Table 4 Literature review of clinical studies concerning metformin use on breast cancer

Clinical studies of the treatment effect of metformin on breast cancer

RCT, Phase III

850 mg b.i.d for 5 years

No

American Indian or Alaska Native (0.5%)

ER/PgR−:

Median (range)

ER/PgR−: not significant

Goodwin et al. [55]

Case: 1268/control: 1265

Case: 51 (25–74)

DFS:HR = 1.01 (95% CI 0.84–1.21)

Asian (2.8%)

OS:HR = 1.10 (95% CI 0.86–1.41)

Control: 52 (23–74)

Black or African American (4.3%)

Hispanic (4.9%)

ER/PgR+:

Case: 52 (25–74)

ER/PgR+: not significant

Case: 556/control: 560

DFS:HR = 1.01 (95% CI 0.79–1.30)

Native Hawaiian or Pacific Islander (0.4%)

OS:HR = 0.89 (95% CI 0.64–1.23)

Control: 53 (25–74)

White non-Hispanic (85.7%)

RCT, Phase II

1000 mg b.i.d for 1.5 years

No

Egyptian

Case: 36/control: 38

Mean (± SD)

Not significant

Barakat et al. [5]

Case: 49.14 ± 11.22

PCR:OR = 2.429 (95% CI 0.662–8.914)

Control: 47.13 ± 10.53

ORR:OR = 1.912 (95% CI 0.655 –5.585)

CCR:OR = 3.269 (95% CI 0.921–11.606)

RCT, Phase II

850 mg b.i.d for 6 weeks

Partial

Chinese

Case: 41/control: 35

Case: ≤ 50 (42.0%), > 50 (58.0%)

Not significant

Huang et al. [56]

tpCR (P = 0.777)

Control: ≤ 50 (40.5%), > 50 (59.5%)

bpCR (P = 0.956)

Clinical response (P = 0.930)

RCT, Phase II

850 mg b.i.d for 151 days

No

Canadian

Case: 22/control: 17

Median (range)

Not significant

Pimentel et al. [57]

Case: 55 (39–75)

PFS:HR = 1.2 (95% CI 0.63–2.31)

Control: 57 (41–73)

OS:HR = 1.68 (95% CI 0.79–3.55)

RCT, Phase II

1000 mg b.i.d for 39.6 months

No

Italian

HER2−:

Case: ≤ 50 (26.0%), > 50 (74.0%)

Not significant

Nanni et al. [58]

Case: 57/control: 65

PFS:HR = 1.09 (95% CI 0.75–1.58)

Control: ≤ 50 (21.0%), > 50 (79.0%)

OS:HR = 0.81 (95% CI 0.50–1.30)

ORR (P = 0.901)

RCT, Phase II

1000 mg b.i.d for 6.3 months

No

Black or African American (9%)

HR+, HER2−:

Median (range)

Median PFS: 6.3 months (95% CI 3.8–11.3 months)

Yam et al. [59]

White non-Hispanic (91%)

22

57.2 (37.6–70.5)

Median OS: 28.8 months (95% CI 17.5–59.7 months)

RCT, Phase II

500 mg b.i.d until endpoint

No

Egyptian

Case: 57/control: 50

Mean (± SD)

Not significant

Essa et al. [60]

Case: 49.56 ± 12.53

RR: P = 0.205

Control: 48.40 ± 12.61

PFS: P = 0.753

Case–control observational study

Not mentioned

Yes

Belgium

HR+:

case: ≤ 50 (13.08%), > 50 (86.92%)

Signficant in HR + group

Sonnenblick et al. [61]

Case: 136/control: 95

DFS:HR+:HR = 0.46 (95% CI 0.24–0.89);

HR−:HR = 0.99 (95% CI 0.53–1.87)

HR−:

Control: ≤ 50 (18.82%), > 50 (81.18%)

DFS:HR+:HR = 0.29 (95% CI 0.14–0.63);

Case: 124/control: 91

HR−:HR = 1.05 (95% CI 0.51–2.14)

OS:HR+:HR = 0.27 (95% CI 0.10–0.71);

HR−:HR = 1.09 (95% CI 0.48–2.47)

Cohort study

Not mentioned

Partial

Australian

6717

Mean (± SD)

Significant

Feng et al. [62]

66.8 (± 9.8)

Each 1-year adherence to metformin reduces cancer-specific mortality: adjusted HR = 0.95 (95% CI 0.93–0.97)

Retrospective study

Not mentioned

Yes

Korean

Case: 11,490/control: 22,265

Case: ≤ 65 (70.6%), > 65 (29.4%)

OS:HR = 0.83 (95% CI 0.73–0.94);

Kim et al. [63]

Control: ≤ 65 (68.8%), > 65 (31.2%)

Retrospective study

Not mentioned

Partial

Chinese

Case: (diabetic) 312/control (non-diabetic): 3139

Significant

Hui et al. [64]

Case: ≤ 55 (41.7%), > 55 (58.3%)

OS:HR = 0.386 (95% CI 0.248–0.601)

Control: ≤ 55 (67.3%), > 55 (32.7%)

DFS:HR = 0.384 (95% CI 0.247–0.598)

Retrospective study

Not mentioned

Yes

Finnish

3165

Median (range)

Not significant

Hosio et al. [65]

72 (64–79)

HR= 0.92 (95% CI 0.64–1.31)

Retrospective study

Not mentioned

Partial

Egyptian

Case: 25/control (diabetic): 14/control (non-diabetic): 400

Median (range)

Significant

El-Benhawy et al. [66]

Case: 55 (36–75)

DFS: compared with diabetic control group: P = 0.0001; compared with non-diabetic control group: P = 0.0249

Control (diabetic): 53 (43–64)

OS: compared with diabetic control group: P = 0.0032; compared with non-diabetic control group: P = 0.0350

Control (non-diabetic): 53 (33–65)

Retrospective study

Not mentioned

Yes

Korean

Case: 202/control: 184

Median (range)

Significant

Kim et al. [67]

Case: 55 (± 10.5)

Higher metastasis risk in diabetic control group: HR= 5.37 (95% CI 1.88–15.28)

Control: 59 (± 10.2)

Higher breast cancer death in control group: HR= 6.51 (95% CI 1.88 to 15.28)

Observational studies of the prevention effect of metformin on breast cancer

Prospective study

Not mentioned

Yes

Non-Hispanic white:  case: (69%); control: (86%)

Case: (diabetic)111/control (non-diabetic): 1800

Mean (± SD)

Not Significant in overall breast cancer risk (HR= 0.98; 95% CI 0.83–1.15)

Non-Hispanic black: case: (18%); control: (8%)

Case: 58.2 ± 8.2

Significant in ER + 

Park et al. [68]

Other: case: (13%); control: (7%)

Control: 55.1 ± 8.9

HR= 0.86; (95% CI 0.70–1.05)

 ≥ 10 years metformin use: HR 0.62 (95% CI 0.38–1.01)

Case–control observational study

Not mentioned

Yes

White: case: (80.58%); control: (65.60%)

Case: 690/control: 2747

Mean (± SD)

Significant

Black: case: (7.54%); control: (10.74%)

Case: 70.06 ± 5.00

 > 500 mg/day metformin use had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46–0.82)

Chikermane et al. [69]

Asian: case: (5.22%); control: (11.47%)

Control: 69.92 ± 4.84

Hispanic: case: (2.17%); control: (7.10%)

Other: case: (4.49%); control: (5.10%)