title: Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.
abstract: Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Mura Delle Cappuccine 14, 16128, Genoa, Italy, andrea.decensi@galliera.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: DeCensi
authors.forename: Matteo
authors.initials: M
authors.lastname: Puntoni
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Harriet Ann
authors.initials: HA
authors.lastname: Johansson
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: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.forename: Serena
authors.initials: S
authors.lastname: Mora
authors.forename: Valentina
authors.initials: V
authors.lastname: Aristarco
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
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: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008687:Metformin / Q000627:therapeutic use*
chemical_list: D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D008687:Metformin