Use of metformin has been associated with reduced breast cancer risk in observational studies in diabetic patients, but evidence for antitumor activity in randomized clinical studies is lacking. In a randomized trial in non-diabetic women with operable breast cancer who were allocated after tumor biopsy to either metformin, 850 mg bid (n=100) or placebo (n=100) for 4 weeks prior to surgery, we recently showed that the effect of the drug on breast cancer proliferation (Ki-67 labeling index) varies according to insulin resistance as assessed by HOMA index. Here we report effects of metformin on circulating markers of insulin resistance, including C-peptide, IGFBP-1, testosterone, SHBG and adiponectin. We observed a non-homogenous effect of metformin on some of these biomarkers, in a manner that is related to the dual effect of metformin on tumor Ki-67. Overall, metformin did not affect C-peptide (p=0.74) or IGFBP-1 levels (p=0.48), but there was a significant interaction with BMI (p=0.02), with a 19% decrease in C-peptide (p=0.105) in women with BMI >27 (75th percentile), and a 4% increase (p=0.367) in women with BMI β27. In women with baseline IGFBP-1 levels <2.0 ng/ml (20th percentile; n=43), metformin was associated with a 20% decrease in Ki-67 at surgery (95% CI: –36.1 to –0.01; P=0,05), while a 10% increase was observed in women with IGFBP-1 β2.0 ng/ml (95% CI: –1.7 to 22.2; p=0,099; n=153). Consistently, we observed a strong inverse correlation between baseline IGFBP-1 levels and HOMA index (spearman's rho = –0.455, p<0.0001), and BMI (spearman's rho = –0.279, p<0.0001). Interestingly, we found a significant correlation between baseline IGFBP-1 levels and Ki-67 (p=0.032; r= –0.120), independent of treatment. Metformin decreased testosterone levels by 20% in postmenopausal women only (p=0.002, n=99), regardless of BMI and HOMA index. Ki-67 at surgery was not significantly associated with testosterone levels at baseline (p=0.737), nor did we observe any interaction between testosterone and treatment on Ki-67. Metformin did not affect SHBG levels (p=0.787), nor did we observe any modification of SHBG by HOMA (p=0.9) or BMI (p=0.7). Finally, we observed a decrease by a mean of 0.94 ug/ml (95% CI: 0.90 to 0.99) in adiponectin levels under metformin (p=0.009) as compared with placebo, without any interaction with Ki-67. Conclusions: Serum IGFBP-1 concentration is inversely related to breast cancer proliferation as measured by Ki-67 labelling index, and defines a subpopulation of breast cancer patients in which metformin decreases tumor proliferation. These findings support the hypothesis that insulin resistance influences breast cancer biology, and have implications regarding both the mechanism of action of metformin at dose used and the optimum design of future clinical trials of biguanides in cancer prevention and treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3561. doi:1538-7445.AM2012-3561