Effect of Metformin For Decreasing Proliferative Marker in Women with Endometrial Cancer: A Randomized Double-blind Placebo-Controlled Trial

Petchsila, Kittisak; Prueksaritanond, Nisa; Insin, Putsarat; Yanaranop, Marut; Chotikawichean, N.

doi:10.31557/apjcp.2020.21.3.733

Cited by 21 publications

(12 citation statements)

References 30 publications

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“…For hypoglycemia, metformin might be tolerated in patients with metastatic/recurrent breast cancer or those receiving adjuvant endocrine therapy, although no data were found in the neoadjuvant setting. Our findings were approximately consistent with previous studies 36,37 that reported that no patients with cancer who received metformin experienced SAEs, including hypoglycemia and lactic acidosis. Therefore, the addition of metformin to chemotherapy or endocrine therapy may be safe for use in patients with breast cancer.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2021

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“…167 Taken together, metformin used in cancer therapy is one of the most successful cases of drug repurposing and several clinical trials, which have advanced to Phase III and Phase IV, are currently investigating the therapeutic potential of metformin in oral, prostate, breast, endometrial, and pancreatic cancers. [168][169][170][171] Disulfiram: Disulfiram was originally used in rubber vulcanization, but subsequently has been used for more than 60 years as an alcohol-aversion drug to treat alcohol abuse. 172,173 Mechanistically, disulfiram inhibits the activation of acetaldehyde dehydrogenase (ALDH), triggering severe nausea and vomiting symptoms contributing to abstinence.…”

Section: Non-oncology Drugs In Drug Repurposingmentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

391

315

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Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

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“…Nevertheless, a meta-analysis of the above studies supports a greater overall survival in metformin users compared to nonusers [ 133 ], although the low number of studies and the lack of randomized studies compromise the evidence level of the meta-analysis. Clinical trials using metformin for atypical endometrial hyperplasia (AEH) or EC have recently accumulated evidence for its efficacy [ 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. Most studies used the presurgical window approach, in which patients diagnosed by endometrial biopsy were treated with metformin during the period prior to hysterectomy, and some studies targeted patients who underwent fertility-sparing treatments in combination with progestins.…”

Section: What About Metformin? Is the Pi3k-akt Pathway A Target?mentioning

confidence: 99%

Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies

Kyo

Nakayama

2020

IJMS

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Endometrial cancer (EC) is one of the most common malignancies of the female reproductive organs. The most characteristic feature of EC is the frequent association with metabolic disorders. However, the components of these disorders that are involved in carcinogenesis remain unclear. Accumulating epidemiological studies have clearly revealed that hyperinsulinemia, which accompanies these disorders, plays central roles in the development of EC via the insulin-phosphoinositide 3 kinase (PI3K) signaling pathway as a metabolic driver. Recent comprehensive genomic analyses showed that over 90% of ECs have genomic alterations in this pathway, resulting in enhanced insulin signaling and production of optimal tumor microenvironments (TMEs). Targeting PI3K signaling is therefore an attractive treatment strategy. Several clinical trials for recurrent or advanced ECs have been attempted using PI3K-serine/threonine kinase (AKT) inhibitors. However, these agents exhibited far lower efficacy than expected, possibly due to activation of alternative pathways that compensate for the PIK3-AKT pathway and allow tumor growth, or due to adaptive mechanisms including the insulin feedback pathway that limits the efficacy of agents. Overcoming these responses with careful management of insulin levels is key to successful treatment. Further interest in specific TMEs via the insulin PI3K-pathway in obese women will provide insight into not only novel therapeutic strategies but also preventive strategies against EC.

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Effect of Metformin For Decreasing Proliferative Marker in Women with Endometrial Cancer: A Randomized Double-blind Placebo-Controlled Trial

Abstract: However, women diagnosed with advanced-stage or recurrence disease have a very poor prognosis with a 5-year survival rate of below 50% (SEER, 2019). The increasing incidence of EC has been attributed to various factors, including obesity, diabetes, reproductive

Cited by 21 publications

References 30 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

Overcoming cancer therapeutic bottleneck by drug repurposing

Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies

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