeCensi
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D010919:Placebos; D017697:Premenopause / Q000097:blood; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage*; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D010919:Placebos; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride