title: Randomized biomarker trial of anastrozole or low-dose tamoxifen or their combination in subjects with breast intraepithelial neoplasia.
abstract: OBJECTIVE
  In the Anastrozole, Tamoxifen Alone or in Combination trial, the combination arm was inferior to anastrozole alone in terms of disease-free survival possibly due to an adverse pharmacokinetic interaction or a predominant estrogenic effect of tamoxifen under estrogen deprivation. We assessed whether the addition of a lower dose of tamoxifen influenced anastrozole bioavailability and favorably modulated biomarkers of bone fracture, breast cancer, cardiovascular disease, and endometrial cancer risk. The influence of CYP2D6 genotype on tamoxifen effects was also determined.
  
  
  METHODS
  Seventy-five postmenopausal women with breast intraepithelial neoplasia were randomly allocated to either 1 mg/d anastrozole or 10 mg/wk tamoxifen or their combination for 12 months. Study endpoints were plasma drug concentrations and changes of C-telopeptide, osteocalcin, estradiol/sex hormone binding globulin (SHBG) ratio, estrone sulfate, insulin-like growth factor-I (IGF-I)/insulin-like growth factor binding protein-3 (IGFBP-3), C-reactive protein, antithrombin-III, endometrial Ki-67 expression, and thickness.
  
  
  RESULTS
  Anastrozole concentrations were not affected by the combination with low-dose tamoxifen, whereas endoxifen levels were lower in poor CYP2D6 metabolizers. C-telopeptide increased by 20% with anastrozole and decreased by 16% with tamoxifen and by 7% with their combination (P < 0.001); osteocalcin showed similar changes. Compared with anastrozole, the combination arm showed lower IGF-I/IGFBP-3 levels (-17% versus -9%; P = 0.004) and lower estradiol/SHBG and estrone sulfate reductions (-15% versus -29% and -30% versus 38%, respectively). However, IGF-I/IGFBP-3 and estradiol/SHBG did not decrease in poor CYP2D6 metabolizers. Endometrial thickness was not greater in the combination than in the anastrozole arm.
  
  
  CONCLUSIONS
  The addition of a weekly tamoxifen administration did not impair anastrozole bioavailability and modulated favorably its safety profile, providing the rationale for further studies.
authors.affiliation: Divisions of Cancer Prevention and Genetics, European Institute of Oncology, Milan, University of Milan School of Medicine, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Enrico
authors.initials: E
authors.lastname: Cassano
authors.forename: Sabina
authors.initials: S
authors.lastname: Oldani
authors.forename: Ernst A
authors.initials: EA
authors.lastname: Lien
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D010597:Pharmacogenetics; D011230:Precancerous Conditions / Q000473:pathology*; D012306:Risk; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole; D019389:Cytochrome P-450 CYP2D6