Effect of metformin on survival outcomes in diabetic patients with triple receptor‐negative breast cancer

Bayraktar, Soley; Hernadez-Aya, Leonel F.; Lei, Xiudong; Meric‐Bernstam, Funda; Litton, Jennifer K.; Hsu, Limin; Hortobágyi, Gabriel N.; González-Angulo, Ana M.

doi:10.1002/cncr.26439

Cited by 161 publications

(155 citation statements)

References 58 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…A similar, also historical, series of epithelial ovarian cancer has demonstrated clinical benefit with increased progression-free survival and overall survival in diabetics taking metformin and receiving taxane/carboplatin chemotherapy compared with nondiabetics or diabetics not on metformin (68). However, incidental metformin use has not demonstrated survival benefit in two case series of diabetics with breast cancer (5,67). This concept of combining metformin with neoadjuvant chemotherapy is in prospective trials of metformin alongside paclitaxel and FAC; docetaxel, epirubicin, and cyclophosphamide AE metformin; and in ISPY2 (ganitumab þ metformin).…”

Section: Metformin and Breast Cancer Trialsmentioning

confidence: 96%

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson

2014

Clinical Cancer Research

View full text Add to dashboard Cite

Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-ofopportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508-15. Ó2014 AACR.

show abstract

Section: Metformin and Breast Cancer Trialsmentioning

confidence: 96%

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson

2014

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…30-35 ) associated with metformin exposure must be balanced against others that do not show such associations (e.g., refs. [36][37][38][39]. Some studies suggest unexpected variables that might modify the effects of metformin, including pharmacoepidemiologic evidence that exposure to both a statin drug and metformin is necessary for an important antineoplastic effect to be observed ( 40 ) and laboratory evidence that administration of proton pump inhibitors limits cellular uptake of metformin ( 41 ).…”

Section: Pharmacoepidemiology: Hypothesis-generating Cluesmentioning

confidence: 99%

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

2012

View full text Add to dashboard Cite

Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. Significance: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design. Cancer Discov; 2(9); 778–90. ©2012 AACR.

show abstract

“…Some pharmacoepidemiologic studies have suggested that metformin may have antineoplastic activity (21)(22)(23)(24)(25)(26)(27) but others have not supported this view (28)(29)(30)(31). Similarly, some (10) but not all (32) laboratory studies suggest that metformin has antineoplastic activity.…”

Section: Introductionmentioning

confidence: 99%

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

Javeshghani¹,

Zakikhani²,

Austin³

et al. 2012

Cancer Research

View full text Add to dashboard Cite

Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. Cancer Res; 72(23); 6257-67. Ó2012 AACR.

show abstract

Effect of metformin on survival outcomes in diabetic patients with triple receptor‐negative breast cancer

Cited by 161 publications

References 58 publications

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

Contact Info

Product

Resources

About