The Effect of Metformin on Biomarkers Associated with Breast Cancer Outcomes: a Systematic Review, Meta-analysis, and Dose-response of Randomized Clinical Trials

Overview

Journal Clin Transl Oncol

Specialty Oncology

Date 2019 Apr 23

PMID 31006835

Citations 10

Authors

J Rahmani

N Manzari

J Thompson

S K Gudi

M Chhabra

G Naik

S M Mousavi

H K Varkaneh

C Clark

Y Zhang

Affiliations

Soon will be listed here.

Abstract

Purpose: Breast cancer is a leading cause of cancer mortality in developed countries. We performed a meta-analysis of randomized clinical trials to investigate the effect of metformin on biomarkers associated with breast cancer outcomes and to explore the dose-response relationship.

Methods: A systematic search was performed from onset of the database to January 2019 in MEDLINE/PubMed, SCOPUS, and Cochrane library to identify randomized clinical trials investigating the impact of metformin on insulin, glucose, CRP, leptin, body mass indices (BMI), cholesterol, Ki-67, and Homeostatic Model Assessment for Insulin-Resistance (HOMA-IR). Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models.

Results: Nine studies providing 1,363 participants were included in the meta-analysis. Pooled results showed a significant reduction in insulin (WMD: - 0.99 U/ml, 95% CI - 1.66, - 0.33), glucose (WMD: - 1.78 ml/dl, 95% CI - 2.96, - 0.60), CRP (WMD: - 0.60 mg/l, 95% CI - 0.88, - 0.33), HOMA-IR (WMD: - 0.45, 95% CI - 0.77, - 0.11), leptin (WMD: - 2.44 ng/ml, 95% CI - 3.28, - 1.61), BMI (WMD: - 0.55 kg/m, 95% CI - 1.00, - 0.11), and Ki-67 (WMD: - 4.06, 95% CI - 7.59, - 0.54). Results of the subgroup analyses showed that insulin, glucose, and BMI decreased more significantly when the duration of administering metformin intervention was above 4 weeks. We did not observe non-linear changes in the dose-response relationship between metformin and biomarkers as outcomes.

Conclusions: Breast cancer patients receiving metformin as treatment for diabetes showed significant reduction in levels of insulin, fasting glucose, CRP, HOMA, leptin, BMI, and Ki-67.

Citing Articles

Metformin and long non-coding RNAs in breast cancer.

Gholami M, Klashami Z, Ebrahimi P, Mahboobipour A, Farid A, Vahidi A J Transl Med. 2023; 21(1):155.

PMID: 36849958 PMC: 9969691. DOI: 10.1186/s12967-023-03909-x.

Examining the relationship between metformin dose and cancer survival: A SEER-Medicare analysis.

Scarton L, Jo A, Xie Z, ONeal L, Munoz Pena J, George T PLoS One. 2022; 17(10):e0275681.

PMID: 36260549 PMC: 9581409. DOI: 10.1371/journal.pone.0275681.

Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents.

Zhu S, Bai Q, Li L, Xu T Comput Struct Biotechnol J. 2022; 20:2839-2847.

PMID: 35765655 PMC: 9189996. DOI: 10.1016/j.csbj.2022.05.057.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

Goodwin P, Chen B, Gelmon K, Whelan T, Ennis M, Lemieux J JAMA. 2022; 327(20):1963-1973.

PMID: 35608580 PMC: 9131745. DOI: 10.1001/jama.2022.6147.

Impact of Metformin on Cancer Biomarkers in Non-Diabetic Cancer Patients: A Systematic Review and Meta-Analysis of Clinical Trials.

Farkhondeh T, Amirabadizadeh A, Aramjoo H, Llorens S, Roshanravan B, Saeedi F Curr Oncol. 2021; 28(2):1412-1423.

PMID: 33917520 PMC: 8167716. DOI: 10.3390/curroncol28020134.

References

Patterson R, Marinac C, Sears D, Kerr J, Hartman S, Cadmus-Bertram L . The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes. J Natl Cancer Inst. 2018; 110(11):1239-1247. PMC: 6235688. DOI: 10.1093/jnci/djy040. View

Zheng J, Woo S, Hu X, Botchlett R, Chen L, Huo Y . Metformin and metabolic diseases: a focus on hepatic aspects. Front Med. 2015; 9(2):173-86. PMC: 4567274. DOI: 10.1007/s11684-015-0384-0. View

Sana M, Malik H . Current and emerging breast cancer biomarkers. J Cancer Res Ther. 2015; 11(3):508-13. DOI: 10.4103/0973-1482.163698. View

Morales D, Morris A . Metformin in cancer treatment and prevention. Annu Rev Med. 2014; 66:17-29. DOI: 10.1146/annurev-med-062613-093128. View

Giuliano A, Connolly J, Edge S, Mittendorf E, Rugo H, Solin L . Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; 67(4):290-303. DOI: 10.3322/caac.21393. View

Gronich N, Rennert G . Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol. 2013; 10(11):625-42. DOI: 10.1038/nrclinonc.2013.169. View

Tang G, Satkunam M, Pond G, Steinberg G, Blandino G, Schunemann H . Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev. 2018; 27(6):627-635. DOI: 10.1158/1055-9965.EPI-17-0936. View

Wulffele M, Kooy A, de Zeeuw D, Stehouwer C, Gansevoort R . The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004; 256(1):1-14. DOI: 10.1111/j.1365-2796.2004.01328.x. View

Seifarth C, Schehler B, Schneider H . Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes. 2012; 121(1):27-31. DOI: 10.1055/s-0032-1327734. View

10.

Gong Z, Aragaki A, Chlebowski R, Manson J, Rohan T, Chen C . Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women's health initiative. Int J Cancer. 2015; 138(8):1915-27. PMC: 4830266. DOI: 10.1002/ijc.29944. View

11.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

12.

Pernicova I, Korbonits M . Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014; 10(3):143-56. DOI: 10.1038/nrendo.2013.256. View

13.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

14.

Pollak M . Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008; 8(12):915-28. DOI: 10.1038/nrc2536. View

15.

Lega I, Austin P, Gruneir A, Goodwin P, Rochon P, Lipscombe L . Association between metformin therapy and mortality after breast cancer: a population-based study. Diabetes Care. 2013; 36(10):3018-26. PMC: 3781496. DOI: 10.2337/dc12-2535. View

16.

Col N, Ochs L, Springmann V, Aragaki A, Chlebowski R . Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. 2012; 135(3):639-46. DOI: 10.1007/s10549-012-2170-x. View

17.

Davis S, Robinson P, Jane F, White S, Brown K, Piessens S . The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2018; 89(5):605-612. DOI: 10.1111/cen.13830. View

18.

Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A . Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012; 30(21):2593-600. DOI: 10.1200/JCO.2011.39.3769. View

19.

Ko K, Ma S, Yang J, Hwang Y, Ahn C, Cho Y . Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2015; 153(2):361-70. DOI: 10.1007/s10549-015-3519-8. View

20.

Zelenko Z, Gallagher E . Diabetes and cancer. Endocrinol Metab Clin North Am. 2014; 43(1):167-85. DOI: 10.1016/j.ecl.2013.09.008. View