Introduction
Methods
Patients
Statistical analysis
Metformin | Non metformin | Non diabetic |
P-value | ||||
---|---|---|---|---|---|---|---|
(n = 202) | (n = 184) | (n = 6,581) | |||||
Number | % | Number | % | Number | % | ||
Age at operation, years
| |||||||
Median (range) | 55(10.5) | 59(10.2) | 46(9.6) | <0.001 | |||
<50 | 68 | 33.7 | 40 | 21.7 | 4370 | 66.4 | |
≥50 | 134 | 66.3 | 144 | 78.3 | 2211 | 33.6 | |
Body mass index, kg/m
2
| |||||||
<18.5 | 0 | 0 | 4 | 2.2 | 242 | 3.7 | <0.001 |
≥18.5, <25 | 84 | 41.6 | 75 | 40.8 | 4644 | 70.8 | |
≥25 | 118 | 58.4 | 105 | 57.1 | 1669 | 25.5 | |
Serum glucose, mg/dL
| |||||||
Median | 165.5 | 150.5 | |||||
≤150 | 83 | 40.7 | 93 | 50 | 0.068 | ||
>150 | 121 | 59.3 | 93 | 50 | |||
HbA1C, %
| |||||||
<7 | 51 | 32.1 | 29 | 35.8 | 0.566 | ||
≥0.5108 | 67.9 | 52 | 64.2 | ||||
Tumor size, cm
| |||||||
≤2 | 100 | 49.5 | 93 | 50.5 | 3535 | 53.7 | 0.356 |
>2 | 102 | 50.5 | 91 | 49.5 | 3046 | 46.3 | |
Node metastasis
| |||||||
No | 110 | 54.5 | 110 | 59.8 | 3860 | 58.7 | 0.463 |
Yes | 92 | 45.5 | 74 | 40.2 | 2721 | 41.3 | |
Chemotherapy
| |||||||
No | 66 | 32.7 | 80 | 43.5 | 1799 | 27.3 | <0.001 |
Yes | 136 | 67.3 | 104 | 56.5 | 4782 | 72.7 | |
Endocrine therapy
| |||||||
No | 58 | 28.7 | 54 | 29.3 | 2013 | 30.6 | 0.801 |
Yes | 144 | 71.3 | 130 | 70.7 | 4568 | 69.4 | |
Subgroup according to IHC using ER, PR and HER2
| |||||||
Hormone receptor+, HER2- | 107 | 53.0 | 98 | 53.3 | 3390 | 51.5 | 0.385 |
Hormone receptor+, HER2- | 27 | 13.4 | 18 | 9.8 | 916 | 13.9 | |
Hormone receptor-, HER2+ | 35 | 17.3 | 25 | 13.6 | 928 | 14.1 | |
Hormone receptor-, HER2- | 33 | 16.3 | 43 | 23.4 | 1347 | 20.5 |
Results
Patient demographic and clinical characteristics
Disease-free survival | Cancer-specific survival | |||||
---|---|---|---|---|---|---|
P-value | Hazard ratio | 95 % CI |
P-value | Hazard ratio | 95 % CI | |
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.05 | 1.50 | 1.0 to 2.25 | 0.02 | 1.69 | 1.07 to 2.68 |
Non-DM versus metformin | 0.39 | 0.87 | 0.64 to 1.19 | 0.29 | 0.83 | 0.58 to 1.18 |
Age, years
| ||||||
≤50 | 0.652 | 0.97 | 0.87 to 1.09 | 0.023 | 0.83 | 0.73 to 0.96 |
BMI, kg/m2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.141 | 1.24 | 0.94 to 1.64 | 0.362 | 1.17 | 0.84 to 1.64 |
Normal versus high | 0.132 | 0.91 | 0.80 to 1.03 | 0.064 | 0.87 | 0.75 to 1.01 |
Tumor size, cm
| ||||||
T ≥2 | <0.001 | 2.59 | 2.30 to 2.91 | <0.001 | 3.10 | 2.68 to 3.59 |
Node metastasis
| ||||||
Node-positive | <0.001 | 2.79 | 0.49 to 3.13 | <0.001 | 3.58 | 3.10 to 4.13 |
Estrogen receptor status
| ||||||
Positive | 0.026 | 0.78 | 0.63 to 0.97 | <0.001 | 1.85 | 1.62 to 2.11 |
Progesterone receptor status
| ||||||
Positive | 0.001 | 0.72 | 0.60 to 0.87 | <0.001 | 1.93 | 1.69 to 2.21 |
HER2 status
| ||||||
Positive | <0.001 | 1.44 | 1.28 to 1.62 | <0.001 | 1.56 | 1.37 to 1.79 |
Chemotherapy
| ||||||
Yes | 0.098 | 0.82 | 0.65 to 1.04 | <0.001 | 0.38 | 0.31 to 0.46 |
Endocrine therapy
| ||||||
Yes | 0.108 | 0.83 | 0.67 to 1.04 | <0.001 | 1.78 | 1.56 to 2.03 |
Breast cancer survival according to diabetes mellitus and metformin treatment
Disease-free survival | Cancer-specific survival | |||||
