title: Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial.
abstract: OBJECTIVE
  Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.
  
  
  METHODS
  After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.
  
  
  RESULTS
  Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).
  
  
  CONCLUSIONS
  Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, Genoa, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.forename: Matteo
authors.initials: M
authors.lastname: Puntoni
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gennari
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Trabacca
authors.forename: Viviana
authors.initials: V
authors.lastname: Galimberti
authors.forename: Paolo
authors.initials: P
authors.lastname: Veronesi
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Valentina
authors.initials: V
authors.lastname: Aristarco
authors.forename: Fabio
authors.initials: F
authors.lastname: Bassi
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Matteo
authors.initials: M
authors.lastname: Lazzeroni
authors.forename: Clara
authors.initials: C
authors.lastname: Varricchio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Paolo
authors.initials: P
authors.lastname: Bruzzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007333:Insulin Resistance; D007558:Italy; D019394:Ki-67 Antigen / Q000097:blood; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D019394:Ki-67 Antigen; D008687:Metformin