Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer

Goodwin, Pamela J.; Chen, Bingshu E.; Gelmon, Karen A.; Whelan, Timothy J.; Ennis, Marguerite; Lemieux, Julie; Ligibel, Jennifer A.; Hershman, Dawn L.; Mayer, Ingrid A.; Hobday, Timothy J.; Bliss, Judith; Rastogi, Priya; Rabaglio-Poretti, Manuela; Mukherjee, Som D.; Mackey, John R.; Abramson, Vandana G.; Oja, Conrad D.; Wesolowski, Robert; Thompson, Alastair; Rea, Daniel; Stos, Paul M; Shepherd, Lois E.; Stambolic, Vuk; Parulekar, Wendy R.

doi:10.1001/jama.2022.6147

Cited by 125 publications

(61 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the high concentrations of metformin used in in vitro studies might not be readily translated to effects in preclinical and clinical studies 24,189 , which raises questions as to what the appropriate drug exposure to obtain a direct anticancer effect might be. Importantly, supportive evidence for a protective effect of metformin on cancer risk was not always consistent 190,191 . Thus, validation of the advantage of metformin treatment as a single agent or as an adjuvant in cancer therapy, notably for its emerging role in regulating cancer immunity, awaits further clarification.…”

Section: An Anticancer Agentmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

View full text Add to dashboard Cite

Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

show abstract

Section: An Anticancer Agentmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

View full text Add to dashboard Cite

show abstract

“…However, human clinical trials have yielded mixed results. In a large phase 3 trial, patients with high-risk operable breast cancer who received adjuvant treatment with metformin did not experience any relapse-free survival prolongation compared to placebo (NCT01101438) [24]. In patients with advanced breast cancer, two phase 2 studies failed to show any progression-free survival or overall survival benefit of metformin use in combination with chemotherapeutic agents, including non-pegylated liposomal doxorubicin plus cyclophosphamide, capecitabine, platinum, or taxanes (NCT01885013) (NCT01310231) [16].…”

Section: Metformin In Clinical Trialsmentioning

confidence: 99%

Why Metformin Should Not Be Used as an Oxidative Phosphorylation Inhibitor in Cancer Patients

Sakellakis¹

2023

Chemotherapy

View full text Add to dashboard Cite

Background: Preclinical studies have suggested that metformin exerts antitumor effects on various types of cancers. However, the results of human clinical trials have been inconsistent. Summary: Metformin is widely considered to be a prime example of a clinically relevant compound that inhibits oxidative phosphorylation (OXPHOS). However, the efficacy of metformin in inhibiting OXPHOS in cancer patients remains uncertain. The available evidence suggests that the plasma concentration of metformin remains within the micromolar range when administered at therapeutic doses. While millimolar concentrations are necessary to inhibit complex I activity in isolated mitochondria, there is no evidence supporting the idea that metformin accumulates within the mitochondria. Metformin exerts a modest effect on the adenosine diphosphate to adenosine triphosphate (ATP) ratio, resulting in AMP-activated protein kinase activation, which promotes ATP-generating catabolic pathways and restores cellular energy balance. Key Messages: The value of metformin as an OXPHOS inhibitor for cancer treatment is debatable, and caution should be exercised while using metformin for this purpose.

show abstract

“…96 Targeting leptin, therefore, appears a rational approach to anti-MM therapy and in the solid cancer arena this has garnered some interest, although a trial of metformin in breast cancer as a leptin-reducing metabolic agent was unsuccessful. 97 However, other approaches have been explored, and in the case of MM, LEPR antagonism has been proposed to restore immune surveillance in preclinical models. 96 Contrasting the leptin effect, serum levels of adiponectin, an adipokine that is paradoxically downregulated in obesity, have been observed to be inversely proportional to MM risk, 98 likely due to adiponectin's ability to activate MM apoptosis via activation of protein kinase A and AMPactivated protein kinase pathway.…”

Section: MMmentioning

confidence: 99%

“…Leptin has also been proposed as an immune checkpoint in the MM niche due to its immunosuppressive effect on invariant Natural Killer T cells that favours MM growth 96 . Targeting leptin, therefore, appears a rational approach to anti‐MM therapy and in the solid cancer arena this has garnered some interest, although a trial of metformin in breast cancer as a leptin‐reducing metabolic agent was unsuccessful 97 . However, other approaches have been explored, and in the case of MM, LEPR antagonism has been proposed to restore immune surveillance in preclinical models 96 …”

Section: Role Of Bmad In Haematological Malignancymentioning

confidence: 99%

Turning the spotlight on bone marrow adipocytes in haematological malignancy and non‐malignant conditions

et al. 2023

View full text Add to dashboard Cite

Summary Whilst bone marrow adipocytes (BMAd) have long been appreciated by clinical haemato‐pathologists, it is only relatively recently, in the face of emerging data, that the adipocytic niche has come under the watchful eye of biologists. There is now mounting evidence to suggest that BMAds are not just a simple structural entity of bone marrow microenvironments but a bona fide driver of physio‐ and pathophysiological processes relevant to multiple aspects of health and disease. Whilst the truly multifaceted nature of BMAds has only just begun to emerge, paradigms have shifted already for normal, malignant and non‐malignant haemopoiesis incorporating a view of adipocyte regulation. Major efforts are ongoing, to delineate the routes by which BMAds participate in health and disease with a final aim of achieving clinical tractability. This review summarises the emerging role of BMAds across the spectrum of normal and pathological haematological conditions with a particular focus on its impact on cancer therapy.

show abstract

Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer

Cited by 125 publications

References 29 publications

Metformin: update on mechanisms of action and repurposing potential

Metformin: update on mechanisms of action and repurposing potential

Why Metformin Should Not Be Used as an Oxidative Phosphorylation Inhibitor in Cancer Patients

Turning the spotlight on bone marrow adipocytes in haematological malignancy and non‐malignant conditions

Contact Info

Product

Resources

About