The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials

Wu, Zhonghua; Qu, Bicheng; Huang, Xiaoxian; Song, Yongxi; Gao, Peng; Shi, Jinxin; Zhou, Cen; Wang, Zhenning

doi:10.21037/atm-20-4441

Cited by 10 publications

(16 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results suggest that the addition of metformin to chemotherapy or endocrine therapy may have little efficacy in nondiabetic patients with metastatic/recurrent breast cancer. A meta-analysis 14 reported that adding metformin to standard treatment improved the overall response rate (ORR) in patients with metastatic breast cancer compared with standard treatment alone but did not improve OS and PFS. There are some differences in the methods used between the present study and the Wu et al study.…”

Section: Discussionmentioning

confidence: 99%

“…There are some differences in the methods used between the present study and the Wu et al study. 14 First, 2 empirical studies 24 showed a moderate correlation between the response rate and OS. However, no report showed that ORR is a potential surrogate for OS and PFS.…”

Section: Discussionmentioning

confidence: 99%

“…9 In contrast, several randomized controlled trials (RCTs) revealed that metformin and the concomitant use of chemotherapy or endocrine therapy showed no significant survival efficacy. [10][11][12] Two meta-analyses 13,14 showed the efficacy of metformin with chemotherapy/endocrine therapy in patients with metastatic/recurrent breast cancer or those receiving adjuvant therapy, respectively. However, these systematic reviews did not evaluate the efficacy of metformin according to treatment setting, including neoadjuvant, adjuvant, and metastasis/recurrence.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Interestingly, our preclinical data demonstrated that metformin represents anti-tumor/anti-metastatic effect only when prescribed with a DPP-4 inhibitor; nevertheless, metformin alone had no impact on basal breast cancer proliferation and metastasis in vivo [ 38 ]. Indeed, some randomized trials showed no impact of metformin on breast cancer progression and prognosis [ 141 , 142 , 143 ], even though several preclinical data have reported the anti-tumor effect of metformin in breast cancer. Further mechanistic investigation is definitely needed, using metformin as an anti-tumor agent in a clinical setting.…”

Section: Perspective: Co-prescription With Metforminmentioning

confidence: 99%

CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

Kawakita

Koya

Kanasaki

2021

Cancers

View full text Add to dashboard Cite

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.

show abstract

“…Recently, as epidemiologic data supported metformin may reduce cancer risk in diabetics, metformin has drawn attention in both cancer prevention and therapy 4,5 . Repurposing metformin as a cancer treatment is being tested in a wide range of clinical trials for a variety of cancers, including renal cell carcinoma, head and neck carcinomas and pancreatic carcinoma 3,6,7 . In addition, combining metformin with chemotherapies has been attempted in various cancers 1,8,9 .…”

Section: Introductionmentioning

confidence: 99%

Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

Zhuang

Wang

Zuo

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Objective To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. Methods CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. Results Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. Conclusions Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.

show abstract

The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials

Cited by 10 publications

References 46 publications

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

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

CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

Contact Info

Product

Resources

About