|
| References | Patient cohort | Age group | Ethnicity | BCa type | Key findings |
|
| Currie et al. 2012 [29] | 112408 (8392 DM)
(i) 24393 BCa (no DM)
(ii) 1182 BCa (with DM) | >35 years | N/S | N/S | No mortality differences with/without metformin at diagnosis |
|
| Chlebwoski et al. 2012 [99] | 68,019 patients (3401 DM)
(i) 3273 invasive BCa | Postmenopausal | Mixed race | ER+ PR+
HER2+
HER2−
Noninvasive
Invasive | Women with diabetes were older and were more likely to be black and obese.
Women with diabetes on metformin had a reduced BCa risk:
Associated with PR+ ER+
Associated with HER2+?
No association with HER2−
Lower incidence of invasive BCa |
|
| Kiderlen et al. 2013 [100] | 3124 (505 DM)
(i) nonmetastatic BCa | Postmenopausal | N/S (Netherlands) | ER/PR+
ER/PR−
Not defined | Patients with diabetes had overall better relapse-free survival (possibly through the effect of metformin, speculated not proven) |
|
| Xiao et al. 2014 [101] | 5785 Luminal-type BCa (680 DM)
(i) 1384 luminal A (201 diabetes)
(ii) 3393 luminal B, high Ki67+
(341 DM)
(iii) 1008 luminal B (her-2/neu+)
(138 DM) | Pre-and postmenopausal | Asian | Luminal A
Luminal B (Ki67)
Luminal B (HER2+) | BMI was not a prognostic factor in these studies
Metformin versus nonmetformin:
Better prognosis for all subtypes
Compared to metformin group, risk of death was higher in nonmetformin group. No significant difference between metformin and control groups.
Diabetic patients:
Metformin better prognosis for Luminal A and Luminal B (HER2+)
Metformin poorer prognosis for Luminal B (high Ki67) |
|
| Bonanni et al. 2012 [102] | 200 (non-DM)
(i) 100 metformin
(ii) 100 placebo | >18 years both pre and postmenopausal | N/S
(Milan) | Luminal A
Luminal B (Ki67)
Luminal B (HER2+)
TNBC | Metformin treatment:
Overall, no change in Ki67
Overall, positive effect on insulin resistance
Luminal B tumours-trend, decreased proliferation.
Overweight or obese-trend, decreased proliferation |
|
| Besic et al. 2014 [103] | 573 (invasive BCa)
(i) 253 patients (+DM)
(ii) 128 + metformin
(iii) 125 no metformin.
(iv) 320 BCa (no DM) | 38–93 years
(median age, 67) | N/S
(Slovenia) | Luminal A
Luminal B
HER2
TNBC | DM + metformin—lower grade BCa compared to no metformin
No change in ER/PR status with metformin
Noted: Long-term metformin treatment was correlated with different BCa subtype distribution |
|
| Berstein et al. 2011 [104] | 90 (BCa and DM) | 48–82 years postmenopausal | N/S | ER+
PR+ | Metformin increased PR in diabetic patients.
Potentially increasing endocrine therapy success |
|
| Lega et al. 2014 [105] | Meta-analyses—Cancer patients with diabetes (all cancer types) | All ages | N/S | All types | No correlation between BCa and metformin and increased survival |
|
| Lega et al. 2013 [106] | 2361 (BCa and DM) | >66 years | Ontario
Ethnicity N/S | All types | No significant reduction in mortality or DFS in patients using metformin |
|
| Oppong et al. 2014 [107] | 2889 (BCa + chemotherapy)
(i) 141 (BCa + DM)
(ii) 104 (DM at BCa diagnosis)
(iii) 37 (DM + BCa diagnosed 6 mth) | 38–80 years
Majority
Postmenopausal | Caucasian (72)
African/American (52),
Asian (10),
Hispanic (4) | ER+, ER−
PR+, PR−
HER2+, HER2− | No difference between metformin and nonmetformin users in RFS, OS, and contralateral BCa |
|
| Bayraktar et al. 2012 [108] | 1448 (triple negative BCa—TNBC)
(i) 63 diabetic + metformin
(ii) 67 diabetic no metformin
(iii) 1318 non diabetic | More diabetic patients were postmenopausal | black, and obese | Triple negative | Metformin does not significantly impact on survival in TNBC.
Trend toward decreased risk of distant metastasis in DM patients receiving metformin compared to non-DM |
|
| Ferro et al. 2013 [109] | 110 (BCa)
(i) 51 + metformin (DM)
(ii) 28 no metformin (DM)
(iii) 51 non-DM | >50 | Mixed (white, black, other) | All types | Radiation therapy and metformin treatment
Metformin associated with increased local radiation toxicity compared to nonmetformin users |
|
| Kim et al. 2014 [110] | 208 (BCa—no DM)
(i) 104 + Letrozole
(ii) 104 + letrozole + metformin | Postmenopausal | Asian
(Korean) | ER+ | Study in progress |
|
|
Kalinsky et al. 2014 [111] | 33 non DM patients (Obese)
(i) 9 DCIS
(ii) 24 invasive BCa | >21 years | 80% Hispanic | 85% HR+
20% triple negative | Metformin treatment pre-surgery—No reduction in proliferation of BCa tumour. Reduction in diabetic markers (insulin resistance) |
|
| Cazzaniga et al. 2013 [112] | 100 BCa patients-Analysed
(i) 45 metformin
(ii) 42 placebo. | 45–62 years | N/S
(Milan) | Luminal A
Luminal B
Her2+
Triple negative | Metformin treatment pre-surgery—No reduction in proliferation of BCa tumour. Reduction in diabetic markers (insulin resistance) |
|
Hadad et al.
2011 [113] | 55 (BCa—no DM)
(i) 25 completed met.
(ii) 22 no metformin | 41–82 years
Pre- and postmenopausal | N/S | N/S | This trial supports antiproliferative effects of metformin in BC patients |
|