---|---|---|---|---|---|---|
P-value | Hazard ratio | 95 % CI |
P-value | Hazard ratio | 95 % CI | |
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.025 | 1.59 | 1.06 to 2.39 | 0.009 | 1.85 | 1.17 to 2.92 |
Non-DM versus metformin | 0.483 | 0.90 | 0.66 to 1.22 | 0.519 | 0.89 | 0.62 to 1.27 |
Age, years
| ||||||
≤50 | 0.584 | 1.04 | 0.92 to 1.17 | 0.106 | 0.89 | 0.77 to 1.03 |
Body mass index, kg/m2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.009 | 1.17 | 1.1 to 1.17 | 0.018 | 1.52 | 1.08 to 2.14 |
Normal versus high | 0.639 | 1.03 | 0.91 to 1.17 | 0.597 | 1.04 | 0.90 to 1.21 |
Tumor size, cm
| ||||||
T ≥2 | <0.001 | 2.03 | 1.78 to 2.31 | <0.001 | 2.18 | 1.86 to 2.56 |
Node metastasis
| ||||||
Node positive | <0.001 | 2.59 | 2.26 to 2.96 | <0.001 | 3.09 | 2.63 to 3.64 |
Estrogen receptor status
| ||||||
Positive | 0.009 | 0.79 | 0.66 to 0.94 | 0.026 | 0.78 | 0.63 to 0.97 |
Progesterone receptor status
| ||||||
Positive | 0.004 | 0.80 | 0.68 to 0.93 | 0.001 | 0.72 | 0.60 to 0.87 |
HER2 status
| ||||||
Positive | <0.001 | 1.27 | 1.13 to 1.44 | <0.001 | 1.29 | 1.12 to 1.49 |
Chemotherapy
| ||||||
Yes | <0.001 | 0.70 | 0.58 to 0.84 | 0.098 | 0.82 | 0.65 to 1.04 |
Endocrine therapy
| ||||||
Yes | 0.312 | 0.91 | 0.75 to 1.10 | 0.108 | 0.83 | 0.67 to 1.04 |
Disease-free survival | Cancer-specific survival | |||||
---|---|---|---|---|---|---|
P-value | Hazard ratio | 95 % CI |
P-value | Hazard ratio | 95 % CI | |
Hormone receptor-positive, HER2-negative
| ||||||
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.340 | 1.35 | 0.73 to 2.47 | 0.072 | 1.92 | 0.94 to 3.90 |
Non-DM versus metformin | 0.484 | 0.85 | 0.54 to 1.34 | 0.64 | 0.87 | 0.50 to 1.54 |
Age, years
| ||||||
≤50 | 0.369 | 0.92 | 0.76 to 1.12 | 0.012 | 0.728 | 0.57 to 0.93 |
Body mass index, kg/m
2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.034 | 1.62 | 1.04 to 2.54 | 0.009 | 2.11 | 1.20 to 3.68 |
Normal versus high | 0.772 | 0.97 | 0.80 to 1.18 | 0.87 | 0.98 | 0.76 to 1.26 |
Tumor stage
| ||||||
T ≥2 | <0.001 | 2.10 | 1.73 to 2.54 | <0.001 | 2.44 | 1.88 to 3.16 |
Node stage
| ||||||
Node-positive | <0.001 | 2.13 | 1.76 to 2.58 | <0.001 | 2.92 | 2.25 to 3.80 |
Hormone receptor-positive, HER2-positive
| ||||||
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.002 | 5.37 | 1.88 to 15.28 | 0.001 | 6.51 | 2.06 to 20.55 |
Non-DM versus metformin | 0.648 | 1.23 | 0.50 to 3.02 | 0.502 | 1.41 | 0.52 to 3.84 |
Age, years
| ||||||
≤50 | 0.120 | 0.79 | 0.59 to 1.06 | 0.006 | 0.623 | 0.45 to 0.87 |
Body mass index, kg/m
2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.050 | 2.15 | 1.00 to 4.63 | 0.446 | 1.50 | 0.53 to 4.30 |
Normal versus high | 0.053 | 1.41 | 1.00 to 1.99 | 0.085 | 1.41 | 0.95 to 2.09 |
Tumor stage
| ||||||
T ≥2 | <0.001 | 1.81 | 1.33 to 4.27 | 0.004 | 1.72 | 1.19 to 2.47 |
Node stage
| ||||||
Node-positive | <0.001 | 2.22 | 1.64 to 3.02 | 0.000 | 2.85 | 1.97 to 4.13 |
Hormone receptor-negative, HER2-positive
| ||||||
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.897 | 1.07 | 0.39 to 2.95 | 0.452 | 0.61 | 0.16 to 2.24 |
Non-DM versus metformin | 0.310 | 0.72 | 0.38 to 1.36 | 0.156 | 0.61 | 0.31 to 1.21 |
Age, years
| ||||||
