Efficacy of Metformin in Patients With Breast Cancer Receiving Chemotherapy or Endocrine Therapy: Systematic Review and Meta-analysis

Abstract

Background Previous studies have suggested that metformin might improve survival outcomes in patients with breast cancer. However, findings on the efficacy of metformin with chemotherapy or endocrine therapy are inconsistent. Objective To clarify the efficacy of metformin with chemotherapy or endocrine therapy in breast cancer patients according to the treatment setting, including neoadjuvant, adjuvant, and metastasis/recurrence. Methods We systematically searched for randomized controlled trials (RCTs) in MEDLINE, CENTRAL, and EMBASE from inception through July 2020. Overall survival (OS), progression-free survival (PFS), and hypoglycemia rate were the primary outcomes. Secondary outcomes included severe adverse events (SAEs) and relapse-free survival. We used the Grading of Recommendations Assessment, Development, and Evaluation approach and performed a meta-analysis to evaluate the efficacy and safety of metformin with chemotherapy and endocrine therapy in patients with breast cancer. Results Our systematic review included 412 participants from 5 trials. Metformin showed little to no difference in OS (hazard ratio [HR] = 1.13; 95% CI = 0.71-1.81; certainty of evidence [COE], moderate) and PFS (HR = 1.14; 95% CI = 0.86-1.50; COE, moderate) in patients with metastasis/recurrence. The evidence was very uncertain about the effect of metformin on survival outcomes in patients who received metformin with neoadjuvant or adjuvant treatment. Metformin showed little to no difference in hypoglycemia and SAEs. Conclusion and Relevance Metformin should be discouraged routinely in nondiabetic patients with metastatic/recurrent breast cancer. Further RCTs are needed to verify whether metformin with chemotherapy or endocrine therapy results in significant clinical benefits in the neoadjuvant or adjuvant setting.

Efficacy of Metformin as Adjuvant Therapy in Metastatic Breast Cancer Treatment

“…A previous study on BC patients receiving neoadjuvant chemotherapy revealed that diabetic patients who were treated with metformin demonstrated a better response to treatment as compared to those diabetic patients receiving other types of anti-diabetic drugs, as well as non-diabetic BC cases [ 21 ]. Adding metformin to chemotherapy in patients with metastatic breast cancer improved the objective response rate compared to the placebo group but had no effect on the progression-free survival or overall survival in a recent meta-analysis study [ 22 ]. Based on the results of the current systematic and meta-analysis review, adding metformin to chemotherapy or endocrine therapy in non-diabetic MBC females does not improve RR, PFS, or OS compared to chemotherapy or endocrine therapy alone [ 22 , 23 ].…”

“…Adding metformin to chemotherapy in patients with metastatic breast cancer improved the objective response rate compared to the placebo group but had no effect on the progression-free survival or overall survival in a recent meta-analysis study [ 22 ]. Based on the results of the current systematic and meta-analysis review, adding metformin to chemotherapy or endocrine therapy in non-diabetic MBC females does not improve RR, PFS, or OS compared to chemotherapy or endocrine therapy alone [ 22 , 23 ]. In addition, the hypothesis that metformin-based methods may be less beneficial in metastatic illness than in early stage cancer was highlighted in the phase I research of metformin plus erlotinib [ 24 ].…”

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…However, randomized trials in phase 2 trials fail to show benefit of metformin. In non-diabetic patients, no survival effect of metformin in metastatic/recurrent breast cancer was seen when used as adjunctive therapy [ 88 , 89 , 90 ].…”

“…Additionally, in patients diagnosed with breast cancer, metformin was associated with lower risk of a second breast tumor, recurrence or breast-cancer-related death [ 82 , 83 ]. However, randomized trials in metastatic disease and recurrent breast cancer fail to show a benefit of metformin as adjunctive therapy [ 88 , 89 ].…”

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials

“…However, the available results are controversial. Several studies and meta-analyses have indicated that metformin therapy is associated with reduced cancer-related mortality [8][9][10][11][12], while others point out that concomitant medication with metformin showed no significant effect on cancer-related mortality [13][14][15][16][17][18] or even led to inferior outcomes [19]. In the last decade, several randomized controlled trials (RCTs) have been conducted to assess the effectiveness of metformin monotherapy or adjunctive therapy in antitumor medications.…”