• Andrea DeCensi, Matteo Puntoni, Sara Gandini, Aliana Guerrieri-Gonzaga, Harriet Ann Johansson, Massimiliano Cazzaniga, Giancarlo Pruneri, Davide Serrano, Matthias Schwab, Ute Hofmann, Serena Mora, Valentina Aristarco, Debora Macis, Fabio Bassi, Alberto Luini, Matteo Lazzeroni, Bernardo Bonanni, and Michael N Pollak.
• Division of Medical Oncology, E.O. Ospedali Galliera, Mura Delle Cappuccine 14, 16128, Genoa, Italy, andrea.decensi@galliera.it.
• Breast Cancer Res. Treat. 2014 Nov 1; 148 (1): 81-90.

AbstractTreatment 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.

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