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Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.

DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, Pruneri G, Serrano D, Schwab M, Hofmann U, Mora S, Aristarco V, Macis D, Bassi F, Luini A, Lazzeroni M, Bonanni B, Pollak MN - Breast Cancer Res. Treat. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Mura Delle Cappuccine 14, 16128, Genoa, Italy, andrea.decensi@galliera.it.

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.

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Subpopulation treatment effect pattern plots (STEPP) of the change (difference between endpoint surgery and baseline biopsy) of ki-67 according to the following covariates: C-peptide (panel A), free IGF-I (panel B), IGFBP-3 (panel C), IGFBP-1 (panel D). Positive change, metformin worse; negative change, metformin better. p values for interaction with treatment from the linear regression model (response variable: change of ki-67, adjusted for: ki-67 and BMI at baseline, age): C-peptide, p = 0.3 (threshold: median, 1.53 ng/mL); free IGF-I, p = 0.03 (continuous variable); IGFBP-3, p = 0.04 (median, 4.2 μg/mL); IGFBP-1, p = 0.016 (20th p.le, 1.91 ng/mL)
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Fig2: Subpopulation treatment effect pattern plots (STEPP) of the change (difference between endpoint surgery and baseline biopsy) of ki-67 according to the following covariates: C-peptide (panel A), free IGF-I (panel B), IGFBP-3 (panel C), IGFBP-1 (panel D). Positive change, metformin worse; negative change, metformin better. p values for interaction with treatment from the linear regression model (response variable: change of ki-67, adjusted for: ki-67 and BMI at baseline, age): C-peptide, p = 0.3 (threshold: median, 1.53 ng/mL); free IGF-I, p = 0.03 (continuous variable); IGFBP-3, p = 0.04 (median, 4.2 μg/mL); IGFBP-1, p = 0.016 (20th p.le, 1.91 ng/mL)

Mentions: Figure 2 illustrates the STEPP analyses of the change of ki-67 (the difference between endpoint surgery and baseline biopsy) in the metformin arm relative to the placebo arm according to the continuous scale for the following markers of insulin resistance: C-peptide, IGFBP-3, IGFBP-1, and free IGF-I. Metformin had a heterogeneous effect depending on markers of insulin resistance, which manifested itself in a tendency to decrease ki-67 levels in women with insulin resistance (approximately a quarter), defined by high levels of HOMA, C-peptide, IGFBP-3, and by low levels of free IGF-I and IGFBP-1, whereas it showed a trend to an increase of ki-67 in the majority of the remaining women. Except for C-peptide (p-interaction = 0.3), all variables illustrated in Fig. 2 as well as hs-CRP significantly modified the effect of metformin on ki-67 at p < 0.1. Variables not exhibiting a significant interaction with metformin were: weight, BMI, glucose, insulin, adiponectin, and total IGF-I.Fig. 2


Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial.

DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, Pruneri G, Serrano D, Schwab M, Hofmann U, Mora S, Aristarco V, Macis D, Bassi F, Luini A, Lazzeroni M, Bonanni B, Pollak MN - Breast Cancer Res. Treat. (2014)

Subpopulation treatment effect pattern plots (STEPP) of the change (difference between endpoint surgery and baseline biopsy) of ki-67 according to the following covariates: C-peptide (panel A), free IGF-I (panel B), IGFBP-3 (panel C), IGFBP-1 (panel D). Positive change, metformin worse; negative change, metformin better. p values for interaction with treatment from the linear regression model (response variable: change of ki-67, adjusted for: ki-67 and BMI at baseline, age): C-peptide, p = 0.3 (threshold: median, 1.53 ng/mL); free IGF-I, p = 0.03 (continuous variable); IGFBP-3, p = 0.04 (median, 4.2 μg/mL); IGFBP-1, p = 0.016 (20th p.le, 1.91 ng/mL)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4196136&req=5

Fig2: Subpopulation treatment effect pattern plots (STEPP) of the change (difference between endpoint surgery and baseline biopsy) of ki-67 according to the following covariates: C-peptide (panel A), free IGF-I (panel B), IGFBP-3 (panel C), IGFBP-1 (panel D). Positive change, metformin worse; negative change, metformin better. p values for interaction with treatment from the linear regression model (response variable: change of ki-67, adjusted for: ki-67 and BMI at baseline, age): C-peptide, p = 0.3 (threshold: median, 1.53 ng/mL); free IGF-I, p = 0.03 (continuous variable); IGFBP-3, p = 0.04 (median, 4.2 μg/mL); IGFBP-1, p = 0.016 (20th p.le, 1.91 ng/mL)
Mentions: Figure 2 illustrates the STEPP analyses of the change of ki-67 (the difference between endpoint surgery and baseline biopsy) in the metformin arm relative to the placebo arm according to the continuous scale for the following markers of insulin resistance: C-peptide, IGFBP-3, IGFBP-1, and free IGF-I. Metformin had a heterogeneous effect depending on markers of insulin resistance, which manifested itself in a tendency to decrease ki-67 levels in women with insulin resistance (approximately a quarter), defined by high levels of HOMA, C-peptide, IGFBP-3, and by low levels of free IGF-I and IGFBP-1, whereas it showed a trend to an increase of ki-67 in the majority of the remaining women. Except for C-peptide (p-interaction = 0.3), all variables illustrated in Fig. 2 as well as hs-CRP significantly modified the effect of metformin on ki-67 at p < 0.1. Variables not exhibiting a significant interaction with metformin were: weight, BMI, glucose, insulin, adiponectin, and total IGF-I.Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Mura Delle Cappuccine 14, 16128, Genoa, Italy, andrea.decensi@galliera.it.

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.

Show MeSH
Related in: MedlinePlus