Table 4.
Literature review of clinical studies concerning metformin use on breast cancer
| Study design | Metformin dose | T2DM | Population | Sample size | Age (years) | Outcomes | References |
|---|---|---|---|---|---|---|---|
| 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%) | |||||||
RCT, randomized clinical trial; T2DM, type 2 diabetes; SD, standard deviation; OR, odds ratio; CI, confidential interval; PFS, progression-free survival; DFS, disease-free survival; ORR, objective response rate; OS, overall survival; HR, hormone receptor/hazard ratio; tpCR, total pathological complete response; bpCR, pathological complete response in the breast; ER, estrogen receptor; PgR, progesterone receptor