≤50 | 0.310 | 1.17 | 0.89 to 1.54 | 0.385 | 1.15 | 0.84 to 1.57 |
Body mass index, kg/m
2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.06 | 1.81 | 0.98 to 3.35 | 0.189 | 1.63 | 0.79 to 3.38 |
Normal versus high | 0.615 | 0.93 | 0.68 to 1.25 | 0.471 | 0.88 | 0.63 to 1.24 |
Tumor stage
| ||||||
T ≥2 | <0.001 | 1.98 | 1.45 to 2.71 | <0.001 | 2.39 | 1.63 to 3.51 |
Node stage
| ||||||
Node-positive | <0.001 | 3.03 | 2.24 to 4.11 | <0.001 | 3.94 | 2.71 to 5.72 |
Hormone receptor-negative, HER2-negative
| ||||||
Metformin
| ||||||
Metformin | 1 | 1 | ||||
Non-metformin versus metformin | 0.311 | 1.62 | 0.64 to 4.12 | 0.329 | 1.66 | 0.60 to 4.56 |
Non-DM versus metformin | 0.89 | 1.05 | 0.50 to 2.24 | 0.867 | 1.07 | 0.47 to 2.42 |
Age, years
| ||||||
≤50 | 0.350 | 1.13 | 0.88 to 1.44 | 0.989 | 1.00 | 0.76 to 1.32 |
Body mass index, kg/m
2
| ||||||
High | 1 | 1 | ||||
Low versus high | 0.993 | 1.00 | 0.54 to 1.83 | 0.629 | 1.17 | 0.62 to 2.23 |
Normal versus high | 0.750 | 1.04 | 0.81 to 1.34 | 0.583 | 1.08 | 0.82 to 1.43 |
Tumor stage, cm
| ||||||
T ≥2 | <0.001 | 1.62 | 1.26 to 2.08 | <0.001 | 1.76 | 1.32 to 2.34 |
Node stage
| ||||||
Node-positive | <0.001 | 2.25 | 1.78 to 2.84 | <0.001 | 2.45 | 1.88 to 3.19 |
Subgroup analyses according to intrinsic subtype using immunohistochemical staining of ER, PR, and HER2
Subgroup analyses according to systemic treatment of breast cancer among nondiabetic patients, diabetic patients receiving metformin, and diabetic patients not receiving metformin
Discussion
Study | Year | Study population of breast cancer | Number (met/non-met/non-DM) | DFS | CSS | OS | Follow up (months or years) | HR (met versus non-met)1; 95 % CI | Special subgroup | Duration of metformin treatment | Tumor characteristics |
---|---|---|---|---|---|---|---|---|---|---|---|
He et al. [15] | 2012 | Stage II, HER2+ only | 88/66/1829 | N | Y | Y | 47.6 | OS (HR 0.52; 0.28 to 0.97) | NA | Done | |
CSS (HR 0.47; 0.24 to 0.90) | |||||||||||
Bayraktar et al. [17] | 2012 | Triple-negative only | 63/67/1318 | Y | Y | Y | 62 | OS (HR 1.22; 0.66 to 2.28) | NA | Done | |
RFS (HR 1.37; 0.78 to 2.40) | |||||||||||
DMFS (HR 1.63; 0.87 to 3.06) | |||||||||||
Peeters et al. [12] | 2013 | All | 508/550/NA | N | Y | Y | OS (HR 0.74; 0.58 to 0.96) | Increased risk in the first 12 months after discontinuation | Done | NA | |
CSS (HR 0.88; 0.59 to 1.29) | |||||||||||
Lega et al. [14] | 2013 | All | 1094/1267/NA | N | Y | Y | 4.5 (years) | OS (HR 0.97; 0.92 to 1.02) | Done | NA | |
CSS (HR 0.91; 0.81 to 1.03) | |||||||||||
Hou et al. [18] | 2013 | All | 419/594/4612 | N | N | Y | 68 | OS2 (HR 0.762; 0.6 to 0.986) | NA | Done | |
OS3 (HR 1.708; 1.461 to 1.997) | |||||||||||
Xiao et al. [19] | 2014 | Luminal | 275/405/5105 | N | Y | Y | 70 | OS (HR 3.579; 1.506 to 8.506) luminal A | NA | Done | |
OS (HR 3.232;1.839 to 5.678) luminal B (high Ki67) | |||||||||||
OS (HR 2.034;1.019 to 4.059) Luminal B (HER2+) | |||||||||||
Kim et al. (present study) | All | 202/184/6581 | Y | Y | Y | 100 | OS (HR 1.87;1.25 to 2.81) | 1.Hormone receptor+/HER2 + | NA | Done | |
CSS (HR1.85;1.17 to 2.92) | 2.Chemotherapy and endocrine therapy | ||||||||||
DFS (HR 1.59, 1.06 to 2.39) |